Derivatives of indole or pharmaceutically acceptable salt

 

(57) Abstract:

Derivatives of indole of the formula I

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< / BR>
where

n = 1; m = 1; R1=H; C1-C8alkyl; QR4;

where

R4-COR9; where R9- C1-C8alkyl; Q = C1-C3alkyl; R11- H

or their pharmaceutically acceptable salts, which are agonists of serotonin (5-HT). 3 S. and 18 C.p. f-crystals, 1 table.

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

In the U.S. patents NN 4 839 377 and 4 855 314, as well as in the publication of the European patent application N 313397 disclosed 5-substituted 3-aminoalkylindole. As indicated in these works mentioned compounds intended for the treatment of migraine. In the patent application UK N 040279 disclosed 3-aminoalkyl-1H-indol-5-thioamides and carboxamide. In this application indicates that these compounds can be used to treat hypertension, syndrome of Raymond and migraines.

In the publication of the patent Evrst agonist of serotonin (5-HT1in respect of the receptor binding and have vasoconstrictor activity, so they can be used for treatment of migraine.

The publication of the application for Europatent N 354777 describes N-piperidinyl: indolyl ethyl-alkanesulphonic derivatives. These compounds are agonists of 5-HT1and have vasoconstrictor activity, so they can be used to treat headaches.

In publications of applications for Europatent NN 438230, 494774, and 497512 disclosed indole-substituted 5-membered heteroaromatic compounds. As stated in the application, these compounds have 5-HT1receptor agonistic activity, and therefore they can be used to treat migraine and other disorders for which treatment requires the use of selective agonists for these receptors.

In International patent application PCT/GB91/00908 and in European patent application N 313397A disclosed derivatives of 5-heterocyclic indoles. As stated in the application, these compounds have properties that enable their use for the treatment and prevention of migraine, "histamine headaches and pain associated with vascular disorders. CRU relative to 5-HT1.

The invention relates to compounds of the formula

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where W is a

< / BR>
n represents 0, 1 or 2; m represents 0, 1, 2 or 3; Y and G independently represent oxygen or sulfur; Z represents-O-, -S-, -NH-, or-CH2-; R1represents hydrogen, C1-C8-alkyl, C1-C8-alkyl, substituted by one hydroxy group, a C3-C8alkenyl, C3-C8-quinil, aryl, C1-C3-alkylaryl, C1-C3-alkylether, or-Q-R4; R2and R3independently represent hydrogen, C1-C6is alkyl, aryl, C1-C3-alkylaryl, or C1-C3-alkylglycerol; R4represents cyano, trifluoromethyl, -COR9, -CO2R9, -CONR9R10, -OR9, -SO2NR9R10or-S(O)q; R9and R10independently represent hydrogen, C1-C8-alkyl, C1-C3-alkylaryl, aryl; or R9and R10taken together, may form a 3-7-membered alkyl ring or a 3-7-membered heteroalkyl ring having a heteroatom of oxygen; R11represents hydrogen, -OR12or-NHCOR12; R12represents a C3-alkyl; a first chiral carbon atom indicated by an asterisk; a second chiral carbon atom marked and these aryl groups or aryl part of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl which can be substituted one, two, or three groups selected from C1-C4-alkyl, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C1-C4-alkoxy;

and, in addition, the invention relates to pharmaceutically acceptable salts of the described compounds. These compounds can be used to treat migraine and other disorders.

The compounds of the invention also include all optical isomers of formula I (for example, R - and S-stereoisomers in any chiral center), racemic, diastereomeric or epimeria mixture. While preferred are epimere absolute configuration S and with a center of chirality at the carbon atom (in the formula I indicated). If R11represents hydrogen are preferred epimere with absolute configuration R and chiral carbon atom (in the formula I is indicated by an asterisk). If R11represents-OR12the first centre at the carbon atom (in the formula I is indicated by an asterisk). If R11represents-OR12or-NHCOR12and n 0, the most preferred are CIS-epimer absolute configuration of (2S, 3S) azetidinone ring. If R11is a OR12or-NHCOR12and n 1, the most preferred are CIS-epimer absolute configuration of (2S, 4R) pyrolidine ring. If R11represents-OR12or-HCOR12and n 2, the most preferred are CIS-epimer absolute configuration of (2R, 5R) in the pyridine ring.

If it is not specifically mentioned, the alkyl, alkeline and alkyline group, and alkyl and alkylene part of other groups (such as alkoxy may be linear or branched, and cyclic (for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or they can be linear or branched and contain cyclic part.

Preferred compounds of the invention are the compounds of formula I, where W is (i), (ii) or (iii); n 1; m 1; R1is hydrogen, C1-C3-alkyl or-CH2CH2OCH3; R2is hydrogen; and R3is hydrogen or-CH2Ph (Ph is phenyl). From the S and chiral carbon atom, marked (see formula I). Of these preferred compounds, in which R11is hydrogen, the most preferred are epimere with absolute configuration R and with a chiral center at the carbon atom indicated by the asterisk in formula I. among these preferred compounds, in which R11represents-OR12or-NHCOR12more preferred are epimere absolute configuration S and with a chiral center at the carbon atom indicated by the asterisk in formula I. among these compounds, in which R11represents-OR12or-NHCOR12most preferred are CIS-epimer absolute configuration of (2S, 4R) pyrolidine ring.

Especially preferred are the following compounds:

3-[(N-2-Methoxyethyl)pyrrolidin-2R-ylmethyl] -5-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1H-indole;

5-(2-Oxo-1,3-oxazolidin-4S-ylmethyl)-3-(pyrrolidin-2R-ylmethyl)-1 H-indole;

3-(N-Methylpyrrolidine-2R-ylmethyl)-5-(2-oxo-1,3-oxazolidin-4R, S-ylmethyl)-1H-indole.

The invention also relates to pharmaceutical compositions intended for the treatment of diseases such as hypertension, depression, anxiety, narusegawa" headache, migraine, pain, chronic paroxysmal hemicrania and headache associated with vascular disorders; and specified the pharmaceutical composition includes a certain amount of the compounds of formula I or its pharmaceutical salts, are effective for treatment of the above disorders, and a pharmaceutically acceptable carrier.

The invention also relates to a method for treatment of conditions such as hypertension, depression, anxiety, disorders associated with food intake, obesity, drug abuse, or drugs, histamine headache, migraine, pain, chronic paroxysmal hemicrania and headache associated with vascular disorders, which is that the mammal (e.g. human) in need of such treatment, introducing a certain amount of the compounds of formula I or its pharmaceutically acceptable salt, is effective for treatment of these conditions.

In addition, the invention relates to pharmaceutical compositions intended for the treatment of disorders associated with insufficient serotonergic neurotransmission (such as depression, anxiety, disorders, Xia headache, migraine, chronic paroxysmal hemicrania and headache associated with vascular disorders), and includes a certain amount of the compounds of formula I or its pharmaceutically acceptable salt, is effective for treatment of these disorders and a pharmaceutically acceptable carrier.

The invention also relates to a method of treatment of disorders associated with insufficient serotonergic neurotransmission (such as depression, anxiety, disorders associated with food intake, obesity, abuse of drugs or with drugs, histamine headache, migraine, chronic paroxysmal hemicrania and headache associated with vascular disorders), which is that the mammal (e.g. human) in need of such treatment, introducing a certain amount of the compounds of formula I or its pharmaceutically acceptable salt, is effective for treatment of these conditions.

In addition, the invention relates to a compound of the formula

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where W is a

< / BR>
n is 0, 1 or 2; m is 0, 1, 2 or 3; Y and G independently represent oxygen or sulfur; Z represents the, C1-C3-alkyl-aryl, and C1-C3-alkylglycerol; R5represents a C1-C6-alkyl; aryl, or C1-C3-alkylaryl (preferably benzyl); R11represents hydrogen, -OR12or-NHCOR12; R12represents hydrogen, C1-C6is alkyl, aryl, or C1-C3-alkylaryl,

moreover, in this formula, the first chiral carbon atom indicated by an asterisk, the second chiral carbon atom marked and these aryl groups or aryl part of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl which can be substituted one, two or three groups selected from C1-C4-alkyl, halogen (for example fluorine, chlorine, bromine or iodine), hydroxy, cyano, carboxamido, nitro and C1-C4-alkoxy. Preferred are epimere absolute configuration S and with a chiral center at the carbon atom indicated in the formula II where R11represents hydrogen are preferred epimere with absolute R configuration at the chiral center at the carbon atom marked with an asterisk in formula II. If R11represents-OR12or-NHCOR12and n 0 and the and, indicated in the formula II with an asterisk. If R11represents-OR12or-NHCOR12and n 2, are preferred epimere with absolute configuration R and with a chiral center at the carbon atom indicated in the formula II with an asterisk. If R11represents-OR12or-NHCOR12and n is 0, are preferred CIS-epimer absolute configuration of (2S, 3S) azetidinone ring. If R11represents-OR12or-NHCOR12and n is 1, preferred are CIS-epimer absolute configuration of (2S, 4R) pyrolidine ring. If R11represents-OR12or-NHCOR12and n 2, are preferred CIS-epimer absolute configuration of (2R, 5R) piperidinium ring. The compounds of formula II can be used as intermediates in obtaining the compounds of formula I.

The invention also relates to the compound of the formula

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where

W represents a

< / BR>
n is 0,1 or 2; m is 0, 1, 2 or 3; Y and G independently represent oxygen or sulfur; Z represents-O-, -S-, -NH or-CH2; R2and R3independently represent hydrogen, C1-C6is alkyl, aryl, C1-C3-als1-C3-alkylaryl (preferably benzyl); R6represents a halogen (preferably bromide);

R7represents-COCF3, -SO2CH3, -SO2Ph, or-CO2C(CH3)3; R11represents hydrogen, -OR12or-NHCOR12; R12represents hydrogen, C1-C6is alkyl, aryl or C1-C3-alkyl-aryl; and in the formula of the first chiral carbon atom indicated by an asterisk, the second chiral carbon atom marked and these aryl groups and the aryl parts of the above alkyl-aryl groups independently are phenyl or substituted phenyl which can be substituted by 1-3 groups selected from C1-C4-alkyl, halogen (for example fluorine, chlorine, bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C1-C4-alkoxy. Preferred are epimere absolute configuration S and with a chiral center at the carbon atom indicated in formula III. If R11is hydrogen, are preferred epimere with absolute configuration R and with a chiral center at the carbon atom indicated in the formula III with an asterisk. If R11represents-OR12or NHCOR1211represents-OR12or-NHCOR12and n 2, are preferred epimere with absolute configuration R and with a chiral center at the carbon atom indicated in the formula III with an asterisk. If R11represents-OR12or-NHCOR12and n 0, the most preferred are CIS-epimer absolute configuration of (2S, 3S) azetidinone ring. If R11represents-OR12or-NHCOR12and n is 1, preferred are CIS-epimer absolute configuration of (2S, 4R) pyrolidine ring. If R11represents-OR12or-NHCOR12and n 2, the most preferred are CIS-epimer absolute configuration of (2R, 5R) piperidinium ring. The compounds of formula III can be used as intermediates in obtaining the compounds of formula II.

In addition, the invention relates to a compound of the formula

< / BR>
where n is 0, 1 or 2; J represents-OH or-CO2R13; R1represents hydrogen, C1-C8-alkyl, substituted C1-C8-alkyl, which is substituted by one hydroxy group; C3-C8alkenyl, C3-C8and yet a cyano, trifluoromethyl, -COR9, -CO2R9, -CONR9R10, -OR9, -SO2NR9R10or S(O)qR9; R9and R10independently represent hydrogen, C1-C8-alkyl, C1-C3-alkylaryl; or R9and R10taken together, may form a 3-7-membered alkyl ring, or a 3-7-membered heteroalkyl ring having 1 heteroatom of oxygen; R11represents hydrogen, -OR12or-NHCOR12; R12represents hydrogen, C1-C6is alkyl, aryl, or C1-C3-alkyl-aryl; R13represents a C1-C6is alkyl, aryl, or C1-C3-alkyl-aryl; q is 0, 1, or 2; Q represents C1-C3-alkyl; and in the formula of the first chiral carbon atom indicated by an asterisk; a second chiral carbon atom marked and these aryl groups and the aryl parts of the above alkyl-aryl groups are phenyl or substituted phenyl which can be substituted one, two or three groups selected from C1-C4-alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C1-C4-alkoxy. Preferred are epimere absolute configuration S and hepatically are epimere with absolute configuration R and with a chiral center at the carbon atom, indicated in the formula XVII with an asterisk. If R11represents-OR12or-NHCOR12and n is 0 or 1, are preferred epimere absolute configuration and with a chiral center at the carbon atom indicated in the formula XVII with an asterisk. If R11represents-OR12or-NHCOR12and n 2, are preferred epimere with absolute configuration R and with a chiral center at the carbon atom indicated in the formula XVII with an asterisk. If R11represents-OR12or-NHCOR12and n 0, the most preferred are CIS-epimer absolute configuration of (2S, 3S) azetidinone ring. If R11represents-OR12or-NHCOR12and n 1, the most preferred are CIS-epimer absolute configuration of (2S, 4R) pyrolidine ring. If R11represents-OR12or-NHCOR12and n 2, the most preferred are CIS-epimer absolute configuration of (2R, 5R) piperidinium ring. The compounds of formula XVII can be used as intermediates in obtaining the compounds of formula I.

The invention also relates to the compound of the formula

< / BR>
where n is 0, 1 or 2; R1is th hydroxy-group C3-C8alkenyl, C3-C8-quinil, aryl, C3-C8-alkylaryl, C1-C3-alkylether, or-Q-R4; R5represents a C1-C6is alkyl, aryl, or C1-C3-alkylaryl; R4represents cyano, trifluoromethyl, -COR9, -CO2R9, -CONR9R10, -OR9, -SO2NR9R10or-S(O)qR9; R9and R10independently represent hydrogen, C1-C8-alkyl, C1-C3-alkylaryl, aryl, or R9and R10taken together, may form a 3-7-membered alkyl ring or a 3-7-membered heteroalkyl ring having one heteroatom of oxygen; R11represents hydrogen, -OR12or-NHCOR12; R12represents hydrogen, C1-C6is alkyl, aryl, or C1-C3-alkyl-aryl; R13represents a C1-C6is alkyl, aryl, or C1-C3-alkyl-aryl; q is 0, 1 or 2; Q represents C1-C3-alkyl; and in the formula of the first chiral carbon atom indicated by an asterisk, and the above aryl groups and the aryl parts of the above alkyl-aryl groups are phenyl or substituted phenyl, which can be replaced the UB>-C4-alkoxy. Preferred are epimere absolute configuration S and with a chiral center at the carbon atom indicated in the formula XIV. If R11represents hydrogen are preferred epimere with absolute configuration R chiral center at the carbon atom indicated in the formula XIV with an asterisk. If R11represents-OR12or-NHCOR12and n is 0 or 1, are preferred epimer having an absolute configuration S with a chiral center at the carbon atom indicated in the formula XIV with an asterisk. If R11represents-OR12or-NHCOR12and n 2, are preferred epimere with absolute configuration R chiral center at the carbon atom indicated in the formula XIV with an asterisk. If R11represents-OR12or-NHCOR12and n 0, the most preferred are CIS-epimer having an absolute configuration of (2S, 3S) azetidinone ring. If R11represents-OR12or-NHCOR12and n 1, the most preferred are CIS-epimer having an absolute configuration of (2S, 4R) pyrolidine ring. If R11represents-OR11or-NHCOR12and n 2, lice. The compounds of formula XIV can be used as intermediates in obtaining the compounds of formula XVII.

Compounds of the invention receive in accordance with the following reaction scheme

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The compounds of formula III can be obtained by reaction of azocoupling Mitsunobu (Mitsunobu) compounds of formulas IV and V, where R5, R6(preferably bromide or iodide), R7(preferably triptorelin-COCF3and R11are the same as defined above with the use of phosphine and azodicarboxylate in an inert solvent. Suitable phosphines are trialkylphosphine and triarylphosphine, and are preferred triphenylphosphine. Suitable azodicarboxylate are dialkyldithiocarbamate, and preferably diethyldithiocarbamate. Suitable solvents are methylene chloride, ethers (tetrahydrofuran, diethyl ether, and 1,4-dioxane), N,N-dimethylformamide and acetonitrile. The preferred solvent is tetrahydrofuran. The above reaction is carried out at a temperature of from about 0oC to about 65oC, and most preferably at about 25oC.

The compounds of formula II can be proceedural bromine or iodine), R7(preferably triptorelin COOF3and R11defined above, in an appropriate solvent and using interphase catalyst and substrate. Suitable catalysts based on transition metals are palladium salt, such as acetate or palladium (II) chloride; and salts of rhodium, such as chloride three(triphenyl)rhodium (I). Of these, the preferred catalyst is palladium (II) acetate. Suitable solvents are N,N-dimethylformamide, acetonitrile and N-methylpyrrolidinone. The preferred solvent is N, N-dimethylformamide. Suitable interphase catalysts are halide of tetraalkylammonium, and preferably, chloride, Tetra-n-butylamine. Suitable bases are tertiary amines, sodium bicarbonate and sodium carbonate. The preferred base is triethylamine. The described reaction is carried out at a temperature from about 60oC to about 180oC, and preferably from about 80oC to about 100oC.

The compounds of formula IA, where R1is hydrogen, are obtained by catalytic reduction of compounds of formula II, where W, n, m, and R5defined above (R5is predpochtitelen hydrogen source, such as the format of ammonia or formic acid, in an inert solvent. Suitable catalysts are palladium carbon, Nickel Raney catalyst and platinum oxide. Moreover, the preferred catalyst is palladium charcoal. Suitable solvents are C1-C6-alcohols, N,N-dimethylformamide, ethyl acetate, and acetonitrile. The preferred solvent is ethanol. The above reaction is carried out at a temperature from about 0oC to about 60oC and preferably at approximately 25oC.

The compounds of formula IB, where R1is not hydrogen, can be obtained by alkylation reaction of compounds of formula IA (where R1is hydrogen, and W, n and m are defined above) using an alkylating agent of formula R1LG and base in an inert solvent, where LG is an appropriate leaving group, and R1is as it was defined above, except that it is not hydrogen. Examples of acceptable leaving groups are-I, -Br, -Cl, -OSO2Ph, -OSO2CH3and-OSO2CF3. Suitable alkylating agents are alkylhalides (chlorides, bromides, or iodides), alkylsulfate, alkanolamine amides, a, -unsaturated NITRILES, a, -unsaturated sulfones and N, N-unsaturated sulfonamides. While preferred are alkylhalides (e.g. iodides). Suitable bases are triethylamine, sodium carbonate, sodium bicarbonate and sodium hydroxide. The preferred base is triethylamine. Suitable solvents are methylene chloride, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, propanol, and methanol. The preferred solvent is acetonitrile. The above reaction is carried out at a temperature from about 0oC to about 150oC, and preferably from about 25oC to about 65oC.

The compounds of formula IV can be obtained in accordance with the following reaction scheme

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The compounds of formula IX can be obtained by reaction of compounds of formula XI (where W and m are defined above) with a chloride, bromide or iodide in an inert solvent in the presence of a base. Preferred is the reaction with bromide. Suitable solvents are C1-C6-alcohols, methylene chloride, chloroform or carbon tetrachloride. The preferred solvent is one that the preferred base is sodium bicarbonate. The above reaction is carried out at a temperature from about 0oC to about 65oC and preferably at approximately 25oC.

The compounds of formula IV can be obtained by reaction of compounds of formula IX (where W, m, and R6defined above) with an acid chloride or symmetrical anhydride of the formula R7OH in an inert solvent and in the presence of a base. The preferred acid chloride or symmetrical anhydride is the anhydride triperoxonane acid. Suitable solvents are methylene chloride, chloroform, and ethers, including tetrahydrofuran, diethyl ether, and 1-4 dioxane. While the preferred solvent is methylene chloride. Suitable bases are triethylamine, pyridine and sodium bicarbonate. Of them, preferred is pyridine. The above reaction is carried out at a temperature from about 0oC to about 65oC and preferably at approximately 25oC.

The compounds of formula XI can be obtained by the known methods described, for example, in International patent application N PCT/GB91/00908 and in European patent application N 313397A.

The compounds of formula V can be obtained in accordance with the following reaction sleep solvent, containing compounds of formulas VII and VII, where n, R5and R11defined above, and R8represents a C1-C6is alkyl, aryl, or C1-C3-alkylaryl. Suitable solvents are ethers, such as diethyl ether, tetrahydrofuran and 1,4-dioxane. Of them, preferred is tetrahydrofuran. The above reaction is carried out at a temperature from about -78oC to about 80oC and preferably at approximately 25oC.

The compounds of formula V can be obtained by hydride recovery of the compounds of formula VI (where n, R5, R8and R11defined above) using a hydride reducing agent in an inert solvent. Suitable hydride reducing agents are alumoweld lithium, borohydride lithium, borohydride sodium hydride of diisobutylamine. The preferred reagent is a hydride of diisobutylamine. Suitable solvents are ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferred solvent is tetrahydrofuran. The reduction is carried out at a temperature from about -100oC to about 0oC, and preferably from about -80

The compounds of formula VIII are commercially available or they can be obtained by the known methods described, for example, L. Fieser Fieser M. (Reagents for Organic Synthesis, John Wiley Sons, New York Vol.1, page 112(1967).

The compounds of formula I, where W is (i), Z is 0; m is 1, and each of R3and R2is hydrogen, can be obtained according to the following scheme:

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Z 0, m 1, R3H, R2H.

where W is (i).

The compounds of formula XII (where n, R1and R11defined above, and K is chloro, bromo, or iodine (preferably bromo)) can be obtained by the known methods described, for example, in WO 9206973.

The compound of formula XIV, where n, R1, R11and R5defined above, and R13represents a C1-C6is alkyl, aryl, or C1-C3-arylalkyl, can be obtained by a reaction between the compounds of formula XII with dehydroalanine derivative of formula XIII (where R5(preferably benzyl), and R13(preferably methyl) defined above) using the Heck reaction, well known in the art. For this reaction preplate (II) in the presence of phosphine, such as triphenylphosphine or tri-o-tolualdehyde, preferably tri-o-tolualdehyde. Suitable for the Heck reaction bases are trialkylamine, preferably triethylamine, and suitable solvents are acetonitrile and N,N-dimethylformamide, preferably acetonitrile. The above reaction is carried out at a temperature of from about 60oC to 150oC, and preferably at a temperature of distillation of the solvent.

The compounds of formula XV where R13, R1, R11and n are defined above) can be obtained from compounds XIV (where R5is preferably benzyl), by catalytic reduction in a hydrogen atmosphere, at a pressure of preferably from about 1 to about 3 ATM, or using a hydrogen source, such as the format of ammonia or acetic acid in an inert solvent. Suitable for this purpose, the catalysts are palladium carbon, Nickel Raney catalyst and the platinum oxide; however, preferred is palladium charcoal. Solvents suitable for these reactions are C1-C6-alcohols, N,N-dimethylformamide, ethyl acetate and acetonitrile. While the preferred solvent is ethanol. This is these are the same solvents, as identified above, and preferred is ethanol. All these reactions are carried out at a temperature from about 0oC to about 60oC and preferably at approximately 25oC.

The compounds of formula XVI (where n, R1, R11defined above) can be obtained from compounds of formula XV by reaction of the restoration carried out in an inert solvent. As reductants can be used borohydride alkali metals, such as borohydride sodium or lithium; or alumoweld lithium. Of them, preferred is borohydride sodium. Solvents suitable for borohydride reductants are C1-C6-alcohols, preferably ethanol. Solvents suitable for alumohydride reductants are ethers, such as tetrahydrofuran and diethyl ether, preferably tetrahydrofuran. This reaction is carried out at a temperature from about 25oC to about 80oC, and preferably at a temperature of distillation of the solvent.

The compounds of formula I, where W is (i); Z is 0; m is 1; R3and R2both are H, and Y are defined above, can be obtained by condensation of compounds of formulas is lantow phosgene, Y is O, can be used N,N-carbonyldiimidazole, diethylcarbamyl and trichlorochloroform. However, the preferred reagent is the phosgene. Suitable solvents are hydrocarbons or ethers, and preferably toluene. Suitable bases are inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate. This reaction can also be carried out using the corresponding thio-vazgenovich equivalents, where Y is S, such as N,N-thiocarbonyldiimidazole. In the reaction with thio-phosgene are using the same reaction conditions as in the reaction with phosgene.

The compounds of formula I, which by their nature are basic can form a variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, but in practice it is often preferable to first identify the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then to convert this salt into the free base by treatment with an alkaline reagent with subsequent conversion of the obtained free OS is Britania can be easily obtained by processing this basic connection, basically, the equivalent amount of the appropriate mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. The desired solid salt obtained after careful evaporation of the solvent.

To obtain pharmaceutically acceptable acid additive salts of basic compounds of the invention are acids which form non-toxic acid additive salts, i.e. salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, and pamoate (i.e., 1,1-methylene-bis-(2-hydroxy-3-aftout).

The compounds of formula I, which, by their nature, are acidic, i.e., where R1contains carboxylate, can form basic salts with various pharmaceutically acceptable cations. Examples of such salts can serve as salts of alkaline or alkaline-earth metals, in particular sodium and potassium salts. All of these salts can be obtained by standard methods. Chemical obretenia, are such grounds, which form non-toxic basic salts with these acidic compounds of formula I. These non-toxic basic salts come from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, etc., These salts can be easily obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, with subsequent evaporation of the resulting solution to dryness, preferably under reduced pressure. Alternative such salts can be obtained by mixing solutions of the acidic compounds in the lower alcohols with the appropriate alkali metal alkoxide, followed by evaporation to dryness the resulting solution, as described above. In any case, to ensure maximum output of the target product, it is preferable to use stoichiometric amounts of reactants.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to active compounds of the invention are valuable psychotherapeutic means, and a strong agonist of serotonin (5-HT1), and therefore they can be used to treat depression; motion or drugs; "histamine" headache, migraine, chronic paroxysmal of hemicrania; headache associated with vascular disorders; pain and other disorders associated with deficient serotonergic neurotransmission. These compounds may be also used as gipotenzivnyj and vasodilators Central action.

Evaluation of the active compounds of the invention as anti-migraine may be performed by determining the extent to which these compounds can mimic sumatriptan in contact with the selected strip saphenous vein of the dog (P. P. A. Humphrey and other Br.J.Pharmacol. 94, 1128(1988). This effect can be blocked by methiothepin known antagonist of serotonin. Sumatriptan is a known cure for migraines, which are capable of producing a selective increase in carotid vascular resistance have shot the dog. It has been suggested (W. Fenwick and other Br.J.Pharmacol, 96, 83 (1989)) that this fact underlies the effectiveness of this tool.

The activity of compounds of the invention as agonists of serotonin (5-HT) may be determined using in vitro analysis on the binding with the receptor, such as OPI is isovale the cerebral cortex of the rat, and as the radioactive ligand used [3H] -8-OH-PAT; and, as described by P. E. Heuring and S. J. Peroutks (J. Neurosience, vol.7, 894 (1987)) for receptor 5-HT1Dwhere as the source of the receptor used bullish tail core, and as a radioactive ligand used [3H] serotonin; and in any of these analyses on binding to the receptor agonistic activity was assessed using agents with affintity (IC50250 nm or less (table).

The implementation of the invention illustrated in the examples. Available commercial reagents can be used without additional purification. Room temperature is 20-25oC.

Example 1. General procedure for the alkylation reaction of (R)-3-pyrrolidin-2-ylmethyl-1H-indoles.

To a stirred solution of (R)-3-(pyrrolidin-2-ylmethyl)-1H-indole (1.00 mm) and triethylamine (0.126 g, 1.25 mm, 1.25 EQ.) either in anhydrous methylene chloride or anhydrous acetonitrile, or in absolute ethanol or i-propanol (10 ml) at room temperature and under nitrogen atmosphere, was added drop alkylating agent (1.25 mm). The resulting reaction solution was stirred at room temperature and in a nitrogen atmosphere or heated with about edstone was chromatographically on a column of silica gel (approximately 25 g), elwira mixture of methylene chloride:methanol: ammonium hydroxide (9:1:0,1), resulting in a received target connection.

Using a similar procedure, received the following connection:

3-[(N-2-Methoxyethyl)pyrrolidin-2R-ylmethyl] -5-(2-oxo-1,3-oxazolidin - 4S-ylmethyl)-1H-indole.

This used the 5-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-3-(pyrrolidin-2R-ylmethyl)-1H-indole and 2-bromoethylamine ether. As the reaction solvent used a mixture of acetonitrile/ethanol (1:1). The resulting reaction mixture was heated under reflux for 3 hours After column chromatography was obtained target compound (36%) as a pale brown foamy substance.

13C-NMR (CD3OD) 160; 9; 135,9; 127,2; 126,3; 123,8; 123,1; 118,5; 111,3; 109,2; 69,1; 68,1; 67,6; 60,9; 57,8; 54,6, 53,8; 40,4; 29,5; 27,2; 21,3; []25+12o(C= I, MeOH); FAB-LRMS (m/z, relative intensity) 359(23), 358 (MH+,100), 188(26); EI-LRMS (m/z, relative intensity) 357(0,1), 355(2), 143(25), 128(100); VRMS: for C20H27N3O3: calculated: 357,2054; found: 357,2062.

Example 2. General procedure for the catalytic reduction of 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indoles with formation of 3-(pyrrolidin-2-ylmethyl)-1-H-indoles.

Cm is canola (15 ml) was shaken in a hydrogen atmosphere (3 ATM) for 4-24 hours depending on the substrate. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under reduced pressure. The residue was chromatographically on a column of silica gel (approximately 50 g), elwira when this solution of methylene chloride: matanya: ammonium hydroxide (8:2:0,2) or other appropriate solvent system, resulting in a received corresponding 3-(pyrrolidin-2-ylmethyl)-1H-indole.

In accordance with the described procedure has been the following link:

5-(2-Oxo-1,3-oxazolidin-4S-ylmethyl)-3-(pyrrolidin-2R-ylmethyl-1H-indole.

For this reaction used 3-(N-benzyloxycarbonyl-pyrrolidin-2R-ylmethyl)-5-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1H-indole. After column chromatography was obtained target compound (89%) as an amorphous solid: Rf0,30 in a mixture of methylene chloride/methanol/hydroxyamine (6:2:0,2);1H-NMR (CD3OD) 7,43 (Shir.with. 1H); 7,30 (d, J=8,3 Hz, 1H); 7,10 (C. 1H); to 6.88 (DD, J=1,4 and 8.3 Hz, 1H); 4,90 (approximately 3H, exchangeable), to 4.38-or 4.31 (m, 1H); 4,20-4,11 (m,2H); 3,52-of 3.42 (m, 1H); 3,10-2,82 (m, 6N), 2,01-of 1.74 (m, 3H); 1,58 of 1.46 (m, 1H);13C-NMR (CD3OD) d 162,3; 137,3; 129,2; 127,5; 124,5; 124,0; 119,9; 112,8; 112,6; 70,7; 61,2; 47,0; 46,7; 42,2; 32,1; 31,1; 25,5; LRMS (m/z, relative intensity) 299 (3, M+); 230 (31); 144 (18); 70 (100); VRMS for C17H21

A mixture of 1-(pyrrolidin-2-yl)-3-(N-(2-halogenarenes)-N-trichoroethylene)propene (2.00 mm), tetrabutylammonium chloride (2.00 mm), and palladium (II) acetate (0,089 g, 0.40 mm, 0.2 EQ.) in a solution of triethylamine (8 ml) and anhydrous N, N-dimethylformamide (4 ml) was heated under reflux in nitrogen atmosphere for 2 hours the reaction mixture is 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 ethyl acetate (25 ml). The organic extracts were combined, dried with magnesium sulfate and evaporated under reduced pressure. The residue was chromatographically on a column of silica gel (approximately 50 g), elwira appropriate solvent system, resulting in a received corresponding 3-(pyrrolidin-2-ylmethyl)-1H-indole.

In accordance with the described procedure has been the following link:

3-(N-benzyloxycarbonylamino-2R-ylmethyl)-5-(2-oxo-1,3 - oxazolidin-4S-ylmethyl)-1H-indole.

For this reaction used 1-(N-benzyloxycarbonylamino-2R-yl)-3-[N-(2-bromo-4-2-oxo-1,3-oxazolidin-4-ylmethyl)phenyl)-N-trichoroethylene propene. After column chromatography (ethyl acetate/hexane=1:1) was obtained tetsunori) 433 (10, M+), 298(4), 229(18), 204(31), 160(67), 143(20), 91(100), VMRS for C25H27N3O4: calculated 433, 2003; found 433,2018.

Example 4. The General procedure to obtain 1-(pyrrolidin-2-yl)-3-(N-(2-halogenarenes)-N-trichoroethylene)propanol by azocoupling reaction Mitsunobu 2 halogeno-N-trifloromethyl-anilines with 1-(pyrroline-2-yl)-3-hydroxypropane.

To a stirred solution of triphenylphosphine (0,655 g, 2.50 mm, 1.25 EQ.) and diethylazodicarboxylate (of 0.39 ml, 2,48 mm, 1.25 EQ.) in anhydrous tetrahydrofuran (15 ml) at 0oC in nitrogen atmosphere, one drop of solution was added 2-halogeno-N-trichoroethylene (2.5 mm, 1.25 EQ.) in anhydrous tetrahydrofuran (5 ml). Then, one drop of solution was added 1-(pyrrolidin-2-yl)-3-hydroxypropane (R or S, or a racemate, 2.00 mm) in anhydrous tetrahydrofuran (5 ml). The reaction solution was slowly heated to 25oC for 2 h, and then stirred at this temperature (25oC) and in nitrogen atmosphere for another 12 hours the resulting reaction solution was evaporated under reduced pressure, and the residue was chromatographically on a column of silica gel (approximately 150 g), elwira appropriate solvent system, resulting in a received corresponding 1-(pyrrolidin-2-yl)-3-(N-(2-galegeae connection:

1-(N-benzyloxycarbonylamino-2R-yl)-3-[N-(2-bromo-4- (2-bromo-4-(2-oxo-1,3-oxazolidin-4S-ylmethyl)phenyl)-N - trichoroethylene]propene.

For this reaction was used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropane and 2-bromo-4-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1-trichoroethylene. After column chromatography was obtained target compound (100%) as a colorless transparent oily substance; Rf0,45 in ethyl acetate; FAB-LRMS (m/z, relative intensity 612 (5, [MH+with81Br]), 610 (8, [MH+with79Br]), 568(5), 566(8), 502(3), 476(4), 279 (100); VRMS for C27H27BrF3N3O5: calculated 609,1087; found 609,0952.

Example 5. (R)-3-Hydroxy-1-(N-methylpyrrolidine-2-yl)propene.

To a stirred solution of lithium aluminum hydride (0.73 g, 19,24 mm, 2.2 EQ.) in anhydrous tetrahydrofuran (20 ml) at 0oC one drop of solution was added (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropane (2,30 g 8,80 mm) in anhydrous tetrahydrofuran (20 ml). The resulting reaction mixture was heated under reflux in nitrogen atmosphere for 3.5 hours and Then the mixture was cooled and slowly and carefully added decahydrate sodium sulfate (10 g). The resulting mixture was stirred at room t is shivali at room temperature and under nitrogen atmosphere over night. After that, the mixture was filtered through Celiteand the filtrate evaporated under reduced pressure. The oily residue was chromatographically on a column of silica gel (approximately 200 g), elwira mixture of methylene chloride /methanol/ammonium hydroxide (9:1:0,1), resulting in a received target compound (1.13 g, 8.0 mm, 91%) as a clear, colorless liquid:13C-NMR CDCl3) 132,6; 132,5; 69,0; 62,7; 56,6; 40,2; 31,8; 22,1; Analysis for C8H15NO0,175 H5NO (ammonium hydroxide): calculated: C 65,21; H 10,88; N 11,34; Found: C 65,01; H 10,71; N 10,81.

Example 6. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan.

To a stirred solution of ethyl(R)-3-(N-benzyloxycarbonylamino-2-yl)-2-propionate (3.03 g, 10,00 mm) in anhydrous tetrahydrofuran (75 ml) at -78oC and in an atmosphere of nitrogen at a drop of solution was added hydride diisobutylaluminum (1.0 M in hexane, to 22.0 ml, 22,0 mm, 2.2 EQ.). The resulting solution was stirred at -78oC and in an atmosphere of nitrogen for 30 minutes and Then the reaction solution was left for 2 h to warm to room temperature. After this was added a saturated solution of sodium bicarbonate (50 ml) and the aqueous mixture was extracted with ethyl acetate (3 x 50 ml). The extracts were combined, dried with magnesium sulfate is), and received the target compound in the form of clear, colorless product (1,41 g of 5.40 mm, 54%).

1H-NMR (CDCl3d 7,40-7,25 (m, 5H); 5,75-5,63 (m, 2H); 5,20-5,00 (m, 2H); to 4.38 (Shir.m, 1H); 4,06 (Shir.d, J=13,7 Hz, 2H); 3.45 points (Shir.t, J=7,0 Hz, 1H); 2,03 by 1.68 (m, 4H); []25+34oMeOH, c=1,0); VRMS for C15H19NO3calculated 261,1365; found: 261,1356.

Example 7. Ethyl(R)-3-(N-benzyloxycarbonylamino-2-yl)-2-propenoate.

To a stirred solution of N-carbobenzoxy-2-carboxaldehyde (1,17 g, 5.00 mm) in anhydrous tetrahydrofuran at -78oC) was added in portions (solid parts) (carbomethoxyamino)triphenylphosphorane (2,09 g, 6,00 mm, 1.2 EQ.). The reaction mixture is stirred 2 h at room temperature and under nitrogen atmosphere, and then heated under reflux for 1 h in nitrogen atmosphere. After that, the reaction mixture is evaporated under reduced pressure, and the residue was chromatographically on a column of silica gel (approximately 100 g), elwira 20% diethyl ether in hexane, resulting in a received target compound in the form of a colorless transparent oily product (1,11 g, 3,65 mm, 73%);1H-NMR (CDCl3-o6) 7,34-7,25 (m, 5H); 6,89-6,76 (m, 1H); 5,88-5,74 (m, 1H); 5,18-of 5.05 (m, 2H); 4,60-4,43 (m, 1H); 4,17 (sq J=7,1 Hz,Oh inversion of nitrogen, NMR spectroscopy was found two conformer products) d 166,3; 154,7; 147,9; 147,4; 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.

Example 8. General procedure for the synthesis of 2-halogeno-N-trichoroethylene.

To a stirred mixture of N-trichoroethylene (2.00 mm) and sodium bicarbonate (0.21 g, 2:50 mm, 1.25 EQ.) in methanol (10 ml) at 0oC drop) was added bromine (0,113 ml, 2,19 mm, 1.1 equiv.). The reaction mixture is stirred 30 min at 25oC. Then the reaction mixture is evaporated under reduced pressure, and the residue was placed in water, acidified to pH 3 using HCl (10 ml). This aqueous mixture was extracted with ethyl acetate (3 x 15 ml). The extracts were combined, dried with magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (approximately 50 g), elwira appropriate solvent system, resulting in a received corresponding 2-bromo-N-trichoroethylene.

In accordance with the described procedure has been the following link:

2-bromo-4-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1-trichoroethylene.

For this procedure, used 4-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1-trichoroethylene. After to the society: so pl. 157,0-160,0oC;13C-NMR (acetone-d6d 159,3; 139,5; 134,6; 132,9; 130,3; 128,1; 119,9; 118,8; 115,0; 69,4; 53,7; 40,7; []25-28o(MeOH, c=1); VRMS for C12H10Br F3N2O3356,9827 found 365,9824.

Example 9. General procedure for the synthesis of N-triftoratsetilatsetonom.

To a stirred solution of aniline (2.00 mm) and pyridine (of 0.18 ml, 2,22 mm, 1.1 equiv.) in anhydrous methylene chloride (10 ml) at 0oC in nitrogen atmosphere for one drop was added to the anhydride triperoxonane acid (0,31 ml, 2,19 mm, 1.1 equiv. ). The reaction mixture is stirred 3 h at 0oC in nitrogen atmosphere. Then added water (15 ml), and the resulting aqueous mixture was extracted with ethyl acetate (3 x 15 ml). The extracts were combined, dried with magnesium sulfate and evaporated under reduced pressure. If necessary, the residue was subjected to column chromatography on silica gel (approximately 50 g), elwira gradient of ethyl acetate in hexane, resulting in a received corresponding N-trichoroethylene.

In accordance with the described procedure has been the following link:

4-(2-Oxo-1,3-oxazolidin-4S-ylmethyl)-1-trichoroethylene.

For this procedure, used 4-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1-aminobenzo (WO 91/ALC solid product: so pl. 132,0-136,0oC; Rf0,35 in ethyl acetate; []25-14o(MeOH, c=1); analysis for C12H11N2F3O3: calculated: C repossessed a 50.01; H of 3.85; N 9,72; found C 50,29; H 3,81; N 9,67.

Example 10. 5-(2-Benzyloxycarbonylamino-2-methoxycarbonylamino-1-yl)- 3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole.

5-Bromo-3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole (4,65 g, 15,9 mm), N-menthoxycarbonyl-dehydrohalogenation ester (5.0 g, 21.3 mm), tri-o-tolworthy (1.4 g, 4.6 mm), palladium acetate (11) (350 mg, 1.6 mm) and triethylamine (4,7 ml, 33.8 mm) was dissolved in acetonitrile (50 ml) and was heated, with stirring, under reflux overnight under nitrogen atmosphere. After cooling to room temperature the reaction mixture was distributed between ethyl acetate and 2M aqueous sodium carbonate. The organic phase is washed with saline, dried with sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel, elwira gradient of dichloromethane:ethanol (100:0 80:15), resulting in a received target compound (1.4 g) as a foamy substance: Rf0.3 dichloromethane methanol 0,880 aqueous ammonia (90:10:1);1H-NMR (CDCl3) 8,35 (Shir. C. 1H); 7,80 (s, 1H); 7,56 (s, 1H); 7,50 (d, 1H); 7,40-7,28 (m, 6N); 7, 1,90-and 1.54 (m, 4H); Analysis for C26H29N3O40,1 CH2CH20,25 H2O: calculated: C 68,07; H 6,50; N 9,12; found: C 67,94; H 6,51; N 9,29.

Example 11. 5-(2R, S-Amino-2-methoxycarbonylethyl)-3-(N-methylpyrrolidine - 2(R)-ylmethyl)-1H-indole.

5-(2-Benzyloxycarbonylamino-2-methoxycarbonylamino-1-yl)-3- (N-methylpyrrolidine-2R-ylmethyl)-1H-indole (150 mg, 0,34 mm) was dissolved in an ethanol solution of hydrogen chloride (obtained from ethanol (4 ml) and acetylchloride 90,048 ml, 0.68 mm), and the resulting solution was first made during the night in the presence of 10% palladium carbon (100 mg) at room temperature and at a hydrogen pressure of 15 psi (1.05 kg/cm2). The reaction mixture was filtered through a pad of Arbarello and evaporated under reduced pressure. The obtained residue was distributed between ethyl acetate and 2M aqueous sodium carbonate, the aqueous phase was again extracted with ethyl acetate, and the combined organic phases are washed with saline, dried with sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel, elwira gradient of dichloromethane:ethanol (90:10 80:20), and then with a gradient of dichloromethane:methanol:0,880 aqueous ammonia(80:20: 0 80: 20:1), in the che is>573o(c= 0,1, CH3OH);1H-NMR (CDCl3) 8,78 (Shir.s, 1H); 7,37 (s, 1H); from 7.24 (d, 1H); 7,00-to 6.95 (m, 2H); 5,28 (C, 0,2 H, CH2Cl2); 3,28-of 3.78 (m, 1H); and 3.72 (s, 3H); 3.25 to 3,18 (m, 3H); 3,00 of 2.92 (m, 1H); 2,62-of 2.56 (m, 1H); 2,5-2,4 (m, 4H); 2,28-to 2.18 (m, 1H); 1.9 to 1,5 (m, 6N); analysis for C18H25N3O20,1 CH2Cl2calculated: C 67,11; H to 7.84; N 12,97; found: C 67,57; H of 7.90; N 12,77.

Example 12. 5-(2R,S-Amino-3-hydroxyprop-1-yl)-3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole.

5-(2R, S-Amino-2-methoxycarbonylethyl)-3-(N-methylpyrrolidine-2R-ylmethyl)- 1H-indole (or 0.57 g, 1.8 mm) was dissolved in ethanol (2.5 ml) and water (2.5), and the resulting solution slowly at 0oC was added to a stirred suspension of sodium borohydride (72 mg, 1.9 mm) in water (2.5 ml) and ethanol (2.5 ml). Then the solution was heated under reflux for 3 h and cooled to room temperature. After evaporation under reduced pressure the residue was extracted with dichloromethane (8 x 30 ml), the extract was filtered to remove solid material and the filtrate evaporated under reduced pressure. The obtained residue was subjected to azeotropic treatment with the use of dichloromethane (2x), which was obtained 130 mg of the target compound as a white foamy product: Rf0.1 dichloromethane:ethanol:0,880 water am the 3,44-to 3.38 (m, 1H); 3,20-3,10 (m, 3H); 2.95 and-is 2.88 (m, 1H); 2,70-to 2.65 (m, 2H); 2.50 each-of 2.38 (m, 4H); 2.26 and-to 2.18 (m, 1H); 1,90 of 1.00 (m, 7H); Analysis for C17H25N3O 0,33 CH2Cl2: calculated: C 65,94; H 8,19; N 13,31; found: C 65,75; H 8,28; N 12,93.

Example 13. 5-(2-Oxo-1,3-oxazolidin-4R, S-ylmethyl)-3- (N-methylpyrrolidine-2R-ylmethyl)-1H-indole.

5-(2R, S-Amino-3-hydroxyprop-1-yl)-3-(N-methylpyrrolidine-2R-ylmethyl)1 - H-indole (50 mg, 0.17 mm) was dissolved in toluene (2.5 ml). Sodium hydroxide (50 mg) was dissolved in water (0.8 ml) and this solution was added to the obtained toluene solution. The resulting mixture was cooled (ice bath) and stirring, was added a solution of phosgene in toluene (12.5 percent of 0.56 ml). After cooling in an ice bath for 15 min, the reaction mixture was stirred over night at room temperature. The organic phase was separated, the aqueous layer was extracted with ethyl acetate and then dichloromethane, and the organic phase evaporated under reduced pressure, resulting received a white foamy substance. After purification by chromatography on a column of silica gel (suirable with dichloromethane and then with a gradient of dichloromethylene: 0,880 aqueous ammonia(90:10:1 70:30:2) received 15 mg of target compound: Rf0.7 V dichloromethane: methanol: 0,880 aqueous ammonia (70); 4,50 was 4.42 (m, 1H); 4,22-to 4.14 (m, 2H); 3,22 is 3.15 (m, 2H); 3,02-is 2.88 (m, 2H); of 2,75 2,40 (m, 5H); 2,35-of 2.20 (m, 1H); 1,90 of 1.50 (m, 4H). Analysis for C18H23N3O20,5 CH2Cl2: calculated: C 62,43; H to 6.80; N 11,81; found: C 62,66; H of 6.26; N 11,71.

1. Derivatives of indole of General formula I

< / BR>
where W is a

< / BR>
n 1;

m 1;

R1hydrogen, C1WITH8-alkyl or Q-R4where R4COR9, R9C1C8-alkyl, Q - C1C3-alkyl;

R11hydrogen

* the first chiral carbon atom;

second chiral carbon atom,

or their pharmaceutically acceptable salts.

2. Connection on p. 1 of General formula

< / BR>
3. Connection on p. 2, representing CIS-epimer.

4. Connection on p. 1 of formula I, which represents the S-epimer with a second chiral carbon atom.

5. Connection on p. 1, where R1hydrogen, C1- C6-alkyl or-Q-R4.

6. Connection on p. 5 the General formula I

< / BR>
7. Connection on p. 6, which is CIS-epimer.

8. Connection under item 5 of the formula I, which represents the S-epimer with a second chiral carbon atom.

9. Connection on p. 1, where n 1, m 1, R1the hydrogen.

10. Coedine.9 formula I, representing the S-epimer with a second chiral carbon atom.

13. Connection on p. 1, selected from the following compounds: 3-[(N-2-methoxyethyl)pyrrolidin-2R-ylmethyl] -5-(2-oxo-1,3 - oxazolidin-4S-ylmethyl)-1H-indole, 5-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-3-(pyrrolidin-2R-ylmethyl)-1H-indole and 3-(N-methylpyrrolidine-2R-ylmethyl)-5-(2-oxo-1,3-oxazolidin-4R, S-ylmethyl)-1H-indole.

14.The compound of General formula II

< / BR>
where W is a

< / BR>
n 1;

m 1;

R5WITH1WITH6is alkyl, aryl or1- C3-alkylaryl;

R11hydrogen

* the first chiral carbon atom;

second chiral carbon atom.

15. Connection on p. 14 General formula II

< / BR>
16. Connection on p. 15, which is CIS-epimer.

17. Connection on p. 14 General formula II, which represents the S-epimer with a second chiral carbon atom.

18. The compound of General formula III

< / BR>
where W is a

< / BR>
n 1;

m 1;

R5WITH1WITH6is alkyl, aryl or1- C3-alkylaryl;

R6halogen;

R7-COCF3, -SO2CH3, -SO2Ph or-CO2C(CH3)3;

R11hydrogen;

* first hee is R>
< / BR>
where W, R5R7, R11n and m above.

20. Connection on p. 19, which is CIS-epimer.

21. Connection on p. 18 General formula III, which is the S-epimer with a second chiral carbon atom.

 

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< / BR>
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Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to new indole derivative, a process for the production of these compounds and to pharmaceutical compositions used as medicines especially in the treatment of hyperlipidemia and atherosclerosis

The invention relates to new derivatives of 3-methylene-2-oxindole, method of production thereof, to pharmaceutical compositions containing these compounds and to their use as therapeutic agents

The invention relates to agriculture, namely, to the drugs designed to combat ectoparasites of farm and domestic animals and can be used in collective farms, state farms, joint stock and cooperative agricultural associations and farms
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