Derivatives acylaminoalkyl and derivatives aminoindole

 

(57) Abstract:

The invention can be used as pharmaceuticals for the treatment of diseases resulting from a lack of serotonin neurotransmission. The connection is produced by interaction of the corresponding derivatives of aminoindole with carboxylic acid in the presence of an agent activating the carboxylic acid, in an inert solvent. The preferred agent activating the acid is carbonyldiimidazole. As the solvent used diethyl ether 1,4-dioxane or THF and the reaction is carried out at a temperature of from 0 to 65°C (R)-3-(N-benzyloxycarbonylamino-2-ylcarbonyl)-5-dibenzylamino-1H-indole, so pl. 176 - 177oC, ||25= + 112o(tetrahydrofuran, S=1,0). 2 S. p. and 5 C.p. f-crystals, 1 table.

The invention relates to the derivatives of acylaminoacyl and intermediate products for their production. Active compounds of the present invention can be used to treat migraines and other diseases.

In U.S. patent 4839377 and 4855314 and European patent application 313397 described 5-substituted 3-aminoalkylindole. These compounds, as indicated, can be used in the treatment of migraine headaches.

Britanique, can be used in the treatment of hypertension, Raymond syndrome and migraine.

Heb. patent 303506 relates to 3-poly: hydro-pyridyl-5 - elementnum 1H-indoles. These compounds are agonists of 5-HT1receptors, possess vasoconstrictor effect and can be used in the treatment of migraine.

Heb. patent 354777 refers to N-piperidinyl: indolyl: ethylaminomethyl derived. These compounds, as indicated, are agonists of 5-HT1receptors, possess vasoconstrictor effect and can be used in the treatment of headache.

Heb. patents 438230, 494774 and 497512 refer to indorsement five-membered heteroaromatic compounds. These compounds possess agonistic activity towards 5-HT1receptors and can be used in the treatment of migraine and other diseases, for which there are selective agonists of these receptors.

International application PCT/GB91/00908 and Heb. application 313397A belong to the derived 5-heterocyclyl. These compounds, as indicated, have properties that can be used in the treatment and prevention of migraine, "histamine" headache and headache associated with SOS is m

Heb. patent 457701 relates to certain derivatives arylacetamide, which have high affinity for 5-HT1D-serotonin receptors. Indicates that these compounds can be used in the treatment of diseases associated with dysfunction of 5-HT receptors, especially migraines.

The present invention relates to compounds of the formula:

< / BR>
where n is 1; m is 0 or 1; each of Y and W is alanyl, histidyl, i.e. phenylalanyl, glycyl; Deputy R1represents a hydrogen atom, a C1-C6-alkyl; R2is-OR5where R5represents a C1-C3-alkylaryl; R6is a hydrogen atom or their pharmaceutically acceptable salts. These compounds can be used in the treatment of migraine and other diseases.

Compounds of the present invention includes all optical isomers of compounds of formula I (for example, R and S stereoisomer any chiral center) and their racemates, diastereoisomeric or epimeria mixture. Preferred epimere with absolute R-configuration at the chiral carbon atom marked with an asterisk in formula I.

Unless otherwise stated, an alkyl group, referred to in anye or branched group, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or linear or branched and contain linear fragment.

Preferred compounds of the present invention are the compounds of formula I, where n takes on the values 1, m is 0, the substituent R1represents a hydrogen atom, a C1- C4is an alkyl group, the substituent R2represents-OR5.

The following compounds are particularly preferred:

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

5- (N-benzyloxycarbonyl-S-histidyl) amino-3- (N-methylpyrrolidine-2R-ylmethyl) -1H-indole,

5- (N-benzyloxycarbonyl-S-alanyl) amino-3- (N-methylpyrrolidine - 2R-ylmethyl)-1H-indole,

5- (N-benzyloxycarbonyl-S -, i.e. phenylalanyl) amino-3- (N-methyl-pyrrolidin-2R-ylmethyl) -1H-indole.

The present invention also relates to compounds of the formula II:

< / BR>
where n is 1; R1represents a hydrogen atom, a C1-C6-alkyl; R6represents a hydrogen atom. Preferred epimere with absolute R-configuration at the chiral carbon atom marked with an asterisk in formula II. These link>The present invention also relates to pharmaceutical compositions for treating conditions from among hypertension, depression, anxiety, eating disorders, obesity, misuse of medication, "histamine" headache, migraine, pain and chronic of paroxysmal hemicrania and headache associated vascular diseases, which contains a compound of formula I or its pharmaceutically acceptable salt in an amount effective for the treatment of such conditions, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating conditions from among hypertension, depression, anxiety, eating disorders, obesity, misuse of medication, "histamine" headache, migraine, pain and chronic of paroxysmal hemicrania and headache associated vascular diseases, which comprises applying a mammal (e.g. human) in need of such treatment, the compounds of formula I or its pharmaceutically acceptable salt in an amount effective to treat such condition.

The present invention also relates to pharmaceutical compositions for the treatment of diseases that occur due to insufficient neuropenia drugs "histamine" headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders), which contains a compound of formula I or its pharmaceutically acceptable salt in an amount effective for the treatment of such conditions, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treatment of diseases resulting from a lack of serotonin neurotransmission (e.g., depression, anxiety, disorders of the process of food intake, obesity, misuse of medication, "histamine" headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders), which includes the application of a mammal (e.g. human) in need of such treatment, the compounds of formula I or its pharmaceutically acceptable salt in an amount effective to treat such condition.

Compounds of the present invention can be obtained according to scheme 1, is provided at the end of the text.

The compounds of formula I is produced by reaction of the coupling compounds of formula II, where n, R1and R6take the values defined above, with a compound of formulas is howl side and the terminal nitrogen atom on the left side of each residue, moreover, the end C atom substituent W is in the form of a carboxylic acid. The reaction is carried out in the presence of an agent activating the carboxylic acid, in an inert solvent. Acceptable agent that activates carboxylic acid are oxalicacid, thionyl chloride, carbonyldiimidazole, dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide. The preferred agent, activating the carboxylic acid is carbonyldiimidazole. Acceptable solvents are diethyl ether, tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride or N, N-dimethylformamide. The reaction proceeds at temperatures from approximately 0 to approximately 65oC, preferably at a temperature of approximately 25oC (room temperature).

The compounds of formula III are either commercially available products or can be obtained using well-known methods, for example, in accordance with the methods described in the book by M. Bodanszky, Peptide Synthesis, Iohn Wiley and Son, New York (1976).

The compounds of formula II can be obtained in accordance with reaction scheme 2, is provided at the end of the text.

The compounds of formula IIC, where n and the substituent R6take the values defined in place of the compounds of formula IIB, where n and the substituent R6take the values defined above, with an alkylating agent in the presence of a base in an inert solvent. Acceptable alkylating agents are alkylhalogenide (chlorides, bromides, iodides), alkylsulfate, alkylsilane, alkylacrylate, , - unsaturated ketones, a , - unsaturated esters, unsaturated aldehydes, unsaturated amides and unsaturated NITRILES. Preferred alkylhalogenide (iodides). Acceptable solvents are methylene chloride, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, dioxane, N,N-dimethylformamide, ethanol, propanol, methanol. Preferred as the solvent acetonitrile. The reaction is carried out at a temperature between about 0 and 150oC, preferably approximately at a temperature of from 0 to 25oC.

The compounds of formula IIA, where n and the substituent R6take the values defined above, is prepared in the catalytic reduction of the compounds of formula IV where n and the substituent R6take the values defined above, in an atmosphere of hydrogen, preferably at a pressure of from about 1 to 3 atmospheres, or when using a hydrogen source such as formigli, the palladium hydroxide on charcoal, Raney Nickel and platinum oxide. The preferred catalyst is palladium hydroxide on coal. Acceptable solvents are C1-C6-alcohols, N,N-dimethyl - formamide, ethyl acetate and acetonitrile. The preferred solvent is ethanol. The reaction is carried out at a temperature of about 0-100oC, most preferably at a temperature of about 50oC.

The compounds of formula IIB, where n and the substituent R6take the values defined above, are prepared by catalytic reduction of compound of formula V, where n and the substituent R6take the values defined above, in an atmosphere of hydrogen, preferably at a pressure of from about 1 to 3 ATM or using a hydrogen source such as ammonium formate or formic acid in an inert solvent. Appropriate catalysts are palladium on charcoal, palladium hydroxide on charcoal, Raney Nickel and platinum oxide. The preferred catalyst is palladium hydroxide on coal. Acceptable solvents are C1-C6-alcohols, N,N-dimethylformamide, ethyl acetate and acetonitrile. The preferred solvent is ethanol. The reaction of the wire oC.

The compounds of formula IV obtained when the hydride reduction of compound of formula VI using methods known in this field, for example, using methods described in the book by W. A. Reimers "Jndole Aldehydes and ketones" from the series The Chemistry of Heterocyclic Compounds, Vol. 25, Part III, Weissberger, A. and Taylor, E. C. (eds), John Wiley and Sons, New York, p. 403-405 (1979).

The compound of formula VI is obtained using methods known in this field, for example, using methods described in the book by W. A. Reimers "Jndole Aldehydes and ketones" from the series The Chemistry of Heterocyclic Compounds, Vol. 25, Part III. Weissberger, A. and Taylor, E. C. (eds), John Wiley and Sons, New York, pp. 388-389 (1979).

Compound of formula VII get methods known in this field, for example, using methods described in the book Aoyama and T. Shioiri T., Chem. Pharm. Bull. , 3249 (1981). Other halogen atoms can be used instead of chlorine in the compound of formula VII, and get them using methods known in this field, however, the use of compounds with a chlorine atom is preferable.

The compound of formula VIII is prepared using methods known in this field, for example the method described in example 8.

Group-CO2CH2The Ph in the compound of the formula VII and group PhCH2in connection formula is predpochtitelnye. Other protective groups are COCF3, - COCH2CCl3, -CO2C(CH3)3and-CH2OCH2Ph. Compounds of formulas VII and VIII, which contains a protective group, can be prepared using methods known in this field.

The removal of these other protective groups to obtain the compounds of formulas IIA, IIB and IV can also be carried out using known methods, for example, by methods described in the book by T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, New York (1981), p. 218-287.

The compounds of formula I which are basic nature, capable of forming a large number of different salts with various organic and inorganic acids. Although such salts must be pharmaceutically acceptable for use in animals, in practice 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 the latter free base by treatment with an alkaline reagent, followed by conversion of the free base in pharmaceutically acceptable acid additive salt. Acid additive salts of basic compounds of the present invention easily poluchaem solvent or in an acceptable organic solvent, such as methanol or ethanol. With careful evaporation of the solvent to obtain the desired salt.

Acid, which are used to produce pharmaceutically acceptable acid additive salts of basic compounds of the present invention, are selected from among such acids which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, bromohydrin, loggedout, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, pamoat [i.e. 1.1 methylen-bis-(2-hydroxy-3-aftout).

Those compounds of formula I which are also acidic in nature, i.e., when W contains a carboxyl group that can form basic salts with various pharmaceutically acceptable cations. Examples of such salts are salts of alkali and alkaline earth metals, especially sodium and potassium salts. These salts get by normal methods. Chemical bases which are used as reagents to obtain pharmaceutically acceptable basic salts of the present Sobraniye formula I. These non-toxic basic salts are salts derived from such pharmaceutically acceptable cations as sodium, potassium, calcium, magnesium and other These salts can be easily obtained by treatment of the corresponding acidic compounds with an aqueous solution containing pharmaceutically acceptable cations, followed by evaporation of the resulting solution to dryness, preferably under reduced pressure. According to another method they can be obtained by mixing solutions of the acidic compounds in the lower alcohols and desired alkoxides of alkali metals with subsequent evaporation of the resulting solution to dryness similar to the way described above. In any case, it is preferable to use stoichiometric quantities of reagents in order to ensure complete reaction with the formation of the maximum output required of the final product.

The compounds of formula l and their pharmaceutically acceptable salts (in this description referred to as the active compounds of the present invention) are useful psychotherapeutic means and a potential agonist of serotonin (5-HT1) and can be used in the treatment of depression, anxiety, ri, chronically the paroxysmal hemicrania and headache associated vascular diseases, and other diseases caused by insufficient neurotransmission serotonin. The connection can also be used as an active Central antihypertensive and vasodilators. Active compounds of the present invention may be considered as a anti-migraine when checking the extent to which they imitate sumatriptan while reducing isolated strips of the subcutaneous foot vein of a dog (P. P. A. Humphrey et al. , B. J. Pharmacol., 94, 1128, 1988). This effect can be blocked by using methiothepin known antagonist of serotonin. Sumatriptan, as it is known, can be used in the treatment of migraine and causes a selective increase in carotid vascular resistance have shot dogs. It is assumed that this action is the basis of its effectiveness (W. Fenwick et al., Br.J. Pharmacol., 96, 83, 1989).

Serotonin 5-HT1agonistic activity is measured by assessing binding of the receptor in vitro as described for 5-HT1A- receptor using cortex of rats as a source of receptors and (3H)-8-OH-D PAT as radioligand (D. Technica receptor and [3H] serotina as radioligand (R. E. Heuring and S. J. Peroutka, J. Neuroscience, vol. 7, 894, 1987). 5-HT1agonistic activity is attributed to agents in the region have affinity (IC50) 250 nm or below in any binding. The following table shows the pharmacological tests on the binding of the receptors 5-HT1Aand 5-HT1D.

Compositions of the present invention can be retseptoriani conventional ways using one or more pharmaceutically acceptable carriers. Consequently, the active compounds of the present invention can be retseptoriani for oral, transbukkalno, sublingual, vnutripuzarnogo, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation.

The following examples illustrate the compounds of the present invention. Commercial reagents are used without additional purification. Under chromatography understand column chromatography is carried out using 32-63 μm silica gel and pressurized nitrogen (fast chromatography was carried out). Room temperature means a temperature of 20 - 25oC.

Example 1. General meta amino acid (1.1 mmol, 1.4 equiv.) in anhydrous methylene chloride (5 ml) was added with stirring carbonyldiimidazole (180 mg, 1.4 mmol, 1.1 EQ.). The reaction mixture was stirred at room temperature in a nitrogen atmosphere up until the reaction mixture becomes transparent (from 15 min to 24 h, depending on the substrate), and at this point are added directly to the reaction mixture the corresponding derivative of 5-aminoindole (0.80 mmol). The resulting solution was stirred at room temperature under nitrogen atmosphere for 2 h and then directly chromatographic using silica gel (approximately 20 g, eluent methylene chloride/methanol/triethylamine, 8:1:1) and get the product of the reaction of amino acids with 5-aminoindole.

Using this technique, we obtained the following compounds.

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

As reagents are N-benzyloxycarbonyl-glycine and 5-amino-3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole. After chromatography was carried out according to the method described above, get the named compound as a light red foam (74%) :Rf) = 0.3 methylene chloride/methanol/triethylamine 8 : 1 : 1.

Range PMR (CDCl3), M. D.: 9,25 (ush.s, NH), remaining 9.08 (ush.s, NH 2,56 - of 2.36 (m, 2H), a 2.36 (s, 3H), of 2.16 (DD, J =8.7 and 17.3 Hz, 1H), 1,76-of 1.44 (m, 4H).

Mass spectrum (LR): (m/z, relative intensity) 420 (2), 418 (22), 310 (4), 228 (4), 171 (13), 108 (25), 84 (100).

Mass spectrum (HR):

Calculated for C24H28N4O3: 420.216,

Found: 420.208.

B. 5-(N-Benzyloxycarbonyl-S-histidyl) amino-3- (N-methyl - pyrrolidin-2R-ylmethyl)-1H-indole

As reagents are N-benzyloxycarbonyl-S-histidine and 5-amino-3- (N-methylpyrrolidine-2R-ylmethyl)-1H-indole. After chromatography was carried out according to the method described above, get the named compound as a light yellow foam (46%) : Rf=0.4, methyl chloride/methanol/ammonium hydroxide, 8:2:0.1.

An NMR spectrum13C(CD3OD), M. D.: 172.3, 158.3, 138.1, 136.2, 135.7, 130.7, 129.5, 129.0, 128.8, 128.6, 124.8, 117.3, 113.4, 112.3, 68.4, 67.7, 58.3, 57.3, 40.9. 32.2, 31.2, 30.2, 22.4.

Mass spectrum (FAB): (m/z, relative intensity) 501 ([M+], 100), 417 (4), 367 (6), 309 (4), 273 (6).

Elemental analysis:

Calculated for C28H32N6O30.25 H2O:

C 66.58, H 6.49, N 16.63,

Found: C, 66.47, H 6.59, N 16.48,

C. 5-(N-Beneluxtunnel-S-alanyl) amino-3- (N-methyl - pyrrolidin-2R-ylmethyl) -1H-indole

As reagents are N-benzyloxycarbonyl- -S-alanine and 5-amino-3-(N-methylpyrrolidine-2R-elmet the th foam (33%): Rf= 0.1, methylene chloride/methanol/ammonium hydroxide, 9:1:0.1.

An NMR spectrum13C (CDCl3), M. D.: 177.9, 155.9, 138.6, 136.8, 131.4, 128.4, 127.9. 127.6, 124.0, 113.3, 112.3, 109.1, 103.5, 68.6, 66.4, 56.1, 51.3, 39.7, 30.4, 26.4, 21.4, 19.4.

Elemental analysis:

Calculated: C25H30N4O30.5 ethyl acetate (C4H8O2)0.5 methylene chloride (CH2Cl2): C, 63.42, H 6.77, N 10.75.

Found: C, 63.45, H 6.72, N 10.7.

D. 5- (N-Benzyloxycarbonyl-S -, i.e. phenylalanyl) amino-3- (N-methylpyrrolidine-2R-ylmethyl)-1H-indole

As reagents are N-benzyloxycarbonyl-S-phenylalanine and 5-amino-3-(N-methylpyrrolidine-2R-ylmethyl)-1H-indole. After chromatography was carried out according to the method described above, get the named compound as a white foam (90%): Rf=0.7, methylene chloride/methanol/ammonium hydroxide, 9:1:0.1.

An NMR spectrum13C (CDCl3), M. D.:169.4. 156.2, 136.6, 136.1, 134.0, 129.4, 129.0, 128.7, 128.5, 128.2, 128.0. 127.6, 127.0, 123.4, 116.5, 113.6, 111.4, 111.3, 67.1, 66.6, 57.4, 57.1, 40.7, 39.1, 31.4, 29.6, 21.8.

Mass spectrum (FAB): (m/z, relative intensity) 511 ([M+], 77), 281 (11), 147 (100).

Mass spectrum (HR):

Calculated for (C31H34N4O3H)+511.2712.

Found 511.2687.

Elemental analysis:

Calculated for C31H34
To a solution of 5-amino-(R)-3-(pyrrolidin-2-ylmethyl)-1H-indole (1.00 mmol) and triethylamine (0.126 g, 1.25 mmol, 1.25 EQ.) in anhydrous methylene chloride, anhydrous acetonitrile, absolute ethanol or ISO-propanol (10 ml) under stirring and at room temperature in nitrogen atmosphere are added dropwise alkylating agent (1.25 mmol). The resulting solution was then stirred under nitrogen atmosphere at room temperature for 1 to 20 hours depending on the substrate. The resulting mixture was immediately chromatographic on silica gel (approximately 25 g, eluent methylene chloride/methanol/ammonium hydroxide, 9: 1:0.1) and get 5-amino- (R)-3- (N-alkylpyridine-2-ylmethyl) -1H-indole.

Example 3. (R)-5-Amino-3-(pyrrolidin-2-ylmethyl)-1H-indole

A mixture of (R)-3-(N-benzyloxycarbonylamino-2-ylmethyl) -5-dibenzylamino 1H-indole (7.90 g, 14.91 mmol) and wet palladium hydroxide (II) on carbon (catalyst of Perlman, 3.16 g) in absolute ethanol (100 ml) is shaken in hydrogen atmosphere (3 ATM) for 12 h at room temperature. The resulting mixture was filtered through diatomaceous earth and the filtrate evaporated and dried under reduced pressure. Get the named compound as a white foam (3.20 g, 100%).

Range PMR (CD3OD), M. D., 7.18 (doctor J=8.5 Hz, 1H), 7.08 (CD3OD), M. D.: 140.1, 133.4, 129.1, 125.0, 114.6, 113.1, 109.8, 105.1, 62.1, 46.0, 31.1, 29.1, 24.3.

Mass spectrum (IR): (m/z , relative intensity) 215 (M+,2), 198 (1), 146 (100), 128 (7), 117 (9), 70 (60).

Example 4. (R) -3- (N-benzyloxycarbonylamino-2-ylmethyl) -5-diben-thylamino-1H-indole

To a solution of (R)-3-(N-benzyloxycarbonylamino-2-Ilker-bonyl)- 5-dibenyline-1H-indole (1.50 g, 2.75 mmol) in anhydrous tetrahydrofuran (30 ml) is added solid litebrite (0.24 g, 11.0 mmol, 4 EQ.). The reaction mixture is refluxed for 4 hours Then add saturated aqueous sodium bicarbonate solution (10 ml) and the mixture is stirred at room temperature for 30 minutes the resulting aqueous mixture is extracted with ethyl acetate (325 ml), the organic extracts combined, dried with magnesium sulfate and evaporated in vacuum. After column chromatography of the resulting residue on silica gel (approximately 50 g, eluent ethyl acetate/hexane, 1: 3) get a named connection 1.02 g, 70%) as a white foam.

Mass spectrum (FAB): (m/z, relative intensity) 530 (MH+, 87), 529 (M+, 100), 439 (10), 409 (10), 325 (32), 235 (20).

Example 5. (R)-3- (N-Benzyloxycarbonylamino-2-ylcarbonyl) -5 - dibenzylamino-1H-indole

To a mixture of (R)-N-CT is stirring oxalicacid (1.87 ml, 21.62 mmol. 1.5 EQ.). The resulting mixture, in which there is a bubbling gas, stirred at room temperature under nitrogen atmosphere for 1.5 h, the Reaction mass is then evaporated in a vacuum, isolated anhydride (R)-N-carbobenzoxy which is dissolved in anhydrous ether (50 ml). The resulting solution was slowly dropwise added with stirring to a pre-prepared solution of 5-dibenzylamino (9.00 g, 28.81 mmol, 2.0 EQ.) and ethylacetamide (3.0 M solution in ether, 10.08 ml, 30.25 mmol, 2.1 EQ.) in anhydrous ether (75 ml), stirred at room temperature under nitrogen atmosphere for 30 min before adding a solution of the anhydride (R)-N-carbobenzoxy. The resulting reaction mass was stirred at room temperature under nitrogen atmosphere for 30 min and then add ethyl acetate (100 ml) and saturated sodium bicarbonate solution (75 ml). The organic layer is separated and the aqueous layer extracted with ethyl acetate (100 ml). The organic extracts are combined, dried with magnesium sulfate, evaporated in vacuum. Receive oil is green in color, with rubbing with anhydrous ether (50 ml) get the named compound as a white solid (3.20 g, 21%): so pl. 176.0-177.0oC.

25= +112oC (tetrahydrofuran (THF), with a = 1.0.).

Elemental analysis:

Calculated for C35H33N3O3:

C 77.32, H 6.12, N, 7.73.

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

Example 6. (R)-5-Amino-3- (N-methylpyrrolidine-2-ylmethyl) -1H-indole

A mixture of (R) -5-dibenzylamino-3- (N-methylpyrrolidine-2-ylmethyl) -1H-indole (1.08 g, 2.64 mmol) and palladium hydroxide (II) coal (0.6 g) in absolute ethanol (25 ml) is shaken in hydrogen atmosphere (3 ATM) at 40oC for 4 h the mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuum. Get a named connection (0.60, 2.62 mmol, 99%) as a white foam.

Range PMR (DMCO-d6), M. D.: 10.65 (ush.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= +9oC(MeOH, C = 1.0).

Mass spectrum (HR):

Calculated for C14H19N3: 229.1575,

Found: 229.1593.

Example 7. (R)-5-Dibenzylamino-3-(N-methylpyrrolidine-2-ylmethyl)-1H - indole

To a mixture of socialogical (0.96 g, 25.2 mmol, 2.0 EQ.) and anhydrous tetrahydrofuran (125 ml) under stirring and at 0oC is added dropwise a solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylmethyl)-5-dibenzylamino-1H-intoi temperature in nitrogen atmosphere for 30 minutes Then add litebrite (0.55 g, 25.2 mmol, 2.0 EQ.) and the reaction mass is refluxed (66oC) in nitrogen atmosphere for 6 h, the Reaction mass is then cooled and successively added water (1.5 ml), a solution of sodium hydroxide (20%, 1.5 ml) and another portion of water (4.5 ml). The mixture is stirred at room temperature under nitrogen atmosphere for 1 h, filtered through diatomaceous earth and the filtrate evaporated in vacuum, get a green oil (8.8 g). The oil obtained is dissolved in absolute ethanol (90 ml) and added cesium carbonate (8.0 g) and sodium carbonate (8.0 g). The resulting mixture was refluxed for 12 hours the Reaction mass is evaporated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (50 ml) and ethyl acetate (100 ml). The organic layer is separated and the aqueous layer extracted with ethyl acetate (100 ml). The organic extracts are combined, dried with magnesium sulfate and evaporated in vacuum. Get a brown oil. After column chromatography of the separated oil on silica gel (approximately 200 g, eluent methylene chloride/methanol/ammonium hydroxide, 9:1:0.1) get the named compound (4.63 g, 89%) as a light green foam.

Range PMR (CDCl3), m is 52 (DD, J=9.5 and 13.9 Hz, 1H), 2.39-2.15 (m, 2H), 2.30 (s, 3), 1.85-1.40 (m, 4H).

An NMR spectrum 13C (CDCl3), M. D.: 143.2, 139.7, 130.5, 128.5, 128.2, 127.3, 126.8, 122.9, 112.5, 112.2, 111.8, 103.4, 67.0, 57.4, 56.4, 40.6, 31.4, 29.7, 21.9.

Mass spectrum (HR):

Calculated for C28H31N3: 409.2520,

Found 409.2475.

Example 8. 5-Dibenzylamino-1H-indole

To a mixture of 5-aminoindole (3.00 g, 22.7 mmol) and triethylamine (10.5 ml, 74.9 mmol, 3.3 EQ. ) in acetonitrile (30 ml) under stirring and at room temperature in a nitrogen atmosphere is added dropwise benzylbromide (8.2 ml, 68.9 mmol, 3.0 EQ.). The resulting mixture was refluxed under nitrogen atmosphere for 3 h Then the reaction mass is filtered, the filtrate evaporated in vacuum. After column chromatography on silica gel (approximately 200 g, eluent ethyl acetate/hexane, gradient from 1:9 to 1:1) get a named connection in the form of almost white solid product (6.19 g, 87%): so pl. 124.0-126.0oC.

An NMR spectrum13C (acetone-d6), M. D.; 144.3, 140.8, 131.8, 129.9, 129.2, 128.3, 127.5, 125.7, 113.5, 112.4, 106,4, 101.9, 57.0.

TLC (15% ethyl acetate in hexane): Rf= 0.3.

1. Derivatives acylaminoalkyl General formula

< / BR>
where n = 1;

m = 0 or 1;

Y and W each - glycyl, histidyl, alanyl, Penilaian
-alkylaryl;

R6is hydrogen,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, having the General formula

< / BR>
where R1, R2, R6, W, Y, m and n have the meanings specified in paragraph 1.

3. Connection on p. 1, where m = 0.

4. Connection on p. 3, having a General formula

< / BR>
where R1, R2, R6, W and n have the meanings specified in paragraph 1.

5. Connection on p. 1 selected from 5-(N-benzyloxycarbonylglycine)amino - 3-(N-methylpyrrolidine-2R - ylmethyl)-1H-indole, 5-(N-benzyloxycarbonyl - S-histidyl)amino-3-(N - methylpyrrolidine-2R-ylmethyl)- 1H-indole, 5-(N-benzyloxycarbonyl - S-alanyl)amino-3-(N - methylpyrrolidine-2R-ylmethyl)- 1H-indole and 5-(N-benzyloxycarbonyl - S -, i.e. phenylalanyl)amino - 3-(N-methylpyrrolidine-2R-ylmethyl)- 1H-indole.

6. Derivatives aminoindole General formula II

< / BR>
where n = 1;

R1is hydrogen, C1- C6-alkyl;

R6- hydrogen.

7. Connection on p. 6, having the General formula

< / BR>
where R1and R6matter under item 6.

 

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,

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< / BR>
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