Derivatives of indole, their optical isomers and pharmaceutically acceptable salts

 

(57) Abstract:

The essence of the invention: indole derivatives of formula (I), where n is 0,1 or 2, R1-H; R2-H, halogen, cyano, -OR4, -(CH2)m-(C=O)NR5R6, -(CH2)m-SO2NR5R6, -(CH2)m-NR7(C= O)R8, -(CH2)mSOxR8, -CH= CH(CH2)yR10, R3-H, C1-6alkyl; provided that when R2means hydrogen, n is 0 or 1, and their optical isomers and pharmaceutically acceptable salts. The proposed connection can be used to treat migraine and other disorders. 2 C. and 7 C.p. f-crystals, 6 PL.

The invention relates to indole derivatives, methods and intermediate products of their production, pharmaceutical compositions containing these compounds, and their use in medicine. Active compounds presented in the invention can be used to treat migraine and other rasstroistv.

In the U.S. patents NN 4 839 377 and 4 855 314, and also in EP-A 313 397 described 5-substituted 3-aminoalkyl-indoles. Indicated that these compounds can be used for treatment of migraine.

British patent application 040 279 is 3 am is ndrome Raymond and migraines.

B EP-A 303 506 presents 3-poly: hydro-pyridyl-5-substituted 1H-indoles containing NT-receptor agonist and has vasoconstrictor activity, and successfully applied in the treatment of migraine.

EP-A 354 777 is derived N-piperidinyl:indolyl ethyl-alkane-sulfonamides. It is known that compounds contain NT-receptor agonist and different vasoconstrictor activity that resulted can be used to treat headaches.

Brief description of the invention.

The invention relates to compounds with formula (I)

< / BR>
where n is the number 0, 1 or 2,

R1hydrogen

R2hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, OR4, -(CH2)m-(C= O)NR5R6, -(CH2)m-SO2NR5R6, -(CH2)m-NR7(C=O)R8, -(CH2)m-NR7O2R8,

-CH2)m-S(O)xR8, -(CH2)m-NR7(C=O)NR5R6, -(CH2)m-NR7(C=O)OR9and-CH=CH(CH2)yR10.

R3selected from hydrogen and C1-6-linear or branched alkyl,

R4hydrogen, C1-6alkyl or aryl,

R5and R6 and R6together form a 4-, 5 - or 6-membered ring,

R7and R8independently of one another represent hydrogen, C1-3the alkyl, aryl and C1-3-alkyl-aryl,

R9hydrogen, C1-6the alkyl, aryl and C1-3-alkylaryl,

R10-(C=O)NR5R6and-SO2NR5R6,

where

R5and R6have the above significance, as well as represent-NR7(C=O)R8, -NR7SO2R8, -NR7(C=O)NR5R6, -S(O)xR8and-NR7(C=O)OR9,

where R7, R8and R9have the above values,

m 0, 1, 2 and 3

y 0, 1, 2,

x is 1 or 2.

The above aryl group or aryl fragments alcylaryl groups independently of one another may be selected from the group of phenyl or substituted phenyl, with the specified substituted phenyl may be substituted by 1-3 groups selected from C1-4-alkyl, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, carboxamido, nitro or C1-4-alkoxy or their pharmaceutically acceptable salts. These compounds can be used for treatment of migraine or other disorders. The compounds of formula I, where R2is-CH= CH-R10can consider is defended in the invention compounds also include all optical isomers of formula I (for example, R and S-enantiomers and their racemic mixture. Preferred R-enantiomers in the specified chiral center formula I.

If there is no specific reservations, alkyl groups, as well as introducing the alkyl fragments of other groups (e.g., alkoxy), may be linear or branched, and may represent a cycle (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or can be linear or branched and contain cyclic fragments.

Preferred compounds of the invention are the compounds of formula I, where R1hydrogen, R2- -(CH2)m-SO2OTHER5, -(CH2)m-NHSO2R8, -(CH2)m-SO2R8,

-(CH2)m-(C= O)OTHER5or -(CH2)m-NH(C=O)R8, R3hydrogen or methyl, m, R5and R8have the above values, or their pharmaceutically acceptable salts.

From above, the preferred compounds are the most preferred R-enantiomers with chiral centers indicated in formula I.

Most preferred are the following compounds:

(R)-5-methoxy-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole,

(R)-5-bromo-3-(N-methylpyrrolidine-sulfonylated)-3-(N-methylpyrrolidine-2-yl - methyl)-1H-indole,

(R)-5-(2-methylaminomethyl)-3-(pyrrolidin-2-ylmethyl)-1H- -indole,

(R)-5-(2-methylaminoethanol)-3-(N-methylpyrrolidine-2- -ylmethyl)-1H-indole,

(R)-5-carboxamido-3-(T-methylpyrrolidine-2-emetel)-1H-indole,

(R)-5-(2-methylsulfonylamino)-3-(N-methylpyrrolidine-2-yl-methyl)- -1H-indole,

(R)-5-(2-aminosulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)- -1H-indole,

(R)-5-(2-N, N-dimethylaminocarbonylmethyl)-3-(N-methylpyrrolidine-2- -ylmethyl)-1H-indole,

(R)-5-(2-phenylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)- -1H-indole,

(R)-5-(2-phenylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)- -1H-indol-polosukhina,

(R)-5-(2-ethylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)- -1H-indol-polosukhina,

(R)-5-(2-(4-methylphenylsulfonyl)-ethyl)-3-(N-methylpyrrolidine- -2-ylmethyl)-1H-indole,

(R)-5-(3-methylsulfonylamino-1-enyl)-3-(N-methylpyrrolidine- -2-ylmethyl)-1H-indole,

(R)-5-(2-ethylsulfonyl)-3-(N-2-propylpyrrolidine-2-ylmethyl)- -1H-indole,

(R)-5-(2-ethylsulfonyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole,

(R)-5-(2-(4-methylphenylsulfonyl)ethynyl)-3-(N-methylpyrrolidine- -ylmethyl)-1H-indole,

(R)-5-(2-methylsulfonylmethyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole; and

(R)-(2-methylsulfonylmethyl)-3-(N-methylpyrrolidine-2-ylmethyl)- 1H-indole.


(R)-5-fluoro-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole,

(R)-5-acetylamino-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole,

(R)-5-benzyloxycarbonylamino-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole,

(R)-5-(2-aminocarbonylmethyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole,

(R)-5-aminocarbonylmethyl-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole,

(R)-5-methylsulfonate-3-(N-methylpyrrolidine-2-ylmethyl)-1H- -indole; and

(R)-aminosulfonyl-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole.

The invention also concerns pharmaceutical compositions intended for the treatment of hypertension, depression, feelings of fear t anxiety, disturbances of appetite, obesity, improper medication, migraines, pain, and bouts of chronic migraine and headache associated with vascular disorders, containing a certain number of compounds of the formula I or its pharmaceutically suitable salts with a similar activity, with the addition of the corresponding carriers.

The invention also concerns pharmaceutical compositions for violations related to failure serotonergic meditation (e.g., depression, fear, metabolic disorders, obesity, headaches, migraines, blew a certain number of compounds of the formula I or its pharmaceutically acceptable salt, effective in the treatment of these diseases, and a pharmaceutically acceptable carrier.

The invention also concerns a method of treating diseases, such as hypertension, depression, anxiety, metabolic disorders, obesity, headaches, migraine, pain, seizures chronic migraines and headaches caused by vascular disorders involving the introduction of a mammal (e.g. human) requiring such treatment, a certain effective amount of the compounds of formula I or its pharmaceutically acceptable salt with a similar activity.

The invention also concerns a method of treating disorders associated with serotonergic deficiency of neuromedical (e.g., depression, fear, metabolic disorders, obesity, improper medication, headaches, migraine, pain, seizures chronic migraines and headaches caused by vascular disorders involving the introduction of a mammal (e.g. human) required number of compounds of the formula I or its pharmaceutically acceptable salt with a similar activity.

The invention also concerns compounds of fo is C=O,

R1, R2and R3have the meanings indicated in formula I, and

R11represents C1-6-alkyl, benzyl or aryl, and the aryl has the above values.

The compounds of formula V can be used as intermediate compounds for preparing compounds of formula I.

In line with this, one of the groups mentioned above intermediate compounds includes compounds of formula II

< / BR>
in which

n, R1, R2and R11have the above value, and the second group of the above intermediate compounds includes compounds of formula III:

< / BR>
in which n, R1, R3and R10have the above values.

Detailed description of the invention.

The compounds of formula I are obtained by reduction with hydride compounds of the formula II:

< / BR>
in which R1, R2and R11have the above values when using a hydride reducing agent in an inert solvent.

Suitable hydride reducing agents include lithium aluminum hydride, DIBORANE, lithium borohydride and sodium borohydride. The most preferred reagent is a lithium-aluminum-hydride. Poljodjelstvenim solvent is tetrahydrofuran. The reaction is carried out at a temperature of from about 30 to about 100oC, preferably from about 65 to about 70oC.

The compounds of formula I can be obtained by catalytic reduction of compound of formula III:

< / BR>
in which

R1, R3n and R10have the above significance, in an atmosphere of hydrogen, preferably under a pressure from about 1 to about 3 ATM, or using such a source of hydrogen as ammonium formate or formic acid in an inert solvent. Suitable catalysts include palladium on charcoal, Raney Nickel, platinum oxide, rhodium and ruthenium. The most preferred catalyst is palladium on coal. Suitable solvents include C1-6-alcohols, N,N-dimethylformamide, ethyl acetate and acetonitrile. The preferred solvent is ethanol. The reaction is conducted at temperatures from about 0 to about 60oC, most preferably about 25oC.

The compounds of formula I can be obtained by alkylation of compounds of formula I,

in which

R3= H, and

R2and R1have the meanings of formula I,

alkylhalogenide in the presence of a base in an inert solvent. Suitable alkylhalogenide include Ala the m is iodide or bromide in the presence of a suitable source of iodide such as sodium iodide. Suitable bases include tertiary amines and inorganic bases. The preferred base is sodium carbonate. Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide, dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile. The preferred solvent is N,N-dimethylacetamide. The reaction is carried out at a temperature of from about 0 to about 150oC, preferably at a temperature of approximately 120oC.

The compounds of formula II can be obtained by reaction of a magnesium salt of a derivative of indole of formula IV:

< / BR>
in which

R1and R2have the above meaning,

with the acid chloride of N-CO2R11-Proline, N-CO2R11-azetidin-2-carboxylic acid or N-CO2R11-pipecolinic acid (R, S, or racemate), where R11has the above values.

Magnesium salt of indole was first obtained in the reaction of the indole of formula IV with an alkyl - or aryl-mangalavanam, preferably with ethylmagnesium. The reaction is usually run in an inert solvent at a temperature from about -30 to about 65oC, preferably about 25oC. Suitable solvents include diethyl ether, tetrahydrofuran or brugermanual acid or pipecolinic acid get in a separate reactor by reacting N-CO2R11-Proline, N-CO2R11-azetidinone acid or N-CO2R11-pipecolinic acid (R, S, or racemate) oxalylamino in methylene chloride at temperatures from -10 to 25oC (Helv. Chim. Acta, 1920(1976)). Suitable solvents include diethyl ether, tetrahydrofuran, other alkalemia ether and methylene chloride. Proline, azatin-2-carboxylic acid or pipecolinate acid protected at the N-protecting group to prevent reaction of the nitrogen with the acid chloride, when formed. Suitable protective groups can be substituted by aryl or substituted allylcarbamate (for example, benzyloxycarbonyl). Preferably the solution of acid chloride of N-CO2R11-Proline in an inert solvent (e.g. diethyl ether) slowly add in the solution of the magnesium salt of the indole of formula IV at a temperature of from about -30 to about 50oC, preferably about 25oC.

The compounds of formula III can be obtained by reaction of compounds of formula:

< / BR>
in which

R1, R3and n have the above values, and

X represents chlorine, bromine or iodine, preferably bromine, with a compound containing the vinyl group (for example, ativaninfo - or N-methylphenylsulfonyl) catalysts include palladium salts (II), preferably the palladium (II) acetate. Suitable solvents include acetonitrile, N, N-dimethylformamide and tetrahydrofuran. Preferred solvent-three-0-tolworthy. Preferable base include tizanidine amines. The preferred base is triethylamine. The reaction is conducted at temperatures ranging from about 25 to about 150oC, preferably about 80oC.

The compounds of formula I and intermediate compounds for preparing compounds of formula I can be obtained by reduction with hydride compounds of the formula:

< / BR>
in which R2n and R11have the above values, hydride regenerating agent. Suitable hydride reducing agents include sociallyengaged, DIBORANE, litebrite, and sodium amide. The preferred reactant sociallyengaged. Suitable solvents include diethyl alcohol, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferred solvent is tetrahydrofuran. The restoration is carried out at temperatures of from about 30 to about 100oC, preferably in the range from about 65 to about 70oC.

The compounds of formula I and intermediate compounds for preparing compounds of formulas/BR>R2n and R11have the above values,

in the atmosphere of hydrogen, preferably at a pressure of from about 1 to about 3 ATM or using such a source of hydrogen as ammonium formate or formic acid in an inert solvent. Acceptable catalysts include palladium on charcoal, Raney Nickel and platinum oxide. The preferred catalyst is palladium on coal. Used for this purpose solvents include C1-6-alcohols, N,N-dimethylformamide, ethyl acetate and acetonitrile. The preferred solvent is ethanol. The reaction is conducted at temperatures from about 0 to about 60oC, preferably about 25oC.

The compounds of formula VI can be obtained by cyclization at the expense of catalyst transition metal compound of the formula VII:

< / BR>
in which

R2n and R11have the above values, and

X represents chlorine, bromine or iodine, preferably bromine or iodine), and

R12is-OR11as described above, or acrylic, aryl or trifluoromethyl (preferably trifluoromethyl), in a suitable inert solvent using a catalyst transfer phase and the substrate. Suitable catalysts include palladium salts, such as acetate iienaiiie the solvent is N,N-dimethylformamide, acetonitrile and N-methylpyrrolidine. The preferred solvent is N, N-dimethylformamide. Suitable catalysts for the transfer phase include tetraalkylammonium, preferably Tetra-n-butylammonium. Suitable bases include tertiary amines, sodium bicarbonate and sodium carbonate. The preferred base is triethylamine. The reaction is carried out at a temperature of from about 80 to about 180oC, preferably from about 150 to about 160oC.

The compounds of formula VI can also be obtained by hydride recovery of the compounds of formula II:

< / BR>
in which

R2n and R11have the above value when using a hydride reducing agent in an inert solvent. Suitable hydride reducing agents can be considered litebrite, sodium borohydride and cyanoborohydride sodium. The preferred reagent is literalized. Acceptable in this case the solvent include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferred solvent is tetrahydrofuran. The restoration is carried out at a temperature of from about 30 to about 100oC, preferably in the range from 65 to 70oC.

< in which

R2n and R11and R12have the above meaning,

when using phosphine and azodicarboxylate in a suitable solvent. Suitable for this purpose phosphines include trialkylphosphine and triarylphosphine, preferably triphenylphosphine. Suitable azodicarboxylate include diltiazemcream, preferably diethylazodicarboxylate. Applicable solvents include methylene chloride, ethers, including tetrahydrofuran, diethyl ether and 1,4-dioxane, N,N-dimethylformamide and acetonitrile. The most preferred solvent is tetrahydrofuran. The reaction is carried out at a temperature of from about 0 to about 65oC, most preferably about 25oC.

The compounds of formula VIII, if none are available, can be obtained by reaction of compounds of formula X:

< / BR>
in which R2and X have the above values,

with the acid chloride or symmetrical anhydride R12CO2H in a suitable solvent with a suitable base.

The preferred acid chloride or acid anhydride is triperoxonane anhydride. Suitable solvents include ethers, like tetrahydrofuran, diethyl ether and 1,4-Gioia include triethylamine, pyridine and sodium bicarbonate. The preferred base is pyridine. The reaction is conducted at temperatures from about 0 to about 65oC, preferably about 25oC.

If the compound of formula X is not available commercially, they can be obtained in the interaction of the compounds of formula XI:

< / BR>
where R2has these values,

either chlorine, bromine, or iodine in a suitable solvent, with a suitable base. The most preferred reaction with bromine. Suitable solvents include C1-6-alcohols, methylene chloride, chloroform, or carbon tetrachloride. The preferred solvent is methanol. Suitable bases include triethylamine, pyridine, sodium carbonate and sodium bicarbonate. The preferred base is acidic sodium carbonate. The reaction is carried out at a temperature of from about 0 to about 65oC, preferably about 25oC.

The compounds of formula IX can be obtained in the recovery process hydride compounds of the formula XII:

< / BR>
in which

R11has the above values, and

R13represents a C1-C6is alkyl, aryl or alkylaryl, hydride regenerating agent in an inert solvent. Pius and Diisobutyl-aluminiumhydride. The preferred reagent diisobutylaluminium-hydride. The preferred reagent diisobutylaluminium-hydride. Suitable for this purpose solvents include ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferred solvent is tetrahydrofuran. The restoration is carried out at a temperature of from about -100 to about 0oC, preferably in the range of from about -80 to about -70oC.

The compounds of formula XII can be obtained during the Wittig reaction in a suitable solvent, including compounds of formulas XIII and XIV:

< / BR>
in which R11and R13have the above values.

Suitable for this purpose, the solvent can be an ether such as diethyl ether, tetrahydrofuran and 1,4-dioxane. Most preferred as the solvent tetrahydrofuran. The reaction is carried out at a temperature of from about -78 to about 30oC, preferably about -78oC.

The compounds of formula XIII can be obtained in accordance with the data of S. Kiyooka al. J. Org. Chem. 5409 (1989) and Y. Hamada al. Chem. Pharm. Bull, 1921 (1982).

The compounds of formula XIV can be purchased or obtained in accordance with the data of L. Fieser and M. Fieser, reagents for organizes the above reactions is not critical. Usually the reactions are under pressure from 1 to 3 atmospheres, preferably ambient pressure (about 1 ATM).

The compounds of formula I which are basic in nature are capable of forming a large number of different salts with numerous inorganic and organic acids. Although such salts must be suitable for administration to animals (from the point of view of the pharmaceutical industry), it is often desirable to first isolate the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert it again into the free base by treatment with an alkaline reagent, and then to turn the free base in a pharmaceutically acceptable salt product accession acid. Salt accession acids the major compounds presented in this invention can easily be obtained by processing the primary connection equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent to obtain the desired solid salt.

The acid used to obtain formats what are those which form non-toxic salts accession acids, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)) by salt.

The compounds of formula I that are acidic in nature, i.e., those in which R2contains carboxylate, can form basic salts with various pharmacologically acceptable cations. As examples of such salts should be called salts of alkali and alkaline earth metals and, in particular, sodium and potassium salts. These salts are obtained from the use of traditional methods. Chemical bases that are commonly used as reagents to obtain pharmaceutically acceptable basic salts of the invention are those which form non-toxic basic salts described here, the acidic compounds of formula I. These non-toxic basic salts include salts derived from such pharmacologically acceptable cations as nanini aqueous solutions, containing the desired pharmaceutically acceptable cations, with subsequent evaporation of the resulting solution to dryness, preferably under reduced pressure. As an alternative, can be obtained also by mixing lower albanology solutions of the acidic compounds and alcoholate of an alkali metal with subsequent evaporation of the resulting solution to dryness by the same method. In any case, it is preferable to use stoichiometric amounts of reagents, which ensures the completeness of the reaction to obtain the maximum yield of the desired final product.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as the active compounds of the invention represent valuable psychotherapeutic tool, which is a strong agonist of serotonin (5-HTI), and can be used to treat depression, feelings of fear, metabolic disorders, obesity, improper medication, seizures, chronic headaches, migraines, headaches caused by vascular disorders, as well as bouts of chronic cranial changes, pain and other disorders caused by a deficiency serotonergic not the STV, acting on the Central nervous system.

Present invention the active compounds were characterized as anti-migraine when assessing the extent to which they like sumatriptan were able to cause a reduction in allocated saphenous vein of the dog (P. P. A. Humphrey al. Br. J. Pharmacol. 94, 1128 (1988)).

This effect managed to block with methiothepin, known antagonist serotonin. As you know, sumatriptan may be useful in the treatment of migraine and causes a selective increase in vascular resistance of the carotid artery in the dog under anesthesia. It was assumed (W. Fenwiek al. 96, 83 (1989)) that this is based on its effectiveness.

Compositions of the invention can be prepared according to traditional methods of using one or more of pharmaceutically acceptable carriers. Thus, the active compounds of the invention can be prepared for oral, cheek application, insertion through the nasal, parenteral (e.g. intravenous, intramuscular or subcutaneous administration) or rectal administration, as well as in a format suitable for insertion through ingestion and inhalation.

For oral administration the drug of applied pharmaceutical additives, such as connecting means (for example, pre-galatasarayfanpage corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate), lubrication (for example, magnesium stearate, talc or silica), disintegrators (e.g., potato starch, sodium glycolate-starch) or wetting agents (e.g. sodium lauryl sulfate). Tablets can be enclosed in the shell by known techniques. Liquid forms for oral administration can be prepared, for example, in the form of solutions, syrups or suspensions, or they may be a dry product that can be connected with water or other suitable for this purpose liquids immediately before use. Such liquid forms can be obtained by traditional means using acceptable pharmaceutical additives such as suspendresume means (for example, sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous liquid (for example, almond oil, oily esters or ethyl alcohol), and preservatives (e.g. methyl or prigotovleny in the form of tablets or lozenges, made by traditional methods.

Present invention the active compounds may be prepared for parenteral administration by injection, including using conventional methods through the catheter or intravenous injections. Formulations for injection can be made in the form of a single dosage form, e.g., in ampoules or mnogochasovykh containers, with the addition of preservatives. Compositions can be prepared in the form of suspensions, solutions or emulsions in oily or aqueous media containing suspendresume substances, stabilizers and/or dispersing agents. In another embodiment, the active ingredient may be in the form of powder to be converted before use, suitable for this purpose liquids, for example, sterilized, containing no pyrogen water.

Present invention the active compounds can also be prepared in the form of compositions for rectal application, such as suppositories or retention enemas, e.g. containing conventional suppozitornoj bases such as cocoa butter or other glycerides.

For insertion through the nose or inhalation present invention the active compounds are usually made eat when using a suitable propellant, for example, DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other gas. In the case of aerosol forms a single dose is a certain measured amount. In the vessel under pressure may contain a solution or suspension of the active compound. Capsule or shell (made, for example, from gelatin) for use in the inhaler or the apparatus for injection may contain a powdery mixture of compounds corresponding to the object of the invention and a suitable powder base, such as lactose or starch.

The proposed dose of the active compounds for oral, parenteral and hominids use for the average adult human for the treatment of the above diseases, for example, migraine is from 0.1 to 200 mg of active component on a single dose, which should be entered, for example, 1-4 times a day.

Aerosol formulations for treatment of the above diseases (e.g., migraine) for the average adult should be prepared so that each metered dose or "zilch" of aerosol contains from 20 to 1000 μg present invention compounds. The total daily dose is EP, 2, 3, 4, or 8 times, so that the patient received, for example, 1, 2 or 3 doses each time.

The following examples illustrate the formation of compounds provided by the invention. The melting point is given without amendment. These NMR inspectors are given in ppm and referenced locking signal deuterium from the solvent. The specific rotation was measured at room temperature using sodium line D (589 nm).

Commercially available reagents are used without further purification. Held chromatography analysis on a column when using 32-63 μm silica gel performed under nitrogen pressure (flash chromatography). Room temperature is 20-25oC.

Example 1. A common way to restore benzyloxy-carbonyl-pyrrolidin-2-ylcarbonyl-1H-indole, N-benzyloxy-carbonyl-azetidin-2-Ilker-bonyl-1H-indoles or N-benzoyloxy-carbonyl-piperidine-2-ilkar boil-1H-indoles. The formation of 3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indoles, 3-(N-methyl-azetidin-2-ylmethyl)-1H-indoles or 3-(N-methylpiperidin-2-ylmethyl)-1H-indoles, respectively.

To a stirred solution of (R)- or (S)-(N)-benzyloxy-carbonyl-pyrrolidin-2-ylcarbonyl)-1H-indole, (R)-, (S), or (R)-, (S)- or (R, S)-(N-benzyloxy is the atur in nitrogen atmosphere carefully add socialministeriet (0,57 g, 15.0 mmol, 3.0 EQ.) in powder form, and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h the mixture is Then boiled under reflux (66oC) in nitrogen atmosphere for 12 hours the Reaction is stopped by sequentially adding water (0.5 ml), aqueous sodium hydroxide (20% 0.5 ml) and again water (1.0 ml) and the resulting mixture is filtered through diatomaceous earth (trade name celite). Solids are washed with a large amount of ethyl acetate (50 ml). United after the filtrate washed with water (20 ml), dried (MgSO4), evaporated under reduced pressure. Then the residue is treated khromotograficheskie on a column of silica gel (50 g) and elute the appropriate solvent system, receiving 3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole, 3-(N-methylaziridine-2-ylmethyl)-1H-indole or 3-(N-methylpiperidin-2-ylmethyl)-1H-indole. This way we obtain the following connections:

A. (S)-5-methoxy-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole.

Use (S)-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-methoxy-1H-indole. Used khromatograficheskoi analysis of the eluent consisted of 8% triethylamine in ethyl acetate, resulting in the received specified in the header connection (output is 8.13 (Shir. C. 1H), 7.23 (d,J=8.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.97 (d,J=2.2 Hz, 1H), 6.84 (dd, J=2.4 and 8.8 Hz, 1H), 3.86 (s, 3H), 3.17 3.10 (m, 2H), 2.58 (dd, J= 9.9 and 13.9 Hz, 1H), 2.50 2.40 (m, 1H), 2.47 (s, 3H), 2.26 2.217 (m, 1H), 1.89 1.72 (m, 2H), 1.70 1.52 (m, 2H),13With NMR (CDCl3) 153.8, 131.4, 128.2, 122.7, 113.9, 111.8, 111.7, 101.1, 66.6, 57.5, 56.0, 40.8, 31.5, 30.0, 21.9, the mass spectrum of the low resolution. m/z (relative intensity) 244 (M+, 7), 160 (20), 145 (16), 117 (21), 84 (100), the mass spectrum of High quality. bit.

Calculated for C15H20N2O: 244.1563 Found: 244.1575, ()25-96oC (CHCl3, c=1.0).

C. (R)-5-methoxy-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole.

Used (R)-(N-benzyloxycarbonylamino-2-Ilker-bonyl)- -5-methoxy-1H-indole. As eluent was used by 8% triethylamine in ethyl acetate, thus obtaining specified in the title compound (yield ranged from 13 to 61%), in the form of oil, physical and chemical properties which were identical physical and chemical properties specified in the connection header shown in example 1A except for the specific rotation of the plane of polarization of light:()25 +100oC (CHCl3with 1.0), the mass spectrum of High quality. bit.

Calculated for C15H20N2O: 244, 1573. Found: 244,1547.

C. (R)-5-dibenzylamino-3-methylpyrrolidine-N-indole In the chromatographic processing on the column, elwira mixture of methylene chloride/methanol/ammonium hydroxide (9:150.1), get mentioned in the title compound as a pale green foam:1H NMR (CDCl3) 7.82 (sh. s, NH), 7.35-7.19 (m, 10H), 7.20 (d, J 8.6 Hz, 1H), 6.95 (d, J 2.1 Hz, 1H), 6.85 (dd, J 2.3 and 8.7 Hz, 1H), 6.80 (D, J 2.2 Hz, 1H), 4.65 (s, 4H), 3.25 3.02 (m, 2H), 2.52 (s, J 9.5 and 13.9 Hz, 1H), 2.39 2.15 (m, 2H), 2.30 (s, 3H), 1.85 1.40 (m, 4H),13With NMR (CDCl3d 143.2, 139.7, 130.5, 128.5, 128.2, 126.8, 122.9, 112.5, 112.2, 111.8, 103.4, 67.0, 57.4, 56.4, 40.6, 31.6, 31.4, 29.7, 21.9. The mass spectrum of High quality. bit.

Calculated for C28H31N3: 409.2520. Found: 409.2475.

D. (R)-5-methoxy-3-(N-methylpiperid-2-ylmethyl)-1H-indole.

Used (R)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-methoxy-1H-indole. In the chromatographic treatment on column elwira 6% triethylamine in ecigarette get mentioned in the title compound as a white foam:13With NMR (CDCl3), d 153.7, 131.4, 128.3, 123.3, 111.7, 111.6, 101.2, 64.4, 57.2, 55.9, 43.3, 31.0, 28.8, 25.9, 24.1, ()25+67oC (CDCl3with 1.0). The mass spectrum of High quality. bit.

Calculated for C16H22N2O: 258.1734. Found: 258.1710.

E. (S)-methoxy-3-(N-methylacetamide-2-ylmethyl)-1H-indole.

Used a solution of (S)-3-(N-benzyloxycarbonylamino-2- -ylcarbonyl)-5-methoxy-1H-indole. As the head of the compound in the form of a white solid product: So pl. 118 - 120.0oC, 13With NMR (CDCl3) 153.8, 131.6, 128.0, 122.9, 112.3, 111.0, 101.0, 68.5, 56.0, 53.1, 44.7, 32.4, 25.0, ()25-44oC (CHCl3, c 1.0).

Data analysis for C14H18N2O:

Calculated: C, 73.01; H, 7.01; N, 12.16.

Found: C, 72.65; H, 7.91; N, 12.06.

F. (R,S)-5-methoxy-3-(N-methylaziridine-2-ylmethyl)-1H-indole.

Used (R, S)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-methoxy-1H - indole. As eluent in chromatography treatment using 10% triethylamine in ethyl acetate, getting mentioned in the title compound as a solid product. So pl. 116-119.0oC.

Data analysis for C14H18N2O:

Calculated: C, 73.01; H, 7.88; N, 12.16.

Found: C, 72.61; H, 7.99; N, 12.10.

Example 2. General method for the hydrogenation of 5-(2-sulfonylamino)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indoles with formation of 5-(2-sulfonylated)-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indoles.

A solution of 5-(2-sulfonylamino)-3-(N-methylpyrrolidine-2-yl)-1H- -indole (0.47 mmol) and 10% palladium on coal (0.150 g) in ethanolic HCl (obtained from absolute ethanol (10 ml) and acetylchloride) (43 μl), and N,N-dimethylformamide (7.5 ml) is shaken in an atmosphere of hydrogen (1.05 kg/cm2) at room temperaturet), washed with absolute ethanol and the combined filtrates evaporated under reduced pressure. The residue was distributed between ethyl acetate and water. The organic phase was separated, washed with water (3x), brine solution (2x), dried (over sodium sulfate) and evaporated under reduced pressure to obtain a yellow oil. In khromatograficheskoi processing on a column of silica gel using as eluent a mixture of melancholia, absolute ethanol and ammonia, taken in the ratio (90:10:1) get the corresponding 5-(2-ethylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole. In accordance with the specified method are the following compounds:

A. (R)-5-(2-ethylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole.

(R)-5-TRANS-(2-ethicalpolitical)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (example 4A) restore as described above. In the chromatographic processing receive specified in the title compound (0.33 mmol), 70% resin; thin layer chromatography (CH2Cl2: EtOH:NH3, 90: 10:1): Rf0.3, ()25+62oC (methanol, 0.10).

Data analysis:

Calculated for C18H26N2O2S 0.05 CH2Cl
(R)-5-TRANS-(2-methylamidosulphate)-3-(N-methylpyrrolidine) -2-ylmethyl)-1H-indole (example 4B) restore as described above. In the chromatographic processing receive specified in the title compound (65%) as a foam.

The results of the analysis for C17H25N3O2S 0.1 CH2Cl2:

Calculated: C, 59.71; H, 7.39; N, 12.12.

Found: C, 59.66; H, 7.14; N, 11.90.

Example 3. The overall reaction for the synthesis of 3-(N-benzyloxycarbonylamino-2-yl-carbonyl)-1H-indoles, 3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-1H-indoles or 3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-1H-indoles

Two solutions containing the reagents were obtained separately according to the following procedure. To a stirred solution of N-carbobenzoxy (D or L, 3,10 g, 12.4 mmol) 1 EQ.) or N-carbobenzoxy-2-carboxylic acid (R or S or a racemate, 12.4 mmol) or N-corbamessagemediatorimpl acid (R or S racemate, 12.4 mmol) in anhydrous methylene chloride (7 ml) with the addition of one drop of dimethylformamide was added oxalicacid (1.69 ml, 18.4 mmol, 1.5 equiv.) and the resulting foam solution was stirred at room temperature under nitrogen atmosphere for 1.5 hours Then the solution is evaporated under reduced pressure shall orangered N-benzyl-oxcarbazepine. At the same time the solution ethylacetamide (3.0 M in ether, 4.13 ml, 12.4 mmol, 1 EQ.) was added to a stirred solution of indole (12.4 mmol) in anhydrous ether (50 ml) and the cloudy solution was boiled under reflux in nitrogen atmosphere for 1.5 hours to obtain the salt of indolalkylamine. Then the Proline acid chloride was dissolved in methylene chloride or ethyl ether (3 ml) and the resulting solution was added dropwise at room temperature to stir the salt solution indolalkylamine; and the resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 h To the reaction mixture were added a saturated solution of sodium bicarbonate and 50 ml of ethyl acetate, and the mixture was intensively stirred for 15 minutes the mixture was filtered through diatomaceous earth (trade name celite), the solid product was washed with excess amount of ethyl acetate, an ethyl acetate layer was separated from the aqueous layer, which was extracted with ethyl acetate (CH ml). All an ethyl acetate extracts were combined, dried and evaporated under reduced pressure. The remainder, representing a mixture of oil and solid product was treated with chromatographic instant evaporation on silica gel (250 g) using the one-2-ylcarbonyl)indole, 3-(N-2-ylcarbonyl)-1H-indole or 3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-1H-indole.

A. (S)-3-(N-benzoquinonemonoimine-2-ylcarbonyl)- -5-methoxy-1H-indole.

Used N-carbobenzoxy-L-Proline. In the chromatographic treatment using a gradient elution of 40% to 60% of ecigarette in hexano got mentioned in the title compound (yield ranged from 27% to 43%) as a white powder. After recrystallization from a mixture of ethyl acetate and hexanol received analytical sample which is a solid white crystalline product. So pl. 164.0 165.0oC, IR (KBr) 3250, 1695, 1660, 1585, 1520, 1485, 1450, 1425 cm-2,1H NMR (DCl3) (note: spectra specified in the connection header is 1:3 mixture of Desarollo, due to slow inversion amide nitrogen in the time scale of NMR. As a consequence,1H NMR can be interpreted for each connection separately, and redundant conformer is given first. (redundant conformer) 9.38 (Shir. S, 1H), 7.53 (d, J 3.4 Hz, 1H), 7.42 - 7.30 (m, 6H), 7.00 (d, J 8.9 Hz 1H), 6.69 (dd, J 2.4 and 9.0 Hz, 1H), 5.25 (d, J 12.9 Hz, 1H), 5.14 (d, J 12.5 Hz, 1H), 5.07 4.99 (m, 1P), 3.74 (c, 1H), 3.74 (c, 3H), 3.78 3.55 (m, 2H), 2.28 1.84 (m, 4H) and d (conformer which less) 9.28 (ECtHR, LRMS (relative intensity) 379 (8), 378 (M+, 33), 204 (31), 174 (64), 160 (41), 146 (10), 91 (100).

Data analysis for C22H22N2O4:

Calculated: C, 69.83; H, 5.86; N, 7.40.

Found C, 69.81; H, 5.67; N, 7.40.

B. (R)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-methoxy-1H- -indole.

Used N-carbonylations-D-Proline. Chromatographic treatment with gradient elution using 40-60% ethyl acetate in hexano, gave specified in the header connection (outputs ranged from 25 to 36%) as a white powder. After recrystallization from a mixture of ethyl acetate with hexane received analytical sample as a white crystalline product. So pl. 165-166.0oC. spectral Data analysis and physical characteristics specified in the title compound was identical with the corresponding data, it enantiomer (meaning specified in the title compound from example 3A). The data of the mass spectrum High. bit.

Calculated for C22H22N2O4: 378.1582. Found: 378.1573.

C. (R)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5 di-benzylamino-1H-indole.

Used N-carbobenzoxy-D-Proline. After careful blausee a solid product. So pl. 176.0-177.0oC, the mass spectrum of the low-resolution (m/z, relative intensity) 543 (1000, M+), 453 (10), 407 (7), 339 (40), 307 (10), 247 (10), 154 (38), ()25+112o(tetrahydrofuran, 1.0).

Data analysis for C35H33N3O3:

Calculated: C, 77.32; H, 6.12; N, 7.73

Found: C, 77.35; H, 6.30; N, 7.66

D. (R)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-methoxy- -1H-indole.

Used N-carbobenzoxy-D-pipecolinic acid. In the chromatographic processing by elution with 10% ether in methylene chloride has been specified in the title compound in the form of yellowish-brown foam: Mass spectrum of the low resolution LRMS (m/z, relative intensity), 392 (90, M+), 348 (27), 284 (13), 273 (12), 258 (15), 237 (47), 217 (58), 173 (100). Data mass spectrum:

Calculated for C35H33N3O2: C, 69.22; H, 5.53; N, 7.69.

Found: C, 69.35; H, 5.33; N, 7.64

E. (S)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5- -methoxy-IH-indole.

Used (S)-N-carbobenzoxy-2-carboxylic acid. Thorough trituration of the residue from extraction with absolute methanol receive specified in the title compound, which represents a white solid product. So pl. 199.0-200.0

Found: C, 69.35; H, 5.33; N, 7.64.

F. (R, S)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5- -methoxy-IH-indole.

Used (R, S)-carbobenzoxy-2-carboxylic acid. Thorough trituration of the residue after extraction with absolute methanol receive specified in the title compound, which are solid white product. So pl. 199.0-200.0oC.

Data analysis for C21H20N2O4:

Calculated: C, 69.22; H, 5.53; N, 7.69.

Found: C, 68.65; H, 5.47; N, 7.57.

Example 4. A common way of obtaining (synthesis) 5-TRANS-(2-sulfonylamino)-3-(N-methylpyrrolidine-2-ylmethyl)- -1H-indoles.

A mixture of the corresponding vinylsulfonic (1.17 mmol, 1.4 equiv.) three-ortho-tolylphosphino (0.075 g 0.25 mmol, 0.33 equiv.) of palladium acetate (11) (0.013 g), triethylamine (0.25 ml, 1.79 mmol, 2 EQ.) and (R)-5-bromo-3-(N-methylpyrrolidinyl-methyl)-1H-indole (0.25 g, 0.85 mmol) in anhydrous acetonitrile (3 ml) was boiled under reflux in nitrogen atmosphere for 17 hours the reaction mixture is evaporated under reduced pressure, and the residue was treated on a chromatographic column with silica gel elwira a mixture of methylene chloride/absolute ethanol/ammonia (90: 8: 1), getting - 2-limeter)-1H-indole.

Used ethylvanillin. In the chromatographic processing has been specified in the title compound (65%) as a white foam: thin layer chromatography using a mixture of (CH2Cl2/EtOH/NH3in the ratio 90: 10:1): gave Rf0.5

The results of the analysis for C18H24N2O2S 0.2 CH2Cl2:

Calculated: C 62.55; H, 7.04; N, 8.02.

Found: C, 62.65; H, 6.94; N, 7.92.

B. (R)-5-TRANS-(2-methylamidosulphate)-3-(N-methyl-Pirro - lidin-2-ylmethyl)-1H-indole.

Used N-methylphenylsulfonyl. In the chromatographic analysis has been specified in the title compound (71%) as a white foam.

The results of the analysis for C17H23N3O2S 0.1 CH2C12:

Calculated: C, 60.06; H, 6.84; N, 12.29.

Found: C, 59.74; H, 6.77; N, 11.97.

Example 5. A common way to restore hydride 3-(N-benzyloxycarbonyl-pyrrolidin-2-ylmethyl)-N-indoles and 3-(N-benzylic-skarbimierz-2-ylmethyl)-1H-indoles. The formation of 3-(N-methylpyrrolidine-2-ylmethyl)-1H-indoles and 3-(N-methyl-piperid-2-ylmethyl)-1H-indoles.

To a stirred mixture of sociallyengaged (0.152 g, 4.00 mmol, 2 EQ. ) in anhydrous tetrahydrofuran (10 ml) quickly mobstability-2-ylmethyl)-1H-indole (2.00 mmole) in anhydrous tetrahydrofuran (5 ml). The resulting mixture was boiled under reflux in nitrogen atmosphere for 3 h Then the reaction mixture was cooled and successively added water (0.25 ml), 15% aqueous sodium hydroxide solution (0.25 ml) and again water in larger quantities (0.75 ml). The resulting mixture was stirred at 25oC for 30 min, filtered, then the filtrate is evaporated under reduced pressure. The residue was treated on a chromatographic column with silica gel (approximately 50 g), using as eluent a solution of methylene chloride:methanol:ammonium hydroxide in the ratio (9: 1:0.1) or other appropriate solvent system to obtain the corresponding 3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole or 3-(N-methylpiperid-2-ylmethyl)-1H-indole.

In accordance with this method were obtained the following compounds:

A. (R)-5-(methylaminoethanol)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

Used (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-(methylaminoethanol)-1H-indole. Obtained after processing water according to the above method, the residue is triturated with absolute methanol, was obtained when this is mentioned in the title compound in the form of a solid white product. So pl. 213.0-214.0o25+89oC (dimethylsulfoxide- 61.0).

Data analysis for C16H23N3SO2:

Calculated: 59.79; H, 7.21; N, 13.07.

Found: C, 59.66; H, 7.29; N, 12.81.

B. (R)-5-aminomethyl-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

Used (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl-5-cyano-1H-indole. In the chromatographic treatment on column elwira a mixture of 9:1:0.1 methylene chloride/methanol/ammonium hydroxide has been specified in the title compound as a white foam:13C NMR 135.6, 132.3, 127.5, 123.0, 122.8, 121.4, 117.1, 112.8, 111.5, 66.8, 57.2, 46.4, 40.5, 31.2, 29.2, 21.5. Mass spectrum: high-resolution.

Data analysis for C15H21N3:

Calculated: 243.1737. Found: 243.1732.

C. (R, S)-5-(methylaminoethanol)-3-(N-methylpiperid-2-ylmethyl)-1H-indole.

Used (R, S)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-(methylaminomethyl)-1H-indole. In the chromatographic processing column, elwira 10% triethylamine in ethyl acetate, was obtained is listed in the title compound as a clear colorless oil: 13C NMR (dim the m/z, relative intensity) 336 (1, M+), 241 (5), 143 (31), 142 (13), 99 (34), 98 (100), 70 (16). The mass spectrum of the high-resolution C17H25N3O2S:

Calculated: 336.1745. Found: 336.1756.

Example 6. A common way catalytic reduction of 3-(N-Benzino-xturboservice-2-ylmethyl)-1H-indoles and 3-(N-benzyl-oxycarbonyl-2-ylmethyl)-1H-indoles. Obtaining 3-(pyrrolidin-2-ylmethyl)-1H-indoles and 3-(piperid-2-ylmethyl)-1H-indoles

A mixture of 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole or 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole (2.00 mmole), 10% palladium on coal (0.20 g) and ammonium formate (1.26 g, 20 mmol, 10 EQ.) in absolute ethanol (15 ml) was stirred under nitrogen atmosphere for 4 hours the reaction mixture was filtered through a hard-shelled land, and the filtrate evaporated under reduced pressure. The residue was treated on a chromatographic column with silica gel (approximately 50 g), elwira mixture of methylene chloride/methanol and ammonium hydroxide ( 8:2:0.2 ) or other appropriate solvent system, while receiving, respectively, 3-(pyrrolidin-2-ylmethyl)-1H-indole or 3-(piperid-2-ylmethyl)-1H-indole.

When using this technique were obtained the following compounds is carbonitriding-2-ylmethyl)-5-(methylaminoethanol)-1H-indole. After the above processing on the chromatography column has been specified in the title compound as off-white resinous substance:13C NMR (dimethylsulfoxide- ) a6) 135.9, 127.5, 123.8, 123.7, 120.9, 119.7, 112.4, 111.1, 59.2, 56.6, 45.7, 31.1, 31,0, 29.0, 24.6, ()25+4o(dimethylsulfoxide-61.0),()25 -14o(EtOH/CHCl3(1:1), 1.0). The mass spectrum of the high-resolution C15H21N3O2SH+:

Calculated: 308.1433. Found: 308.1467.

C. (R)-5-cyano-3-(pyrrolidin-2-ylmethyl)-IH-indole

Used (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-cyano-IH-indole. After the previously described processing of the chromatographic column has been specified in the title compound as off-white resinous substance:13C NMR (CDCl3/CD3OD) 138.1, 127.2, 125.0, 124.4, 124.2, 113.4, 112.2, 101.5, 59.5, 50.1, 45.7, 31.3, 30.3, 24.7, the mass spectrum of the low-resolution (M/z, relative intensity) 225 (M+, 3), 179 (3), 155 (10), 70 (100), the mass spectrum of high resolution for C14H15N3:

Calculated: 225.1268. Found: 225.1245.

C. (R)-3-(pyrrolidin-2-ylmethyl)-IH-indole.

Used (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-IH-indole. The residue after evaporation of the filtrate gives specified in IH), 7.12 6.98 (m, 2H), 6.90 (s, 1H), 4.0 (br s, Amin NH), 3.36-3.24 (m, 1H), 2.95-2.75 (m, 3H), 2.70-2.58 (m, 1H), 1.85-1.50 (m, 3H), 1.45-1.29 (m, 1H), ()25+18o(CHCl3with 1.0).

D. (R)-methoxy-3-(pyrrolidin-2-ylmethyl)-1H-indole.

Used (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-methoxy-1H-indole. The residue after evaporation of the filtrate gives specified in the title compound in the form of resinous substances: Mass spectrum (low resolution) (m/z, relative intensity) 231 (100, M+), 161 (10), 155 (17), 135 (11), 119 (32), ()25-12o(CHCl3with 1.0).

The results of the analysis for C14H18N2O C2H4O2(salt of acetic acid):

Calculated: C, 67.61; H, 7.69; N, 10.17.

Found: C, 67.74; H, 7.53; N, 9.90.

E. (R, S)-5-(methylaminomethyl)-3-(piperid-2-ylmethyl)- -1H-indole.

Used (R, S)-3-(N-benzyloxycarbonylamino-2-ylmethyl) -5-(methylaminoethanol)-1H-indole. After processing the chromatographic column by the above method has been specified in the title compound, which represents a clear, colorless oil: 13C NMR (dimethylsulfoxide-6) 136.0, 127.5, 124.2, 123.8, 121.0, 119.8, 110.9, 56.8, 56.7, 45.8, 31.4, 29.0, 23.9, Mass spectrum (low resolution) (m/z, relative intensity)SUB>O2S: 321.1513. Found: 321.1501.

Example 7. General method for the preparation of 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indoles and 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indoles catalyzed by palladium cyclization of 1-(N-benzyloxycarbonylamino-yl)-3-(N-(2-gpointer)-N - triptoreline and 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-haloethanol)-N - triptoreline)-propanol

A mixture of 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-halophenol)-N-triptoreline)-propene or 1-(N-benzyl-oxycarbonyl-2-yl)-3-(N-(2-halophenol)-N - TRIFLUOROACETYL-amino)-propene (2.00 mmol) of tetrabutylammonium (2.00 mmol) and palladium acetate (11) (0.089 g, 0.40 mmol, 0.2 EQ. ) in a solution of triethylamine (8 ml) and anhydrous N,N-dimethylformamide (4 ml) was boiled under reflux in nitrogen atmosphere for 2 h the resulting mixture was evaporated under reduced pressure, and the residue was distributed between ethyl acetate (25 ml) and water (25 ml). An ethyl acetate layer was removed, and the aqueous layer was extracted with additional ethyl acetate (25 ml). The organic extracts were combined, dried using magnesium sulfate and evaporated under reduced pressure. The residue was treated on the chromatographic column C is economy gradient in methylene chloride with obtaining, accordingly, 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole or 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole.

In accordance with the above method were obtained the following compounds.

A. (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole

Used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3- (N-(2-todefine)-N-TRIFLUOROACETYL-amino)propene. As a result of processing on the chromatographic column has been specified in the title compound in the form of a clear, brown oil:1H NMR (CDCl3) d 8.05 (Shir. s, indole NH), 7.49 7.34 (m, 7H), 7.17 (Shir. t, 1H), 7.02 (Shir. s, 1H), 6.95 (Shir. s, 1H), 5.24 (s, 2H), 4.28-4.14 (Shir. m, 1H), 3.52 3.41 (m, 2H), 3.28 (Shir. d, 1H), 2.79-2.63 (m, 1H), 1.90-1.70 (m, 4H), Mass spectrum (low resolution) (m/z, relative intensity). 334 (10, M+), 204 (16), 160 (39), 130(39), 91 (100).

B. (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-(methyl - aminosulphonylphenyl)-1H-indole

Used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N- (2-bromo-4-methylaminoacetaldehyde)-N-TRIFLUOROACETYL-amino)- propene. After processing the chromatographic column has been specified in the title compound as off-white foam: IR(CHCl3), 1673, 1410, 1358, 1324, 1118, 1092 cm-1, Mass spectrum (low resolution) for C13H27N3O4S:

Calculated: 441.1724. Found: 441.1704.

C. (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl-5-cyano-1H - indole.

Used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N- (2-bromo-4-tianfeng)-N-triptoreline)-propene. After processing the chromatographic column has been specified in the header of the product as a white foam: IR (1% solution in CHCl3), 2215, 1687 cm -113C NMR (note: due to slow nitrogen inversion in the NMR spectrum shows two of conformer product) (CDCl1d 155.1, 137.9, 137.0, 128.8, 128.5, 128.4, 128.0, 127.8, 124.9, 124.6, 121.0, 114.0, 113.9, 112.1, 102.3, 67.2, 66.7, 58.5, 57.6, 47.0, 46.7, 30.3, 30.0, 29.6, 28.8, 23.6, 22.7.

Data analysis for C22H21N3O20.25 C2H4O2(acetic acid):

Calculated: C, 72.17; H, 5.92; N, 11.22.

Found: C, 72.28; H, 5.76; N, 10.95.

D. (R, S)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-(methyl - aminosulphonylphenyl)-1H-indole.

Used (R, S)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N- (2-bromo-4-methylaminomethyl-were)-N-triptoreline)- propene. After processing the chromatographic column has been specified in the title compound in the form of foam off-white colors: 13With NMR (note: due to the slow is 66.8, 57.4, 39.5, 36.5, 31.4, 29.8, 25.8, 25.5, 18.8, Mass spectrum (low resolution) (M/z, relative intensity), 445 (5, M+), 361 (4), 238 (40), 218 (80), 174 (100), 143 (53), mass spectrum (high resolution).

Calculated for C24H29N3O4S: 455.1880. Found: 455.1899.

Example 8. (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl) -5-methoxy-1H-indole

To a stirred mixture of literalized (0.092 g, 4.22 mmol, 2 EQ.) in anhydrous tetrahydrofuran (5 ml) at 0oC was added a solution of (R)-3-(N-benzyloxycarbonylamino-2-yl-carbonyl)-5 - methoxy-1H-indole (0.89 g, 2.11 mmole) in anhydrous tetrahydrofurane (8 ml). The resulting mixture was heated at boiling under reflux in nitrogen atmosphere for 1 h, the Reaction mixture was cooled, carefully added water (1 ml) and then ethyl acetate (20 ml). The resulting mixture was stirred at room temperature for 30 min, dried using magnesium sulfate, filtered through the hard-shelled land, after which the filtrate is evaporated under reduced pressure. The residue was treated on a chromatographic column with silica gel (approximately 50 g). As eluent was used a mixture of ethyl acetate/hexanol (1:1). Received (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl)-5-methoxy-1H-indole in the Xia two conformer product) (CDCl3d 162.5, 136.9, 136.2, 128.4, 127.8, 127.6, 124.5, 123.3, 120.8, 120.3, 111.5, 66.8, 57.4, 39.5, 36.5, 31.4, 29.8, 25.8, 25.5, 18.8, mass spectrum (low resolution) (m/z, relative intensity) 364 (30, M+), 204 (17), 160 (92), 145 (17), 117 (13), 91 (100).

Data analysis for C22H24N2O30.5 H2O:

Calculated: 70.76; H, 6.75; N, 7.50.

Found: C, 70.70; H, 6.94; N, 7.15.

Example 9. A common way to obtain 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-haloethanol)-N - triptoreline)-propanol and 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-halo-ethenyl)-N-triptoreline)-propenol of 2-halogen-N-triptoreline obtained by the reaction of a combination of Mitsunobu, 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropane or 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropane.

To stir a mixture of 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropane or 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxy-propene (R, S or racemate 2.00 mmole), 2-halogen - N-triptorelin (2.5 mmol, 1.25 EQ. and triphenyl-phosphine (0.655 g, 2.50 mmol, 1.25 EQ.) in anhydrous tetrahydrofuran at 0oC in an atmosphere of nitrogen was added dropwise diethyl-azodicarboxylate (0.39 ml, 2.48 mmol, 1.25 EQ.). The reaction solution was slowly heated to 25oC in the Techa is evaporated under reduced pressure, and the residue was treated on a chromatographic column with silica gel (approximately 50 g). As eluent used a gradient of diethyl ether in hexano, or the gradient of ethyl acetate in hexano, while receiving, respectively, 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-haloethanol)-N - triptoreline)-propene or 1-(N-benzyloxycarbonylamino-2-yl)- 3-(N-(2-haloethanol)-N-triptoreline)propene.

In accordance with the specified method were obtained the following compounds:

A. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2 - iodophenyl)-N-triptoreline)-propene.

Used ()-1-(N-benzyloxycarbonylamino-2-yl)- 3-hydroxypropane and 2-iodine-N-cryptanalytically. After processing the chromatographic column has been specified in the title compound as a clear, colorless oil1H NMR (CDCl3) d 7.88 (Shir. d, 1H), 7.43 0 6.89 (m, 10H), 5.70 5.35 (m, 2H), 5.13 (Shir. s, 2H), 5.00 4.75 (m, 1H), 4.40 4.29 (m, 1H), 3.60 3.42 (m, 3H), 2.05 1.45 (m, 4H). Mass spectrum (low resolution) (m/z, relative intensity) 559 (100, (MH)+), 515 (52), 451 (15), 244 (7).

B. (R)-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-bromo-4 - methylaminoacetaldehyde)-N-triptoreline)-propene.

Used (R)-1-is in. After chromatographic processing on a column using as eluent a 4% acetone in methylene chloride, was obtained is listed in the title compound as a white foam (44% ): FAB mass spectrum (m/z, relative intensity) 620 (MH+c81Br), 618 (MN+with79Br), 576 (50), 574 (63), 512 (17), 484 (33).

C. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-bromo - 4-cyanophenyl)-N-triptoreline.

Used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3 - hydroxypropane and 2-bromo-4-cyano-N-triptorelin. After processing through column chromatography using gradient elution diethyl ether (5-100% ) in methylene chloride has been specified in the title compound as a clear colorless oil: IR (CDCl3) 2231, 1702, 1157 cm-1. Mass spectrum (low resolution) (m/z, relative intensity) 537 (MP+with81Br), 13), 535 ((MH+c79Br), 13), 402 (29), 400 (30), 294 (55), 292 (57), 244 (80), 213 (89), 91 (100).

Data analysis for C24BrF3H21N3O30.2 H2O:

Calculated: C, 53.39; H, 3.99; N, 7.78.

Found: C, 53.25; H, 3.95; N, 7.98.

D. (R, S)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-bromo - 4-methylaminoacetaldehyde)-N-triptoreline)-propene.

+with81Br), 26), 632 ((MH+with79Br), 22), 590 (35), 588 (43), 401 (33), 327 (48), 281 (75), 207 (90), 147 (100), FAB Mass spectrum low resolution:

Calculated for C26H29BrF3N3O5S, (H+632.1043). Found: 632.1047 (79Br and32S).

Example 10. General method of synthesis of 2-halogen-N-triptorelin in the reaction of 2-golodaniya and triperoxonane anhydride

To mix the solution golodaniya (2.00 mmol) and pyridine (0.18 ml, 2.22 mmol, 1.1 EQ.) in anhydrous methylene chloride (10 ml) at a temperature of 0oC in an atmosphere of nitrogen was added dropwise triperoxonane anhydride (0.31 ml, 2.19 mmol, 1.1 EQ.). The resulting reaction mixture was stirred at 0oC in nitrogen atmosphere for 3 hours was Added a saturated solution of sodium bicarbonate (15 ml), and this aqueous mixture was extracted with ethyl acetate (3 x 15 ml). The extracts were combined, dried over magnesium sulfate and evaporated under vacuum. The residue was treated on a chromatographic column with silica gel (approximately 50 g). As ouentin.

Using this technique were obtained the following compounds.

A. 2-iodine-N-triptorelin.

Used 1-iodoaniline. After evaporation of an ethyl acetate extracts were obtained is indicated in the title compound as a white solid (directly). So pl. 105.0-106.5oC FAB mass spectrum (low resolution) (m/z, relative intensity). 316 ((MH+), 8), 155 (80), 135 (26), 119 (100),13C NMR (acetone - a6), 206.2, 140.4, 130.2, 130.1, 128.2.

B. 2-bromo-4-methylaminoethanol-N-triptorelin

Used 2-bromo-4-methylaminoanthraquinone. The evaporation of an ethyl acetate extracts gave directly specified in the title compound in the form of solids. So pl. 164.0-166.0oC.

Data analysis for C10H10BrF3N2O3S:

Calculated: C 32.02; H, 2.69; N, 7.47.

Found: C 32.18; H, 2.67; N, 7.30.

C. 2-bromo-4-cyano-N-triptorelin.

Used 2-bromo-4-aminocarbonylmethyl. During this reaction also occurred dehydration of the carboxamide. As a result of processing through column chromatography using as eluent a mixture of acetate with hexane has been specified in the header of the connection is .2 Hz), 7.71 (d, J 8.2 Hz, 1H).

Example 11. A common way of synthesized anilines with obtaining 2-bromo-anilines

To a stirred solution of aniline (2.00 mmol) and sodium bicarbonate (0.21 g, 2.50 mmol, 1.25 EQ.) in methanol (10 ml) at 0oC was added dropwise bromine (0.113 ml, 2.19 mmol, 1.1 EQ.). The resulting reaction mixture was stirred at 25oC for 30 minutes the mixture is Then evaporated under reduced pressure and the resulting residue was placed in a saturated solution of sodium bicarbonate (10 ml). The aqueous mixture was extracted with ethyl acetate (3 x 15 ml). The extracts were combined together, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to processing through column chromatography with silica gel (approximately 50 g). As eluent used a suitable solvent system, while receiving the corresponding 2-bromaniline.

By this technique were obtained the following compounds:

A. 2-bromo-4-methylaminoanthraquinone.

Used 4-methylaminoanthraquinone (M. D. Dowle, and researcher. Eur. Pat. App1, EP 225, 726).As a result of processing through column chromatography using as an eluent of 40% ethyl acetate in hexano has been specified in the header of the connection in view of the UB>O2S:

Calculated: C 34.42; H, 3.97; N, 10.04.

Found: C, 34.66; H, 3.96; N, 9.96.

B. 4-aminocarbonyl-2-bromaniline.

Used 4-aminobenzamide. As a result of processing through column chromatography with gradient elution by ethyl acetate (20 to 50%) in methylene chloride has been specified in the title compound in the form of a solid white product: So pl. 144.5-146.0oC.1H NMR (DMSO-d6) d 7.93 (d, J 2.0 Hz, 1H), 7.70 (Shir. s, amide NH), 7.62 (DD, J 2.0 and 8.5 Hz, 1H), 7.05 (Shir. s, amide NH), 6.77 (d, J 8.5 Hz, 1H), 5.85 (s, aniline, NH2).

Example 12. 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan or 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan

To a solution of either 3-(N-benzyloxycarbonylamino-2-yl-2-propenoate or ethyl-3-(N-benzyloxycarbonylamino-2-yl)-2 of propenoate (R or S, or racemate, 10.00 mmole) in anhydrous tetrahydrofuran (75 ml) under stirring at -78oC in an atmosphere of nitrogen was added dropwise a solution of diisobutylaluminium (1.0 M in hexano, 12.0 mmol, 2.2 EQ.). The resulting solution was stirred at -78oC in nitrogen atmosphere for 30 minutes, the Reaction solution was then allowed to warm to room temperature over 2 h, then was added a saturated solution of Bica is on magnesium sulfate and evaporated under reduced pressure. After processing through column chromatography using as eluent a mixture of diethyl ether with hexane (1:1) has been specified in the header of the connection, respectively, or 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan or 1-(N-benzyloxycarbonyl-piperid-2-yl)-3-hydroxypropan.

In accordance with the above method were obtained the following compounds:

A. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan.

Used (R)-ethyl-3-(N-benzyloxycarbonylamino-2-yl)-2-propenoate. After chromatographic treatment of the residue after extraction was obtained a clear, colorless oil:1H NMR (CDCl3) d 7.40 7.25 (m, 5H), 5.75 - 5.53 (m, 2H), 5.20 5.00 (m, 2H), 4.38 (Shir. m, 1H), 4.06 (Shir. d, J 13.7 Hz, 2H), 3.45 (Shir. t, J 7.0 Hz, 1H), 2.03 1.68 (m, 4H), ()25+34o(MeOH, 1.0), mass spectrum (high resolution).

Calculated for C15H19NO3: 261.1365. Found: 261.1356

B. (R, S)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan

Used (R, S)-ethyl-3-(N-benzyloxycarbonylamino-2-yl)-2 - propenoate. After chromatographic processing residue from extraction has received the above compound in the form of a clear, colorless oil: mass spectrum (low resolution is 0 (m, 5H), 5.70 5.61 (m, 2H), 5.14 (d, J 17.6 Hz, 1H), 5.10 (d, J 17.5 Hz, 1H), 4.88 (Shir. m, 1H), 4.14 4.00 (m, 3H), 2.91 (Shir. t, J 12.7 Hz, 1H), 1.78 1.47 (m, 6N).

Data analysis for C16H21NO30.1 H2O:

Calculated: 69.34; H, 7.71; N, 5.05.

Found: C, 69.38; H, 7.84; N, 5.16.

Example 13. Synthesis of ethyl-3-(N-benzyloxycarbonylamino-2-yl)- 2-propenoate or ethyl-3-(N-benzyloxycarbonylamino-2-yl)-2-propenoate.

To a solution of N-carbobenzoxy-2-carboxaldehyde or N-carbobenzoxy-2-carboxaldehyde (5.000 mmol) (S. Kiyooka, and researcher. J. Org. Chem. 5409 (1989) and Y. Hamada, and researcher. Chem. Pharm. Bull. 1921 (1982)) in anhydrous tetrahydrofuran under stirring at -78oC was added (carletonville)triphenylphosphane (2.09 g, 6.00 mmol, 1.2 EQ.). The addition was made portions solids. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h, then was heated to boiling under reflux in a nitrogen atmosphere and was heated at this temperature for 1 h the reaction mixture is evaporated under reduced pressure, and the residue was treated on a chromatographic column with silica gel ( approximately 100 g). As eluent used 20% diethyl ether in hexano while the oat.

A. (R)-ethyl-3-(N-benzyloxycarbonylamino-2-yl)-2-propenoate

Used (R)-N-carbobenzoxy-2-carboxyl-digid. After chromatographic processing method described above has been specified in the title compound as a clear, colorless oil:1H NMR (CDCl3-d6) d 7.34 7.25 (m, 5H), 6.89 6.76 (m, 1H), 5.18 - 5.05 (m, 2H), 4.60 4.43 (m, 1H), 4.17 (q, J 7.1 Hz, 2H), 3.55 3.40 (m, 2H), 2.11 2.00 (m, 1H), 1.90 1.75 (m, 3H), 1.28 (t, J 7.1 Hz, 3H),13With NMR (CDCl3) (note: due to slow nitrogen inversion in the NMR spectrum shows two of conformer products). d 166.3, 154.7, 147.9, 136.6, 128.4, 127.9, 120.9, 66.9, 65.8, 60.4, 58.1, 57.7, 46.8, 46.4, 31.6, 30.8, 23.6, 22.8, 22.6, 15.3, 14.2

B. (R, S)-ethyl 3-(N-benzyloxycarbonylamino-2-yl)-2-propenoate

Used (R, S)-carbobenzoxy-2-carboxaldehyde. After chromatographic processing by the above method has been specified in the title compound as a clear, colorless oil:1H NMR (CDCl3-d6), 7.36 7.27 (m, 5H), 6.85 (DD, J 4.4 and 16.3 Hz, 1H), 5.80 (DD, J 2.4 and 16.3 Hz, 1H), 5.11 (s, 2H), 5.01 (Shir. m, 1H), 4.17 (q, J 6.7 Hz, 2H), 4.05 (Shir. d, J 12.6 Hz, 1H), 2.87 (Shir. t, 1H), 1.80 1.35 (m, 6N), 1.27 (t, J 6.6 Hz, 3H), FAB mass spectrum (m/z, relative intensity) 318 (MP+), 100), 274 (86), 228 (14), 210 (21), 182 (43), 138 (32).

Example 14. (R)-5-amino-3-(N-Meile is kookie palladium (11) coal (0.6 g) in dehydrated (ethanol) (25 ml) was vigorously shaken in a nitrogen atmosphere (3 ATM) at 40oC for 4 h the mixture was filtered through a hard-shelled land, and the filtrate is evaporated under pressure to get specified the title compound (0.60 g, 2.62 mmol), 99% ) as a white foam:1H NMR (DMSO-d6). d 10.65 (Shir. s, NH), 7.14 (d, J 2.2 Hz, 1H), 7.12(d, J 8.6 Hz, 1H), 6.85 (d, J 1.6 Hz, 1H), 6.60 (DD, J 2.0 and 8.6 Hz, 1H), 3.63 2.83 (m, 7H), 2.78 (s, 3H), 2.05 1.67 (m, 4H), ()25+9o(Mean 1.0), mass spectrum (high resolution):

Calculated for C14H19N3:229.1575. Found: 229.1593.

Example 15. General method for synthesis of 5-carbylamine-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indoles and 5-sulfonylamino-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indoles

To a solution of (R)-5-amino-3-(N-methylpyrrolidine-2-ylmethyl)-indole (0.229 g, 1.00 mmol) and triethylamine (0.21 ml, 1.5 mmol, 1.5 EQ.) in anhydrous acetonitrile (3 ml) at 0oin an atmosphere of nitrogen was added respectively carbonylchloride or sulphonylchloride (1.5 mmol, 1.5 EQ.). The resulting mixture was stirred at room temperature for 12 hours Then the reaction mixture is evaporated under reduced pressure and the resulting residue was treated on a chromatographic column with silica gel (approximately 25 g). As the eluent used in the appropriate solvent system. Received, respectively, 5-HP

In accordance with this methodology yielded the following compounds:

A. (R)-5-benzyloxycarbonylamino-3-(N-methyl-pyrrolidin-2-yl - methyl)-1H-indole

Used benzylchloride. After chromatographic processing on a column using as eluent a mixture of triethylamine/acetone/ethyl acetate (2: 10:88) has been specified in the title compound as off-white foam:13With NMR (CDCl3) 163.3, 136.4, 133.6, 129.8, 128.2, 127.9, 126.0, 123.2, 113.8, 111.4, 110.1, 66.8, 66.5, 57.5, 40.8, 31.5, 29.8, 21.8, Mass spectrum (m/z, relative intensity) 363 (M+, 12), 279 (7), 184 (7), 171 (33), 108 (100), Mass spectrum (high resolution):

Calculated for C22H25N3O20.4 C4H8O4(ethyl acetate): C, 71.09; H, 7.13; N, 10.54.

Found: C, 70.82; H, 7.03; N, 10.58.

B. (R)-3-(N-methylpyrrolidine-2-ylmethyl)-5-methylsulfanyl)-1H - indole

Used methanesulfonanilide. After chromatographic processing on a column using as eluent a mixture of triethylamine/acetone/ethyl acetate (1:3:6) has been specified in the title compound as a white foam:13With NMR (CDCl3d 134.9, 128.3, 128.2, 123.6, 119.3, 115.0, 113.9, 112.0, 66.7, 57.3, 40.7, 38.7, 31.3, 29.4, 21.7 Mass spectrum (high resolution):

Calculated for C15H21N3O213With NMR (acetone-d6d 168.3, 134.4, 132.2, 128.7, 124.1, 115.7, 113.8, 111.6, 110.2, 67.3, 58.0, 40.9, 31.9, 30.5, 24.1, 22.5, mass spectrum (low resolution): (m/z, relative intensity), 271 (M+, 39), 241 (4), 207 (5), 187 (20), 144 (20), 84 (100). Mass spectrum (high resolution):

Calculated for C16H21N3O: 271.1686. Found: 271.1693.

Data analysis for C16H21N3O 1.15 H2O:

Calculated: C At 65.80; H, 8.04; N, 14.39.

Found: C, 65.99; H, 7.90; N, 13.99.

D. (R)-5-N, N-dimethylaminocarbonylmethyl-3-(N-methyl-pyrrolidin - 2-ylmethyl)-1H-indole

Used dimethylcarbamate. After processing through column chromatography using as eluent a mixture of methylene chloride/methanol/ammonium hydroxide (9 1 0.1) has been specified in the title compound as off-white foam:1H NMR (CDCl3d 8.95 (Shir. s, 1H), 7.49 (Shir. s, 1H), 7.15 7.06 (m, 2H), 6.82 (d, J + 1.9 Hz, 1H), 6.44 (Shir. s, 1H), 3.12 3.05 (m, 2H), 3.00 (s, 6N), 2.58 2.40 (m, 2H), 2.40 (s, 3H), 2.18 (Shir. kV, J 8.1 Hz, 1H), 1.83 1.47 (m, 4H,13With NMR (CDCl3d 157.2, 133.8, 130.5, 127.7, 123.2, 117.8, 113.0, 112.0, 111.3, 66.5, 57.4, 40.6, 36.4, 31.4, 29.8, 21.7, � (high-resolution):

Calculated for C17H24N4O: 300.1952. Found: 300.1957.

E. (R)-5-triptorelin-3-(N-methylpyrrolidine-2-ylmethyl)- 1H-indole

Used triperoxonane anhydride. After chromatographic processing on a column using as eluent a mixture of methylene chloride/methanol/ammonium hydroxide (9: 1: 0.1) has been specified in the title compound as off-white foam:1H NMR (CDCl3d 8.99 (Shir. s, 1H), 7.80 (Shir. s, 1H), 7.27-7.19 (m, 2H), 6.95 (d, J 1.4 Hz, 1H), 3.16-3.08 (m, 2H), 2.58 (DD, J 9.4 and 13.5 Hz, 1H), 2.57-2.43 (m, 1H), 2.43 (m, 1H), 2.43 (s, 3H), 2.22 (DD, J 9.2 and 17.5 Hz, 1H), 1.85-1.46 (m, 4H),13With NMR (CDCl3d 134.5, 127.7, 126.9, 123.8, 116.1, 113.9, 111.9, 111.6, 104.1, 66.6, 57.3, 40.6, 31.3, 29.5, 21.7, mass spectrum (high resolution):

Calculated for C16H18F3N3O: 325.1403. Found: 325.1378.

Example 16. (R)-3-(N-methylpyrrolidine-2-ylmethyl)-5-(2-methylsulfanyl-methyl)- 1H-indole

To a mixture of (R)-5-aminomethyl-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole (0.113 g, 0.46 mmole) and pyridine (50 μl, 0.93 mmol, 2.0 EQ.) in a solution of dimethylformamide and acetonitrile (1: 3, respectively, 2 ml in total) under stirring at 0oC in an atmosphere of nitrogen was added dropwise methanesulfonanilide (44 μl, 0.56 mmol, 1.3 EQ.). The resulting reaction solution was stirred shall be oil was processed through column chromatography with silica gel (6 g), using as elution solvent a mixture of methylene chloride/methanol and ammonium hydroxide (9:1:0.1) to obtain specified in the title compound (0.044 g, 0.14 mmol, 30%) as a white foam1H NMR (CDCl3) d 8.25 (Shir. s, NH), 7.54 (Shir. s, 1H), 7.35 (d, J 1.8 Hz, 1H), 7.17 (DD, J 1.6 and 8.4 Hz, 1H), 7.06 (d, J 1.8 Hz, 1H), 4.78 (Shir. s, NH), 4.42 (c, 2H), 3.20 3.12 (m, 2H), 2.87 (s, 3H), 2.64 (DD, J 9.4 and 13.9 Hz, 1H), 2.54 2.43 (m, 1H), 2.47 (S, 3H), 2.25 (DD, J 9.3 and 17.3, 1H), 1.86 1.52 (m, 4H),13With NMR (CDCl3d 135.8, 127.8, 127.3, 123.0, 122.0, 118.5, 113.7, 111.6, 66.7, 57.4, 47.9, 40.9, 40.7, 31.3, 29.5, 21.7, mass spectrum (low resolution) (m/z, relative intensity) 321 (28), 320 (M+, 26), 237 (51), 157 (100), 143 (64), 129 (78), mass spectrum (high resolution):

Calculated for C16H22N3O2S 320.1435. Found: 320.1453.

Example 17. General method of synthesis of arylsulfonamides

A. Arylsulfonic

Specified in the title compound was obtained according to the method of M. A. Belous and I. Ya. Postouski, Zhur. Obschei. Khim. 1950, 20, 1701.

B. N-mailalerthome

Specified in the title compound was obtained by similar method when using methylamine instead of ammonia.

Data analysis for C5H11NO2S:

Calculated: C 40.25; H, 7.43; N, 9.38.

Found: C At 40.51; H, 7.37; N, 9.70.

Example 18. Getting utililization

At the. is the overall method of synthesis of vinylsulfonic

If necessary vinylsulfonic not commercially available, can be obtained in accordance with the methodology described in Zhur. Obschei. Khim. 1959, 29, 1494.

A. N,N-dimethylbenzenesulfonic

To a stirred solution of chloroethylsulphonic (25 g, 153 mmol) in dry diethyl ether (150 ml) at -10oC was added dropwise a solution of dimethylamine (30.5 ml, 460 mmol) in dry diethyl ether (100 ml) for more than 5 minutes After further stirring for 90 min at -10oC the solution was filtered and evaporated in vacuum. The residue was distilled to obtain specified in the title compound (9.5 g, 46%): So Kip. 120-122oC (20 mm RT. Art.).

Data analysis for C4H9NO2S:

Calculated: C 35.54; H 6.71; N, 10.36.

Found: C 35.36; H 6.37; N, 10.19.

B. When using this General method, described above, were obtained the following examples. As the source of material used the corresponding amines. Purification was performed by distillation or column chromatography (PL.1).

Example 20. General method of synthesis of vinylsulfonic

In the case when the desired vinylsulfonic is not commercially available, it can prochityvaetsya illustration (PL.2).

Example 21. General method for the synthesis of indoles with 5-alkenyl-Vice

A. (R)-5-TRANS-(2-N,N-dimethylaminocarbonylmethyl)-3-(N-methyl pyrrolidin-2-ylmethyl)-1H-indole

A mixture of N,N-dimethylacrylamide (134 μl, 1.3 mmol), tri-orthotoluidine (91 mg, 0.3 mmol), palladium acetate (11) (15 mg, 0.07 mmol), triethylamine (280 μl, 2 mmol) and (R)-5-bromo-3-(N-methylpyrrolidine-2-limeter)-1H.indole was dissolved in anhydrous acetonitrile (5 ml) and boiled under reflux for 24 hours under nitrogen atmosphere. The reaction mixture was distributed between ethyl acetate and aqueous sodium carbonate. The dried (Na2SO4) the organic phase is evaporated, and the residue was purified through column chromatography with silica gel, using as eluent CH2Cl2:MeOH:NH4OH 96:3.5:0.5. Got mentioned in the title compound as a white foam (145 mg, 47% ).

Data analysis for C19H25N3O 1/9CH2Cl2< / BR>
Calculated: C, 71.56; H, 7.87; N, 13.10.

Found: C, 71.29; H, 8.15; N, 13.05.

Century examples represent the receipt of the products when using the above method using the corresponding alkenes as starting material, commercially available or obtained in accordance with predelli beta chloramination as starting material instead of the alkene. This reaction is preferably carried out in the presence of 3 to 6 equivalents of triethylamine (PL.4).

Example 22. A common way hydrogenation of 5-alcedinidae

The model can be considered the following methodology:

A. (R)-5-(2-aminosulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)- 1H-indole

(R)-5-(2-aminosulphonylphenyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)- 1H-indole (157 mg, 0.5 mmol) was dissolved in absolute ethanol (10 ml) and added to the ethanol solution of hydrogen chloride (25 ml), obtained from acetylchloride (38 μl, 0.53 mmol), and absolute ethanol (25 ml). Was added 10% palladium on coal (125 mg). This solution was first made in hydrogen atmosphere (15 psi 1.05 kg/cm2) at room temperature for 18 hours the reaction mixture was filtered through diatomaceous earth (trade name celite or Armacell), washed with absolute ethanol and the United filtrates evaporated in vacuum. The residue was purified through column chromatography with silica gel. When gradient elution used a mixture of solvents to CH2Cl2: MeOH: NH4OH 93:7:1 to obtain specified in the title compound as a colourless oil (80 mg, 51% ).

Data analysis for C16H23N3O2S 1/4 M/SUP> (c 0.1, MeOH)

B. Substances presented in the following examples were obtained in a manner analogous to (a) (PL.5).

Example 23. General method for the synthesis of (R)-5-(2-ethylsulfonyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole

A. (R)-3-(N-benzyloxycarbonylamino-2-yl-methyl)-5-bromo-1H - indole

(R)-3-(N-benzyloxycarbonylamino-2-yl-carbonyl)-5-bromo-1H - indole (0.67 g, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and at room temperature in a nitrogen atmosphere was added lithium borohydride (2 M in tetrahydrofuran) ( 1.2 ml, 2.4 mmol). The reaction mixture was stirred at room temperature for 3 h and boiled under reflux for 16 hours After cooling to room temperature, was added dropwise 2 n HCl (10 ml) and the resulting reaction mixture was separated between ethyl acetate and water. Selected organic phase is washed with saturated aqueous sodium bicarbonate (2×), with brine (1 x) dried (Na2SO4), and then evaporated in vacuum to obtain a colorless oil. After purification through column chromatography with silica gel using dichloromethane as eluent, got mentioned in the title compound, as an oil (0.32 g). Analysis by thin-layer chromate is pyrrolidin-2-ylmethyl)-1H-indole

The compound obtained by the method (a), connected with ethylvinylacetate under standard conditions described above, while receiving specified in the title compound in the form of foam.

Data for the analysis of C25H28N2O4S 1/8CH2Cl2:

Calculated: C At 65.15; H, 6.15; N, 6.05.

Found: C, 65.16; H, 6.17; N, 5.97.

()25-50o(0.1, MeOH).

C. (R)-5-(2-ethylsulfonyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole

Obtained by the method (C) the connection was first made in the above standard conditions, while receiving specified in the title compound in the form of foam.

Data analysis for C17H24N2O2S 1/2CH2Cl2:

Calculated: C, 63.07; H, 7.48; N, 8.63.

Found: C, 62.90; H, 7.25; N, 8.58.

()25-11o(c 0.1, MeOH).

Example 24. General method of synthesis of (R)-3-(N-alkyl-pyrrolidin-2 - ylmethyl)-indoles

A. (R)-3-(N-ethylpyrrolidin-2-ylmethyl)-5-(2-ethylsulfanyl)- 1H-indole

To a solution of (R)-3-(pyrrolidin-2-limeter)-5-(2-ethylsulfanyl - ethyl)-1H-indole (0.27 g, 0.8 mmol) in dimethylformamide (dried over sieves 4 (5ml), was added sodium carbonate (90 mg) and ethyliodide (0.07 ml, 0.88 mmol) at room temperature. The mixture was heated at 120oC atmosfeta and water. Selected organic phase was washed (3 x), dried (Na2SO4) and evaporated in vacuo to obtain oil. Purification through column chromatography with silica gel using as eluent a mixture of CH2Cl2:EtOH:NH4OH (90:10:0.5) gave specified in the title compound in the form of resin (100 mg).

Data analysis for C19H28N2O2S1/4CH2Cl21/2H2< / BR>
Calculated: C, 61.04; H, 7.85; N, 7.40.

Found: C, 60.80; H, 7.69; N, 7.48.

()25 +60o(c 0.1, MeOH).

B. the Following examples were obtained by the method (a), but using the suitable alkylhalogenide instead of ethyliodide. Alkylhalogenide may be an iodide or bromide in the optional presence of sodium iodide. As the solvent used dimethylformamide or dimethylacetamide (PL.6).

Example 25. (R)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

(R)-5-bromo-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole (60 mg, 0.2 mmol) was dissolved in ethanol (1 ml) and was first made over 10% palladium on coal (45 g) at 60 p. s.i 4.4 kg/cm2the pressure of hydrogen at room temperature for 16 hours, the Reaction mixture was evaporated to dryness and the residue is divided between ethyl acetate and 10% aqueous carbonate n is on a chromatographic column with silica gel, using as eluent a mixture of (89: 10:1). CH2Cl2:MeOH:NH4OH. Got mentioned in the title compound (28 mg).

Data analysis for C14H18N21/8CH2Cl2:

Calculated: C, 75.42; H, 8.18; N, 12.46.

Found: C, 75.50; H, 8.51; N, 12.09.

()25+60.2o(c 0.088, CHCl3).

Example 26. (R)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-bromo-1H-indole

Two containing the reagent solution were obtained separately as follows: To a stirred solution of N-benzyloxycarbonyl-D-Proline (1.0 g) in anhydrous dichloromethane (2 ml) and N,N-dimethylformamide (1 drop) was added oxalicacid (0.5 ml) and the resulting mixture was stirred at room temperature for 1.5 hours the Solution is evaporated under reduced pressure, and the remaining solvent was removed in high vacuum to obtain chloranhydride N-benzyloxycarbonyl-D-Proline. At the same time, the solution ethylacetamide (1.4 ml of 3 M solution in ether) was added dropwise over 5 min to a stirred solution of 5-bromoindole (0.75 g) in dry ether (18 ml). The mixture was stirred at room temperature for 10 min, boiled under reflux for 2 h, then cooled to -30oC. the Solution is specified we which the stirring was continued for 1 h Added ether (12.5 ml) and saturated aqueous sodium bicarbonate solution (6.5 ml), and the temperature given the opportunity to rise to room temperature. Continued stirring for another 10 minutes, after which the mixture was filtered. The obtained solid product was thoroughly washed with ethyl acetate, the combined filtrate and washings were washed with water, with brine and dried over sudipta magnesium. After evaporation of solvent received the oil, which was subjected to chromatographic purification on a column of silica gel. As eluent was used ethyl acetate, thus obtaining specified in the title compound as a foam (0.82 g). Mass spectrum (low resolution): m/z (relative intensity) 428 (M+with81Br, 5), 426 (M+c79Br, 5), 224 (19), 222 (21), 204 (62), 160 (68), 91 (100).

Data analysis for C21H19BrN2O3:

Calculated: C, 50.02; H, 4.48; N, 6.56.

Found: C At 58.85; H, 4.51; N, 6.38.

Example 27. (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole

A solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5 - bromo-1H-indole (1.04 g) in dry tetrahydrofuran (20 ml) was added dropwise to a stirred suspension of sociallyengaged (0.27 g) in dry tetrahydrofuran (15 ml) at room temperature in atmospherical added sociallyengaged (50 g) and continued to boil for another 3 hours Then the mixture is again cooled, added sociallyengaged (40 g) and kept boiling for another 18 hours the Mixture was cooled and carefully, stopping stirring, was added water (0.44 ml), then 20% aqueous sodium hydroxide solution (0.44 ml) and again water (1.33 ml). The mixture was diluted with ethyl acetate and filtered through Zelany filter. The filtrate was washed with water, brine, and then dried (Na2SO4). After evaporation of solvent received the oil, which is processed chromatography on silica gel. In the elution with a mixture of dichloromethane/ethanol/concentrated aqueous ammonia (90: 10: 0.5) has been specified in the title compound as a solid (0.51 g), So pl. 137-140oC (from a mixture of dichloromethane hexane); IR (KBr) 1620, 1595, 1570, 1480, 1459, 1435 cm-1,1H NMR (DMSO-d6) 11.05 (Shir. s, 1H), 7.65 (Shir. d, 1H), 7.31 (d, J 8.6 Hz, 1H), 7.21 (Shir. d, 1H), 7.16 (DD, J 1.8 and 8.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.47 (DD, J 9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H), 2.33 (s, 3H), 2.09 (DD, J 8.7 and 17.3 Hz), 1.73-1.38 (m, 4H),13With NMR (DMSO-d4d 134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9, 66.1, 57.0, 40.5, 30.9, 29.1, 21.6, mass spectrum (low resolution), m/z (relative intensity) 294 (M+with81Br, 1), 293 (20. 292 (M+with79Br, 1), 210 (14), 208 (15), 154 (8), 129 (42), 128 (19), 101 (26), 85 (57), 84 (100), 83 (30), ()2562o(methanol, 0.10).

Example 28. (R)-5-(2-ethylsulfonyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)- 1H-indole

A mixture of (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (0.25 g), ethylvanillin (0.14 g), tri-ortho-tolylphosphino (0.075 g), palladium acetate (11) (0.013 g), triethylamine (0.25 ml) and acetonitrile (3 ml) was boiled under reflux for 17 h under nitrogen atmosphere. The mixture is evaporated and the residue treated chromatography on a column of silica gel. As eluent used a mixture of dichloromethane/ethanol and concentrated solution of ammonia in water (90:8:1), while receiving specified in the title compound as a foam (0.185 g). Data thin-layer chromatography (dichloromethane/ethanol/concentrated solution of ammonia in water, 90:10:1):Rf0.5

Data analysis for C18H24N2O2S 0.2 CH2Cl2:

Calculated: C, 62.55; H, 7.04; N, 8.02.

Found: C, 62.65; H, 6.94; N, 7.92.

Example 29. (R)-5-(-ethylsulfonyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole

(R)-5-(2-ethylsulfonyl)-3-(N-methyl-pyrrolidin-2-yl-methyl)- 1H-indole (157 mg) was dissolved in a mixture of ethanol solution of hydrogen chloride (obtained by adding acetylchloride (0.043 ml) to ethanol (10 ml), N, N-dimethylformamide (7.5 ml) and water (0.1 is outstay 10% palladium on coal (150 mg). The mixture was filtered through Arkaball (trade name), and the residue is well washed with ethanol. The combined filtrate and washing was boiled away under reduced pressure, and the residue is in the form of butter divided between ethyl acetate and 2 M aqueous solution of sodium carbonate. The organic layer was isolated, washed three times with water, then brine, then dried (Na2SO4).

After evaporation of solvent received the oil, which chromatographic processed on silica gel. As eluent used a mixture of dichloromethane/methanol/concentrated aqueous ammonia (90:10:1). Got mentioned in the title compound in the form of resin (110 mg): analysis using thin-layer chromatography (CH2Cl2/C2H5OH/NH3, 90:10:1):Rf0.3,

()25+62o(methanol, 0.10).

Data analysis for C18H26N2O2S0.5CH2Cl2:

Calculated: C, 63.21; H, 7.67; N, 8.17.

Found: C, 63.55; H, 7.61; N, 8.41.

Example 30. (R)-5-(2-ethylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole - polosukhina

A solution of succinic acid (69 mg) in hot ethanol (3.5 ml) was slowly added with stirring to a solution of (free base) (R)-5-(2-ethylsulfonyl)-3-(N-which began with ether, and then with ethyl acetate. Got mentioned in the title compound as a solid product (375 mg): So pl. 59-62oC:()25 +36o(methanol, 0.10).

Data analysis for C18H26N2O2S 0.5 C4H6O40.25 CH3CO2C2H5< / BR>
Calculated: C, 59.00; H, 7.42; N, 6.68.

Found: C, 59.17; H, 7.37; N, 6.73.

Example 31. (R)-5-(2-benzosulfimide)-3-(N-methyl-pyrrolidin - 2-ylmethyl)-1R-indol-hydrobromide

A mixture of (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (0.25 g), phenylenesulfonyl (0.19 g), tri-ortho-tolylphosphino (0.075 g), palladium acetate (11) (0.0125 g), triethylamine (0.25 ml) and acetonitrile (2.5 ml) and boiled for 42 h in nitrogen atmosphere. The solvent is boiled away, and the residue is chromatographically treated on silica gel. As eluent used a mixture of dichloromethane/methanol/concentrated aqueous ammonia (90:10:1). Got mentioned in the title compound as a foam (0.24 g).

Data analysis for C22H24N2O2HBr 1/3CH2Cl2< / BR>
Calculated: C, 54.77; H, 5.29; N, 5.72.

Found: C, 55.00; H, 4.85; N, 5.58.

Example 32. (R)-5-(2-benzosulfimide)-3-(N-methyl-pyrrolidin - 2-yl-methyl)-1H-indole

A solution of (R)-5-(2-benzols the new ethanol (10 ml), N,N-dimethylformamide (1 ml) and water (2 drops) was shaken in an atmosphere of hydrogen (1.05 kg/cm2) at room temperature for 18 hours the Mixture was filtered through Zelany filter (trade name), and the resulting residue is thoroughly washed with ethanol. The combined filtrate and washings evaporated under reduced pressure and the residue is divided between ethyl acetate and 2 M aqueous solution of sodium carbonate. The organic layer was isolated, washed three times with water, then with brine and dried (Na2SO4). Evaporation of the solvent gave a resin, which is then chromatographically treated on silica gel. As eluent was used a mixture of dichloromethane/methanol/concentrated aqueous ammonia (90:10:0.5). Got mentioned in the title compound as a foam (0.096 g).

Data analysis for C22H26N2O2S H2O

Calculated: C, 65.97; H, 7.05; N, 7.00.

Found: C, 65.51; H, 6.77; N, 7.45.

Example 33. (R)-5-(2-benzosulfimide)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole-polosukhina

A solution of succinic acid (95 mg) in ethanol (5 ml) was added to a solution of the free base of 5-(R)-5-(2-benzosulfimide)-3-(N - methyl-pyrrolidin-2-ylmethyl)-1H-indole (620 mg) in ethanol (5 ml). Dissolve 0.10).

Data analysis for C22H26N2O2S 0.5 C4H6O40.33 C2H5OH 0.5 H2O

< / BR>
Calculated: 63.59; H, 6.92; N, 6.01.

Found: C, 63.52; H, 6.91; N, 6.12.

Example 34. (R)-5-(2-(4-methylphenylsulfonyl)ethynyl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole

A mixture of (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (0.40 g), 4-methylphenylsulfonyl (0.273 g), tri-ortho-tolyl-phosphine (0.085 g), palladium (II) acetate (0.031 g), triethylamine (0.42 g) and acetonitrile (20 ml) was boiled under reflux for 16 h under nitrogen atmosphere. The mixture is then cooled and separated between ethyl acetate and 10% sodium bicarbonate solution in water. The organic layer was washed with brine, dried with Na2SO4and boiled away. Formed in residual orange oil chromatographic processed on silica gel. As eluent was used a mixture of dichloromethane and methanol (90:10), then a mixture of dichloromethane/methanol/concentrated aqueous ammonia (90:10:0.25), while increasing the concentration of an aqueous solution of ammonia to 1% Last contained product fractions evaporated, receiving specified in the title compound as a foam (226 mg):()25 +71o(methanol, 0.10).

Given The/P> Found: C, 68.16; H, 6.54; N, 6.99.

Example 35. (R)-5-(2-(4-methylphenylsulfonyl)ethyl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole

A solution of (R)-5-(2-(4-methylphenylsulfonyl)ethynyl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole (0.18 g) and 10% palladium on coal (0.20 g) in ethanol solution of hydrogen chloride (obtained from absolute ethanol (25 ml) and acetylchloride (35 ml) was shaken in an atmosphere of hydrogen (1.05 kg/cm2) at room temperature for 16 hours Then the mixture was filtered through Zelany filter (trade mark), and the residue is thoroughly washed with ethanol. The combined filtrate and washings evaporated under reduced pressure, and the formed precipitate was separated between ethyl acetate and 2 M aqueous solution of sodium carbonate. The organic phase was isolated, washed three times with water, then with brine and dried over Na2SO4. After evaporation of the solvent was obtained resinous product which chromatographic processed on silica gel. As eluent was used a mixture of dichloromethane/methanol/concentrated aqueous ammonia (90:10:0.25). Got mentioned in the title compound as a foam (108 mg).()25 +30o(methanol, 0.10).

Data analysis for C23H28N2O2

1. Derivatives of indole of General formula I

< / BR>
where n is 0, 1 or 2;

R1hydrogen;

R2hydrogen, halogen, cyano, -OR4, -(CH2)m-(C=O)NR5R6, -(CH2)m-SO2NR5R6, -(CH2)m-NR7(C=O)R8, -(CH2)m-S(O)xR8and-CH CH(CH2)yR10; R3hydrogen or a branched or non-branched C1- C6-alkyl;

R4C1C6-alkyl;

R5and R6independently hydrogen or C1- C6-alkyl, or R5and R6together with the nitrogen atom to which they are attached, form azetidinone, pyrolidine or piperidino ring;

R7and R8independently hydrogen, C1C6-alkyl, phenyl, optionally substituted with one to three C1C4alkyl groups or one to three halogen atoms;

R10-(C=O)NR5R6, -SO2NR5R6, -NR7SO2R8, -NR7(C=O)R8, -S(O)xR8where R5R8have the specified values;

y is 0, 1 or 2;

x is 1 or 2;

m 0, 1, 2 or 3,

provided that when R2hydrogen, n is 0 or 1,

and their optical isomers and pharmaceuticae by p. 1, in which R1hydrogen, R2- -(CH2)m-SO2OTHER5, -(CH2)m-SO2R8or -(CH2)m- NH(C=O)R8, R3hydrogen or methyl, and m, R5and R6matter under item 1.

4. Connection on p. 1, representing one of the following connections:

(R)-5-methoxy-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2 - ethylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-methylaminomethyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-methylaminomethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2-methylaminoethanol)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-carboxamido-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-methylsulfonylamino)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-methylsulfonylmethyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-aminosulphonylphenyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-aminosulfonyl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-N, N-dimethylaminocarbonylmethyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-phenylsulfonyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole-Paulus is sulfonylated)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(3-benzonorbornadiene-1-Anil)-3-(N-methylpyrrolidine-2 - ylmethyl)-1H-indole;

(R)-5-(2-(4-methylphenylsulfonyl)-ethyl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(3 - methylsulfonylamino-1-enyl)-3-(N-methylpyrrolidine-2 - ylmethyl)-1H-indole;

(R)-5-(2-ethylsulfonyl)-3-(N - 2-propylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2 - ethylsulfonyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(2- (4-methylphenylsulfonyl)ethynyl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole;

(R)-5-(2-methylsulfonylmethyl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole.

5. Derivatives of indole of General formula V

< / BR>
in which W-CO2R11;

Q CH2or C=O;

R1hydrogen;

R2halogen, CYANOGEN, -OR4, -(CH2)m-(C=O)NR5R6, -(CH2)m-SO2NR5R6, -(CH2)m-NR7(C=O)R8, -(CH2)m-S(O)xR8and-CH= CH(CH2)yR10;

R4C1C6-alkyl;

R5and R6independently hydrogen, C1C6-alkyl or

R5and R6together with the nitrogen atom to which they are attached, form azetidinone, pyrolidine or piperidino ring;

R7and R8the independent is one or three halogen atoms;

R10-(C=O)NR5R6, -SO2NR5R6, -NR7(C=O)R8, -NR7SO2R8, -S(O)xR8in which R5- R8have the specified values;

R11benzyl;

x is 1 or 2;

y is 0, 1 or 2;

m 0, 1, 2 or 3;

n is 0, 1 or 2.

6. Connection on p. 5, representing the R-enantiomer.

7. Connection on p. 5 the General formula II

< / BR>
in which R1, R2and R11matter under item 9.

8. Connection on p. 7, which is the R-enantiomer.

9. Connection on p. 7, in which R1a hydrogen atom;

R2-(CH2)m-SO2OTHER5, -(CH2)m-SO2R8, -(CH2)m- (C=O)OTHER5or -(CH2)m-NH(C= O)R8where m is 0, 1, 2 or 3, R5hydrogen, C1C6-alkyl, R11- benzyl.

 

Same patents:

The invention relates to the field of synthesis of new biologically active compounds

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

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

The invention relates to the field of organic chemistry, specifically to an improved method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts or their hydrates, as well as intermediates for their synthesis, which can find application in pharmaceutical industry

The invention relates to new biologically active compounds derived pyrimidine-4-or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions on their basis

- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity" target="_blank">

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br

The invention relates to new chemical compounds having valuable pharmacological properties and relates to new pharmacologically active N-substituted derivatives of (3R, 4R)-3-ethyl-4- [(1-methyl-1H-imidazol-5-yl)methyl] -2-Pierre - oligonu that have antiglaucoma action and can find application in medicine

The invention relates to 5,6-disubstituted-3 - pyridylmethylamine compounds of the formula I

< / BR>
where Z is hydrogen, halogen;

Z1represents hydrogen, halogen, cyano and nitro;

X represents Cl, Br, J, or R3SO3;

R3represents C1-C4-alkyl or phenyl, are not necessarily substituted with one to three C1-C4-alkoxygroup, C1-C4- alkyl groups, nitro groups: cyano groups or halogen atoms;

Y and Y1each independently represents OR4, NR4R5or, if they are taken together, YY1represent-O-, -S - or;

R4and R5are each independently hydrogen, C1-C4-alkyl, does not necessarily substituted C1-C4- alkoxygroup, or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup or halogen atoms; or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup atoms or halogen;

R6represents hydrogen or C1- C4- alkyl;

Q is

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

The invention relates to imidazolium and pyridium derived phenylsilane 1,4-dihydropyridines, to the way they are received and containing pharmaceutical compositions

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to new derivatives of pyrrolidine and their pharmaceutically acceptable salts

The invention relates to acryloyl-substituted derivatives of pyrrole of the formula (I)

,

in which n is an integer from 1 to 5; each of R1and R2which may be identical or different, is hydrogen, halogen, -CN, -NO2C1-C4the alkyl, or a group:, R3is hydrogen, halogen, -CN or-NO2
Up!