Aminomethyl-2,3,8,9-tetrahydro-7h-1,4-like[2,3-e] indole - 8-about the connection and the method of treatment

 

(57) Abstract:

Describes new connections-aminomethyl-2,3,8,9-tetrahydro-7H-1-like[2,3-e] indole-8-about the compounds of formula I in which R1and R2are independently hydrogen; or R1and R2taken together, represent benzylidene, optionally substituted by the radical R3defined below, or R1and R2taken together with the carbon to which they are attached, form a carbonyl fragment; R3is hydrogen, halogen, trifluoromethyl, triptoreline, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino in which each alkyl group has 1-6 carbon atoms, alcanada with 2-6 carbon atoms; R4is hydrogen or alkyl with 1-6 carbon atoms; m = one of the whole number 0 or 1; n = 0-6 an integer; Z is hydrogen, hydroxy, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 1-6 carbon atoms, cycloalkyl with 3-8 carbon atoms, a polycyclic alkyl with 7 to 15 carbon atoms, phenyl, optionally substituted by R3defined above, phenoxy, optionally substituted R3defined above, naphthyl, optionally substituted by the radical R3defined above, notary heterocyclic ring heteroaryl or heteroaromatic group selected from thiophene, furan, pyridine, indole, quinoline and the heterocyclic ring is optionally substituted by the radical R3defined above; or their pharmaceutically acceptable salts. Also described is a method of treatment. New connections can be used to treat disorders of the dopaminergic system. 2 C. and 40 C. p. F.-ly, 1 PL.

This application claims priority on the basis of application U.S. N 60/007283, filed November 6, 1995 , and this application is a partial continuation of this earlier application.

In the international PCT application WO 91 13872 disclosed derivatives like [2,3-e] indole following formula, in which R1represents H, alkyl, CO2R2, CONHR2, cyano, halogen, CHO and others , R2represents H, alkyl, (CH2)mY;

Y represents cycloalkyl or cycloalkenyl, (substituted) phenyl, pyridyl, naphthyl, indolyl; m is from 0 to 6; A and B are O, CH2S; and X represents CH2(CH2)mNR2R2as serotonergic and dopaminergic agents useful for the treatment of Central nervous system and cardiovascular disorders.

< / BR>
U.S. patent 5318988 discloses 2-aminomethyl-chromane following formulas are useful for the treatment of CNAME and represent hydrogen, halogen, cyano, azido, nitro, di - or trifluoromethyl, di - or triptoreline, hydroxyl or carboxyl, straight or branched chain alkyl, alkenyl, acyl, alkoxy or alkoxycarbonyl, or mono - or disubstituted or unsubstituted amino, amido or sulfonamide, or A can be determined, as indicated, and B and D, taken together, form a 5 - to 7-membered saturated, partially unsaturated, or aromatic carbocyclic ring or heterocyclic ring

< / BR>
with up to two sulfur atoms, nitrogen or oxygen, not necessarily one or two carbonyl functional groups in the ring and optionally ring substituted by alkyl, branched alkyl or cycloalkyl; E represents a direct bond or represents straight or branched chain alkylene, albaniles or akinyan; G represents aryl having 6 to 10 carbon atoms, or a 5 - to 7-membered, saturated or unsaturated heterocyclic ring, which is not related with nitrogen and has up to 3 heteroatoms from the series comprising nitrogen atoms, oxygen or sulfur, which may be optionally condensed with additional saturated, partially unsaturated or aromatic 6-membered ring or cycloalkyl or bridge the political agents of the formula

< / BR>
in which Z represents aminophenoxy, coumarin, carbonsteel, quinoline or chroman; R1and R2are independently hydrogen, alkyl, alkoxy, Alcoxy, alkanoyloxy, hydroxy, halogen, amino, mono - or dialkylamino, alcanada, or alkanesulfonyl, or R1and R2together represent methylenedioxy, Ethylenedioxy or Propylenediamine; R3represents hydrogen or alkyl; n = 2, 3, or 4.

In accordance with this invention is provided with a group of new antipsychotic agents of the formula I

< / BR>
in which R1and R2are independently hydrogen, alkyl with 1-6 carbon atoms, phenyl or benzyl; or R1and R2taken together, represent benzylidene, optionally substituted by a group R3defined below, or alkylidene with 1-6 carbon atoms, or R1and R2taken together with the carbon atom to which they are attached, form a carbonyl fragment or cycloalkyl) group having 3 to 6 carbon atoms;

R3represents hydrogen, hydroxy, halogen, triforma-Thiel, triptoreline, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, Allakaket with 7-12 carbon atoms, alkanoyloxy with 2-6 carbon atoms, AMI carbon or alkanesulfonyl with 1-6 carbon atoms;

R4represents hydrogen or alkyl with 1-6 carbon atoms;

m = 0, 1, or 2;

n= 0, 1, 2, 3, 4, 5 or 6;

Z represents hydrogen, hydroxy, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 2-6 carbon atoms, alkoxy with 1-6 carbon atoms, cycloalkyl with 3-8 carbon atoms, a polycyclic alkyl with 7 to 15 carbon atoms, phenyl, optionally substituted by a group R3defined above, phenoxy, optionally substituted R3defined above, naphthyl, optionally substituted by R3defined above, or naphthyloxy, optionally substituted R3defined above, heteroaryl or heteroaromatic, in which the heterocyclic ring heteroarenes or heterokaryosis selected from thiophene, furan, pyridine, pyrazine, pyrimidine, indole, indazole, imidazole, chroman, coumarin, barbastella, quinoline, benzisoxazole, benzoxazole, pyrazole, pyrrole, thiazole, oxazole or isoxazol, and heterocyclic ring is optionally substituted by substituent R3defined above;

or their pharmaceutically acceptable salts.

Of these preferred compounds is represented by the compounds in which R1and R2PR is authorized above, or taken together with the carbon to which they are attached, form a carbonyl fragment,3and n have the meanings given above, R4represents hydrogen, m = 0 or 1, and Z represents hydrogen, hydroxy, alkyl with 1-6 carbon atoms, cycloalkyl with 3-8 carbon atoms, a polycyclic alkyl with 7 to 15 carbon atoms, phenyl, optionally substituted by R3defined above, phenoxy, optionally substituted R3defined above, naphthyl, optionally substituted by R3defined above, or naphthyloxy, optionally substituted R3defined above, heteroaryl or heteroaromatic, geterotsiklicheskikh ring heteroaryl or heteroepitaxy selected from thiophene, furan, pyridine, pyrimidine, indole, indazole, chroman, coumarin, barbastella, quinoline, benzisoxazole, benzoxazole, and heterokonta optionally substituted R3defined above.

Most preferred are those compounds in which R1, R2and R4represent hydrogen, m is 0, and R3and Z have the meanings given in the previous paragraph. This invention relates to both the R-and S-stereoisomers of benzodioxathiepin, as well as mixtures of R - and S-stanfigure of benzodioxathiepin not specified embrace the individual R and S enantiomers, and mixtures thereof.

Pharmaceutically acceptable salts are salts made from such organic and inorganic acids as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, almond, malic, hydrochloric, Hydrobromic, phosphoric, nitric, sulfuric, methansulfonate, toluensulfonate and similarly known acceptable acids.

Aminomethyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-ones are obtained as described below. In particular, the appropriately substituted nitroguaiacol alkiliruya allylbromide in the presence of a suitable base such as sodium hydride, and then according to the scheme (1) (see the end of the description) demetiliruetsa reagent, such as sodium hydroxide. The resulting 4-nitro-2-allyloxyphenyl then alkiliruya goldencasinocom or epiglottitis in the presence of a base such as sodium hydride and heated in a high boiling solvent such as mesitylene or xylene, for implementation as rearrangement of allyl group and cyclization of the dioxane ring. The resulting primary alcohol is converted to tosylate using reaction with p-toluols carbon or carbon tetrachloride in combination with triphenylphosphine. Allyl side chain becomes explicilty fragment using oxidative cleavage with potassium permanganate, and the nitro-group is restored in the amine with hydrogen and palladium on coal and cyclization to the lactam aqueous hydrochloric acid. Substitution tosilata or halide substituted appropriately Amin in some high boiling solvent such as dimethyl sulfoxide gives the target compound of this invention.

Metaltail oxidationin described in scheme (1) can also be obtained, as given in the diagram (1a); substituted accordingly salicylaldehyde alkiliruya allylbromide in the presence of a suitable base such as sodium hydride. Aldehyde fragment is then converted into phenol by processing m-chloroperoxybenzoic acid with subsequent cleavage of the intermediate formatage of ester basic alumina in methanol. The resulting 2-allyloxyphenyl then alkiliruya goldencasinocom or epiglottitis in the presence of a base such as sodium hydride and heated in a high boiling solvent, such as mesitylene or xylene to effect the rearrangement and the Nola. After the conversion of alcohol into toilet using p-toluensulfonate in pyridine allyl side chain oxidation split in explicilty fragment using potassium permanganate, and the nitro-group is introduced by treatment with nitric acid in dichloroethane. The restoration of the nitro group and cyclization in the covenants are as described in scheme (1). When R3represents halogen, to restore the preferred catalyst, such as platinum oxide or platinum on solifidianism carbon.

Metaltail oxidation can also be replaced with the appropriate way of benzodioxolyl, as shown in figure (1b) at the end of the description. After the conversion of alcohol into toilet, as described above, the nitro-group is introduced by treatment with nitric acid in dichloromethane and reduced with hydrogen in the presence of a suitable catalyst such as platinum oxide or platinum on solifidianism carbon. Oxindole obtained by modification of the procedure Gassman and others (J. Amer. Chem. Soc. , 96, 5512 (1974)), and the resulting timedelay ether is cleaved by treatment with the use of Raney Nickel.

Alternatively, the allyl side chain mabotai hydrogen peroxide, as illustrated above. The primary alcohol can be oxidized to carboxylic acid with a suitable oxidizing agent such as potassium permanganate, and cilitates in the covenants, as described previously, using aqueous hydrochloric acid. Substitution tosilata or halide substituted appropriately Amin in some high-boiling solvents, such as dimethylsulfoxide, as described above, gives compounds of the invention in which m = 1. Similar to the technology on which the propyl alcohol is converted to the bromide using processing cetarehhloristam carbon and triphenylphosphine, replaced by cyanide by treatment with sodium cyanide in dimethylformamide, and hydrolyzed in homologous acid, can be used to obtain the compounds of the invention in which m = 2, provided that benzodioxolyl appropriately protected during this procedure.

Compounds of the invention in which R1and R2combined with education benzylidene or alkylidene balance can be obtained through condensation of lactams described above, with the appropriate aromatic or aliphatic aldehyde. Compounds of the invention in which R1and R2represent alkyl, can polh conditions. Compounds of the invention in which R1and R2combined with the formation of carbonyl (i.e., satiny) can be obtained by oxidation of the corresponding oxindoles. Appropriate nitroguaiacol are known compounds or can be obtained by any ordinary person skilled in the art. Alternatively, 4-nitro-2-allyl-phenols used in the process (1) described above can be obtained from the appropriate 5 - or 6-substituted salicylaldehyde using the procedure (3) described below, or from the appropriate 3 - or 4-substituted salicylaldehyde using the procedure (4) described below in accordance with [2-(trimethylsilyl)ethoxy] methyl chloride (SEMCI) used as hydroxyamide group during the conversion of aldehyde in formity ether using metacompetencies acid and subsequent hydrolysis of the hydroxy-group. Substituted amines R4-NH(CH2)n-Z, are known compounds or can be freely obtained by specialists in this field. Compounds of the invention can be separated into their enantiomers using conventional methods or, preferably, they can be obtained directly by replacing (2R)-(-)-glycidyl 3-netnatm or tosylate (R-enantiomer) instead of epiglottitis or racemic of glycidylmethacrylate in the above-described procedures.

The compounds of this invention are agonists of autoreceptors dopamine, i.e., they serve to modulate the synthesis and release of the neurotransmitter dopamine. These compounds also act as partial agonists at postsynaptic dopamine D2the receptor can function as either agonists or antagonists depending on the level of dopaminergic stimulation. They also serve to modulate the dopaminergic neurotransmission, and therefore they are useful for the treatment of disorders of the dopaminergic system, such as schizophrenia, datafactory disorders, Parkinson's disease, syndrome Tourette and hyperprolactinemia, and in the treatment of addiction to drugs or any other substances, such as abuse and /or addiction/ ethanol or cocaine, or related diseases.

The effect of the compounds of this invention on the synthesis of dopamine installed according to the method of the authors Walters and Roth, Naunyn-Schmiedeberg''s Arch. Pharmacol. 296; 5-14, 1976, in which rats (male, Sprague-Dawley, Charles River, 200-350 g) were administered vehicle or test drug for ten minutes prior to the introduction of gamma-butyrolactone (GBL, ; 750 mg/kg, I. p. for inhibiting flow dopaminergic pulse) NDS-1015 all rats were decapitated, and extracted nucleus accumbens and striatum for analysis. After extraction tissue perchloro acid extracts were placed on a column of aluminum oxide for collecting concentrate DOPA and other catechins. This eluate was then subjected to analysis B HPLC (high performance liquid chromatography or liquid chromatography high pressure) using electrochemical detection for the quantitative levels of presence of appr. Agonists dopamine autoreceptors used in above conditions inhibit the accumulation stage. When tested in this model, the compound of Example 1, the characteristic representative of the other compounds of the invention inhibited the accumulation of DOPA on 67.5% at the dose of 10 mg/kg, SC (subcutaneously).

Antipsychotic activity of the compounds of the invention was further established by determining the ability of compounds to reduce locomotor activity of mice according to the method of Martin and Bendensky, J. Pharmacol. Exp. Therap. 229: 706-711, 1984, in which mice (males, CF-1, Charles River, 20-30 g) were injected with vehicle or different doses of each medication, and locomotor activity was measured for 30 minutes when using automated monitors IR activity (Omnitek - 8 x 8 inch open field), located in salemn the NYM 10 - 20 minutes after a dose medication using analysis of nonlinear regression with backward prediction. The results of the test with compounds of the invention are described below.

The affinity to the dopamine D2the receptor was determined by a modification of the standard experimental test procedure of the authors Seemen and Schaus, European Journal of Pharmacology 203: 105-109, 1991/ by which gomogenizirovannogo building fabric of rat brain incubated with3H-henerala and various concentrations of test compound, filtered and washed, and counted using a Betaplate scintillation counter. The results of the test with compounds characteristic of the invention, are given below.

The results of standardized testing procedures, described in the previous two paragraphs, are given in the table.

Thus it is seen that the compounds of this invention have a strong affinity for dopamine receptors and significantly affect the synthesis of the neurotransmitter dopamine. Therefore, they are useful for the treatment of dopaminergic disorders such as schizophrenia, schizoaffective disorders, Parkinson's disease. Syndrome Tourette etenia can be assigned to receive orally or parenterally, in its pure form or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricating agents, solubilization, suspendresume agents, fillers, agents promoting sliding (swallowing), compression AIDS, binders or dezintegriruetsja tablets agents or encapsulating materials. In powders, the carrier is a finely powdered solid substance that is mixed with finely ground active ingredient. In tablets, the active ingredient is mixed with carrier having the necessary compression properties in suitable proportions, and it is compressed so that it was given the desired shape and size. The powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid media can be used to obtain solutions, suspensions, emulsions, syrups and e is acceptable liquid carrier, such as water, organic solvents, mixtures or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilization, emulsifiers, buffer additives, preservatives, sweetening agents, flavouring and aromatic agents, suspendida, thickening, coloring agents, viscosity regulators, stabilizers or OSMO-regulators. Suitable examples of liquid carriers for oral and parenteral products include water (particularly containing additives as above, e.g. cellulose derivatives, preferably a solution of sodium carboxymethyl cellulose), alcohols (including monatomic and polyatomic alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and peanut butter). For parenteral destination carrier may be an oil ester, such as etiloleat and isopropylmyristate. Sterile liquid carriers are used in a sterile compositions in the form of a liquid for parenteral purposes.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be used, for example, using voteno. For oral purposes, the composition may be either in solid or in liquid form.

Preferably the pharmaceutical composition is a form of a unit dose, for example, in the form of tablets or capsules. In such form, the composition is divided into unit doses containing appropriate quantities of the active ingredient; in the form of unit doses can present composition in a package, for example, powders, sachets, ampoules, vials, pre-filled syringes or sachets containing liquids. The form of a unit dose may be, for example, in the form of capsules or pills, or it can represent the appropriate number of any such compositions in package form.

The dosage used in the treatment of specific psychosis should be determined subjectively by the attending physician. The variables that are taken into account include the particular type of psychosis, and the degree of its age and the nature of the response of the patient. Based on the activity profile and the effectiveness of the compounds of this invention, comparable to the clinically used antipsychotic risperidone, it is considered that a starting dose of approximately 5 mg / day with gradual increase daily dose by approximately tryout obtaining typical representatives of the compounds of this invention.

The intermediate connection 1

3 Allyloxy-4-methoxy nitrobenzene

97.5 g (0.51 mol) of sodium salt of 5-nitroguaiacol was dissolved in one liter of DMF and was added 1.5 equivalent of allylbromide. The reaction mixture was heated to 65oC for two hours, after which most of the dark color disappeared, and TLC (1: 1 methylene chloride/hexane) showed the loss of the source material. The solvent was concentrated in vacuo, and the residue was rinsed with water. The product was separated by filtration and dried in vacuum. This procedure gave 112 g blignault solids. Sample paracrystalline were founded from methanol, giving so pl. 93-94oC.

Intermediate compound 2

2 Allyloxy-4-NITROPHENOL

To one liter of dimethyl sulfoxide was added 750 ml of 2 N. aqueous sodium hydroxide, and the mixture was heated to 65oC. Pale-yellow 3-allyloxy-4-methoxyethanol, obtained above, was added in portions over a 30 minute period, and then the temperature was raised to 95oC and was maintained for 3 hours, after which the original material was spent. The mixture was left to cool and poured into a mixture of 1 l of ice and 2 l 2 N. HCl. Separated 73 g crude, but homogeneous (TLC 1: 1 methyl the initial material was subsequently dissolved in 1: 1 mixture of hexane/methylene chloride and filtered through silica gel, giving 68 g of pale yellow solid, which after recrystallization from a mixture of ethyl acetate and hexane gave so pl. 61-62oC. the Aqueous mother liquor from the initial crystallization, above, was extracted with 2 liters of ethyl acetate. This substance was dried over sodium sulfate, filtered and evaporated to a dark oil. Column chromatography on silica using 1: 1 mixture of methylene chloride/hexane gave an additional 12 g of the target compound as a yellow solid. Elution with 2% methanol in trichlormethane gave 12 g of dark oil which slowly crystallized in vacuum. The substance turned out to be a product of Clausena, 3-allyl-4-nitrocatechol.

Intermediate compound 3

2-(2-Allyloxy-4-nitrophenoxy)-oxiran

20 g (0.50 mole) of 60% sodium hydride in mineral oil was placed in a two-liter flask was rinsed with 500 ml of hexane. Was added to 1 l of DMF, and then (77 g and 0.40 mole) of 2-allyloxy-4-NITROPHENOL obtained in the previous phase. The addition of phenol was carried out portions in an argon atmosphere. After stirring the mixture for 30 minutes at room temperature in an argon atmosphere was added 108 g (0.48 mol) of (R)-glycidol is camping in vacuum and replaced with one liter of methylene chloride. This mixture was washed with 500 ml portions of 2 N. HCl, saturated sodium bicarbonate and saturated saline and dried over sodium sulfate. The mixture was filtered, concentrated to an oil under vacuum and chromatographically on silicagel column using a 1: 1 mixture of hexane and methylene chloride as eluent. This gave 43 g of product contaminated with traces of two initial substances, and then 21 g of pure product as a pale yellow solid. The impure material was precrystallization from 1.2 l of 10% ethyl acetate/hexane, yielding 34 g of pure (homogeneous on silica gel TLC with 1: 1 hexane: methylene chloride) (R)-2-(2-allyloxy-4-nitrophenoxide)oxirane (so pl. 64oC).

Elemental analysis for C12H13NO5< / BR>
Calculated: C, 57.37, H 5.21, N 5.58.

Found: C, 57.50, H 5.21, N, 5.43.

Intermediate compound 4.

(3-Allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol

(R)-2-(2-Allyloxy-4-nitrophenoxy)-oxiran (20 g, 80 mmol), obtained above, was heated at 155oC mesitylene in 24 hours in nitrogen atmosphere. The filter black solid, which was formed, gave 1.5 g of very polar substances. Evaporation of the solvent in the Vake is divided by the initial substance and 7.5 g of the desired rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, which slowly crystallized upon standing under vacuum (so pl. 67oC. Yield per selected source material was 75%.

Elemental analysis for C12H13NO5< / BR>
Calculated: C, 57.37, H 5.21, N 5.58

Found: C, 57.26, H 5.20, N 5.35

The intermediate compound 5.

Toluene-4-sulfonic acid allyl-7-nitro-2,3-dihydro-benzo(1,4) dioxin-2-ymetray ether

9.55 g (38.0 mmole) of (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4) dioxin-2-yl)-methanol was dissolved in 465 ml of pyridine, was added 465 ml of pyridine, 29.0 g (152 mmole) p-toluensulfonate, and the mixture is stirred at room temperature under nitrogen atmosphere over night. Then, water was added to the repayment of excess taillored, and the solvent was removed in vacuum and replaced with methylene chloride. This solution was washed 2 N. HCl, saturated sodium bicarbonate and saturated saline, and dried over magnesium sulfate. Filtration, evaporation in vacuo and column chromatography on silica gel with 1: 1 hexane: methylene chloride as eluent gave of 12.6 g (92) (R)-allyl-7-nitro-2,8-dihydro-benzo(1,4)dioxane-2-Eletropaulo ester toluene-4-sulfonic acid, which slowly crystallized upon standing, giving SUB>< / BR>
Calculated: C, 56.29, H 4.72, N 3.45

Found: C, 56.13, H 4.58, N 3.44

The intermediate compound 6.

(6-Nitro-3-(toluene-4-sulfonyloxy)-2,3-dihydro-benzo(1,4) dioxin-5-yl)-acetic acid

Potassium permanganate (11.7 g, 0.074 mol) were placed in the flask, which was equipped with a mechanical stirrer, addition funnel, and an ice bath. To the flask was added 150 ml of water and tetrabutylammonium /1.0 g, 3.7 mmole/ under stirring. Through the addition funnel was slowly added (R)-allyl-7-nitro-2,3-benzo(1,4)dioxin-2-ymetray ester toluene-4-sulfonic acid, obtained above, dissolved in 100 ml of benzene, and the reaction mixture was additionally mixed for 30 minutes in an ice bath. The ice bath was then removed and the mixture is stirred for 24 hours at room temperature. To the mixture with good stirring in an ice bath was added 30 g of sodium bisulfite and the mixture was padillas concentrated HCl up until the pH value will not be less than 3. The acidified transparent yellow solution was then extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate. The concentrated residue was chromatographically on silicagel column using ethylacetate acid as a pale yellow solid. Crystallization from methylene chloride gave a light yellow solid with so pl. 158-159oC.

Elemental analysis for C18H17NO9S1/4 H2O

Calculated: C, 50.52, H 4.12, N 3.27

Found: C At 50.51, H 3.83, N 3.12.

Intermediate compound 7

2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

Carboxylic acid (6.0 g, 0.0142 mol): obtained above, were ground into fine-dispersed powder. To this powder was added 300 ml of water and 5 ml of 2.5 N. NaOH up until the pH will not be 8, and the heterogeneous solution was mixed for 30 minutes before until the solid is not dispersibles evenly. Then was added 1.0 g of 10% palladium on charcoal, and the mixture was gerasoulis in a Parr shaker for 24 hours at a hydrogen pressure 52 psi /3.656 kg/sq. cm/. The catalyst was filtered off and rinsed with water. The volume of the filtrate was then halved, and the filtrate was pagkilala 15 ml of concentrated HCl with stirring in an ice bath, and the deposited white solid acid product, (R)-(6-amino-3-(toluene-4-sulfonyloxy)-2,3-dihydro - benzo(1,4)dioxin-5-yl)-acetic acid. This heterogeneous solution was then heated at 50oC for 24 hours. On Prochorus a lactam, and the reaction mixture became immediately clear, and then began to precipitate the target compound as a white solid. After the mixture was cooled to room temperature and stirred for an additional hour, the white solid was filtered off, washed with diethyl ether and dried in vacuum at room temperature. The product (R)-2(toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indol-3-one (so pl. 225-227oC) was clean without additional recrystallization and weighed 4.2 g (79%).

Elemental analysis for C18H17NO6< / BR>
Calculated: C, 57.59, H 4.57, N 3.73

Found: C, 57.34, H 4.55, N 3.69.

Example 1

2-/Benzylamino-methyl/-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.80 g, 2.13 mmole) and 99.5% benzylamine /1.42 g, 11.72 mmole/ were combined in 15 ml of dry DMSO, through the solution was barotiwala strong stream of nitrogen. The mixture was heated to 75oC for 3 hours. The reaction mixture was cooled and taken in 400 ml of ethyl acetate. The mixture was washed with six 100 ml portions of water. United water flushing fluid back was extracted with six 50 ml portions of the floor which has been filtered and concentrated giving a brown oil. This oil was subjected to chromatography on silicagel column using a 0.75% methanol/methylene chloride to remove impurities. A mixture of 1% methanol/methylene chloride was swirbul the desired product, which was obtained in the form of oil (1.85 g, 65%). This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0.76 g, 6.57 mmole) in hot isopropanol, giving of 2.21 g (S) enantiomer of the target compound as a pale yellow solid cybertiger of monopolarity, so pl. 202oC.

Elemental analysis for C18H18N2O3C4H4O40,25 H2O

Calculated: C, 61.32, H 5.26, N 6.50

Found: C, 61.31, H 5.01, N 6.42.

Example 2

2-(Benzylamino-methyl)-1-benzylidene-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

The target compound was separated as a by-product after prolonged heating of the reaction mixture described in example 1. Benzylamine used in this reaction, contained, as it later was determined that approximately 0.5% of benzaldehyde. The target connection freely separated using column chromatography on silica gel using as eluent a mixture of 0.75% of the methane is solution of fumaric acid in hot isopropanol, yielding 0.30 g of a bright orange solid cybertiger of profumata (S) configuration, so pl. 206oC.

Elemental analysis for C25H22N2O30.50 C4H4O40.25 H2O

Calculated: C, 70.35, H 5.36, N 6.08

Found: C, 70.31, H 5.13, N, 6.04.

Example 3

2-{ [3-(Indol-3-yl)-propylamino] -methyl} -2,3,8,9-tetrahydro-7H-1,4 - like-[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.5 g, 4.2 mmole) in DMSO (80 ml) was slowly added through a dropping funnel for 3-(3-aminopropyl)indole /1.1 g, 6.3 mmole/ in DMSO (50 ml) and the mixture was heated at 75oC for 17 hours. Most of the DMSO was removed under reduced pressure, and the residue is then distributed between water and a solution of dichloromethane/isopropanol (3: 1). The separated organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and subjected to column chromatography on silica gel using first a mixture of ethyl acetate/hexane (7: 3), then ethyl acetate and finally 5% methanol in ethyl acetate as eluents. The expected product was separated, processed 0.25 M ethanolic fumaric acid and deposited the minimum amount of hexane, yielding 70 mg (P>+/.

Example 4

2-{ [2-(1H-Indol-3-yl)-ethylamino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.2 g, 3.2 mmole) and tryptamine (1.5 g, 9.6 mmol) in DMSO (50 ml) was placed in a three-neck flask equipped with condenser, thermometer and nitrogen bubbler immersed in a solution. The reaction mixture was heated at 75oC for 5 hours, cooled to room temperature and distributed between water and ethyl acetate. An ethyl acetate layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and subjected to column chromatography on silica gel using first ethyl acetate and then with 2.5%, 5%, 10% methanol in ethyl acetate as eluents. The free base of the desired product was obtained (of 0.85 g, 2.3 mmole) in the form of oil, which was dissolved in 50 ml of a mixture of ethanol and diethyl ether (1: 1) in the form of a solution and processed 10.3 ml of 0.25 M fumaric acid in ethanol. The addition of hexane gave 0.30 g (S) enantiomer of the target compound in the form of not quite white solid three quarters hydrate of profumata, so pl. 175-176oC.

Elemental analysis for: C21H21N3O31/2 C4Hydroxy-propylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.37 g, 1.0 mmole) 3-amino-1-propanol (20 ml) was heated at 75oC for 15 hours. During this period, the heterogeneous reaction mixture was beginning to brighten. The reaction mixture was cooled to room temperature and was distributed between dichloromethane solution/IPA (3: 1) and a salt solution. The separated aqueous layer was extracted with a mixture of dichloromethane/IPA (3: 1), and the combined extracts were washed with saturated sodium bicarbonate solution and with water to remove aminopropanol, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was chromatographically on a column of basic alumina using 5% methanol in dichloromethane as eluent, giving the free base (0.2 g, 72%) of the expected product. The free base was dissolved in ethanol (10 ml) was treated with excess of 0.25% ethanolic fumaric acid, and precipitated with hexane, giving 0.090 g (S) enantiomer of the target compound as a pale yellow solid cybertiger of profumata, so pl. 192-193oC.

Elemental analysis for: C14H18N2O41/2 C4H4O41/4 H2O

Calculated: C, 56.38, H quinoline-8-he

1 M Solution Wnzthp (11.00 ml, 11.00 mmol) was placed in a 100 ml round bottom flask equipped with input of nitrogen, addition funnel and thermometer. The solution was cooled to 0oC in a bath of ice and water. To this cooled solution was added 8-allyl-7-nitro-2,3-dihydro-benzo[1,4] -dioxin-2-ymetray ether (R)-toluene-4-sulfonic acid (2.25 g, 5.56 mmole) in 10 ml of dry THF dropwise over a 10 minute period. The reaction mixture was left to reach room temperature, and then stirred over night. Then it was cooled tooC, and to it was added dropwise 2.42 ml of absolute ethanol and 6.16 ml /18.5 mmole/ 3 n sodium hydroxide solution. After a few minutes during the 20-minute period was added 4.2 ml of 30% aqueous hydrogen peroxide solution. The mixture was heated to 48oC for three hours. The mixture then was cooled to 0oC, and to it was added 6.08 g of potassium carbonate. The mixture is stirred for 0.5 hour and then was left to stand over night. The next morning the solid disappeared. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and consemative ether (R)-toluene-4-sulfonic acid.

In a 50 ml 3-necked flask, equipped with magnetic stirrer, thermometer, input of nitrogen and addition funnel, was added potassium permanganate (1.24 g, 9.25 mmole), water (15 ml) and Tetra-n-butylammonium (0.17 g). The purple solution was cooled to 0oC, and to it was added dropwise 8-(3-hydroxy-propyl)-7-nitro-2,3-dihydro-benzo[1,4] -dioxin-2-ymetray ether (R)-toluene-4-sulfonic acid (1.20 g, 2,84 mmole), obtained above, in 10.3 ml of benzene. The reaction mixture was stirred at room temperature overnight, and then was added 4.40 g of sodium bisulfite. The color of the mixture disappeared after 5 minutes of mixing. After an additional 10 minutes of stirring was added 4 N. isopropanolate HCl to bring the pH to about 1. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed four times with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated, giving a clear yellow oil (0.95 g, 77%) of 3-[6-nitro-3-(toluene-4-sulfonyloxy)-2,3-dihydro-benzo[1,4] dioxin-5 - yl] -propionic acid.

3-[6-Nitro-3-(toluene-4-sulfonyloxy)-2,3-dihydro - benzo-[1,4] dioxin-5-yl] -propionic acid (0.95 g, 2.17 mmole) was taken in 8 ml of isopropanol and transferred vastor was flushed a strong stream of nitrogen, and to it was added 10% palladium on coal (0.32 g). The mixture was gerasoulis in a Parr apparatus at 57 pounds/square inch (4.008 kg/cm) hydrogen. After twenty hours the mixture was filtered and the catalyst was rinsed with water. To the aqueous filtrate was added 2.3 ml of concentrated HCl, and the solution was heated overnight at 55oC. When the solution was cooled, deposited 0.45 g of (R)-2-(toilet-methyl)-2,3,9,10-tetrahydro-7H-1,4-like[2,3-f] quinoline-8-it was collected by filtration and dried in vacuum.

(R)-2-(Toluene-4-sulfonyloxy)-2,3,9,10-tetrahydro-7H-1,4 - like[2,3-f] quinoline-8-he (0.45 g, 1.16 mmole) and 99.5% of benzylamine /0.68 g, 6.33 mmole/ were combined in 15 ml of dry DMSO and heated to 80oC for 7 hours in a nitrogen atmosphere. To this solution was added 150 ml of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated, giving a light brown solid. This solid was subjected to column chromatography on silica gel using 0.75% methanol/methylene chloride to remove impurities. A mixture of 4% methanol/methylene chloride was swirbul the desired product, which was obtained as a white Twi acid (0.11 g, 0.94 mmol) in hot isopropanol, yielding 0.32 g /S/ enantiomer of the target compound as a light white solid monopolarity, so pl. 219oC.

Elemental analysis for C19H20N2O3C4H4O4< / BR>
Calculated: C 62,72, H 5.49, N 6.36

Found: C, 62.34, H 5.32, N 6.19

Example 7

(2-[(4-Methylbenzylamino)-methyl)-2,3,8,9-tetrahydro-7H-1,4 - like-[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0,80 g, 2.13 mmol) and 4-methylbenzylamine /1.42 g, 11.7 mmole/ were combined in 15 ml of dry DMSO and heated to 85oC for 4 hours in nitrogen atmosphere. The reaction mixture in a nitrogen atmosphere. The reaction mixture was cooled and distributed between 70 ml of ethyl acetate and 200 ml of deionized water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated, giving a brown-orange oil. This oil was subjected to chromatography on silica gel using a mixture of 0.75% methanol/methylene chloride to remove impurities. A mixture of 2% methanol/methylene chloride was swirbul the desired product, which was isolated as an oil (0.40 g, 58). The oil was crystallized from isopropanol with the addition of a solution of fumaric white solid fumaric salt, so pl. 204-205oC, which was contaminated with an additional one-half equivalent of fumaric acid.

Elemental analysis for: C25H26N2O91.5 C4H4O4< / BR>
Calculated: C, 60.24, H 5.26, N 5.62

Found: C, 60.18, H 5.26, N 5.79

Example 8

2-Aminomethyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (3.0 g, 8.0 mmol) and sodium azide (1.6 g, 24.0 mmole) were placed in 300 ml of DMF, and the reaction mixture was heated at 45oC for 15 hours. Most of the DMF was removed, and the residue was distributed between dichlormethane and water. The dichloromethane layer was separated,

were dried over anhydrous magnesium sulfate and concentrated. The residue was pure enough without further purification and was identified as the desired product, (S)-2-azidomethyl-2,3,8,9-tetrahydro-7H-1,4-like-[2,3-e] indole-8-he. Aliquot the amount of azide (0.8 g, 3.2 mmole) in ethanol (50 ml) was gerasoulis using 10% palladium on coal (100 mg) for 15 hours. The resulting mixture was padillas 4 N. isopropanolic HCl up until the pH value became less than 3. The catalyst was then filtered, and the filtrate was concentrated. The remainder rastello solid 1.25 hydrate hydrochloride (0.7 g, 85%), so pl. 278-280oC.

Elemental analysis for: C11H12N2O3HCl1.25 H2O

Calculated: C, 47.32, H 5.59, N 10.03

Found: C, 47.48, H 5.44, N 10.08.

Example 9

2-(Cyclohexylethylamine-methyl)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.80 N. , 2.13 mmole) and cyclohexylethylamine (1.33 g, 11.7 mmol) were combined in 15 ml of DMSO and heated to 80oC for 6 hours in nitrogen atmosphere. The reaction mixture was left to cool and was distributed between 100 ml of ethyl acetate and 150 ml of deionized water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated, giving a black oil. This oil was subjected to column chromatography on silica gel using a mixture of 0.75% methanol/methylene chloride to remove impurities. A mixture of 2% methanol/methylene chloride was swirbul the desired product, which was in the form of oil (0,38 g, 56%) after concentration in vacuum. This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0.15 g, 1.3 mmole) in hot isopropanol, yielding 0.39 g (S) enantiomer of the target compound in the form of not Tverdov>O3C4H4O40.5 H2O

Calculated: C 59,85, H 6.62, H 6.34

Found: C 59,81, H, 6.61; N, 6.28

Example 10

2-[(2-Pyridin-3-yl-ethylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - Like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.80 g, 2.1 mmole) and 3-(2-amino-ethyl)pyridine (1.30 g, 10.6 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 9 hours under nitrogen atmosphere. The reaction mixture was left to cool, and then was distributed between methylene chloride and deionized water. The aqueous layer was extracted with additional methylene chloride. The organic fractions were combined, were washed with saline, dried over magnesium sulfate, filtered and concentrated, giving an orange oil. This oil was subjected to chromatography on silicagel column using a mixture of 0.75% methanol/methylene chloride to remove impurities. Elution with a mixture of 3-5% methanol/methylene chloride gave the desired product, which was obtained as a beige solid (0,48 g, 69%) after concentration in vacuum. This substance was precrystallization from isopropanol with the addition of 4 N. isopropanolic HCl, giving 0.27 g (S) enantiomers of zalewo the private analysis for: C18H19N3O32 HCl0.75 H2O

Calculated: C, 52.50, H 5.51, N 10.00

Found: C, 52.19, H 6.29, N 10.00

Example 11

2-{ [(3-Dimethylamino-phenoxy)-propylamino] -methyl} -2,3,8,9 - tetrahydro-7H-1,4-Like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.80 g, 2.13 mmole) and 3-(3-dimethylaminopropoxy)Propylamine (2.07 g, 10.6 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 4 hours in nitrogen atmosphere. The reaction mixture was taken in 150 ml of methylene chloride and was washed six times with 40 ml portions of water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo giving a brown oil. This oil was subjected to chromatography on silicagel column using a mixture of 0.75% methanol/methylene chloride to remove impurities. Elution with a mixture of 12% methanol/methylene chloride gave the desired product, which was obtained in the form of an oil (0.27 g, 32%) after concentration in vacuum. The oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0,086 g, 0.75 mmole) in hot isopropanol, yielding 0.17 g /S/ enantiomer of the target compound as a brown solid monopolarity, so pl. 136-138
Found: C, 61.17, H 6.21, N 8.3

Example 12

2-{ [(Thiophene-2-ylmethyl)-amino] -methyl} -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.80 g, 2.13 mmole) and thiophene-2-methylamine (1.45 g, 12.80 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 6 hours in nitrogen atmosphere. The reaction mixture was taken in 150 ml of methylene chloride and was washed six times with 40 ml portions of water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo giving a dark orange oil. This oil was subjected to chromatography on silicagel column using a mixture of 0.75% methanol/methylene chloride to remove impurities. Elution with a mixture of 1-2% methanol/methylene chloride gave the desired product, which was obtained in the form of an oil (0.44 g, 54%) after concentration in vacuum. The crude product is crystallized from isopropanol with the addition of a solution of fumaric acid (0.18 g, 1.5 mmole) in hot isopropanol, giving of 0.48 g (S) enantiomer of the target compound as a pale yellow solid cybertiger of monopolarity, so pl. 210-211oC.

Elemental analysis for: C16H16

Example 13

2-{ [3-(Quinoline-7-yloxy)-propylamino] -methyl} -2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0,80 g, 2.13 mmole) and 3-(quinoline-7-yloxy)Propylamine (2.15 g, 10.6 mmol) were combined in 15 ml of dry DMSO and heated to 85oC for 6 hours in nitrogen atmosphere. The reaction mixture was taken in 150 ml of methylene chloride and was washed six times with 40 ml portions of water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated, yielding a dark brown oil. This oil was subjected to chromatography on silica gel using a mixture of 0.75% methanol/methylene chloride to remove impurities. Elution with a mixture of 4-5% methanol/methylene chloride gave the desired product, which was obtained as a beige solid (0.30 g, 35%) after concentration in vacuum. The crude solid was precrystallization from isopropanol with the addition of 4 N. isopropanolic HCl, yielding 0.14 g (S) enantiomer of the target compound as a pale yellow solid hydrate of the dihydrochloride, so pl. 176-177oC.

Elemental analysis for: C23H23N3O42HClH2O

Calculated: C, 55.65, the on - 7H-1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0,70 g, 1.87 mmole) and 1-adamantanemethylamine (1.55 g, 9.35 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 6 hours in nitrogen atmosphere. The reaction mixture was taken in 150 ml of ethyl acetate and was washed six times with 40 ml portions of water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding a dark brown oil. This oil was subjected to column chromatography on silica gel using a mixture of 0.75% methanol/methylene chloride as eluent, yielding 0.51 g (74%) of the desired product as a beige solid. The crude product was precrystallization from isopropanol with the addition of a solution of fumaric acid (0.18 g, 1.5 mmole) in hot isopropanol, lava20,49 g (S) enantiomer of the target compound in the form of not quite white solid hemihydrate of monopolarity, so pl. 201-202oC.

Elemental analysis for: C22H28N2O3C4H4O40.5 H2O

Calculated: C, 63.25, H 6.73, N 5.67

Found: C, 63.23, H 6.87, N 5.60

Example 15

2-(Benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(S)-2-(Toloo as the (R) enantiomer, described above, with the substitution of (R)-glycidylmethacrylate (S)-goldencasinocom, and benzylamine (2,9 ml, 26.7 mmole) was placed in 20 ml of fresh DMSO under nitrogen atmosphere. The mixture then was heated to 75-80oC under stirring for 3 hours. After cooling at room temperature the reaction mixture was distributed between ethyl acetate and brine. DMSO layer was extracted with ethyl acetate, an ethyl acetate and the combined extracts were washed with water to remove traces of DMSO was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was chromatographically on silicagel column using ethyl acetate as eluent, giving the free base (1.4 g, 4.5 mmole, 83%) of the expected product in the form of a hardened oil under reduced pressure. The free base was dissolved in 20 ml of ethanol was processed 0.25 M ethanolic fumaric acid (10 ml) and was precipitated in diethyl ether, giving the target compound as a pale yellow solid fumaric salts, predominantly (R)-configuration, so pl. 195-196oC. This sample, the pharmacological results of which are reported in this application, according to the definition by using chiral HPLC, contained 9% (S)-enantiomer.

Elementaita: C, 61.96, H 5.13, N 6.51

Example 16

2-(Pentylamine)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (0.80 g, 2.13 mmole and pentylamine (0,93 g, 10.6 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 6 hours in nitrogen atmosphere. The reaction mixture was taken in 150 ml of methylene chloride and was washed six 40 ml portions of water. The organic layer was washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo giving a brown oil, which was chromatographically on a column of silica gel using a mixture of 0.75% methanol/methylene chloride to remove impurities. Elution with a mixture of 1-2% methanol/methylene chloride gave the desired product, which was obtained in the form of an oil (0.20 g, 32%) after concentration in vacuum. The product was crystallized from isopropanol with the addition of a solution of fumaric acid (0.090 g, 0.77 mmole) in hot isopropanol, giving 0.10 g (S) enantiomer of the target compound in the form of not quite white solid hemifumarate, so pl. 238-239oC.

Elemental analysis for: C16H22N2O30.5 C4H4O4< / BR>
Calculated: C, 62.05, H 6.94, N 8,04

Found: C, 61.54, H 6)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.00 g, 2.66 mmole) and 4-methoxybenzylamine (1.4 ml, 10.7 mmole) were combined in 10 ml of dry DMSO and heated to 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 150 ml of water, and the mixture was extracted twice with 250 ml portions 35% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to column chromatography on silica gel using a mixture of 2% methanol/methylene chloride as eluent. The free base of the target compound (0.51 g, 64%) was obtained in the form of oil after concentration in vacuum. The product was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.44 g (S) enantiomer of the target compound in the form of not quite white solid cybertiger fumarata, so pl. 205-205.5oC.

Elemental analysis for: C19H20N2O4C4H4O40.25 H2O

Calculated: C, 59.93, H 5.36, N 6.08

Found: C, 59.93, H 5.23, N 6.14

Example 18

2-(Naphthalene-1-yl-methylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-was heated to 85oC for 4 hours in nitrogen atmosphere. After cooling to room temperature, was added 150 ml of water, and the mixture was extracted twice with 250 ml portions 35% ethyl acetate in hexane. The combined organic extracts were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to column chromatography on silica gel using a mixture of 1% methanol/methylene chloride as eluent. The free base of the target compound (0.27 g, 27%) was obtained in the form of oil after concentration in vacuum. The product was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.25 g (S) enantiomer of the target compound as a pale yellow solid hemihydrate fumarata, so pl. 167-168oC.

Elemental analysis for: C22H20N2O3C4H4O40.5 H2O

Calculated: C 64,32, H 5.19, N 5.77

Found: C, 64.19, H 5.48, N 5.47

Example 19

2-(4-Trifluoromethyl-benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.03 g, 2.75 mmole) and 4-triftormetilfosfinov (1.60 ml, 11.2 mmole) were combined oops temperature was added 150 ml of water, and the mixture was extracted twice with 250 ml portions 35% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to column chromatography on silica gel using a mixture of 5% methanol/methylene chloride as eluent. The free base of the target compound (0.56 g, 54%), thus obtained, crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.06 g (S) enantiomer of the target compound in the form of not quite white solid fumarata, so pl. 211-212oC.

Elemental analysis for: C19H17F3N2O3C4H4O4< / BR>
Calculated: C 55,87, H 4.28, N 5.67

Found: C 55,56, H 3.93, N 5.75

Example 20

2-(4-Fluoro-benzylamino)-methyl-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.15 g, 3.07 mmole) and 4-forbindelsen (1.56 ml, 13.6 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 150 ml of water, and the mixture was extracted twice with 250 is over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was chromatographically on silicagel column using a mixture of 0.75% methanol/methylene chloride as eluent. The free base of the target compound (0,62 g, 62%), thus obtained, crystallized from ethanol with the addition of one equivalent of fumaric acid, giving 0.69 g (S) enantiomer of the target compound in the form of not quite white solid fumarata, so pl. 218-220oC.

Elemental analysis for: C18H17FN2O3C4H4O4< / BR>
Calculated: C 59,46, H 4.76, N 65.30

Found: C, 59.04, H 4.67, N 6.23

Example 21

2-(4-phenyl-butylamino)-methyl-2,3,8,9-tetrahydro-7H-1,4 - like-[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H - like[2,3-e] indole-8-he (1.05 g, 2.80 mmole) and phenylethylamine (1,99 ml, 12.5 mmole) were combined in 15 ml of dry DMSO and heated at 85oC for 4 hours in nitrogen atmosphere. After cooling to room temperature, was added 200 ml of water, and the mixture was extracted twice with 300 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuum, dava/SUB>Cl2as eluent. The free base of the target compound (0.26 g, 30%), thus obtained, crystallized from ethanol with the addition of one equivalent of fumaric acid, giving 0.2 g of the enantiomer of the target compound in the form of a reddish-brown solid hemihydrate fumarata, so pl. 185-186oC.

Elemental analysis for: C21H24N2O3C4H4O40.5 H2O

Calculated: C, 62.88; H, 6.12; N, 5.87

Found: C, 62.88; H, 6.04; N, 5.79.

Example 22

2-(4-fluoro-benzylamino-methyl)-9-(4-fluoro-phenyl-ethylidene)-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he

The target compound was separated as a byproduct after prolonged heating of the reaction mixture described in Example 20. It was determined that 4-forbindelsen used in this reaction, contains 4-forbindelse. The target compound was separated from the early fractions from the chromatography described in Example 20. The condensation product was obtained as orange oil and crystallized from a solution of fumaric acid in hot ethanol, yielding 0.06 g of orange solid hemihydrate of profumata (S) configuration, so pl. 202oC.

Elemental analysis for: C25H20
Example 23

N-(3-{ 3-[(8-oxo-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-2 - ylmethyl)-amino} -propoxy} -phenyl)-ndimethylacetamide

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.04 g, 2.77 mmole) and 3-(3-acetamidophenol)Propylamine (2.6 g, 12.5 mmole) were combined in 15 ml of dry DMSO and heated to 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 200 ml of water, and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to chromatography on silicagel column using a mixture of 2% methanol/CH2Cl2as eluent. Thus obtained the free base of the target compound (0.68 g, 62%) was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.56 g (S) enantiomer of the target compound as a pale yellow solid hemihydrate of profumata, so pl. 197-198oC.

Elemental analysis for: C22H25N3O50.5 C4H4O40.5 H2O

Calculated: C, 61.23; the Ino[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.03 g, 2.75 mmole) and propargylamine of 0.85 ml, 12.3 mmole) were combined in 20 ml of dry DMSO and heated to 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 100 ml of water, and the mixture was extracted twice with 200 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to chromatography on silicagel column using a mixture of 1% methanol/CH2Cl2as eluent. Thus obtained free base (0.50 g, 71%) was crystallized from isopropanol with the addition of one equivalent of fumaric acid, giving 0,42 g (S) enantiomer of the target compound as a pale yellow fumarata, so pl. 167-168oC.

Elemental analysis for: C14H14N2O3C4H4O4< / BR>
Calculated: C, 57,75; H, 4.85; N, OF 7.48

Found: C, 57.93; H, 5.16; N, 7.28

Example 25

2-[(3-Trifluoromethyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - the MCO and was heated to 85oC for 4 hours in nitrogen atmosphere. After cooling to room temperature, was added 200 ml of water, and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to chromatography on silicagel column using a mixture of 2% methanol/CH2Cl2as eluent. The free base of the target compound (0.20 g, 20%), thus obtained, crystallized from isopropanol with the addition of one equivalent of fumaric acid, giving 0.17 g (S) enantiomer of the target compound as a pale yellow solid hemihydrate fumarata, so pl. 158-160oC.

Elemental analysis for: C19H17F3N2O3C4H4O40.5 H2O

Calculated: C, 54.87; H, 4.41; N, 5.56

Found: C, 54.70; H, 4.09; N, 5.57

Example 26

2-(Benzylamino-methyl)-2,3-dihydro-7H-1,4-like[2,3-e] indol-8,9-dione

0,60 g (1.94 mmole) of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-it is obtained as described in Example 1 was taken in 200 ml of N. NaOH and 150 ml of methanol was mixed without protection from the hcpa is given 200 mg of a dark red oil. This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (79 mg, 0.68 mmole) in hot isopropanol, yielding 0.12 g (S) enantiomer of the target compound as a dark red solid, so pl. 177oC (decomp. )

Elemental analysis for: C19H17F3N2O3C4H4O4< / BR>
Calculated: C, 55,87; H, 4.28; N, 5,67

Found: C, 55,56; H, 3,93; N, 5.75

Example 27

2-[(4-Triptoreline-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he

(R)-2-(Toluene-4-sulfonyloxy)-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he (1.0 g, 2.7 mmole) and 4-cryptomaterial (2.0 g, 11 mmol) were combined in 30 ml of dry DMSO and heated to 90oC for 4 hours in nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 400 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 400 ml of saturated sodium bicarbonate solution, two 250 ml portions of water and saturated salt solution. The mixture was dried over sodium sulfate, filtered and concentrated in vacuo, yielding an oil, which was subjected to chromatography on silicagel column using a mixture of 1% methanol/HCl3as eluent. Thus obtained freedoms of the OIC acid, giving 0,29 g (S) enantiomer of the target compound as a white solid fumarata, so pl. 201-202oC.

Elemental analysis for: C19H17F3N2O3C4H4O4< / BR>
Calculated: C, 54.12; H, 4.15; N, 5.49

Found: C, 55.80; H, 3.97; N, 5.36

INTERMEDIATE COMPOUND 8

(R)-2-(Toluene-4-sulfonyloxy)-6-methyl-2,3 - dihydrobenzo[1,4] dioxin

(S)-(6-methyl)-2,3-dihydrobenzo(1,4 dioxin-2-yl)-methanol (10.1 g, 56,2 mmole) was dissolved in 375 ml of pyridine. To this solution was added 21.4 g (0.11 mole) of p-toluensulfonate and the mixture is stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was cooled in a bath of a mixture of ice/water, and to it was slowly added to 400 ml of water. The mixture is stirred at room temperature for 4 hours and then the solvent was removed in vacuo, yielding a dark brown oil. It was dissolved in ethyl acetate and washed 2 N. HCl (aq. ), water and saturated saline and dried over magnesium sulfate. Filtration, evaporation in vacuo and chromatography on silicagel column using 40% hexane in dichloromethane as eluent gave 15.1 g (89%) of target compound as a colourless oil.

1
(R)-2-(Toluene-4-sulfonyloxy)-6-methyl-7-nitro-2,3 - dihydrobenzo-[1,4] dioxin

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-2,3-dihydrobenzo[1,4] -dioxin (15.1 g, 50 mmol) was dissolved in 154 ml of dichloroethane and cooled to 0oC in a bath of a mixture of ice/water. To this chilled solution for 10 minutes was added dropwise a solution of nitric acid (tank weight 1.49) in 38 ml of dichloroethane. The mixture is stirred at 0oC in nitrogen atmosphere for 1 hour, after which the reaction mixture was cooled by adding ice. The mixture was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate solution, water, saturated salt solution and dried over magnesium sulfate. Filtration and evaporation in vacuo gave 16.8 g of the target compound as a yellow solid.1H (DMSO-d6) doublet, 7.80 (2H); doublet, 7.45 (2H); singlet, 7.40 (1H); singlet, 6.98 (1H); multiplet, 4.57 (1H); multiplet, 4.40 (2H); multiplet, 4.20 (1H); multiplet, 4,10 (1H); singlet, 2.43 (3H); singlet, 2.40 (3H).

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-7-amino-2,3 - dihydrobenzo[1,4] dioxin

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-7-nitro-2,3 - dihydrobenzo[1,4] dioxin (16.8 g, 44,6 mmole) was added to a suspension of 1.8 g of 10% palladium on coal in 150 ml of methane which was intervals through celite, and the catalyst was rinsed with ethyl acetate. The filtrate was concentrated in vacuo, yielding 11.7 g of the target compound as a pale yellow solid.1H (DMSO-d6) doublet, 7.80 (2H); singlet, 6.40 (1H); singlet, 6.08 (1H); singlet, 4.40 (2H); multiplet, 4.30 (2H); multiplet, 4.10 (2H); multiplet, 3.80 (1H); singlet, 2.40 (3H); singlet, 1.90 (3H).

INTERMEDIATE COMPOUND 11

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he

In a three-neck flask equipped with addition funnel, thermometer, and input of nitrogen was placed 5.56 g (41.4 mmole) of ethylmethylamine and 130 ml of dry methylene chloride. The solution was cooled to -78oC using a bath of a mixture of dry ice/isopropanol, and thereto was dropwise added 5.20 g (of 38.4 mmole) of sulphonylchloride within a 3-minute period. To the resulting mixture, after 15 minutes was added a solution of (R)-2-(toluene-4-sulfonyloxy)-6-methyl-7 - amino-2,3-dihydrobenzo[1,4] dioxin (11.7 g, a 33.6 mmole) and Proton Sponge (8,64 g, 40.3 mmole) in 220 ml of methylene chloride. The mixture is stirred at -78oC for two hours, then within 10 minutes dropwise added to 5.2 g (40.3 mmole) of diisopropylethylamine, and stirring was continued for additional one hour at -78oC is alas over night under nitrogen atmosphere. The resulting solution was diluted to 500 ml with methylene chloride and was washed with saturated saline, dried over magnesium sulfate, filtered and concentrated in vacuo giving a brown oil. It was dissolved in 140 ml of glacial acetic acid and stirred for 1.5 hours at room temperature in a nitrogen atmosphere. The solvent was removed in vacuum and replaced with 500 ml of methylene chloride. The mixture was washed with 300 ml portions of a saturated aqueous solution of bicabonate sodium and saturated saline solution, dried over magnesium sulfate, filtered and concentrated in vacuo to an orange foam. The foam was dissolved in 175 ml of THF and added to a suspension of approximately 100 g of Raney Nickel (nick-Ren suspended in the form of a slurry in water), which were washed with water, 0.5% aqueous solution of acetic acid, again with water and finally THF. The reaction mixture was stirred at room temperature for 48 hours, then the solution was decontrols, and the catalyst was carefully filtered THF. The combined organic fractions were reduced in volume until, until the formed precipitate. The target compound (5.15 g, 50%) was allocated in the form of a beige solid, so pl. 233-235oC, with the aid of the .93; H, 4.99; N, 3.56

Found: C, 57,72; H, 4.96; N, 3.56

Example 28

2-[(4-methyl-benzylamino)-methyl] -6-methyl-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-2,3,8,9 - tetrahydro-7H-like[2,3-e] indole-8-he (1.20 g, 3.10 mmole) and 4-methylbenzylamine (2.07 g, 17.0 mmol) were combined in 22 ml of dry DMSO and heated to 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 150 ml of water, and the mixture was extracted twice with 250 ml portions 35% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, giving 0,38 g light yellow solid. Thus obtained the free base of the target compound was crystallized from ethanol with the addition of fumaric acid (0.24 g, 1.2 mmole), yielding 0.43 g (S) enantiomer of the target compound as a yellow solid cybertherapist fumarata, so pl. 225-227oC.

Elemental analysis for: C20H22N2O3C4H4O40,25 C2H6O

Calculated: C, 63,27; H, 5.78; N, 6.08

Found: C, 63,46; H, 5.79; N, 5.97

Example 29

2-{ [(thiophene-2-ylmethyl)-amino] -methyl} -6-methyl-2,3,8,9-tin[2,3-e] indole-8-he (1.00 g, 2.57 mmole) and thiophene-2-methylamine (1.42 g, 12.6 mmole) were combined in 15 ml of dry DMSO and heated to 90oC for 6 hours in nitrogen atmosphere. After cooling to room temperature was added 250 ml of water, and the precipitate precipitated brown solid. It was dissolved in methylene chloride, dried over magnesium sulfate, filtered and concentrated in vacuo, giving the sky an orange solid, which was subjected to chromatography on silicagel column using a mixture of 1.5% methanol/CH2Cl2as eluent. Thus obtained the free base of the target compound (0.27 g) was crystallized from isopropanol with the addition of fumaric acid (0.10 g, 0.90 mmole), yielding 0.28 g (S) enantiomer of the target compound as a pale orange solid fumarata, so pl. 211-212oC.

Elemental analysis for: C17H18N2O3SC4H4O4< / BR>
Calculated: C, 56,49; H, 4.97; N, 6.27

Found: C, 56,21; H, 4.99; N, 6.41

Example 30

6-methyl-2-{ [(naphthalene-1-ylmethyl)-amino] -methyl} -2,3,8,9-7H - tetrahydro-1,4-like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-he (0.80 g, 2.1 mmole) and 1-naphthalenemethylamine the donkey cooling to room temperature, was added 250 ml of water, and the mixture was extracted twice with 250 ml portions 35% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo, giving a light orange oil. The oil was subjected to chromatography on silicagel column using a mixture of 1.5% methanol/CH2Cl as eluent, yielding 0.39 g of the free base of the target compound as a pale yellow solid. It crystallized from isopropanol with the addition of fumaric acid (0.13 g, 1.2 mmole), yielding 0.36 g (S) enantiomer of the target compound as a pale yellow solid cybertherapist fumarata, so pl. 194-195oC.

Elemental analysis for: C23H22N2O3C4H4O4< / BR>
Calculated: C, 66.11; H, 5.34; N, 5.71

Found: C, 66.03; H, 5.34; N, 5.80

Example 31

2-(benzylamino-methyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-he (1,57 g, 4.04 mmole) and benzylamine (2.18 g, 5.6 mmole) were combined in 10 ml of dry DMSO and heated to 85oC for 3 hours in nitrogen atmosphere. After cooling to room temperature was added 15 the basics were washed with saline, were dried over magnesium sulfate, filtered and concentrated in vacuo, giving an orange oil. Chromatography on silicagel column using a mixture of 2% methanol/CH2Cl2as eluent gave 1.08 g of the free base of the target compound as a light beige solid. It crystallized from isopropanol with the addition of fumaric acid (0.42 g, 3.7 mmole) to give 0.49 g (S) enantiomer of the target compound in the form of a beige solid fumarata, so pl. 219-220oC.

Elemental analysis for: C19H20N2O3C4H4O4< / BR>
Calculated: C, 62,72; H, 5.49; N, 6.36

Found: C, 62.44; H, 5.29; N, 5.57

Example 32

2-[(4-fluoro)-benzylamino-methyl] -6-methyl-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-methyl-2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-he (0.28 g, 0.72 mmole) and 4-forbindelsen (0.45 g, 3.6 mmole) were combined in 10 ml of dry DMSO and heated to 90oC for 4 hours in nitrogen atmosphere. After cooling to room temperature, was added 150 ml of water, and the mixture was extracted twice with 250 ml portions 35% ethyl acetate in hexane. The combined organic phases were washed with saline, dried over sulfate is and silicagel column using a mixture of 1% methanol/CH2Cl2as eluent gave the free base of the target compound as a brown oil. It crystallized from isopropanol with the addition of fumaric acid (0.20 g, 1.7 mmole) to give 0.06 g (S) enantiomer of the target compound in the form of a beige solid fumarata, so pl. 233-234oC.

Elemental analysis for: C19H19FN2O3C4H4O4< / BR>
Calculated: C, 60.26; H, 5.06; N, 6.11

Found: C, 59.96; H, 4.87; N, 6.14

INTERMEDIATE COMPOUND 12

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3-dihydrobenzo[1,4] dioxin

(S)-(6-fluoro)-2,3-dihydrobenzo(1,4-dioxin-2-yl)methanol (17 g, 92 mmole) was dissolved in 1 liter of pyridine. To this solution was added 38 g (0.20 mole) of p-toluensulfonate, and the mixture is stirred at room temperature under nitrogen atmosphere for three days. The reaction mixture was cooled in a bath of a mixture of ice/water and to it was slowly added 10 ml of water. The mixture is stirred at room temperature for 2 hours and then the solvent was removed in vacuum and replaced with 800 ml of methylene chloride. This solution was washed twice with 500 ml of 1 N. aqueous HCl solution, saturated aqueous sodium bicarbonate and saturated saline and dried over whether 50% hexane in dichloromethane as eluent gave 25.1 g (89%) of target compound in the form of not-quite-white solid.

1H (CDCl3) doublet, 7.86 (2H); doublet, 7.32 (2H); doublet of doublets, of 6.65 (1H); multiplet, 6.58 (2H); multiplet, 4.34 (1H); multiplet, 4.20 (3H); multiplet, 4.00 (1H); singlet, 2.43 (3H).

INTERMEDIATE COMPOUND 13

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-7-nitro-2,3 - dihydrobenzo[1,4] dioxin

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3-dihydrobenzo[1,4] dioxin (25,1 g, 74 mmole) was dissolved in 250 ml of dichloroethane and cooled to 0oC in a bath of ice/water. To this chilled solution for 15 minutes was added dropwise a solution of nitric acid (adeln. weight 1.49) in 60 ml of dichloroethane. The mixture is stirred at 0oC in nitrogen atmosphere for two hours, after which the reaction was slaked by adding 500 g of ice. The mixture was diluted to 700 ml with methylene chloride and washed with saturated aqueous sodium bicarbonate solution, water, saturated salt solution and dried over sodium sulfate. Filtration and evaporation in vacuo gave 25 g of the crude product. He was subjected to chromatography on silicagel column using a mixture of 1: 1 hexane/ethyl acetate as eluent, giving 21 g of the target compound as a yellow solid.

1H (CDCl3) doublet, 7.80 (2H) doublet, 7.50 (1H); doublet, 7.38 (2H the CONNECTION 14

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-7-amino-2,3 - dihydrobenzo-[1,4] dioxin

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-7-nitro-2,3 - dihydrobenzo[1,4] dioxin (21 g, 55 mmol) was added to a suspension of 2.0 g of 10% palladium on coal in 250 ml of methanol. To it was added 15 ml of 4 N. isopropanolic HCl. The mixture was gerasoulis for 20 hours by using a Parr apparatus under a nitrogen pressure of 50-60 pounds per square inch (3.515-4.219 kg/sq. see ). The mixture was then filtered through celite, and the catalyst was rinsed with additional methanol. The filtrate was concentrated in vacuo, giving 21,4 g of target compound as a gray solid hydrochloride.

1H (DMSO-d6) doublet, 7.80, (2H); doublet, 7.47 (2H); doublet, 6.95 (1H); doublet, 6.85 (1H); multiplet, 4.40 (1H); multiplet, 4.25 (3H); multiplet 4.00 (1H); singlet, 2.40 (3H).

INTERMEDIATE COMPOUND 15

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he

In a three-neck flask equipped with addition funnel, thermometer, and input of nitrogen was placed 6.15 ml (48.0 mmol) of ethylmethylamine and 65 ml of dry methylene chloride. The solution was cooled to -78oC using a dry bath ice/isopropanol, and to him for 5 minutes was added dropwise a solution of 3.80 g (47.0 mmol) of the minutes. Within 1 hour dropwise to the mixture was added a solution of (R)-2-(toluene-4-sulfonyloxy)-6-fluoro-7-amino-2,3 - dihydrobenzo[1,4] dioxin (15.7 g, 45.0 mmol) and Proton Sponge. (11.7 g, 47.0 mmol) in 150 ml of methylene chloride. The mixture is stirred at -78oC for 2 hours, then within 10 minutes was added dropwise a solution of 9.5 g (54 mmole) of diisopropylethylamine in 20 ml of dichloromethane, and stirring was continued for an additional hour at -78oC, after which the reaction mixture was allowed to reach room temperature where it stirred for 8 hours in nitrogen atmosphere. The resulting solution was diluted to 500 ml with methylene chloride and was washed with saturated saline, dried over magnesium sulfate, filtered and concentrated in vacuo to education brown oil. It was dissolved in 200 ml of glacial acetic acid and stirred for 10 hours at room temperature in a nitrogen atmosphere. Then the solvent was removed in vacuum and replaced with 500 ml of methylene chloride. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate solution and saturated saline, dried over magnesium sulfate, filtered and concentrated in vacuo, giving Corinna in methylene chloride as eluent. Thus obtained light brown solid (13.0 g, 66%) was dissolved in 200 ml of THF and added to a suspension of approximately 200 g of Raney Nickel (nick-Ren suspended in the form of a slurry in water) in 600 ml of THF, which was rinsed with water, 0.5% aqueous acetic acid, again with water and finally THF. The reaction mixture was stirred at room temperature for 8 hours, then the solution was decontrols, and the catalyst was carefully filtered THF. The combined organic fractions were concentrated in vacuo, and the product was subjected to chromatography on silicagel column using methylene chloride as eluent. The target compound (4.54 g, 40%) stood out as not quite white solid substance, so pl. 205-206oC.

Elemental analysis for: C18H16FNO6S 0.25 H2O

Calculated: C, 54.34; H, 4.18; N, 3.52

Found: C, 54.12; H, 4.24; N, 3.41

Example 33

2-(benzylamino-methyl)-6-fluoro-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he (1.0 g, 2.5 mmole) and benzylamine (1.3 g, 12.5 mmol) were combined in 30 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After the cooling gap is spent aqueous sodium bicarbonate solution and two 250 ml portions of water, were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, giving 0.65 g of the free base of the target compound as pale yellow oil. It crystallized from methanol with the addition of one equivalent of fumaric acid, giving 0,62 g

(S) enantiomer of the target compound as a yellow solid fumarata, so pl. 205-207oC.

Elemental analysis for: C18H17FN2O3C4H4O4< / BR>
Calculated: C, 59.46; H, 4.76; N, 6.30

Found: C, 59.34; H, 4.81; N, 6.18

Example 34

6-fluoro-2-[(4-fluoro-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-he (1.0 g, 2.5 mmole) and 4-forbindelsen (1.25 g, 10 mmol) were combined in 30 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and the si of 0.5% methanol/CHCl3as eluent, yielding 0.55 g of the free base of the target compound as pale yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.50 g (S) enantiomer of the target compound as a white solid fumarata, so pl. 205-207oC.

Elemental analysis for: C18H16F2N2O3C4H4O4< / BR>
Calculated: C, 57.15; H, 4.36; N, 6.06

Found: C, at 56.85; H, 4.31; N, 5.92

Example 35

6-fluoro-2-[(4-methyl-benzylamino)-methyl] -9-(4-methyl-benzylidene)- 2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he (1.0 g, 2.5 mmole) and 4-methylbenzylamine (1.2 g, 10 mmol) were combined in 30 ml of dry DMSO and heated at 80oC for 4 hours without protection from atmospheric air. After cooling to room temperature the mixture was concentrated in high vacuum while heating at 100oC. was Added 300 ml of methylene chloride, and the solution was washed with 250 ml of saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography the first base of the target compound as a yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.49 g (S) enantiomer of the target compound as an orange solid monohydrate fumarata, so pl. 239-241oC.

Elemental analysis for: C27H25FN2O3C4H4O4H2O

Calculated: C, 64.35; H, 5.40; N, 4.84

Found: C, 64.65; H, 5.26; N, 4.60

Example 36

6-fluoro-2-[(4-methyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he (1.0 g, 2.5 mmol) and 4-methylbenzylamine (1.2 g, 10 mmol) were combined in 30 ml of dry DMSO and heated at 80oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent and crystallized from ethanol with the addition of fumaric acid, giving 0.57 g (S) enantiomer of the target compounds is
FN2O3C4H4O4< / BR>
Calculated: C, 60.26; H, 5.06; H, 6.11

Found: C, 60.13; H, 4.90; N, 6.01

Example 37

2-{ [3-(3-dimethylamino-phenoxy)-propylamino] -methyl} -6-fluoro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he (1.0 g, 2.5 mmole) and 3-(3-dimethylaminopropoxy)-Propylamine (1.92 g, 10 mmol) were combined in 30 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 1% methanol/CHCl3as eluent, yielding 0.25 g of the free base of the target compound as a yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, giving 0.19 g (S) enantiomer of the target compound in the form of a reddish-brown solid fumarata, so pl. 121-123oC.

Elemental analysis for: C22H26FN3O 2-{ [(adamantane-1-ylmethyl)-amino] -methyl} -6-fluoro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he (1.0 g, 2.5 mmole) and 1-adamantanemethylamine (1.6 g, 10 mmol) were combined in 30 ml of DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature, the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, yielding 0.70 g of the free base of the target compound as a colorless oil. It was crystallized from ethanol with the addition of 4 N. isopropanolic HCl, yielding 0.54 g (S) enantiomer of the target compound in the form of a white solid of crystalline hydrochloride, so pl. 260oC.

Elemental analysis for: C22H27FN2O3HCl

Calculated: C, 62.48; H, 6.67; N, 6.62

Found: C, 62,13; H, 6.82; N, 6.56

Example 39

6-fluoro-2-{ [3-(1H-indol-3-yl)-propylamino] -methyl} -2,3,8,9 - tetrahydro-l-8-he (1.0 g, 2.5 mmole) and 3-(3-aminopropyl) indole (1.74 g, 10 mmol) were combined in 30 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, yielding 0.33 g of the free base of the target compound as pale yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.29 g (S) enantiomer of the target compound as a yellow solid fumarata, so pl. 133oC.

Elemental analysis for: C22H22FN3O3C4H4O4< / BR>
Calculated: C, 61.05; H, 5.12; N, 8.21

Found: C, 61.39; H, 5.40; N, 8.24

Example 40

2-[(4-chloro-benzylamino)-methyl] -6-fluoro-2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he (0.55 g, 1.4 mmole) and 4-chlorobenzylamino (1.4 g, 10 mmol) Obyedinennaya temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, yielding 0.13 g of the free base of the target compound as pale yellow oil. It was crystallized from ethanol with the addition of one equivalent of (R)-almond acid, yielding 0.06 g (S) enantiomer of the target compound in the form of a peach-colored solid salt of (R)-almond acid, so pl. 187-188oC.

Elemental analysis for: C18H16ClFN2O3C8H8O3< / BR>
Calculated: C, 60.65; H, 4.70; N, 5.44

Found: C, 60.48; H, 4.49; N, 5.37

Example 41

6-fluoro-2[((4-trifluoromethyl-benzylamino)-methyl] -2,3,8,9 - tetrahydro-7H-like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9-tetrahydro - 7H-1,4-like[2,3-e] indole-8-he (0,93 g, 2.37 mmole) and 4-triftormetilfosfinov (1.65 ml, 11.6 mmole) were combined in 13 ml of dry DMSO and heated at 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 200 ml of water, and the mixture was extracted with two 250 ml portions of a mixture of 1: 1 ethyl acetate/hexane, and the combined extracts were washed with saline, with whom and on silicagel column using a mixture of 2% methanol/CH2Cl2as eluent, giving 0,70 g of the free base of the target compound as a yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.32 g (S) enantiomer of the target compound as a white solid three-quarter hydrate fumarata, so pl. 192oC.

Elemental analysis for: C19H16F4N2O3C4H4O40.75 H2O

Calculated: C, at 52.53; H, 4.12; N, 5.33

Found: C, 52.27; H, 3.85; N, 5.28

Example 42

6-fluoro-2-[(4-phenyl-butylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-fluoro-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he (0,85 g, 2.16 mmole) and 4-phenylbutyramide (1.55 ml, 9.8 mmole) were combined in 20 ml of dry DMSO and heated at 85oC for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, was added 200 ml of water, and the mixture was extracted with two 250 ml portions of a mixture of 1: 1 ethyl acetate and hexane, and the combined extracts were washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CH2oC.

Elemental analysis for: C21H23FN2O30.5 C4H4O40,25 H2O

Calculated: C, 63.80; H, 5.94; N, 6.47

Found: C, 63.81; H, 5.75; N, 6.33

THE INTERMEDIATE CONNECTION 16

2 allyloxy-5-chlorophenol

To 14 g (0.35 mole) of a 60% dispersion of sodium hydride in mineral oil in a two-liter flask was added 500 ml of hexane. A mixture of short mixed, solid matter was deposited, and floating on top of the liquid decentralise. Was added DMF (800 ml) followed by a solution of 47 g (0.30 mole) of 5-chlorosalicylaldehyde in 50 ml of DMF. The mixture was mixed at room temperature in nitrogen atmosphere for 30 minutes, then was added to 54.5 g (0.45 mol) of allylbromide. The mixture was heated at 65oC in nitrogen atmosphere for 18 hours. The solvent was removed in vacuum and replaced with one liter of methylene chloride. This solution was washed with water and saturated saline and dried over sodium sulfate. Then it was filtered and added 150 g (0.50-0.75 mole) 57-86% m-chloroperoxybenzoic acid, and the mixture was mixed at room temperature in about sodium bicarbonate solution and saturated saline solution, were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was dissolved in 750 ml of methanol was mixed with 150 g of basic aluminum oxide for 15 hours. Then the mixture was filtered and evaporated in vacuo, and the crude product was distributed between 500 ml each of 1 N. aqueous NaOH and methylene chloride. The organic phase was extracted with an additional 500 ml of the base, and the combined basic extracts were washed with 500 ml of methylene chloride. Finally, the basic extracts were carefully podkolis concentrated HCl and was extracted with two 400 ml portions of methylene chloride. The combined organic extracts were washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuo, giving 37.3 g of the target compound as a yellow oil.

1H (CDCl3) singlet, 6.90 (1H); Quartet, 6.70 (2H); singlet, 6.20 (1H, OH); multiplet, 5,97 (1H); Quartet, 5.25 (2H); doublet, 4.50 (2H).

INTERMEDIATE COMPOUND 17

(R)-2-(2-allyloxy-5-chlorphenoxy)-oxiran

To 4.0 g (79 mmol) of a 60% dispersion of sodium hydride in mineral oil in one litre flask were added 300 ml of hexane. A mixture of short mixed, the solid precipitated is RA 14.6 g (79 mmol) of 2-allyloxy-5-chlorophenol in 100 ml of DMF. The mixture was mixed at room temperature in nitrogen atmosphere for 30 minutes, then was added 18.0 g (79 mmol) of (R)-glycidylmethacrylate. The mixture was heated in nitrogen atmosphere at 80oC for 24 hours. The solvent was evaporated in vacuum and replaced with 750 ml of methylene chloride. The solution was washed with 500 ml portions of 2 N. aqueous HCl, saturated aqueous sodium bicarbonate solution, saturated salt solution, dried over sodium sulfate, filtered and evaporated in vacuo, yielding 20 g of the crude resin. She was subjected to chromatography on silicagel column using methylene chloride as eluent, yielding 9.2 g of the target compound as a colourless oil.

1H (CDCl3) singlet, 6.93 (1H); doublet, 6.90 (1H); doublet, 6.80 (1H); multiplet, 6.05 (1H); doublet, 5.40 (1H); doublet, 5.25 (1H); doublet 4.55 (2H); doublet of doublets, 4.25 (1H); doublet of doublets of 3.97 (1H); multiplet, the 3.35 (1H); triplet, 2.95 (2H); triplet, 2.75 (1H).

INTERMEDIATE COMPOUND 18

(S)-(8-allyl-6-chloro-2,3-dihydro-benzo[1,4] dioxin-2-yl)-methanol

(R)-2-(2-allyloxy-5-chlorphenoxy)-oxiran (9.2 g, 38 mmol) was dissolved in 500 ml of mesitylene and was heated under reflux in nitrogen atmosphere for 48 hours. The solvent was removed in vacuum and zamore in nitrogen atmosphere for 24 hours. The mixture was then filtered and concentrated in vacuum. The solvent was replaced with 500 ml of methylene chloride, and the solution was washed with water and saturated saline solution, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was subjected to chromatography on silicagel column using chloroform as eluent, giving 8.9 g of the target compound as a colourless oil.

1H (CDCl3) singlet, 6.80 (1H); singlet 6.73 (1H); multiplet, 5.95 (1H); doublet, 5.10 (1H); doublet, 5.05 (1H); multiplet, 4.25 (2H); multiplet, 4.10 (1H); multiplet, 3.85 (2H); multiplet, 3.30 (2H); broad singlet, 2.00 (1H).

INTERMEDIATE COMPOUND 19

(R)-8-allyl-6-chloro-2,3-dihydro-benzo-(1,4) dioxin-2-yl-methyl ester toluene-4-sulfonic acid

8.9 g (37 mmol) of (S)-8-allyl-6-chloro-2,3-dihydro-benzo[1,4] -dioxin-2-yl)methanol was dissolved in 500 ml of pyridine, was added 14.3 g (75 mmol) of p-toluensulfonate, and the mixture is stirred at room temperature under nitrogen atmosphere for 3 days. Then, water was added to absorb excess taillored, and the solvent was removed in vacuum and replaced with 500 ml of methylene chloride. This solution was washed twice with 300 ml of 2 N. aqueous HCl, saturated solution of bicarbonate nutrithrive on silicagel column with a mixture of 1: 1 hexane/methylene chloride as eluent gave up 10.9 g of the desired tosilata in the form of a colorless oil.

1H (CDCl3) doublet, 7.80 (2H); doublet, 7.30 (2H); singlet, 6.75 (1H); singlet, 6.70 (1H); multiplet, 5.85 (1H); singlet, to 5.08 (1H); doublet, 5.03 (1H); multiplet, 4.40 (1H); multiplet, 4.20 (2H); doublet of doublets, of 4.05 (1H); multiplet, 3.20 (2H); singlet, 2.45 (3H).

INTERMEDIATE COMPOUND 20

(R)-(7-chloro-3-(toluene-4-sulfonyloxy)-2,3-dihydro-benzo(1,4) dioxin-5-yl)-acetic acid

Potassium permanganate (14 g, 87 mmol) was dissolved in 140 ml of water were placed in a water bath. To it was added 1.4 g (4.9 mmole) chloride, Tetra-n-butylamine, and then for 30 minutes was added dropwise a solution of 10.9 g (R)-8-allyl-6-chloro-2,3-dihydro-benzo[1,4] -dioxin-2-Eletropaulo ester toluene-4-sulfonic acid (28 mmol) in 100 ml of benzene. The mixture is stirred at room temperature overnight. Then was added sodium bisulfite (17 g, 0.12 mol) and the mixture was padillas concentrated HCl and was extracted with two 300 ml portions of ethyl acetate. The combined extracts were washed with water and saturated saline and dried over sodium sulfate. Filtration, concentration in vacuo and chromatography on silicagel column using a mixture of 3% methanol in methylene chloride gave 5.9 g of target compound in the form of a viscous yellow oil.

THE INTERMEDIATE CONNECTION 21

(R)-(7-chloro-6-nitro-3-(toluene-4-sulfonyloxy)-2,3 - dihydrobenzo-(1,4)dioxin-5-yl)-acetic acid

To a mixture of 3.0 g (7.3 mmole) of (R)-(7-chloro-3-(toluene-4-sulfonyloxy)-2,3 - dihydrobenzo(1,4)dioxin-5-yl) -vinegar Noah acid in 50 ml of dichloroethane in a bath of ice/water was added a solution of 3.6 ml (85 mmol) of nitric acid (adeln. weight 1.49) in 50 ml of dichloroethane. The mixture was given to reach room temperature tours, and it is stirred overnight. For damping the reaction was added to ice, and the mixture was diluted to 300 ml with methylene chloride, washed with water and saturated saline solution, dried over sodium sulfate. Concentration in vacuo gave 2.8 g of the target compound in the form of not-quite-white solid.

1H (DMSO-d6broad singlet, 12.75 (1H); doublet, 7.80, (2H); doublet, 7.45 (2H); singlet, 7.15 (1H); multiplet, 4.60 (1H); multiplet 4.37 (2H); multiplet, 4.15 (2H); singlet, 3.45 (2H); singlet, 2.40 (3H).

INTERMEDIATE COMPOUND 22

(R)-2-(toluene-4-sulfonyloxy)-6-chloro-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he

To a solution of 2.8 g (6.1 mmole) of (R)-(7-chloro-6-nitro-3-(toluene-4-sulfonyloxy)-2,3 - digial in a Parr apparatus at a pressure of 50 lbs/sq. inch (3.515 kg/sq. cm) for 4 hours. The mixture was filtered through celite and concentrated in vacuo, giving 2.8 g of crude amino acid. She was re-dissolved in 250 ml of methanol was added 50 ml of 4 N. isopropanolic HCl. The mixture was heated at 50oC for 24 hours. The solvent was removed in vacuo and added 400 ml of ethyl acetate. This solution was washed with 200 ml of water, 200 ml of saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 1% methanol in methylene chloride as eluent, giving 1.4 g of the target compound in the form of not-quite-white solid.

1H (DMSO-d6) singlet, 10.63 (1H); doublet, 7.80 (2H); doublet, 7.45 (2H); singlet, 6.75 (1H); multiplet, 4.55 (1H); multiplet, 4.35 (1H); multiplet, 4.20 (2H); doublet of doublets, 4.03 (2H); AB Quartet, 3.25 (2H); singlet, 2.40 (3H).

Example 43

6-chloro-2-[((4-chloro-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] Iida-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-chloro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he (0.80 g, 2.0 mmole) and 4-chlorobenzylamino (1.1 g, 8.0 mmol) were combined in 25 ml is mperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, yielding 0.36 g of the free base of the target compound as pale yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.28 g (S) enantiomer of the target compound in the form of a reddish-brown solid hemihydrate fumarata, so pl. 207-209oC.

Elemental analysis for: C18H16Cl2N2O3C4H4O40.5 H2O

Calculated C, 52.39; H, 4.20; N, 5.55

Found: C, 52.37; H, 4.01; N, 5.61

Example 44

6-chloro-2-[(4-methyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-chloro-2,3,8,9-tetrahydro-7H - like[2,3-e] indole-8-he (to 0.80 g, 2.0 mmole) and 4-methylbenzylamine(1.0 g, 8.0 mmol) were combined in 25 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried imageline column using a mixture of 0.5% methanol/CHCl3as eluent, yielding 0.43 g of the free base of the target compound as pale yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, yielding 0.32 g (S) enantiomer of the target compound as a white solid fumarata, so pl. 218 - 219oC.

Elemental analysis for: C19H19ClN2O3C4H4O4< / BR>
Calculated: C, 58.17; H, 4,88; N, 5.90

Found: C, 57.84; H, 4.53; N, 5.97

Example 45

2-(benzylamino)-methyl-6-chloro-2,3,8,9-tetrahydro-7H-1,4 - dioxin[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-chloro-2,3,8,9 - tetrahydro-7H-1,4-like[2,3-e] indole-8-he (0.80 g, 2.0 mmole) and benzylamine (0,86 g, 8.0 mmol) were combined in 25 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, yielding 0.33 g of the free base of the target is mirovoi acid, giving 0.28 g (S) enantiomer of the target compound as a white solid fumarata, so pl. 192-193oC.

Elemental analysis for: C18H17ClN2O3C4H4O4< / BR>
Calculated: C, 57,34; H, 4.59; N, 6.08

Found: C, 57,45; H, 4.48; N, 6.26

Example 46

6-chloro-2-[(4-fluoro-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4 - like[2,3-e] indole-8-he

(R)-2-(toluene-4-sulfonyloxy)-6-chloro-2,3,8,9-tetrahydro-7H - 1,4-like[2,3-e] indole-8-he (0.80 g, 2.0 mmole) and 4-forbindelsen (1.0 g, 0.80 mmole) were combined in 25 ml of dry DMSO and heated at 80-90oC for 4 hours in argon atmosphere. After cooling to room temperature the mixture was diluted with 500 ml of a mixture 1: 1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate solution and two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silicagel column using a mixture of 0.5% methanol/CHCl3as eluent, giving 0,41 g of the free base of the target compound as pale yellow oil. It was crystallized from ethanol with the addition of one equivalent of fumaric acid, giving 0,29 g (S) enantiomer of the target compound in the form as the/SUB>ClFN2O3C4H4O40,25 H2O

Calculated: C, 54.67; H, 4.27; N, 5.79

Found: C, 54.54; H, 4.08; N, The Ceiling Of 5.60

1. Aminomethyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-about the compounds of formula I

< / BR>
in which R1and R2are independently hydrogen, or R1and R2taken together, represent benzylidene, optionally substituted by the radical R3defined below, or R1and R2taken together with the carbon to which they are attached, form a carbonyl fragment;

R3is hydrogen, halogen, trifluoromethyl, triptoreline, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, amino, mono - or dialkylamino in which each alkyl group has 1-6 carbon atoms, alcanada with 2-6 carbon atoms;

R4is hydrogen or alkyl with 1-6 carbon atoms;

m = 0 or 1;

n = 0 - 6, an integer;

Z is hydrogen, hydroxy, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 1-6 carbon atoms, cycloalkyl with 3-8 carbon atoms, a polycyclic alkyl with 7 to 15 carbon atoms, phenyl, optionally substituted by R3defined above, phenoxy, optionally substituted R3defined above, naphthyl, neo is R3defined above, heteroaryl or heteroaromatic, in which the heterocyclic ring heteroaryl or heterokaryosis selected from thiophene, furan, pyridine, indole, quinoline and the heterocyclic ring is optionally substituted by the radical R3defined above,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1and R2is hydrogen or together form benzyliden, optionally substituted by the radical R3defined in paragraph 1, or taken together with the carbon to which they are attached, form a carbonyl fragment;4is hydrogen; m = 0 or 1 and Z is hydrogen, hydroxy, alkyl with 1-6 carbon atoms, cycloalkyl with 3-8 carbon atoms, a polycyclic alkyl with 7 to 15 carbon atoms, phenyl, optionally substituted by R3defined in paragraph 1, phenoxy, optionally substituted R3defined in paragraph 1, naphthyl, optionally substituted by R3defined in paragraph 1, naphthyloxy, optionally substituted 3defined in paragraph 1, heteroaryl or heteroaromatic, in which the heterocyclic ring heteroaryl or heterokaryosis selected from thiophene, furan, pyridine, indole, quinoline and heterocyclic ring long is in p. 2, in which R1, R2and R4is hydrogen, m = 0, or its pharmaceutically acceptable salt.

4. Connection on p. 1, which is 2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

5. Connection on p. 1, which is a

2-(benzylamino-methyl)-1-benzylidene-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he,

2-(benzylamino-methyl)-2,3,9,10-tetrahydro-7H-1,4-like[2,3-f] quinoline-8-he,

2-aminomethyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he,

2-[(2-pyridin-3-yl-ethylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he,

2-(prop-2-ineliminably)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he,

2-{ [thiophene-2-ylmethyl)-amino] -methyl} -6-methyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he,

6-fluoro-2-[(4-methyl-benzylamino)-methyl] -9-(4-methyl-benzylidene)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-it, or its pharmaceutically acceptable salt.

6. Connection on p. 1, which is 2-{ [3-(1H-indol-3-yl)-propylamino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

7. Connection on p. 1, which is 2-{ [2-(1H-indol-3-yl)-ethylamino] -methyl} -2,3,8,9-t 1, which is 2-[(3-hydroxy-propylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

9. Connection on p. 1, which is 2-[(4-methyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

10. Connection on p. 1, which is 2-(cyclohexylethylamine-methyl)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

11. Connection on p. 1, which is a 2{ [3-(3-dimethylamino-phenoxy)-propylamino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

12. Connection on p. 1, which is a 2{ [(thiophene-2-ylmethyl)-amino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

13. Connection on p. 1, which is 2-{ [3-(quinoline-7-yloxy)-propylamino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

14. Connection on p. 1, which is 2-{ [(adamantane-1-ylmethyl)-amino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he or his farmaci is ahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

16. Connection on p. 1, which is 2-[(4-methoxy-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

17. Connection on p. 1, which is 2-(naphthalene-1-yl-methylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

18. Connection on p. 1, which is 2-(4-trifluoromethyl-benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

19. Connection on p. 1, which is 2-(4-fluoro-benzylamino)-methyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

20. Connection on p. 1, which is 2-(4-phenyl-butylamino)-methyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

21. Connection on p. 1, which is N-(3-{ 3-[(8-oxo-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-2-ylmethyl)-amino] -propoxy} -phenyl)-ndimethylacetamide or its pharmaceutically acceptable salt.

22. Connection on p. 1, which is 2-[(3-trifluoromethyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indole-8-he or ate)-2,3-dihydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

24. Connection on p. 1, which is 2-[(4-triptoreline-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

25. Connection on p. 1, which is 2-[(4-methyl-benzylamino)-methyl] -6-methyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

26. Connection on p. 1, which is 6-methyl-2-{ [naphthalene-1-ylmethyl)-amino] -methyl} -2,3,8,9-7H-tetrahydro-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

27. Connection on p. 1, which is 2-(benzylamino-methyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

28. Connection on p. 1, which is 2-[(4-fluoro)-benzylamino-methyl] -6-methyl-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

29. Connection on p. 1, which is 2-(benzylamino-methyl)-6-fluoro-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

30. Connection on p. 1, which is 6-fluoro-2-[(4-fluoro-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] and the 6-fluoro-2-[(4-methyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

32. Connection on p. 1, which is 2-{ [3-(3-dimethylamino-phenoxy)-propylamino] -methyl} -6-fluoro-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

33. Connection on p. 1, which is 2-{ [(adamantane-1-ylmethyl)-amino] -methyl} -6-fluoro-2,3,8,9-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

34. Connection on p. 1, which is 6-fluoro-2-{ [3-(1H-indol-3-yl)-propylamino] -methyl} -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

35. Connection on p. 1, which is 2-[(4-chloro-benzylamino)-methyl] -6-fluoro-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

36. Connection on p. 1, which is 6-fluoro-2-[(4-trifluoromethyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

37. Connection on p. 1, which is 6-fluoro-2-[(4-phenyl-butylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

38. Connection on p. 1, which is 6-chloro-2-[(4-chloro-benzylamino)-methyl] -2,3 by p. 1, which represents a 6-chloro-2-[(4-methyl-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

40. Connection on p. 1, which is 2-(benzylamino)-methyl-6-chloro-2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

41. Connection on p. 1, which is 6-chloro-2-[(4-fluoro-benzylamino)-methyl] -2,3,8,9-tetrahydro-7H-1,4-like[2,3-e] indol-8-one or its pharmaceutically acceptable salt.

42. A method for the treatment of dopaminergic disorders in schizophrenia, schizoaffective disorders, Parkinson's disease, syndrome Tourette or hyperprolactinemia by oral or parenterale the introduction of sufficient quantities of the compounds of formula I

< / BR>
in which R1and R2are independently hydrogen, or R1and R2taken together, represent benzylidene, optionally substituted by the radical R3defined below, or R1and R2taken together with the carbon to which they are attached, form a carbonyl fragment;

R3is hydrogen, halogen, trifluoromethyl, triptoreline, alkyl with 1-6 carbon atoms, alkoxy with 1-6 atoms by operatorname carbon;

R4is hydrogen or alkyl with 1-6 carbon atoms;

m = 0 or 1;

n = 0 - 6, an integer;

Z is hydrogen, hydroxy, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 1-6 carbon atoms, cycloalkyl with 3-8 carbon atoms, a polycyclic alkyl with 7 to 15 carbon atoms, phenyl, optionally substituted by R3defined above, phenoxy, optionally substituted R3defined above, naphthyl, optionally substituted by R3defined above, or naphthyloxy, optionally substituted R3defined above, heteroaryl or heteroaromatic, in which the heterocyclic ring heteroaryl or heterokaryosis selected from thiophene, furan, pyridine, indole, quinoline and the heterocyclic ring is optionally substituted by the radical R3defined above,

or its pharmaceutically acceptable salt.

Priority points and features:

06.11.1995 on PP. 1-16;

15.10.1996 on PP. 17-46 and signs: R1and R2- benzyliden, optionally substituted by a group R3where R3- tripterocarpa, Z-alkenyl with 2-6 carbon atoms, quinil with 2-6 carbon atoms, and as a disease that can be treated with compounds of the formula I,

 

Same patents:

The invention relates to new substituted benzo/a/acridinium formula (II), where R1and R2are independently IT, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R1and R2together represent-OCH2O-; R3represents H; R5and R6are independently H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R5and R6together represent-co2O-; R7represents H or (C1-C8)alkyl, or R1, R2, R3, R5, R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R1and R2together represent-OCH2O-; R2and R3together represent-co2O-; R5and R6together represent-OCH2O-; R7represents H or (C1-C8)alkyl, provided that one of R1and R2is (C1-C8)alkoxy, or R1and R2together represent-co2O-, or R1, R5and R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R2

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to new derivatives of benzimidazole and their salts formed by the addition of acids, the way they are received and microbicide tool based on them

The invention relates to a new process for the synthesis of some derivatives of dihydro-2,3-benzodiazepine and is particularly applicable to the process of obtaining these compounds with high enantiomeres purity and outputs

The invention relates to 3-substituted derivatives of 3H-2,3-benzodiazepine, method of production thereof and to pharmaceutical compositions based on them

The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system

The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system

The invention relates to novel condensed derivative indana formula I

< / BR>
in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-
The invention relates to an anhydrous crystalline form of the hydrochloride R(-)-M-(4,4-di(3-methyltin-2-yl)but-3-enyl)-nicotinebuy acid, free from associated organic solvent (1), which is nephroscopes and thermally stable under normal storage conditions

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to benzothiadiazine General formula I, in which X represents hydrogen or halogen, Y represents-CN or-NR1R2where l denotes an integer of 1 or 2, m represents an integer of 0, 1 or 2, n denotes an integer equal to 2, 3 or 4, except for the case when Y - SP, n may be equal to 1, R1denotes hydrogen, (C1-C6)alkyl or alkoxycarbonyl, R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6)alkylsulphonyl, phenylcarbinol, possibly substituted with halogen, cryptomaterial, thienylboronic or benzotriazolyl, or R1and R2together with the nitrogen atom to which they are bound, form a loop formula II, where a denotes C=0 or CH2In stands WITH a= 0, SNON, CH2or CH2CH2and Z represents hydrogen, and their pharmaceutically acceptable additive salts of acids, provided that when X=N, n can be 4, and R1and R2cannot be both hydrogen

The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity

The invention relates to new pyrimidine derivative of the formula (I-1) and (I-2), where R1and R5that may be the same or different, independently represent hydrogen or C1-C3alkyl group or, taken together, form cyclopentene or tsiklogeksilnogo ring; a represents a group of formula (II) in which R1and R2represent independently from each other hydrogen or C1-C3alkyl group, and R3represents hydrogen, C1-C3alkyl group or halogen; B is 1-(substituted) -1,2,3,4-tetrahydroisoquinoline-2-yl of the formula (III-1) or 7-(substituted) -4,5,6,7-tetrahydrothieno(2,3-C)-pyridine-6-yl of the formula (III-2), where R6is hydrogen or C1-C3alkyl group, and their pharmaceutically acceptable salts, which have excellent antisecretory activity, to pharmaceutical compositions that contain the specified active ingredient, and a new intermediate compounds and processes for their preparation

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts
Up!