6-oxo-asiminoaei compounds and their physiologically tolerated acid salt accession, pharmaceutical composition and methods for their production

 

(57) Abstract:

Usage: in the pharmaceutical industry in drug discovery, regulating the motility of the stomach or possessing effective against migraine serotonin-agonistic effect. The inventive derived 3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole of the formula:

< / BR>
where R1- H, lower alkyl or phenyl-lower alkyl group which may be mono - or tizamidine phenyl ring, lower alkoxy or lower alkyl; R2- H or lower alkyl; R3- H or halogen; n = 1 or if - (CH2)n- the chain is in the position ring, 2; R4- H, C1-5-alkyl, C3-6-cycloalkyl, C4-cycloalkyl, phenyl-lower alkyl group; R5- H, C1-5-alkyl or phenyl-lower alkyl group; D is a bond or-N=CH-group, and their physiologically acceptable salts, methods for their preparation and pharmaceutical compositions containing them as active ingredient. 9 C. and 5 C.p. f-crystals, 3 tables.

The invention relates to 6-oxo-asiminoaei compounds, namely to new derivatives of 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with, if necessary, in the 3rd or 4th position of the skeleton of the ring samediseases these compounds, process for the preparation of these compounds and intermediates for their preparation.

In Japanese patent application N 1034988 described 6-oxo-tetrahydroazepine-indoles as intermediates for obtaining diuretichesky existing tetrahydroazepine. From Japanese patent application N 57144286 known tetrahydroazepine with coronary vasodilator properties.

The objective of the invention to obtain new compounds 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with valuable pharmacological properties.

It was found that new derivatives of 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with 3-rd and 4-th position of the skeleton of the ring, if necessary bearing substituted aminomethyl or aminoethyl group, have valuable pharmacological properties and, in particular, have a beneficial pharmacological effect on the gastrointestinal tract and are characterized by the action of promoting gastric motility. Compounds have, in addition, serotonin-agonistic effect on the receptors of the 5-HT1providing a beneficial effect in migraine. Based on their actions of the compounds according to the invention are suitable for treating disorders of gastric podviga formula

< / BR>
where R1means hydrogen, lower alkyl or cycloalkyl-alkyl group or phenyl-lower alkyl group, which if necessary can be mono - or disubstituted in the phenyl ring by lower alkoxyl, hydroxyl, halogen or lower alkyl;

R2means hydrogen or, if necessary, a lower alkyl group substituted in the-position to the nitrogen atom of the lower alkoxyl;

R3means hydrogen, lower alkyl, halogen or, in the case where the substituents R1, R2, R4and/or R5does not include lower alkoxy groups, hydroxyl;

n means 1 or, if in the 4th position of the ring there is - (CH2)n-chain and 2.

R4denotes hydrogen, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, cycloalkenyl with 4 to 9 carbon atoms or, if necessary, phenyl-lower alkyl group, mono - or disubstituted in the phenyl ring by lower alkyl, lower alkoxyl, hydroxyl or halogen;

R5denotes hydrogen, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, cycloalkenyl with 4 to 9 carbon atoms or, if necessary, phenyl-lower alkyl group, mono - or disubstituted in the phenyl is Ohm nitrogen, to which they are bound, form a heterocycle of General formula a

< / BR>
where B denotes a bond, a methylene group, oxygen or imino group,- NR6- where

R6means hydrogen, lower alkyl or, if necessary, phenyl or benzyl substituted in the phenyl ring by lower alkyl, lower alkoxyl, hydroxyl or halogen; and

D link or, if R4and R5not mean hydrogen, represents-N= CH-group or their physiologically compatible acid salt of the merger.

Since the compounds of formula I contain as substituents of lower alkyl groups, these alkyl groups may be linear or branched and contain, in particular 1 to 4, preferably 1 to 2, carbon atoms and are preferably methyl. If the substituents are halogen or contain halogen substituents, it is, in particular, fluorine, chlorine or bromine, preferably chlorine.

Deputy R1represents preferably hydrogen. If R1is a lower alkyl group, it may be linear, branched or cyclic and contain preferably 1 to 4 carbon atoms and is preferably methyl. If R1may contain cycloalkyl group with 3 to 6 carbon atoms and alkylenes chain with 1 to 3 carbon atoms.

Deputy R2is preferably hydrogen. If R2represents a lower alkyl group, it may contain 1 to 4, especially 1 or 2 carbon atoms and may be substituted, preferably lower alkyl, especially metaxylem and represents, for example, methoxymethyl group.

Deputy in Asenova ring is preferably in the 3rd position. R4and/or R5can represent hydrogen or linear or branched alkyl having up to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, such as cyclopropyl or cyclohexyl, or cycloalkenyl from 4 to 9, in particular from 4 to 7 carbon atoms, such as cyclopropylmethyl or cyclohexylmethyl, or, if necessary, means substituted phenyl-lower alkyl group which may contain an alkyl chain with 1 to 4 carbon atoms and the phenyl ring can the om, by hydroxyl or lower alkyl. The most favorable are the substituents azepino ring, where D represents a relationship and one of the substituents R4and R5is hydrogen, for example, R4means hydrogen or alkyl, cycloalkyl or cycloalkenyl group having up to 5 carbon atoms, and R5means hydrogen. Since R4in case of necessity represents a substituted phenyl-lower alkyl group, preferably, if necessary, substituted benzyl, R5is preferably hydrogen. Since R4and R5together with the nitrogen atom to which they are connected, form a heterocycle, they can be pyrrolidine, piperidine, morpholine or, if necessary, replaced piperazinone ring. Thus, suitable, for example, unsubstituted or substituted, if necessary, substituted phenyl piperazinovogo ring.

According to the invention the new compounds of formula I and their acid salts accession get in the known methods, so that:

a) to obtain compounds of General formula Ia

< / BR>
where R1have the above significance and R3has the value you specify for R3with the exception of hydroxyl, the em lower alkoxycarbonyl group or a CN group, cyclist in terms of recovery or

b) to obtain compounds of General formula Ib

< / BR>
where R1, R3, R4, R5and n have the above significance and R2represents hydrogen or lower alkyl, the compounds of General formula III

< / BR>
where R1, R2, R3and n have the abovementioned meaning and X represents nucleophile tsepliaeva volatile group, interact with compounds of General formula IV

< / BR>
where R4and R5have the above significance, or

c) to obtain compounds of General formula Ic

< / BR>
where R1, R2, R3and n have the abovementioned meaning, interpret the group Y in the amino group in compounds of General formula V

< / BR>
where R1, R2, R3and n have the abovementioned meaning and Y represents the azide - or phthalimido group, if n is 1, 3 is also the CYANOGEN group, or

d) to obtain compounds of General formula Id

< / BR>
where R1, R2, R3, R5and n have the above significance and R4"above for R4with the exception of hydrogen, the compounds of General formula VI

< / BR>
where R1, R2, R3and n have the above significance and R8means water is-lower alkyl group, mono - or disubstituted, if necessary, lower alkyl, lower alkoxyl, hydroxyl or halogen, or protective elkingrey alkylate and all protective amino again otscheplaut, or

e) to obtain compounds of General formula Ie

< / BR>
where R1, R3, R4, R5and n have the above meanings and R2"if necessary, a lower alkyl group substituted in 2-position to the nitrogen atom of the lower alkyl

where R3and n have the above meaning, R1has the value specified for R1or means the protective amino group, R4and R5have the meanings mentioned for R4and R5while, however, NR4R5group, where R4and/or R5mean hydrogen, so protected least easily tsepliaeva amino protecting group that it does not react with allerease alkylating reagents, and R9is the lowest 1-hydroxyalkyl-group transfer 1-hydroxyalkyl group in the residue R2and again otscheplaut fully aminosidine group, or

f) to obtain compounds of General formula If

< / BR>
where R1, R3, R4, R5and n have the above significance and R2means lower al/SUP> and R5"'have the meanings indicated for R1, R4and R5with the exception of hydrogen, or represent an amino protective group, interact with compounds of General formula XII

R2"'X

where R2"'and X have the abovementioned meaning, and then again otscheplaut amino-protective group, or

g) to obtain compounds of General formula Ig

< / BR>
where R2, R3', R4, R5and n have the above significance and R1"is specified for R1value, with the exception of hydrogen, the compounds of General formula IX

< / BR>
where R2, R3', R4', R5'and n have the abovementioned meaning, interact with compounds of General formula X

R1"X

where R1"and X have the abovementioned meaning, and then again otscheplaut all amino-protective group, or

h) to obtain compounds of General formula Ih

< / BR>
where R1, R2, R3', R4"and n have the above significance and R5"is specified for R5value, with the exception of hydrogen, the compounds of General formula Ii

< / BR>
where R1, R2, R3'and n have the above significance, enter aminoethanoic the remainder of the General formula b

< / BR>
where R4"and R is t and/or R1, R4and/or R5include a methoxy group, a methoxy group into the hydroxy-group and/or the resulting compounds of the formula I, where R1, R4, R5and/or in the resulting compounds of the formula I, where R1, R4, R5and/or R6are substituted, if necessary, benzyl group, benzyl this group is hydrolytically cleaved and the free compounds of formula I transferred at the request of their acid salts joining or acid salt accession translate into the free compounds of formula I.

Reductive cyclization of compounds of formula II into compounds of formula Ia can be carried out by a known method according to the variant of method (a) the fact that the compounds of formula II with a reducing agent capable of selective restore the aliphatic nitro-group to the amino group, without recovery of the cyanide group or alkoxycarbonyl residue processing suitable for the conditions of reaction inert solvent. As the reducing agent is suitable, for example, hydrazine in the presence of Raney Nickel or, if R7is not cyanide, and hydrogen, in the presence of a hydrogenation catalyst, preferably PA is that in the case of hydrogenating treatment with hydrogen can be administered in mixture with water. Recovery of hydrazine in the presence of a catalyst of Raney Nickel can occur at a temperature between room temperature and approximately 80oC, preferably at the boiling temperature of the solvent. Restored by means of catalytic hydrogenation can be carried out at a hydrogen pressure of 3 to 120 bar and temperatures between room temperature and about 120oC. When the genus of the conditions of the hydrogenation of substituted if necessary benzyl residue R1can also be chipped off during catalytic hydrogenation, in this case, it is advisable to choose the recovery of hydrazine. The interaction of compounds of formula III with amino compounds of the formula IV according to the variant of method (b) can be conducted by conventional methods aminoalkylsilane. The interaction is carried out on the reaction conditions are the most appropriate in an inert solvent under basic conditions.

As nucleophile tsepliaeva residue X of the compounds of formula III are suitable halogen such as chlorine, bromine or iodine, or also acyloxy-balance O-E, where E represents the lowest alkanoyl-balance or sulfoxylate residue, for example the balance low alkanesulfonyl, such as methanesulfonate or alogena, for example, toluenesulfonic acid or bromobenzonitrile. As inert solvents are suitable, in particular, dimethylformamide, lower alcohols such as ethanol, cyclic ethers, such as dioxane or tetrahydrofuran, halogenated hydrocarbons, aromatic hydrocarbons or mixtures of the previously mentioned solvents. For fixation formed during the reaction of the acid it is advisable to add organic or inorganic bases. You can also apply an excess of amine of formula IV and use it as the inert substrate. Examples of organic bases are tertiary organic amines, in particular tertiary lower alkylamines followed, such as triethylamine, Tripropylamine, N-lower alkylphosphine or N-lower alkyl-piperidine. Suitable inorganic bases are, in particular, carbonates or bicarbonates of alkali metals. The reaction temperature can be between room temperature and 100oC, is preferable to operate at elevated temperatures, for example at temperatures between 50 and 80oC.

The selection of the amino compounds of the formula Ic, according to a variant of the method c) from the corresponding azides, cyanides, and phthalimido farmhouse amines conventional method. So it is possible to hydrolyze, for example, phthalimide formula V by a previously known method and split, for example, by treatment with hydrazine to compounds of formula Ic. Azides and cyanides of the formula V can restore a known per se manner in an inert solvent under the reaction conditions to the corresponding amino compounds. Thus it is necessary to choose reaction conditions, so that is not destroyed lactam bond of the ring skeleton. To restore the azides of formula V suitable, for example, treatment with hydrazine in the presence of Raney Nickel, treatment with zinc chloride in methanol processing detribalized in the two-phase system of an aqueous phase and is not miscible with water, an organic solvent, such as halogenated hydrocarbons as dichloromethane, or an aromatic hydrocarbon like toluene, in the presence of a catalyst phase transfer, for example salts of tetraalkylammonium, as tetraoctylammonium processing triptoreline in the aquatic environment or catalytic hydrogenation. The catalytic hydrogenation can be performed by the known method suitable for the conditions of the reaction, an inert solvent, for example, lower alcohols, in the presence of a hydrogenation catalyst at pressure>in case of need is not substituted benzyl group, also palladium on coal. Recovery of cyanide of the formula V is preferable to carry out the catalytic hydrogenation in the presence of Raney Nickel in a mixture of lower alcohol and ammonia at a pressure of hydrogen between 50 and 150 bar.

Obtaining compounds of formula Id can occur, according to the variant of method (d), by alkylation of compounds of formula VI are known per se method, the usual alkylation of amines. Thus, the compounds of formula Id can be obtained by the interaction of the compounds of the formula VI with compounds of General formula XIIIa or, if R8in the compounds of formula VI denotes hydrogen, also compounds of General formula XIIIb

R4IVX

X-CH2-CH2-B-CH2-CH2-X

where B and X have the above significance and R4IVmeans alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, cycloalkenyl with 4 to 9 carbon atoms or phenyl-lower alkyl group, mono - or disubstituted, if necessary, in the phenyl ring by lower alkyl, lower alkoxyl, hydroxyl or halogen, in the usual aminoalkylsilane conditions or reductive alkylation of compounds of formula VI with illegitimately R4IVbut containing 1 atom of hydrogen is less than C at least 2 carbon atoms.

The interaction of compounds of the formula VI with compounds of formula XIIIf or XIIIb can be performed by a method known per se conventional for the alkylation of amines, suitable for the conditions of a reaction inert solvent under basic conditions. It can happen, for example, by the method described for the interaction of the compounds of the formula III with compounds of formula IV. Since R8represents an amino protective group, it can be previously known hydrogenations or hydrolytically tsepliaeva protecting group. As hydrogenations tseplyaesh groups are suitable, in particular, in this case substituted benzyl - or bentelhalal group, which then easily can be gidrirovanii, for example, in the presence of palladium/carbon catalyst. As an example, hydrolytically tsepliaeva protective group suitable low accelgroup, such as formyl, acetyl or TRIFLUOROACETYL group. Since R8in the compounds of formula VI represents hydrogen, generally in the interaction with compounds of formula XIIIa is formed a mixture of mono - and disubstituted compounds, where the content of the disa is XIIIa and the reaction conditions. Monosubstituted and disubstituted compounds can be separated from each other, known by themselves methods, for example by chromatography on kieselgel.

Reductive alkylation of compounds of formula VI may occur in known per se manner by interactions of formula VI with an aldehyde or ketone of formula XIIIc in reducing conditions. For example, the compounds of formula VI can interact with the compounds of formula XIIIc in passing on the conditions of the reaction, an inert solvent in the presence of a reducing agent, such as formic acid, borane di-lower alkylamines or nutritionpolicy. The compounds of formula VI may, however, also interact primarily with compounds of formula XIIIa in a suitable for the conditions of the reaction, the inert solvent and to recover then premiumone formed Schiff's base in situ or after isolation by treatment with a reducing agent that does not destroy lactam bond in the ring skeleton. Recovery of intermediate aminosidine can occur in known per se manner by treatment with borane-di-lower alkylammonium, for example borane-dimethylamine, or DIBORANE/pyridine complexometry acid and the lower alcohol. Optionally, the recovery of Schiff bases can be performed by catalytic hydrogenation. The catalytic hydrogenation can be performed, for example, in the presence of Raney Nickel or palladium on coal in the lower alcohol under mild conditions, for example at a pressure of hydrogen of 1 to 3 bar at room temperature.

Translation 1-hydroxyalkyl residue R9compounds of formula VII in the residue R2"according to a variant of the method e) to obtain the compounds of formula Ie can be carried out in a known per se methods.

So a hydroxyl group, R9the known per se method can be restored to the corresponding alkyl group and hydroxyalkyl group, R9in the presence of acid to peresterilizovali lower alcohol under acidic conditions known per se manner.

Recovery hydroxyalkyl groups to alkyl groups can be carried out in suitable conditions for reaction inert organic solvent, using a hydrogenating agent, which makes able hydroxyalkyl group to recover without destroying lactam communication. As a reducing agent suitable, in particular, detribalized in the presence of strong organiste suitable solvent, for example, esters with an open-chain or cyclic ethers, in particular cyclic ethers, such as tetrahydrofuran or dioxane, or halogenated hydrocarbons like dichloromethane. The reaction can be conducted at several elevated temperatures, for example at temperatures between about 30 and 100oC, preferably at a temperature of phlegmy reaction mixture.

The etherification hydroxyalkyloxy group, R9the lower alcohol can be carried out in the usual acid-catalyzed formation of ether conditions. So the compound of the formula VII can interact with the lower alcohol with the addition of catalytic amounts of a strong acid. Interaction best conducted at elevated temperature, for example by heating the compounds of formula VII, in a lower alcohol at a temperature of phlegmy the reaction mixture. As suitable acids are inorganic acids such as sulfuric acid, or strong organic acids, it is better organic sulfonic acids, for example lower alkanesulfonyl, such as methanesulfonate, or aromatic sulfonic acids, such as benzosulfimide or substituted lower alkyl, or halogen of benzosulfimide, Il' amino-protective group is cleaved known in itself by the way.

The interaction of compounds of formula VIII with compounds of formula XII may occur according to a variant of the method (f), known in itself by the way in the conditions usual for alkylation of amides. So the interaction can be carried out in suitable conditions reaction inert solvent in the presence of a strong base, which makes him able to deprotonate the nitrogen atom of the lactam group. As suitable bases, for example, organolithium bases, such as lower alkylate, in particular utility, or sitedisability, tert. butyl potassium. As a suitable solvent, for example, esters with an open-chain and cyclic, such as diethyl ether, tetrahydrofuran or dioxane. Interaction expediently carried out at temperatures in the range from -78oC to room temperature. After the reaction of the amino protective groups are completely hatshepsuts known in itself by the way.

The interaction of compounds of the formula IX with compounds of formula X according to the variant of method (g) can occur by a method conventional in itself for the alkylation of indoles. In the compounds of the Fort is soedineniyah formula III. Particularly suitable halogen, preferably iodine or bromine, or organic sulfonylurea residues. Interaction best conducted in suitable conditions reaction inert organic solvent in the presence of strong bases. As strong bases are suitable, for example, hydrides of alkali metals, such as sodium hydride, or an organolithium base, for example lower alkylate, especially utility, or sitedisability, tert.butyl potassium. Since R2means hydrogen, it first reacts with strong nucleophilic nitrogen of the indole. To avoid additional alkylation of lactam nitrogen, the amount of base should be limited so that it was not enough to double alkylation. If necessary, the free amino group can be protected also known in itself by the way, the introduction of protective formylpropyl, which again hydrolytically cleaved during subsequent processing.

As a suitable solvent dimethylformamide or esters with an open-chain or cyclic ethers, such as diethyl ether, tetrahydrofuran or dioxane. The reaction is expediently carried out at elevated temps known in itself by the way.

Introduction aminomethylphenol balance b) in the amino compounds of the formula Ii according to the variant of method h) can be done in the usual way for education amidino. Thus the compounds of formula Ii can communicate in a known per se manner with galogenidami salts of the General formula XIa

< / BR>
where R4"and R5"have the above meaning and Hal denotes chlorine or bromine and A means of acid anion, or acetals of General formula XIb

< / BR>
where R4"and R5"have the above significance and R13means lower alkyl.

The interaction of compounds of the formula Ii with galogenidami salts of formula XIa can be done to compounds of formula Ih is known per se method under the conditions usual for education amidino. The salts of formula XIa radical A can be the anion of halogen acids, in particular chloride. The interaction should be carried out in suitable conditions reaction inert solvent, for example dimethylformamide, ether complex with an open-chain or cyclic, halogenated hydrocarbon or a mixture of these solvents at temperatures from room temperature to 100oC.

The interaction of compounds of the formula Ii with whom I amidino, for example, the conditions described above for the reaction of compounds of the formula Ii with compounds of formula XIa.

As the amino-protective group in the above compounds can choose a well-known themselves protective groups, which are then known per se method can be split convolutions or hydrogenations. Fit easily again useplease protective groups for amino groups are known, for example, from E. Mc Omie "Protective group in Organic Chemistry" Plenum Press 1971.

As the amino-protective groups are suitable, for example, hydrolytically otsepleniya acyl group, preferably triptoreline, or replaced if necessary benzyl group, which can be known in itself a way to re-chipped off. However, the amino-protective group must be chosen, naturally, whereas other residues contained in the protected compounds so that the amino group was protected enough by the reaction conditions prevailing for receiving and/or further processing, and then the protective group is easy hatshepsuts under conditions in which other residues contained in the molecule, are not destroyed. As hydrogenations tsepliaeva protective group used pre is porcelina group. Since NR4R5the group represents NH2group, applying protective trifluoracetyl group, it is sufficient if one of the hydrogen atoms replaced by this protecting group. For the introduction of protective trifluoracetyl group protected compound can interact with triftoratsetata known in itself by the way. If R2means hydrogen, at such acylation may take place as a partial acylation on the amide nitrogen, and is formed lactamania function. This type lactamania function but again cleaved in the further processing of acidified product aqueous saturated solution of sodium bicarbonate to neitralizatsii formed acid and for getting rid of excess acid anhydride. As the substituents R1, R4and/or R5contain phenolic hydroxy-group can optionally be protected during the above reactions atmasamyama for further processing of the previously known ether protective groups such as benzyl.

In the compounds of formula I, where R3means methoxyl and/or R1and/or R4and/or R5contain metoksifenilny group, methoxy-Gramin on its own way. For example, the ether cleavage can occur by treatment with hydrogen iodide or hydrogen bromide in a suitable for the conditions of a reaction inert solvent, such as acetanhydride or acetic acid, or by treatment with attributively in the presence of a base or borrisrandom in a halogenated hydrocarbon, such as dichloromethane.

In the compounds of formula I, where R1and/or R4and/or R5and/or R6represents a benzyl group, substituted if necessary phenyl ring, then this group can be hydrogenations split a known per se manner. The hydrogenolysis may be carried out in suitable conditions reaction inert solvent, for example in a lower alcohol, catalytic hydrogenation under hydrogen pressure of 3 to 50 bar and temperatures between room temperature and about 120oC in the presence of a hydrogenation catalyst, for example palladium on coal. Cleavage of the benzyl can also be produced by treatment with formic acid in the presence of alcohol or treatment with sodium in liquid ammonia.

The compounds of formula I are known per se method to isolate from the reaction mixture and ochistitelem transferred in a known manner in a pharmacologically-tolerated acid salt of the merger.

As the pharmacologically acceptable acid salts of the accession of the formula I are suitable, for example, their salts with inorganic acids, such as halogen acids, preferably florodora acid, sulfuric acid or phosphoric acid, or with organic acids, for example lower aliphatic mono - or dicarboxylic acids such as maleic acid, fumaric acid, lactic acid, tartaric acid or acetic acid, or sulfonic acids, for example lower alkanesulfonyl, such as methanesulfonate, or benzosulfimide, substituted if necessary in the benzene ring by halogen or lower alkyl, such as p-toluensulfonate, or cyclohexylsulfamate.

The compounds of formula I contain a chiral center in the position in which the side chain -(CH2)n-D-NR4R5associated with azepino ring, and can exist in multiple optical active enantiomeric forms or racemates. This invention includes both the racemic mixture and the pure optical isomers of compounds of formula I. If the synthesis of the racemate lead of starting compound of formulas III, V, VI, VII, VIII or IX, I get connection Faure, the active compounds of formula I. Optically active compounds of formula I can be obtained from racemic mixtures known per se manner, for example by chromatographic separation on chiral separating media or interaction with suitable for this purpose optically active acid, tartaric acid or malic acid, their optical antipodes by fractional crystallization of the salts obtained.

The initial products of formula II are valuable intermediates for obtaining pharmacologically active compounds, for example compounds of formula I.

The compounds of formula II can be obtained in known per se manner, based on the indole compounds of General formula XIV

< / BR>
where R1, R3'and R7have the above significance, while the compounds of formula XIV above all formuliruiutsia to aldehydes of General formula XV

< / BR>
where R1, R3'and R7have the above significance, and the resulting aldehyde compounds of formula XV react with nitromethane.

Formirovanie of indole compounds of formula XIV can be carried out by interaction with known formulirowki means methods usual for formirovaniya of aromatics. telharmonic in the presence of phosphoroxychloride or phosgene by Vilsmeier-method. The solvent may be an excess of dimethylformamide, or can be administered as aromatic hydrocarbons, such as benzene or chlorobenzene. The interaction can be performed at temperatures between room temperature and approximately 80oC.

Received formaldehyde compounds of formula XV, where R1means hydrogen, can be converted by reacting with compounds of formula X in such compounds of formula XV, where R1has the same meaning as R1"the residue. The interaction may be performed, for example, in the conditions described above for the interaction of the compounds of the formula IX with compounds of the formula X.

The reaction of interaction of the compounds of formula XV with nitromethane can be carried out in the presence of a base under conditions normal for the interaction of aldehydes with C-H-oldname connections. The solvent may be an excess of nitromethane. Optionally, you can also apply the following organic solvents, such as, for example, lower alcohols, halogenated hydrocarbons such as dichloromethane, or a cyclic ester, such as tetrahydrofuran. Interaction can take place at temperatures between room and Ie as the base. So are suitable, for example, hydroxides of alkali metals, carbonates or acetates, ammonium acetate or carbonate, basic ion-exchange resin or tertiary organic bases, such as three-ness.the bonds alkylamines or in particular 1,8-diazabicyclo [5.4.0] undec-7-ene (1,5 5) (=DBU) or 1,5-diazabicyclo [4.3.0) nonan-5-ene (=DBN). When the interaction may form a mixture of compounds 3-(1,3-dinitropropane-2-yl)-indole of formula II and the corresponding compounds 3-(2-nitroethylene)-indole of General formula XVI

< / BR>
where R1, R3'and R7have the above significance. The mixture of compounds of formula II and compounds of formula XVI can be divided formerly known manner by distillation or by column chromatography. The ratio of compounds of formula XVI to compounds of formula II in the reaction mixture may vary depending on the type and strength of the applied base or the reaction conditions. In order to immediately obtain the compounds of formula II or a mixture with a very high content of compounds of formula II, as the reason it is expedient to introduce 1,8-diazabicyclo [5.4.0] undec-7-ene (1,5-5) or 1,5-diazabicyclo [4.3.0] nonan-5-ene. To obtain the compounds of formula XVI, or a mixture with a very high content of compounds of formula XV is de R1means hydrogen, optionally, by interaction with the compound in the formula X translate in such compounds of formula XVI, where R1means R1". Reaction interaction can make an ordinary in itself a method for alkylation of indoles and, for example, carried out under conditions described above for the interaction of compounds of the formula IX with compounds of the formula X.

The compounds of formula XVI can be translated by the interaction with another nitromethane in the presence of a base suggested above to obtain compounds of formula II as particularly suitable, in the compounds of formula II.

The compounds of formula XVI can also be obtained by the interaction of the compounds of formula XIV with 1-nitro-2-dimethylaminoethanol.

Indole compounds of formula XIV are known or can be obtained by known methods or analogously to known methods. Obtaining compounds of formula XIV are described, for example, in U.S. patent N 3732245.

The initial compounds of formula III are novel compounds which are valuable intermediates for obtaining pharmacologically active compounds, for example compounds of formula I. the compounds of formula III can be obtained well-known the actual article above is, by transferring the hydroxy-group in the volatile group. Thus, known in itself by way of compounds of formula XVII interact, for example, for introduction of halogen residue X with thionyl chloride or with postgadolinium, such as passportisation, known in itself by the way in an inert solvent suitable for the reaction conditions, for example a halogenated hydrocarbon, such as chloroform. Sulfoxylate remains of X can be introduced by a known per se manner by acylation of compounds of formula XVII with the corresponding halides, sulfonic acids. Thus, the alcohols of formula XVII can interact with the sulfonic halide, preferably chloride, sulfonic acids by methods conventional for the formation of esters. For example, the reaction of interaction can be carried out in the presence of a base at temperatures between about room temperature and 100oC in an inert solvent suitable for the reaction conditions. As suitable bases, for example tertiary organic amines, such as triethylamine or pyridine, which may simultaneously serve as solvents for the reaction.

The compounds of formula XVII are new compounds, which are valuable polypr formula XVIIa

< / BR>
where R1, R2'and R3'have the abovementioned meaning, can be obtained in known per se manner, selective recovery complex ester group to the corresponding esters of General formula XVIII

< / BR>
where R1, R2'and R3'have the above significance and R10means lower alkyl. As a suitable reducing agent, for example, hydride reducing agents capable of restoring esters, which however do not destroy lactam bond of the ring skeleton. So, it appears expedient, for example, restoring diisobutylaluminium or borhydride alkali metals, such as detribalized, literalized or letitre-ness.allivalite, or nutritionallyenhanced in a solvent mixture of a cyclic ether such as tetrahydrofuran or dioxane, a lower alcohol at temperatures between room temperature and the boiling temperature of the reaction mixture. When applying diisobutylaluminium as the reductant can restore carried out in a cyclic ether, such as tetrahydrofuran, or an aromatic hydrocarbon such as benzene or toluene, at temperatures between -20oC and komnatnaya value can be obtained on the basis of such compounds of formula V where Y represents a cyano, a translation of ceanography known manner in alkoxycarbonyl group and subsequent selective hydrogenation to hydroxymethylene group. As a reducing agent suitable hydride reducing agents described above for the selective reduction of the ester group in compounds of formula XVIII.

Compounds of General formula XVIIIa

< / BR>
where R1, R3'and R10have the abovementioned meaning, can be obtained in known per se manner, proceeding from compounds of General formula XIX

< / BR>
where R1, R3'and R10have the above significance and R7'means lower alkoxycarbonyl group, the fact that the compounds of formula XIX restore the conditions of the cyclization. For this purpose the compounds of formula XIX are interacting in an inert solvent suitable for the reaction conditions, with a reducing agent, which is capable of selectively recover the aliphatic nitro group to amino group without recovery of destruction alkoxycarbonyl balance. As a suitable reducing agent, e.g. hydrogen in the presence of catalytic hydrogenation or hydrazine in Pris is Orada from 3 to 50 bar and at temperatures between room temperature and about 120oC. as the hydrogenation catalyst is suitable, in particular, palladium on coal. As suitable solvents are preferably aromatic hydrocarbons, such as toluene or xylene. If by the nature of the conditions of the hydrogenation can also be broken down and replaced, if necessary, the phenyl ring of R1when catalytic hydrogenation, in this case it is advisable to choose the recovery of hydrazine. When recovering compounds of formula XIX under specified conditions occurs, in General, a mixture of compounds of General formula XX

< / BR>
where R1, R3', R7'and R10have the above value, and the corresponding cyclic compounds of formula XVIIIa. To complete cyclization this mixture is heated for 0.5 to 3 hours to temperatures between 100 and 150oC.

The compounds of formula XVIIIa, where R1means hydrogen can interact with the compounds of formula X are translated into the compounds of formula XVIIIa, where R1means the residue R1". Reaction interaction can be performed by a method conventional in itself for the alkylation of indoles, and, for example, under the conditions described above for the reaction of compounds of formula IX with compounds of the formula X.

Ptak, the compounds of formula XVIIIa can interact under conditions normal for the alkylation of amides, compounds of formula XII. Reaction interaction can be carried out in an inert, suitable for the conditions of the reaction, the solvent in the presence of a strong base which is capable of deprotonating the nitrogen atom of the lactam group. As the bases are suitable above for the alkylation of compounds of formula VII according to method f) grounds, in particular utility. As a suitable solvent, for example, cyclic ethers or esters with an open circuit, such as tetrahydrofuran or dioxane, or diethyl ether. The reaction is expediently carried out at temperatures in the range from -80oC to room temperature. Since R1means hydrogen, it is necessary to protect a known manner indole communication normal amino group, which is then again otscheplaut.

The compounds of formula XIX can be obtained in known per se manner, proceeding from compounds of General formula XXI

< / BR>
where R1, R3'and R7'have the above significance and R11and R12respectively denote lower alkyl, or both together represent alkylenes chain with 1-4 carbon atoms, the h the SPS reaction in the flask is subjected to interaction with the lower alkilany ether nitroxyl acid. So you can, for example, the compound of formula XXI to expose the interaction with alkilany ether nitroxyl acid in an inert, suitable for the conditions of the reaction solvent in the presence of three or lower alkylphosphine, in particular tributylphosphine that intermediate reacts with the amino group of compounds of formula XXI to nucleophile capable of removal of the residue. As a suitable solvent, such as acetonitrile, dimethylformamide or cyclic ether. The reaction is expediently carried out at elevated temperatures, for example at temperatures in the range of 50 80oC. optionally, the compound of formula XXI can also first transfer by interaction with the lower alkylation known in itself by the way in the corresponding Quaternary ammonium salt and then subjected to interaction with the lower alkilany ether nitroxyl acid.

The compounds of formula XXI can be obtained in a known manner from indole compounds of the General formula XIVa

< / BR>
where R1, R3'and R7'have the above meaning, by reacting compounds of formula XIVa with formaldehyde and an amine HNR11R12where R11and R12have the above meanings, by methods common to al the of soedinenii General formula XXII

< / BR>
where R1, R3'and R10have the above meaning, those that restore the double bond in compounds of formula XXII are known per se manner, for example, treating the compounds of formula XXII with nutritioninformation obtained in situ from detribalized and methanol in tetrahydrofuran. The compounds of formula XXII can be obtained in known per se manner by the interaction of compounds with the General formula XVa

< / BR>
where R1, R3'and R7have the above values, with the lowest alkilany ether nitroxyl acid. The reaction can be conducted by known per se methods in the presence of a base when the usual reaction of the aldehyde C-H-oldname compounds, for example, under the conditions suggested above for the reaction of compounds of formula XV with nitromethane.

The compounds of formula V are novel and represent valuable intermediate products for obtaining pharmacologically active compounds of formula I.

The compounds of formula V can be obtained by the fact that the corresponding compounds of formula III are known to interact on their own way with the azide of an alkali metal, phthalimido alkali metal or cyanide with a brush hydrogen, D is a bond and R3is not a hydroxyl or can be obtained from corresponding compounds of formula I, where R5means hydrogen, by introducing amino protective group.

The compounds of formula VII are novel compounds which are valuable intermediates for obtaining pharmacologically active compounds, for example compounds of formula I. the compounds of formula VII can be obtained by the fact that compounds of General formula XXIII

< / BR>
where R1', R3', R4', R5'and n have the above meanings, acelerou to compounds of General formula XXIV

< / BR>
where R1', R3', R4', R5'and n have the above meanings and R9'is an acyl group corresponding to the remainder R9and the resulting compounds of the formula XXIV is then reduced to the compounds of formula VII.

For the acylation of compounds of formula XXIII can be subjected to interaction with allermuir means of General formula XXV

R9'X'

where R9'has the above meaning and X' is halogen or lower alkoxycarbonyl group, at elevated temperatures, for example at temperatures between 30 and 100oC. as lastoskie solvents such as esters with an open-chain or cyclic, chlorinated hydrocarbons, such as dichloromethane or aromatic hydrocarbons, such as benzene. Preferable as the alkylating reagent enter the appropriate acid anhydride. For formirovaniya it is expedient to apply the mixed anhydride formed in situ from formic acid and the lower carboxylic acid anhydride, preferably of acetanhydride.

The recovery of compounds of formula XXIV to compounds of formula VII may occur known in itself in a suitable way according to the conditions of a reaction inert organic solvent, using a hydride reducing funds that make able alcoholly the remainder R9'mixed imaginova group of compounds of formula XXIV to restore to hydroxyalkyloxy without destroying the lactam group oxo-azepino rings can be or amide cleavage of the protective group. It is advisable, for example, to restore dignissim alkylhalogenide, preferably by diisobutylaluminium, DIBORANE or di-lower ancillarydata at low temperatures, for example temperatures between -80oC and room temperature. As R is furan, aromatic hydrocarbons, such as benzene or toluene, or halogenated hydrocarbons such as dichloromethane, or a mixture of such solvents.

The compounds of formula XXIII encompass the compounds of formula I, where R2means hydrogen, D represents a bond, and R4and/or R5not mean hydrogen, or can be obtained in a known manner from the corresponding compounds of formula I, where R4, R5and/or R1mean hydrogen, the introduction of the amino protective group.

The compounds of formula VIII include compounds of formula I, where R2means hydrogen, D represents a bond, and R3is not hydroxyl, or can be obtained in a known manner from the corresponding compounds of formula I, where R1, R4and/or R5mean hydrogen, the introduction of the amino protective group.

Compounds of General formula IX include compounds of formula I, where R1means hydrogen, D represents a bond, and R3is not hydroxyl, and the remains of R4and R5are not hydrogen, or can be obtained in a known manner from the corresponding compounds of formula I, where R4and/or R5mean hydrogen, the introduction of the amino protective group is a value, and Z is hydroxyl or before a certain residue X or Y, cover the compounds of formula III, V and VII, and represent valuable intermediates for obtaining pharmacologically active compounds of formula I.

The compounds of formula I and their pharmaceutically acceptable acid salts accession possess interesting pharmacological properties and have a selective medium for 5-HT1-receptors. They have a particularly important effect on the motility of the gastrointestinal tract, especially the stomach. Thus, in experiments on animals peristaltic waves of the stomach intensified under the influence of the compounds of formula I, the frequency of movements was changed slightly. In addition, the compounds have serotonin-agonistic stimulating effect on the receptors of the 5-HT1in artery basilaris, which is a good object for antimigrainous effective communication.

Description of pharmacological methods.

1. Determination of the minimum toxic dose.

The male mice weighing 20 to 25 g give oral maximum dose of 300 mg/kg analyte. Animals are carefully observed for 3 h on the manifestation of Toxicological effect. During 72 hours after application register dopolnitelbnaya death or severe toxic symptom, the following mice give decreasing the dose to stop the appearance of toxic symptoms. The lowest dose that causes death or severe toxic symptoms that are listed in the table.A as the minimum toxic dose. Are given in table.A number of examples relate to the following examples of the preparation.

2. The determination of the action on the motility of the stomach in anesthetized mice.

For test groups are used, respectively, from 5 to 6 clean rats strain of SIV 50 weight 220 290 g, which analiziruyutsya with a mixture of ketamine/xylazine. Animals receive an intraperitoneal initial dose of a solution of 50 mg/ml ketamine and 10 mg/ml of xylazine at a rate of 1 ml/kg of weight and anesthesiolgy level is maintained by continuous intra-abdominal infusion of the same solution in a quantity of 1 ml/kg/h Animals tracheotomized and laparotomies. After imposition of Pylorus-ligature is introduced into the stomach of the gastric tube and the other end attached through a three-way valve to a calibrated device for measuring pressure (Statham-P element 23 ID. The corresponding probe is introduced reactive to a depth of 8 to 9 cm in the intestine and in the same way connected to a calibrated tonometer of the same type. Then the animals ' stomach is filled with 2 ml of water is by using multirecorder Watanabe (MC 6621) recorded amplitude, the resulting phase motility of the stomach. For individual animals are defined medium geometric values for the first 20 min, which serve as reference amplitude values. After these 20 minutes of entering the test substance. The maximum increase of the amplitude (average of 20-minute period of time when the greatest increase in amplitude) caused by the introduction of the investigated compositions, determined as a percentage of control values before application of the test compositions, and table.A given average value. In addition, the maximum increase of the average gastric tone caused by the use of the test compositions within the experience can be recorded compared to the existing average gastric tone before applying the test compositions. This increased gastric tone is given in table.A in cm H2O (average group of animals). In the gut feel of the song cause fading amplitude fluctuations.

3. The study of the properties indicating ANTIMIGRAINE action of the test compositions.

Migraleve pain associated with excessive Gelateria vascular system of the brain mo the effect on the receptor type 5-HT1in artery basilaris, on the basis of which the conclusion can be made about ANTIMIGRAINE the effect of the compositions. Serotonin-agonistic effect of the compositions on the receptors of the 5-HT1can be determined in vitro on isolated strips of the bodies arteries basilaris pigs. Serotonin causes by stimulation of 5-HT1receptor-dependent concentration of the contraction on isolated strip artery basilaris pigs. This type of contraction is called also feel compositions and is, therefore, good evidence ANTIMIGRAINE action of the composition. The research is conducted according to the method described (Naunyn-Schmiebleb. Avch. Pharmacol. supp. zu Band 341, R 89, 1990 u Eur. J. Pharmacol. 183, 1106 1107, 1990) von van Charldorp and others.

Description experience to determine the in vitro actions, inducing serotonin-agonistic contractions on isolated segments of the artery basilaris pigs.

For experience are spiral segments artery basilaris pigs, which are isolated from the brain of pigs coming from the slaughterhouse.

Each strip is fixed in a bath of 10 ml of modified Tyrode solution (Tyrode-solution is an aqueous solution containing per liter 150,0 mmole NaCl, 4.0 mmole KCl, 1.8 mmole CaCl22H2O, 1,1 mol MgCl26H2-8mol/l indomethacin, 10-7mol/l atropine and 10-7mol/l of propanolol) so that the fabric is under pressure of 10 mn. Tub is filled with a mixture of 95% O2and 5% CO2. After equilibriating phase within 1 h by twice adding serotonin at a concentration of 10-5mol/l is called the contraction of the fabric, and then the drug is washed out. Next contraction action is measured at elevated concentrations of serotonin and built the cumulative curve of action concentration for serotonin. On the same drug after repeated washing is constructed cumulative curve action concentration for the tested compositions.

In table. B given maximum contraction, due to the test compositions in relation to the maximum, caused by serotonin by the contraction and negative logarithm the concentration of the test compositions which induces 50% of the maximum contraction obtained by this test compositions (=pD2), and the relative power of action, as restated pD2the test composition compared to pD2serotonin obtained on the same piece artery.

On the basis of its action is connected the quality medicines for large mammals, especially humans, for the prevention and treatment of motility disturbances of the gastrointestinal tract. So, for example, are suitable for the treatment of various diseases caused by disorders of the gastrointestinal tract, such as nausea, a feeling of overcrowding, abdominal pain or irritable bowel syndrome. In addition, compounds suitable for the prevention and treatment of migraine and related disorders and headaches caused by gelataria of cerebral vessels, possess analgesic effect.

The applied dose may be individualized and vary depending on the condition of the patient, the composition and form of application. For example, parenteral formulations contain, in General, less active substance than drugs, taken orally. However, for application to large mammals, especially humans, mostly still used dosage form with the content of the active substance from 25 to 300 mg orally single dose.

As a medicinal compounds of formula I can be combined in a composition with the usual substances in herbal preparations, such as, for example, tablets, capsules, suppositories or solutions, e.g. the. the ti herbal medicines can be obtained by previously known methods using conventional solid carriers, such as lactose, starch or talcum powder, or liquid paraffins, and with conventional pharmaceutical substances, such as tools for manufacturing of tablets, reagents, dissolution or conservatives.

The invention is characterized by the following examples, which, however, in no way should limit the scope of the present invention.

Example 1. 3-Aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

a) To a solution of 100 g of methyl ester of indole-4-carboxylic acid in 1000 ml of dimethylformamide under ice cooling was pricipally for 30 min 90 ml phosphoroxychloride. After the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours For further processing the reaction mixture under ice cooling and vigorous stirring was diluted with 1000 ml of dichloromethane. Next was added 200 ml of water and 100 ml of 40% aqueous sodium hydroxide with such speed that the temperature did not exceed 40oC. the Organic layer was separated, washed twice with 50 ml of 10% sodium hydroxide solution and concentrated. The remaining oily was serializable product, which was then filtered. After drying obtained by 83.4 g of methyl ester of 3-formylindole-4-carboxylic acid of melting point 134 135oC.

b) 60 g of the product obtained above were mixed at room temperature when mixed with 350 ml of nitromethane and 5 ml of 1,8-diazabicyclo [5,4,0] undec-7-ene (1,5-5) (=DBU) and the reaction mixture is left to react at a temperature of 65oC for 6 hours At the end for further processing, the reaction mixture was concentrated to dryness and the residue dissolved in ethyl acetate. The solution is twice washed with water, dried over sodium sulfate, filtered, and concentrated. The remaining oily crude methyl ester of 3-(1,3-dinitro-propan-2-yl) indole-4-carboxylic acid was dissolved in diethyl ether. From the ethereal solution was crystallized product. Crystallized was filtered and finally washed with diethyl ether and dried. Received 67 g of methyl ester of 3-(1,3-dinitropropane-2-yl)indole-4-carboxylic acid with a melting point of 110 112oC.

c) 67 g of product obtained above was dissolved in a liter of methanol. To the solution was added 5 g of Raney Nickel. Then to the reaction mixture was pricipally 150 ml of hydrazine hydrate. The temperature rose to 40oC (nabludalos the processing of the reaction mixture is cooled, was filtered from the catalyst and concentrated to dryness. The remainder of the raw base material was purified by column chromatography with weakly elevated pressure (Flash chromatography) using methanol/25% aqueous ammonia 96: 4 as eluent. Foamy residue formed after evaporation of solvent mixture, dissolved in methanol and were led. Crystallized was acidified and finally washed with a mixture of methanol/diethyl ether 9:1 and dried. Received of 36.4 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indol-hydrate with a melting point of 119 120oC.

For translation hydrochloride 13 g obtained above hydrate was dissolved in 200 ml of methanol. To the solution with stirring dropwise added excess ethereal solution of hydrogen chloride. Formed at room temperature crystallized was filtered, washed with a mixture of methanol/diethyl ether 9:2 and dried. Obtained 12 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indole-hydrochloride-hydrate with a melting point of 193 204oC.

d) Separation of enantiomers:

Racemic target connection, as follows from its optical antipodes, divided

1a) 3R(+)-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4, the th 3-aminomethyl-3,4,5,6 - tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indol-hydrate was dissolved in 50 ml of boiling methanol and under stirring to the solution was added 5,12 g D(-) -tartaric acid. Then added 5 ml of water and the reaction mixture was stirred at the temperature of the water bath 70oC to until the solution became transparent. Then the solution was stirred at room temperature in an open vessel. The resulting crystallized separated from the mother liquor and washed with a small amount of methanol. After drying the obtained 5.9 g of kristalliset, which recrystallize from a mixture of methanol/water 9:1 and dried. Obtained 3.5 g of 3R(+)-3 - aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indol-D - tartrate with the value of the specific optical rotation angle []2D5= +92,8(c=0,25 in water).

Da2) 2,12 g obtained above tartrate was dissolved in 6.3 ml of water at temperatures up to 95oC. the Solution had a pH value of 3.5. The addition of 25% isopropanolic solution of hydrogen chloride reduced the pH to 0.4 and then the solution was concentrated under reduced pressure (water-jet vacuum pump) to 4 ml of the Resulting crystallized after 24 hours, was filtered from the aqueous reaction mixture, washed with a small amount of methanol and dried. Received 0,94 g of 3R(+)-3-aminomethyl-3,4,5,6-tetrahydro-6 - oxo-1H-azepino [5,4,3-cd] indole-hydrochloride with a melting point up to 295oC (degradation).

Da3) Remaining in Da2) the aqueous filtrate is brought to pH equal to 11, by adding a saturated solution of aqueous sodium carbonate and then evaporated under reduced pressure (water-jet vacuum pump). The residue was purified by chromatography under slightly elevated pressure (Flash chromatography) kieselgel using methanol/ 25% aqueous ammonia 96:4 as eluent. Obtained 0.32 g of amorphous 3R(+)-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole with the value of the specific optical rotation angle []2D5= +104C (c=1 in methanol).

Db1) mother solution obtained in stage DaI), evaporated and the residue was dissolved 20 mg of water at a temperature of 80oC. After cooling the solution to room temperature, thereto was added 4 mg of isopropanol. The solution was stirred for 48 h at room temperature in an open vessel. The resulting crystallized was filtered, dried and recrystallize twice from a mixture of water/isopropanol 20:4. Received 1,05 g 3S(-)-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indol-B-tartrate with the value of the specific optical rotation angle []2D5= to 143(c=1 in methanol).

2D5= -222(c=0,25 in water).

Db3) From aqueous filtrate remaining in the stage of Db2), a method similar to that described in stage Da3), liberated base and brushed it. Obtained 0.15 g of amorphous 3S(-)-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole with the value of the specific optical rotation angle []2D5= -103(c=1 in methanol).

Example 2. 3-benzylamino-3,4,5,6-tetrahydro-6 oxo-1H-azepino-[5,4,3-cd] indole.

6.2 g of 3-Aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indol-hydrate (receipt, see example 1C) were placed in 120 ml of benzene and was added to the mixture of 3.3 ml of benzaldehyde. This reaction mixture is boiled with water separator for 3 hours after the reaction mixture was concentrated to dryness. Raw, in the form of an oily residue, 3-benzyl-denominated-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indol immediately subjected to further processing. It was dissolved in 40 ml of acetic acid and to the solution under ice cooling and stirring portions added 1.2 g of detribalized. Then reactio the ri reduced pressure (water-jet vacuum pump). The oily residue was dissolved in 100 ml of water and the mixture was parselocale by adding a saturated aqueous solution of sodium carbonate to pH 9. Crude target product precipitated in the form of oil, was separated and the aqueous phase was extracted with three times 100 ml of methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated to dryness. The remaining crude target product was purified by column chromatography on kieselgel with weakly elevated pressure (Flash chromatography), using as eluent a mixture of ethyl acetate/methanol 4:1. After evaporation of the solvents obtained 7 g of 3-benzylamino-3,4,5,6-tetrahydro-6-oxo-1H - azepino-[5,4,3-cd] indole in the form of a foamy product.

3y obtained above target compound was dissolved in methanol and, as described in example 1C), was transferred into the hydrochloride. Obtained 2.9 g of 3-benzylamino-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole-hydrochloride with a melting point 179-181oC.

Example 3. 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6 - tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

6.2 g of 3-benzylamino-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole (receipt see example 2) was dissolved in 250 ml of dimethylformamide. To the solution in to the mixture for 3 h and stirred at room temperature. Then for further processing under reduced pressure in a water-jet vacuum pump was removed at 50oC dimethylformamide. The oily residue was dissolved in a mixture of water/dichloromethane 1:1, separated dichloromethane phase and the aqueous phase was extracted twice more with dichloromethane. The organic phase is purified, dried over sodium sulfate, filtered and evaporated. In the remainder of 3.84 g of oily crude product. It was purified by chromatography at moderately high pressure (= chromatography low LPLC at 3-6 bar) on kieselgel (sales product Zichroprer R Si 60), using as eluana a mixture of dichloromethane/methanol 9: 1. Received 3,26 g of oily 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

0.88 g obtained above target compound with light heating was dissolved in 5 ml of isopropanol. To this solution was added a solution of 0.44 g of fumaric acid in a mixture of 9 ml of isopropanol and 1 ml of methanol. The mixture is then mixed with 1 ml tert.butyl methyl ether to light opacity. From this reaction mixture was crystallized fumarate. After filtering kristalliset, washing his tert.butyl ether and drying the obtained 1.07 g of 3-(N-N-meilani the P>C.

Example 4. 3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole.

A1) of 2.38 g of 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6 - tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole (receipt, see example 3) was dissolved in 150 ml of methanol. To the solution in a stream of nitrogen at the tip of a spatula added palladium catalyst/coal (10% ). Then the mixture was first made in an autoclave at a hydrogen pressure up to 3.5 bar at temperatures up to 50oC under stirring. After 3 h the hydrogen was removed, the reaction volume was filled with nitrogen and the catalyst was filtered. The remaining solution was evaporated and the residue is oily crude product was purified by low pressure chromatography on kieselgel using methanol/25% aqueous ammonia 96:4 as eluent. Obtained 0.9 g of 3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indole in the form of a foamy product.

0,62 g obtained above target base was transferred to the hydrochloride as described in example 1C). Obtained 0.56 g of 3-methylaminomethyl-3,4,5,5-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride with a melting point of from 274 to 277oC.

A2) the Introduction of 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indole can be done, ispolzuya (melting point 192oC, with decomposition), which can be obtained analogously to example 3, from 3-[N-(diphenylmethyl)-amino-methyl] -3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole (the melting point of the hydrochloride 291oC, with decomposition, obtaining analogously to example 2, from 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indol-hydrate and benzophenone).

B) Separation of enantiomers.

Racemic compound can be divided into its optical antipodes similar to the method described in example 10. Received:

4a) 3R(+)-3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride, melting point 310oC (decomposition), []2D5=of 218.6]2D5= -224,9(C=1 in methanol).

C) the 2nd method for separating enantiomers.

Ca1) 2.14 g of N-etoxycarbonyl-L-leucine and 2.94 ml of triethylamine were dissolved in 75 ml of dry tetrahydrofuran. The solution was cooled to about -15oC. Then, in a nitrogen atmosphere parts for 10 min was added to 1.37 ml of isobutyl ether of Harborview acid in 10 ml of dry tetrahydrofuran. Next, the reaction mixture is stirred for 10 minutes Then portions over 15 min at approximately -15oC added 2.8 g of racemic 3-METI is mperature and was stirred for 3 hours At the end she was evaporated and the residue was purified by chromatography with weakly elevated pressure (Flash chromatography), using as eluent a mixture of ethyl acetate/methanol 99: 1. 3 g of the pure product was separated by preparative liquid chromatograhy high pressure (HPLC) to (+)- and (-)-enantiomers.

C2) 1.8 g of (+)-enantiomer was dissolved in 25 ml of concentrated hydrochloric acid and the solution was heated on an oil bath to 100oC. After 24 h the solution was evaporated under reduced pressure, the residue was dissolved in ethanol and again evaporated. The residue was dissolved in aqueous ethanol and thereto was added 1.18 g of potassium carbonate. The mixture was concentrated under reduced pressure and the residue was purified by chromatography with weakly elevated pressure (Flash chromatography), using as eluent a mixture of methanol/aqueous ammonia solution of 99.5:0.5 in. Received syrupy product was dissolved in a small amount of absolute ethanol and to the solution was added an excess of ethanolic hydrochloric acid. The precipitate was sucked out on a filter and washed with absolute ethanol and diethyl ether. Received 3R(+) -3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride had a melting point of (methanol).

Cb) Obtained at the stage Ca1) (-)-enantiomer is similar to the method described in stage Ca2), translated in 3S(-) -3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] -indole-hydrochloride with a melting point above 280oC (decomposition) and the value of the specific optical rotation angle []2D5= -224,9(methanol).

Example 5.

a) 3-ethylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

b) 3-diethylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

A) 6g 3-Aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indol-hydrate (receipt see example 1C) was dissolved in 60 ml of dimethylformamide. To the solution were added simultaneously to 2.5 ml of ethylbromide and 5.1 ml of triethylamine in four equal portions over 6,5 hours during this time the temperature of the reaction mixture was maintained 60oC. For further processing, the reaction mixture was evaporated to dryness and the remaining red reaction mixture, consisting of both target compounds were separated by chromatography in the presence of weakly elevated pressure (Flash chromatography) kieselgel using a mixture of dichloromethane/methanol/diethylamine 80:17:3. Obtained 3.4 g of oily crude m is to 5b).

The oily product 5a) was dissolved in methanol. From the solution by adding a small amount of diethyl ether was crystallized 2.3 g of 3-ethylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole with a melting point of 90 to 92oC.

The oily crude product 5b) was dissolved in ethanol and adding ethereal solution of hydrogen chloride obtained as described in example 1C), hydrochloride. Obtained 2.5 g of 3-diethyl-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride with a melting point of 150 153oC.

EXAMPLE 6. 3-isopropylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]-indole.

To a solution of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indol-hydrate (receipt see example 1C) in 80 ml of tetrahydrofuran under stirring added 0,82 g complex, borane-dimethylamine. The solution was boiled for 1 h under reflux and at the end was pricipal at temperatures up to 45oC 10 ml of acetone. The reaction mixture was stirred 2.5 h at temperatures up to 60oC. and Then for further processing, the reaction mixture was evaporated to dryness and the residue was dissolved in a mixture of water and dichloromethane. Separated dichloromethane phase and the aqueous phase was extracted with three times 50 ml semesta chromatography with weakly elevated pressure (Flash chromatography) kieselgel using as eluent a mixture of methanol/ethyl acetate 4:1. The target compound is obtained in the form of butter.

Oily target connection into hyrochloride by the method described in example 1C). Obtained 1.6 g of 3-isopropyl-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indol-hydrate with a melting point 180-183oC.

Example 7. 4-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

A) 100 g of ethyl ester of indole-4-carboxylic acid was dissolved in 500 ml of glacial acetic acid. To the solution at room temperature was pricipally a mixture of 86 ml of 40% aqueous solution of dimethylamine, 55 ml of 37% aqueous formaldehyde solution and 250 ml of glacial acetic acid. After the reaction mixture was stirred at room temperature for 20 hours For further processing to the reaction mixture under ice cooling to achieve pH 9 was added 20% aqueous sodium hydroxide solution. Then was extracted three times with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered, and concentrated. Received 127 g of crude methyl ester 3-dimethyl-aminomethylphenol-4-carboxylic acid as a pale yellow oil.

In) 127 g of product obtained above was dissolved in 600 ml of acetonitrile. To the solution was added tin in 350 ml of acetonitrile. The reaction mixture is boiled under reflux for 2.5 hours At the end for further processing, the reaction mixture was evaporated to dryness and the residue was dissolved in 10% aqueous hydrochloric acid. The solution was extracted three times with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The remaining crude product was purified by column chromatography on kieselgel with weakly elevated pressure (Flash chromatography), using as eluent a mixture of cyclohexan/ethyl acetate 2:1. After evaporation of solvent the residue was led from diethyl ether. Received 66 g of 3-(etoxycarbonyl-2-nitropropyl)-indole-4-carboxylic acid methyl ester with a melting point 106-110oC.

C) 66 g of product obtained above was dissolved in 2 l of toluene. To the solution was added 5 g of palladium/carbon catalyst. Then the reaction mixture for 6 h was first made under hydrogen pressure up to 50 bar at a temperature of 70oC. after the mixture was cooled, the catalyst was filtered and the filtrate was evaporated. The oily residue for the final cyclization was heated at 130oC for 1 h Formed during subsequent cooling of crystallized mixed with eManager-6-oxo-1H-azepino [5,4,3-cd] indole-4-carboxylic acid ethyl ester with a melting point 185-188oC.

D) 41.5 g product obtained above was dissolved in 1.2 l of tetrahydrofuran. To the solution in portions with stirring was added at room temperature of 48.7 g of detribalized. At the end he pricipal 780 ml of ethanol and the reaction mixture is 1.5 h was heated at 50oC. For further processing, the reaction mixture was diluted with dichloromethane and the organic phase was extracted with water. After the aqueous phase was extracted four times with a mixture of dichloromethane/methanol 95: 5. The combined organic phases are dried over sodium sulfate, filtered, and the filtrate was evaporated. Precipitated solid residue was dissolved in methanol and were led. Crystallized was filtered, washed with a mixture of methanol/diethyl ether 8: 2 and dried. Received 31,3 g of 4-hydroxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole with a melting point of 186-187oC.

E) of 31.3 g of product obtained above was dissolved in 190 ml of pyridine. After that the solution while cooling and stirring was added 33 g of p-toluenesulfonic acid chloride. The reaction mixture was stirred at room temperature for 24 h For further processing, the reaction mixture was poured into 300 ml of ice-cold saturated aqueous solution of citric acid. The aqueous acidic phase was christoval and evaporated. The residue was dissolved in methanol and was led by adding diethyl ether. Crystallized was filtered, washed with a mixture of methanol/Dyatlovo ether 7:3 and dried. Received 36.5 g of 4-(p-toluensulfonyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole with a melting point 175-178oC.

F) 5 g of the product obtained above was dissolved in 50 ml of dimethyl formamide. To the solution was added to 5.3 g of sodium azide. Then the reaction mixture was heated to 100oC under stirring for 2 h For further processing it cooled, the reaction mixture was evaporated, the residue dissolved in dichloromethane and the dichloromethane phase is washed twice with water, dried over sodium sulfate, filtered and evaporated. The oily residue was dissolved in ethyl acetate and was led by adding diethyl ether. Obtained 2.8 g of 4-azidomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3,-cd]indole with a melting point of 152-153oC.

G) of 2.8 g of product obtained above was dissolved in 30 ml of methanol. Into the solution was introduced at the tip of a spatula Raney Nickel, then with stirring, added to 2.3 ml of hydrazine hydrate and within 2 h, the reaction mixture was stirred at room temperature. For further processing the catalyst was sucked out on asbestos grinding the e and as described in example IC), was transferred to its hydrochloride. The resulting crystallized was filtered, washed with a mixture of methanol/diethyl ether 8:2 and dried. Obtained 2.8 g of 4-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole-hydrochloride with a melting point 259-265oC.

Example 8. 4-(2-amino-ethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole.

A) 5 g of 4-(p-toluensulfonyl) -3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole (receipt see example 7E) was dissolved in 25 ml of dimethylformamide. To the solution was added to 970 mg of potassium cyanide. The reaction mixture with stirring, was heated for 3 h at 65oC. For further processing of the reaction mixture when cooled, diluted with water and was extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue was dissolved in methanol and the solution is brought to crystallization by adding diethyl ether. Crystallized was aspirated, washed on the filter with a mixture of methanol/diethyl ether 8:2, and dried. Obtained 2.4 g 4-cyanomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole point Board 197-198oC.

B) 1.8 g product obtained above was dissolved in 250 ml of saturated Ave is placed into the autoclave and 5 h were first made under stirring at 50oC under hydrogen pressure up to 50 bar. For further processing the catalyst was filtered and the filtrate was evaporated. The residue was purified by low pressure chromatography on kieselgel using as eluent a mixture of methanol/dichloromethane/diethylamin 17:80:3. The target compound is obtained in the form of butter.

Received above the target base was dissolved in methanol and similar to the method described in example 3, was subjected to interaction with malonic acid. Obtained 1.4 g of 4-(2-amino-methyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd]indol-hydrosalinity with a melting point 209-210oC.

Example 9. 1-methyl-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

A) to a solution of 7 g of methyl ester of 3-formylindole-4-carboxylic acid (receipt see example IA) in nitrogen atmosphere at room temperature portions were added 2.1 g of 80% sodium hydride. The reaction mixture for 1 h, stirred at 50oC. Upon completion of the dropping funnel were added 7 ml of methyl iodide and the reaction mixture was stirred for another 2 h at 50oC. For further processing, the reaction mixture was evaporated under reduced pressure to dryness and the mixture was dissolved in 50 ml of water and 50 ml of dichloromethane. Dichloro yashili over sodium sulfate, filtered and evaporated. The remaining crystalline crude product was recrystallize from diethyl ether. After drying of kristalliset obtained 6.9 g of the methyl ester of 1-methyl-3-formillion-4-carboxylic acid with a melting point of 128-129oC.

In) of 6.9 g of the product obtained above were mixed at room temperature with 70 ml of nitromethane and 1 ml of 1,8-diazabicyclo [5.4.0]-undec-7-Yong(1,5-5) and the reaction mixture 4 h and stirred at a temperature of up to 65oC. after the reaction mixture was processed as described in example IB). Received of 5.1 g of methyl ester of 1-methyl-3(1,3-dinitropropane-2-yl)indole-4-carboxylic acid with a melting point 142-145oC.

C) of 5.1 g of product obtained above was dissolved in 60 ml of methanol and in the presence of Raney Nickel (on the tip of a spatula) was subjected to interaction with 10 ml of hydrazine hydrate according to the method described in example IC). After the reaction the catalyst was filtered and the filtrate was evaporated under reduced pressure. Crude target product, in the form of a foamy residue was dissolved in methanol and, as described in example IC), was transferred into the hydrochloride. Obtained 3.2 g of 1-methyl-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride with a melting point 256-261oC.

oC.

In) 12 g of product obtained above was dissolved in 200 ml of dry dimethylformamide. To a solution under nitrogen atmosphere at room temperature portions were added 3 g of detribalized. Then the reaction mixture was heated to 60oC and a dropping funnel was pricipally 6.3 ml of benzylbromide. Next, the reaction mixture was heated to 80oC and 1 h and stirred at this temperature. For further processing, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in a mixture of water/ethyl acetate. The organic phase is separated and concentrated. The residue was purified by Koh eluent ethyl acetate. The residue formed after concentration of eluent, was led from a mixture of dichloromethane/diethyl ether 1:9. After drying the obtained 10.8 g of crystalline methyl ester of 1-benzyl-3-(2-nitroethylene)indole-4-carboxylic acid, which was immediately subjected to further processing.

C) 10.8 g product obtained above was dissolved in 150 ml of methanol. To the solution at room temperature was added 33 ml of nitromethane and then slowly added 2 ml of diazabicyclo [5.4.0] undec-7-ene (1.5 to 5). After the reaction mixture was stirred at room temperature for 1 h For further processing, the reaction mixture was diluted with 150 ml water and three times with 100 ml was extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The remainder of the oily product is purified by Flash-chromatography on kieselgel using ethyl acetate as eluent. The residue after concentration of the eluate was led from a mixture of isopropanol/ethyl acetate 2:8. After drying the obtained 10.3 g of crystalline methyl ester of 1-benzyl-3-(1,3-dinitropropane-2-yl)-indole-4-carboxylic acid, which was immediately subjected to further processing.

D) 10.3 g obtained above product L hydrazine-hydrate in example 1C). The reaction mixture was processed as described in example 1C). The target compound is obtained in the form of oil. Received above the target base by the method described in example 1C), converted into the hydrochloride. Received of 7.4 g of 1-benzyl-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride with a melting point of 167 169oC.

Example 11. 3-aminomethyl-5-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

A) To 50 ml of anhydride triperoxonane acid with stirring and ice cooling was added by portions 16 g of 3-amino-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indol-hydrate (receipt see example C) for 30 minutes, the Reaction mixture was 2 hours and was stirred in nitrogen atmosphere. Upon completion, the reaction mixture was evaporated under reduced pressure to dryness. The residue was dissolved in 200 ml of ethyl acetate. The addition of a saturated aqueous solution of sodium bicarbonate brought the solution to a pH value of 8.5. Treatment of aqueous saturated sodium bicarbonate solution was neutralized formed triperoxonane acid and excess anhydride triperoxonane acid and simultaneously otsaila again trifluoracetyl residue, located in the 5-position of the nitrogen atom. After the organic phase was separated, the aqueous phase is still trevali and evaporated. The residue was led by adding diethyl ether. After drying obtained 18 g of 3-triftoratsetata-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole with a melting point of 228 232oC.

B) 6 g of the product obtained above was dissolved at room temperature in 40 ml of formic acid (98 to 100%). To the solution at a temperature of from 55 to 65oC for 8 h was pricipally 95 ml of acetic anhydride. The reaction mixture was stirred 12 h at room temperature. Then the solution was evaporated under reduced pressure (water-jet vacuum pump) and the residue was dissolved in ethyl acetate and treated as described in example 11A). Received of 5.3 g of crystalline 3-triptycene-dimetil-5-formyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole with a melting point of 198 205oC.

C) 4 g of the product obtained above was dissolved in 80 ml of absolute tetrahydrofuran, and the solution in a nitrogen atmosphere was cooled to -78oC. At this temperature slowly pricipal of 11.8 g of 1M solution of diisobutylaluminium in toluene. After the cooling was removed. After 2 h, the solution was treated with 80 ml of ethyl acetate and 60 ml of 10% aqueous citric acid solution. The organic phase was separated, and the aqueous phase twice more in 80 ml extra rujnogo pump. After drying the obtained 3.4 g of 3-triftoratsetata-5-hydroxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole with a melting point of 150 151,5oC.

D) To a suspension of 1.08 g detribalized in 60 ml of tetrahydrofuran with ice cooling and vigorous stirring was pricipal of 25.2 ml triperoxonane acid. To this solution under ice cooling for 30 min was pricipally 1.8 g product obtained above in 60 ml of tetrahydrofuran. After the cooling was removed and the reaction mixture was heated at 60oC for 1 h Then the reaction mixture was concentrated in a water jet vacuum pump up to 10 ml, and treated as described in example 11A). The obtained oily product was purified by chromatography at moderately high pressure (low pressure chromatography at 3 to 5 bars). The product was led from a mixture of ethyl acetate/diethyl ether. Obtained 1.2 g of 3-fioricet.medical-5-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole with a melting point of 174 177oC.

E) 1.2 g product obtained above was dissolved in 40 ml of methanol. To the solution was added 40 ml of 5% aqueous potassium carbonate solution. The reaction mixture was stirred 8 h at room temperature. Then for further raffia low pressure at 3 to 6 bars) on kieselgel using as eluent a mixture of methanol/25% aqueous ammonia 97:3. The purified product was led from methanol/diethyl ether. Received of 0.82 g of 3-aminomethyl-5-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole with a melting point of 85 - 87oC.

F) 3-Aminomethyl-5-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole can also be obtained by gidrodinamicheskogo dibenzylamine 1-benzyl-3-benzylamino-5-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole (receipt see example 18) similarly to the method described in example 4, when the hydrogen pressure up to 10 bar.

Example 12. 3-aminomethyl-5-methoxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

To a solution of 1.5 g of 3-fioricet.medical-5-hydroxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole (receipt see example 11C) in 25 ml of methanol was added 0.1 p-toluenesulfonic acid and the solution boiled under reflux for 2 hours Then the reaction mixture was concentrated and the residue by adding aqueous saturated potassium carbonate solution until the pH value of 11 and 4 h was stirred at room temperature. By processing aqueous saturated solution of potassium carbonate was otsaila trifluoracetyl protective group and neutralized p-toluensulfonate. For further processing consistent residue was washed twice with 30 ml of methanol. The combined methanolic phase was evaporated and the residue was purified by chromatography at moderately high pressure ( low pressure chromatography at 3 to 6 bars) on kieselgel using as eluent methanol/25% aqueous ammonia 97:3. The target compound remaining after concentration of the eluate, was led from a mixture of ethanol/ether 9:1. Received 0.5 g 3-aminomethyl-5-methoxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole with a melting point of 160 163oC.

Example 13. 3-aminomethyl-1-(3-phenylpropyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole.

2 g of 3-Triftoratsetata-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd] indole (receipt see example 11A) was dissolved in 40 ml of dry dimethylformamide. To the solution was added 0.8 g of detribalized and in an atmosphere of nitrogen was stirred reaction mixture for 1 h At the end was pricipal of 3.9 ml 3-phenylpropylamine and the reaction mixture 6 h was heated under reflux. After the reaction mixture was evaporated under reduced pressure in a water-jet pump vacuum and the oily residue was dissolved in a mixture of 40 ml of ethyl acetate and 40 ml of 5% citric acid solution. The organic phase was separated and twice 30 ml were extracted with Atilla. The obtained oily crude 3-triftoratsetata-1-(3-phenylpropyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole was purified by chromatography at moderately high pressure (low pressure chromatography) kieselgel using as eluent a mixture of cyclohexane/ethyl acetate 1: 1. The fractions containing the purified product were combined and concentrated. For removal of trifluoracetyl protective group of the obtained product was dissolved in 40 ml of methanol and added to 40 ml of a saturated aqueous solution of potassium carbonate and stirred 8 h at room temperature. Then the reaction mixture was treated by the method described in example 11TH). Received target oily base was dissolved in isopropanol and the solution was added to the ethereal solution of hydrogen chloride. Received 1.0 g of 3-aminomethyl-1-(3-phenylpropyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indol-chloride with a melting point of 118oC.

Example 14. 3-(piperidine-1-ylmethyl) -3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole.

4 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd)indol-hydrate (receipt see example IC) was dissolved in 40 ml dimethylformamide. To the solution was added 2.6 g of triethylamine and then at room temperature processing, the reaction mixture was evaporated under reduced pressure in a water-jet pump vacuum and the residue was dissolved in a mixture of dichloromethane/methanol 9:1. Then to achieve pH 11 was added a saturated aqueous solution of sodium carbonate. The organic phase was separated, and the aqueous phase was washed two more times with 50 ml mixture of dichloromethane/methanol. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The residue was dissolved in ethanol and diluted with ether until a slight turbidity. The resulting crystallized was filtered and dried. Obtained 3.5 g of 3-(piperidine-1-ylmethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole with a melting point 119-122oC.

Example 15. 3-(dimethylaminocarbonylmethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole.

2 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3, -cd]indol-hydrate (receipt see example IC) was dissolved at room temperature in 20 ml of dimethylformamide. To the solution under stirring was added 2.6 g dimethylformamide-dimethylacetal. The reaction mixture was stirred at room temperature for 4 h Then the reaction mixture was concentrated under reduced pressure in a water-jet pump vacuum and the oily residue was dissolved in 50 ml of ethyl acetate. The solution was diluted with diethyl ether until a slight turbidity. Crystallized 2.2 g of crude target base.

oC.

Example 16. 3-(Dimethylaminocarbonylmethyl) -3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole.

1 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indol-hydrate (receipt see example IC) was dissolved at room temperature in 10 ml of dimethylformamide. To this solution was added 1 g of N-chlormethine-N,N-dimethylammoniumchloride. After the reaction mixture was stirred 2 h at room temperature. For further processing, the reaction mixture was evaporated under reduced pressure in a water-jet pump vacuum and the residue was dissolved in a mixture of equal parts water and ethyl acetate. By adding saturated sodium bicarbonate solution reached pH of the aqueous phase of 8.5, then the separated organic phase and the aqueous phase was extracted with ethyl acetate three times in 50 ml the combined organic extracts were concentrated to 25 ml of thus Obtained solution of the target compound was further processed as ndol-hydrochloride with a melting point of 178-179oC.

Example 17. 4-(4-phenylpiperazin-1-ylmethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole.

2.2 g of 4-(p-toluensulfonyl) -3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole (receipt see example 7E) was mixed with 9 ml of 1-phenylpiperazine and then the mixture was stirred 4 h at a temperature of 80oC. Upon further cooling, the crystallized crude target compound. It was filtered and washed with a mixture of equal parts of methanol and water. After drying the obtained 1.7 g of 4-(4-phenylpiperazin-1-ylmethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole with a melting point of 184-185oC.

Example 18. 1-benzyl-3-benzylamino-5-methyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd]indole.

A) 4 g of oily 1-benzyl-3 - aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole (receipt see example 10) according to the method described in example 2, was subjected to interaction with benzaldehyde and formed Softwae base was first made by the method described in example 2. The reaction mixture is further processed as in example 2. Obtained 4.3 g of 1-benzyl-3-benzylamino-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole.

B) 4.3 g product obtained above was subjected to interaction with the anhydride of triptoreline 4.1 g of 1-benzyl-3-[N-(benzyl)-triftoratsetata] -3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole in the form of a foamy product.

C) 4.1 g of product obtained above was dissolved in 100 ml of absolute tetrahydrofurane. The solution was pricipal at temperatures up to -20oC in nitrogen atmosphere to a solution of 1.15 g of tert.-the butyl potassium in 10 ml of tetrahydrofuran. The reaction mixture was stirred at -20oC for 1 h and then at this temperature was pricipally solution of 0.85 ml dimethylsulfate in 5 ml of tetrahydrofuran. Next, the reaction mixture was stirred at -20oC for one hour in nitrogen atmosphere. After the cooling was removed. After reaching room temperature, the reaction mixture was concentrated under reduced pressure in a water-jet pump vacuum to a volume of about 20 ml and then diluted by the addition of saturated aqueous potassium carbonate solution until the pH value of not more than 11. Next, the reaction mixture over a period of hours was very mixed, so that has been good mixing of the two phases, this also happened cleavage trifluoracetyl protective group. After the organic phase was separated and the aqueous was extracted with dichloromethane twice 50 ml combined organic phases are dried over sodium sulfate, filtered and evaporated. The remaining crude product is purified by chromatography PR is setat/cyclohexan 7:3. Obtained 2.1 g of 1-benzyl-3-benzylamino-5-methyl-3,4,5,6 - tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole in the form of a foamy product.

Example 19. 3-[N-hydroxybenzyl] -aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole.

To a solution of 1.5 g of 3-[N-methoxybenzyl]-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole and 2.5 g of 1,4-diazabicyclo 2,2,1 octane (= DABCO) was added 2 ml of trimethylsilylmethyl. The reaction mixture was heated for 24 h in nitrogen atmosphere at 150oC. After cooling to room temperature the reaction mixture was diluted with 25 ml of methanol and acidified using 20% aqueous hydrochloric acid. Then the reaction mixture was strongly stirred at room temperature. For further processing, the reaction mixture was diluted with 30 ml water, the aqueous phase is separated and the organic phase was washed with water twice 20 ml of the combined aqueous phase was neutralized with diluted soda lime and then evaporated under reduced pressure in a water-jet vacuum pump. The remainder of the oily crude product is purified by chromatography on kieselgel with weakly elevated pressure (Flash chromatography) using as eluent a mixture of methanol/25% aqueous ammonia 98:2. Obtained 0.6 g of 3-[N-(4-hydroxybenzyl)-Aogo base was dissolved in 20 ml of methanol and added to a solution of 0.27 g of tartaric acid. After concentrating the mixture obtained 0.87 g of amorphous 3-[N-(4-hydroxybenzyl)-aminomethyl] 3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole.

Example 20. 4-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino -[5,4,3-cd] -indole.

A) 2.5 g -(p-Toluensulfonyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole was dissolved in 40 ml of methanol. To the solution was added 1.4 g of phthalimide potassium. The reaction mixture is boiled under reflux for 6 hours For further processing, the reaction mixture was evaporated to dryness under reduced pressure in a water-jet vacuum pump. The solid residue was dissolved in a mixture of dichloromethane and water 1:1. The organic phase was separated and the aqueous was washed with dichloromethane three times in 50 ml the combined organic extracts were dried over sodium sulfate, filtered and evaporated. Received of 1.9 g of 4 -(N-phthalimidomethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino-[5,4,3-cd] indole, which was immediately used in the next stage.

B) and 1.9 g of product obtained above was dissolved in 50 ml of ethanol. To the solution was added 1 ml of hydrazine hydrate. The reaction mixture for 4 h was heated under reflux. For further processing the resulting cooled to room temperature phthalhydrazide was filtered and washed with ethanol two the STV chromatography at moderately high pressure (=chromatography low LPLC at 3-6 bar) on kieselgel using as eluent a mixture of methanol/aqueous ammonia 98:2. Thus obtained target base into its hydrochloride by the method described in example 7G). Obtained 0.7 g of 4-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride with a melting point 256-260oC.

According to the methods described in the above examples, it is also possible to provide the compounds of formula 1, are shown in the following table.1.

Indicate in the table. 1: POS. the position of the side chain in the ring skeleton, HCl hydrochloride, B the base, HBr hydrogen bromide, Hta hydrogentartrate, bi communications, Ph phenyl, Cycloprop cyclopropyl, Cyclohex cyclohexyl, z - decomposition.

Example. 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-containing pills.

Produced tablets of the following composition per tablet, mg:

3-Aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino [5,4,3-cd] indole-hydrochloride 20

Starch 60

Milk sugar 135

Gelatin (10% solution) 6

The main ingredient, starch and lactose has agglomerated in 10% gelatin solution. The pasta was razmelchite and the resulting granules were placed on a suitable dishes and dried at 45oC. the Dried granules pass through the mill and mixed in a mixer with auxiliary materials, mg:

the-asiminoaei the compounds of formula I

< / BR>
where R1hydrogen, lower alkyl or peninisula alkyl group which may be mono - or tizamidine in the phenyl ring by lower alkoxyl or lower alkyl;

R2hydrogen or lower alkyl which may be substituted in a-position to the nitrogen atom of the lower alkoxyl;

R3hydrogen or halogen;

n is 1 or, if -(CH2-the circuit is in the 4th position of the ring, 2;

R4hydrogen, C1C5-alkyl, C3- C6-cycloalkyl, C4-cycloalkenyl, vanillasky alkyl group which may be mono - or tizamidine in the phenyl ring by lower alkyl, lower alkoxyl, hydroxyl or halogen;

R5hydrogen, C1C5-alkyl or peninisula alkyl group which may be substituted by lower alkoxyl or R4and R5together with the nitrogen atom to which they are connected, form a heterocycle of General formula

< / BR>
where B is a bond, methylene group, oxygen or aminogroup-NR6where R6lower alkyl or phenyl;

D link or if R4and R5not hydrogen, N CH-group,

and their physiologically tolerated acid salt of the merger.

2. 6-Oxo-asiminoaei connection is tion by p. 1 or 2, wherein in the General formula I R4the hydrogen.

4. 6-Oxo-asiminoaei connection PP. 1 to 3, characterized in that in the General formula I R4hydrogen, lower alkyl or substituted, if necessary, benzyl and R5the hydrogen.

5. 6-Oxo-asiminoaei connection PP. 1 to 4, characterized in that in the General formula (I-D connection.

6. 6-Oxo-asiminoaei soedineniya on PP. 1 to 5, characterized in that in the General formula I they contain CH2D NR4R5group at the 3rd position of the skeleton of the ring.

7. The pharmaceutical composition regulating the motility of the stomach, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains effective to promote the motility of the stomach, the number of connections on p. 1.

8. Pharmaceutical composition having effective against migraine serotonin-agonistic action, including active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient contains the active ptiv migraine the number of connections on p. 1.

9. The way to obtain 6-oxo-asiminoaei compounds FD is their General formula II

< / BR>
where R1, R3have the specified values;

R7lower alkoxycarbonyl group or a CN group,

cyclist in terms of recovery.

10. The method of obtaining the compounds of formula Ib

< / BR>
where R1, R3, R4, R5and n are specified in paragraph 1 values;

R2is hydrogen or lower alkyl,

characterized in that the compound of formula III

< / BR>
where R1,R3,R2n have the above meanings;

X nucleophile chip off the group,

subjected to interaction with compounds of General formula IV

< / BR>
where R4and R5have the specified values,

and optionally in the resulting compounds of the formula I, where R1, R4and/or R5contain metoksifenilny group, otscheplaut the methoxy group to hydroxy-group, and in the resulting compounds I where R1, R4or R5represent a substituted benzyl group, benzyl this group hydrogenations otscheplaut with obtaining the target compound in free form or in the form of their acid salts of accession.

11. The method of obtaining compounds of General formula Ic

< / BR>
where R1, R2, R3and n have the specified values is by value;

Y azide-phthalimide or lagrappe,

Y is transferred to the amino group.

12. The method of obtaining compounds of General formula Id

< / BR>
where R1, R2, R3, R5and n have the above meanings;

R4matter listed for R4except for hydrogen,

characterized in that compounds of General formula VI

< / BR>
where R1, R2, R3and n have the above meanings;

R8hydrogen, C1C5-alkyl, C3- C6-cycloalkyl, C4-cycloalkenyl, vanillasky alkyl group, mono - or disubstituted in the phenyl ring by lower alkyl, lower alkoxyl, hydroxyl or halogen, or aminosidine group,

alkylate and again otscheplaut aminosidine group, R8.

13. The method of obtaining compounds of formula Ie

< / BR>
where R1, R3, R4, R5and n have the above meanings;

R2lower alkyl group, a substituted lower alkoxyl in-position to the nitrogen atom,

characterized in that the compounds of General formula VII

< / BR>
where R3n have the above meanings;

R1matter listed for R1or aminosidine group;

R4and RIli R5hydrogen, so secure at least one easily tsepliaeva protective amino group that does not respond allerease and alkylating means;

R91-hydroxyl group,

1-hydroxyl group is transferred to the remainder R2and again otscheplaut aminosidine group.

14. The method of obtaining compounds of General formula I

< / BR>
where R1, R2, R3, R4and n have the above meanings;

R5matter listed for R5except for hydrogen,

characterized in that the compound of General formula Ii

< / BR>
where R1, R2, R3and n have the specified values,

enter aminomethylating the remainder of the General formula

< / BR>
where R4and R5have a specified value.

 

Same patents:

The invention relates to the chemistry of the condensed nitrogen-containing heterocyclic systems and specifically relates to new compounds of the hydrobromide of 2-amino-4-acetylthiazole /5,4-in/indole of formula 1

< / BR>
The inventive compound is a derivative of the heterocyclic system thiazolo/5,4-in/indole type a:

< / BR>
Derivatives of this system, for example, 2,4-dimethylthiazole /5,4-in/indole (In), described as intermediate products for the synthesis of polymethine dyes used as photosensitizers [1 4] however, in the literature there is no information about the biological activity of the system (a) and its derivatives

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties

The invention relates to compounds of formula I:

< / BR>
in which Z is hydrogen, halogen or lower alkyl;

R1is lower alkyl, cycloalkyl or aryl; and

R2is lower alkyl or cycloalkyl;

which are used to mitigate various dysfunctions of memory, which are characterized by a cholinergic deficit such as disease Alzheimer and as analgesic agents

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to methods for new nitrogen-containing compounds of General formula I

Rwhere R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

ororor< / BR>
ororwhere n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R

The invention relates to indole derivative of General formula (l):

(I)

where R and R1such that:

or R and R1the same or different hydrogen atom, a straight or branched lower alkyl, cycloalkyl to 6 carbon atoms;

or R and R1together with the nitrogen atom to which they are bound, form a piperazinil, substituted lower alkyl,

A -:

or chain /CH2/n, where n can take the values 2 or 3,

or circuit< / BR>
X and Y or each a hydrogen atom,

or one hydrogen atom and the other is a hydroxy radical or1-C4-alkyl,

or X and Y together form an oxo radical, a radical alkyltin with 1-4 carbon atoms or a radical N-OR5where R5a hydrogen atom or an alkyl radical with 1-4 carbon atoms, the substituents a, b, c, d such that:

either each hydrogen atom,

or a and b together form a function oxo and C and d are each a hydrogen atom;

Z -:

or a hydrogen atom,

or a moiety of the lower alkyl or the group aminoalkyl formula:

R2NH2,

where R2lowest alkylen;

moreover, these compounds of formula (I) can nachtergaele or organic acids

The invention relates to a new method of getting some 3-substituted indoles and to certain intermediates that are useful in this way

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 1-(3-sulfamoyl-4-chlorobenzoyl)-amino-2-methylindoline. Method involves acylation reaction of 1-amino-2-methylindoline hydrochloride with 4-chloro-3-sulfamoylbenzoyl chloride in dioxane medium. Firstly, 1 mole of triethylamine is added and then 4-chloro-3-sulfamoylbenzoyl chloride in dioxane is added in parallel, and then remaining 1.11 mole of triethylamine in dioxane is added and pH value is maintained in the range 7.5-8. Method provides enhancing yield of the end product up to 88% as compared with 80.5% and to replace using tetrahydrofurane for dioxane.

EFFECT: improved preparing method, enhanced yield of product.

2 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to novel compounds of indoline of the formula (I): , wherein R1 and R3 are similar or different and each means hydrogen atom (H), lower alkyl group or lower alkoxy-group; R2 means -NO2, -NHSO2R6 [wherein R means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)], -NHCONH2 or lower alkyl group substituted with -NHSO2R6 [wherein R6 means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)]; R4 means H, (C1-C20)-alkyl group optionally substituted with hydroxy-group, -COR13 (wherein R13 means H, lower alkyl group), lower alkenyl group, lower alkoxy-lower alkyl group, lower alkylthio-lower alkyl group, (C3-C8)-cycloalkyl group or (C3-C8)-cycloalkyl-(C1-C3)-alkyl group; R5 means (C1-C20)-alkyl group, (C3-C8)-cycloalkyl group or aryl group; R12 means H, lower alkyl group, lower alkoxy-lower alkyl group or lower alkylthio-lower alkyl group wherein aryl represents phenyl or naphthyl, or its pharmaceutically acceptable salt. Compounds possesses the strong inhibitory effect on activity of acyl-coenzyme A:cholesterol acyltransferase and the strong inhibitory effect on lipid peroxidation processes that allows its using as a component of pharmaceutical compositions.

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical compositions.

31 cl, 5 tbl, 68 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted indoline phemylsulfamide derivatives with the common formula , where A means C-R11 group or nitrogen, and R11 means hydrogen or alkyl with 1-4 carbon atoms, X means oxygen, R1 means aryl with 6-10 carbon atoms, unsubstituted or once-triple substituted with the similar or different substitutes, selected from the group which includes halogen, zyano, alkyl with 1-6 carbon atoms, alkoxi with 1-6 carbon atoms, phenoxi, benziloxi, trifluoromethyl, trifluorometoxi, alkenil with 2-6 carbon atoms, phenyl, alkylthio with 1-6 carbon atoms, mono- and dialkylamino with 1-6 carbon atoms in each alkyl group, or means the group with formula , R2 and R3 similar or different and independently from each other mean hydrogen or alkyl with 1-6 carbon atoms, or with the carbon atom they are bound to form the 3-7-membered spiro-compound cycloalkylic ring, R4 means hydrogen or alkyl with 1-6 carbon atoms, R5 R4 means hydrogen or alkyl with 1-6 carbon atoms, R6 means hydrogen or alkyl with 1-6 carbon atoms, R7 means hydrogen, alkyl with 1-6 carbon atoms, R8 - R10 mean hydrogen; as well as to their pharmaceutically compatible salts.

EFFECT: compounds are designated for prevention and/or treatment of cardio-vascular diseases, particularly dislipidemia and ischemic heart disease.

4 cl, 1 dwg, 96 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted 4-hydroxy-6-nitro-2-phenylindole of general formula I where R1 means H, alkyl, R2 means H, and/or alcoxyl, and/or halogen, n equals 0-5, except for 4-hydroxy-6-nitro-2-phenilindole. Compounds I including 4-hydroxy-6-nitro-2-phenilindole have fungicidal activity, which allows their use as fungicidal agents. Compounds are obtained from O-(3,5-dinitrophenyl)ketoxims of general formula III where R1, R2 and n have the aforesaid values, their procession with hydrazine hydrate in aliphatic alcohol with boiling in presence of iron salt and activated coal, with obtaining corresponding substituted O-(3-amino-5-nitrophenyl)ketoxims of general formula IV which are subjected to intramolecular cyclisation in mixture of acid and aliphatic alcohol at temperature of mixture boiling.

EFFECT: obtaining 4-hydroxy-6-nitro-2-phenylindole and compositions on its basis, which possess fungicidal activity.

5 cl, 1 tbl, 9 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds -acidified arylcycloalkylamins of formula I in any of their stereoisomeric forms or in form of their mixture in any ratio, or their pharmaceutically acceptable salts, where in formula I : R1 represents aryl, not obligatory substituted with one or two similar or different substitutes, selected from group that includes C1-C6-alkyl and halogen; R2 represents aryl or heteroaryl, which represents residue of 5-6-member aromatic monocyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom and/or 1 sulfur atom or oxygen atom, or residue of 9-10-member aromatic bicyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom, each of which is unsubstituted or contains 1-3 similar or different substitutes, selected from group, consisting of halogens, NH2, unsubstituted C1-C10-alkyl, C1-C10 -alcoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, and at least monosubstituted C1-C10-alkyl, etc., n represents 1, 2, 3 or 4. Invention relates to pharmaceutical composition, stimulating expression of endothelial NO synthase, based on said compounds, as well as application of compounds of formula I for production of medication for stimulating expression of endothelial NO-synthase and for treatment of such cardiovascular diseases as atherosclerosis, thrombosis, coronary artery disease, hypertension and impaired cardiac function.

EFFECT: invention ensures enhancing composition and treatment method efficiency.

9 cl, 2 tbl, 41 ex

Up!