Derivatives of indole containing pharmaceutical compositions

 

(57) Abstract:

Derivatives of indole of the formula I, where A is a direct bond or alkyl, R1is hydrogen or alkyl, W, X, Y and Z each independently is oxygen, sulfur, nitrogen or carbon, provided that at least one of W, X, Y, or Z is nitrogen, one of R2, R3, R4and R5represents C1-6- alkyl, phenyl, C1-3-alkylphenyl, and the other is hydrogen, and the specified phenyl possibly substituted C1-4- alkyl, halogen, C1-4-alkoxygroup, hydroxyl. Pharmaceutical composition based on compounds of formula I have activity 5-HT1agonist. The active compounds can be used for treatment. The invention relates also to compounds of formulas II and III, which can be used as intermediates in obtaining indole derivatives of the formula I. 4 C. and 16 h.p. f-crystals.

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The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use. The active compounds according to the present invention can be used to treat migraine and other diseases.

In the U.S. patents NN 4839377 and 4855314, Ola. It is reported that these compounds can be used for treatment of migraine.

In British patent application 040279 refer to 3-aminoalkyl-1H-indol-5-thioamides and carboxamide. It is reported that these compounds can be used to treat hypertension, diseases of Rama and migraines.

In European patent application, publication N 303506, refer to 3-polyhydroxyethyl-5-substituted 1H-indoles. It is reported that these compounds have affinity to the receptor 5-HT1and vasoconstrictive action and can be used for treatment of migraine.

In European patent application, publication N 35477, refer to N-piperidinyl: indolyl ethyl-alkanesulphonic derivatives. It is reported that these compounds have affinity to the receptor 5-HT1and vasoconstrictive action and can be used for the treatment of cerebral pain.

In European patent application, publication NN 438230, 494774 and 497512, refer to substituted indole group of five-membered heteroaromatic compounds. It is reported that these compounds have activity, due to the affinity to the receptor type 5-HT1and can be used to treat migraine and other disorders that are prophetic is iswalnum indole of General formula I

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where

A - direct connection or C1-C4-alkyl;

R1is hydrogen or C1-C6-alkyl;

W, X, Y and Z each independently represents oxygen, sulfur, nitrogen or carbon provided that at least one of W, X, Y, or Z is nitrogen;

one of R2, R3, R4and R5represents C1-C6-alkyl, phenyl, C1-C3-alkylphenyl, and the other is hydrogen, and the specified phenyl possibly substituted C1-C4-alkyl, halogen, C1-C4-alkoxygroup, hydroxyl;

as well as its pharmaceutically acceptable salt.

These compounds possess agonistic 5-HT1activity and can be used in the treatment of migraine and other diseases.

Compounds according to the invention include all optical isomers of formula I (for example, R - and S-configuration at any chiral center) and their racemic, diastereomeric or epimeria mixture.

For example, a derivative of indole is a compound of the formula I

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where

the values of A, R1- R5, W, X, Y, and Z above

and it preferably represents a CIS-epimer.

Preferred are derivatives of indole, where R1OST or carbon, for example, a derivative of indole is a compound of the formula

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and it preferably represents a CIS-epimer.

Especially preferred are the following compounds:

(R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-methylpyrrolidine-2 - ylmethyl)-1H-indole,

(R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(pyrrolidin-2-ylmethyl)- 1H-indole,

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(N-methylpyrrolidine-2 - ylmethyl)-1H-indole,

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(pyrrolidin-2-ylmethyl)- 1H-indole,

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(N-methylpyrrolidine - 2-ylmethyl)-1H-indole, and

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(pyrrolidin-2 - ylmethyl)-1H-indole.

The present invention relates also to a pharmaceutical composition having agonistic 5-HT1activity, which contains an effective amount of a derivative of indole of General formula I above, and pharmaceutically acceptable carrier.

The present invention relates to indole derivative of General formula II

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where

A is a direct bond or C1-C4-alkyl;

W, X, Y and Z each independently represents oxygen, sulfur, nitrogen or carbon provided that at least one of W, X, Y and Z is nitrogen;

R>R13- alkylphenyl, and specified phenyl possibly substituted C1-C4-alkyl, halogen, C1-C4-alkoxygroup, hydroxyl,

for example, a derivative of indole is a compound of formula II

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where the values of R2- R5, R13, W, X, Y, and Z above,

and it preferably represents a CIS-epimer.

Of the compounds of General formula II are preferred indole derivatives, where Z is nitrogen, Y is carbon, W and X each independently represents oxygen, sulfur, nitrogen, or carbon, for example, a derivative of indole is a compound of formula II

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and it preferably represents a CIS-epimer.

The compounds of formula II can be used as intermediates in obtaining indole derivatives of General formula I.

The present invention relates to indole derivative of General formula III

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where

A is a direct bond or C1-C4-alkyl;

W, X, Y, Z each independently represents oxygen, sulfur, nitrogen or carbon provided that at least one of W, X, Y, or Z is nitrogen;

one of R2- R5- C1-C6-alkyl, phenyl, C1-C3-alkyl is3,

for example, a derivative of indole is a compound of formula III

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where

values of R2- R5, R13- R15, W, X, Y, and Z above,

preferably it represents a CIS-epimer.

Of the compounds of General formula III, the preferred derivatives of indole, where Z is nitrogen, Y is carbon, W and X each independently represents oxygen, sulfur, nitrogen, or carbon, for example, a derivative of indole is a compound of formula III

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preferably it represents a CIS-epimer.

The compounds of formula III can be used as intermediates in obtaining the derivatives of indole of formula II.

The present invention also relates to pharmaceutical compositions for the treatment of a condition selected from among the following: hypertension, depression, anxiety, disturbance in feeding behavior, obesity, substance abuse, "histamine" headache, migraine, pain, chronic paroxysmal hemicrania and headache associated with vascular disorders, which contains a certain amount of the compounds of formula I or its pharmaceutically acceptable salt, is effective for the treatment of this condition and Pharm is klonoa scheme:

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Compounds of formula III can be obtained by the reaction of a combination of Mitsunobu compounds of formulas IV and V, where n, A, W, X, Y, Z, R2- R5, R11- R15defined above, with the use of phosphine and azodicarboxylate in a suitable solvent. In a number of suitable phosphines include trialkylphosphine and triarylphosphine, preferably triphenylphosphine. Suitable azodicarboxylate include dialkyldithiocarbamate, preferably diethylazodicarboxylate. In a number of suitable solvents include methylene chloride, ethers (tetrahydrofuran, diethyl ether and 1,4-dioxane), N,N-dimethylformamide and acetonitrile. The preferred solvent is tetrahydrofuran. The reaction is carried out at a temperature of from about 0oC to about 65oC, preferably at approximately 25oC.

Compounds with formula II can be obtained catalyzed by transition metals by the reaction of cyclization of compounds of formula III, where n, A, W, X, Y, Z, R2- R5, R11and R13defined above, R14- halogen (preferably bromine or iodine), and R15is-COCF3, -SO2CH3, -SO2Ph or-CO2C(CH3)3preferably Triplane. Suitable catalysts include palladium salt such as palladium (II) acetate or palladium (II) chloride (preferably acetate, palladium and rhodium salt such as Tris(triphenyl)rhodium (I) chloride. Suitable solvents include N,N-dimethylformamide, acetonitrile and N-methylpyrrolidine. The preferred solvent is N,N-dimethylformamide. Suitable interphase catalysts include halides of tetraalkylammonium, preferred is Tetra-n-butylammonium. Suitable bases include tertiary amines, acid sodium carbonate, and sodium carbonate. The preferred base is triethylamine. The reaction is carried out at a temperature of from about 60oC to about 180oC, preferably from about 80oC to about 100oC.

Compounds of formula IB (R1= -CH3) is obtained by hydride recovery connection with formula II, where n, A, W, X, Y, Z, R2- R5defined above, and R13selected from C1-C6the alkyl, aryl and alkylaryl (preferably benzyl), hydride regenerating reagent in an inert solvent. Suitable hydride reducing reagents include sociallyengaged, DIBORANE, lithium borohydride and sodium amide. Predpochtitel the silt 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 30oC to about 100oC, preferably from about 65oC to 70oC.

Compounds of formula IA (R1= H) is obtained by catalytic reduction of the compound with formula II, where n, A, W, X, Y, Z, R2- R5and R13defined above, in an atmosphere of hydrogen, preferably at a pressure of from about 1 to about 3 atmospheres, or when using a hydrogen source such as ammonium formate or formic acid in an inert solvent. Suitable catalysts include palladium on charcoal, Raney Nickel and platinum oxide. The preferred catalyst is palladium on coal. Suitable solvents include C1-C6-alcohols, N,N-dimethylformamide, ethyl acetate and acetonitrile. The preferred solvent is ethanol. The reaction is carried out at a temperature of from about 0oC to about 60oC, preferably at approximately 25oC.

Compounds of formula IC (R1H) is obtained by alkylation of compounds of formula IA (R1= H), where R2- R5, R11, W, X, Y, Z, A and n Predela leaving group, and R1defined above but not hydrogen. Examples of suitable leaving groups include,- I, -Br, -Cl, -OSO2Ph, -OSO2CH3and-OSO2CF3. Suitable alkylating reagents include haloalkyl (chlorides, bromides or iodides), alkylsulfate, alkylsilane, akitriptyline, , - unsaturated ketones, a , - unsaturated esters, unsaturated amides, , - unsaturated NITRILES. Preferred are haloalkyl (iodides). Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethyl ether, dioxane, N,N-dimethylformamide, ethanol, propanol and methanol. The preferred solvent is acetonitrile. The reaction is carried out at a temperature of from about 0oC to about 150oC, preferably from about 25oC to about 65oC.

Compounds of formula V receive according to the following reaction scheme:

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Compounds of formula VI can be obtained using the Wittig reaction in a suitable solvent, which comprises compounds of formulas VII and VIII, where n and R13defined above. R16represents C1-C6is alkyl, aryl or alkylaryl. Suitable solvents include ethers, takin. The reaction is carried out at a temperature from about -78oC to about 30oC, preferably at about -78oC.

Compounds of formula V can be obtained by hydride recovery connection with formula VI, where n, R13and R16defined above, hydride regenerating reagent in an inert solvent. Suitable hydride reducing reagents include sociallyengaged, lithium borohydride, sodium borohydride and the hydride diisobutylaluminum. The preferred reagent is a hydride diisobutylaluminum. Suitable solvents include ethers, such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. The preferred solvent is tetrahydrofuran. The restoration carried out at a temperature from about -100oC to about 0oC, preferably from about -80oC to about -70oC.

Compound with the formula VII may be obtained by methods known in the art, such as described in the works of S. Kiyooka, et al. J. Org. Chem., 5409 (1989) and y Hamado, et al., Chem. Pharm. Bull., 1921 (1982).

Compounds with formula VIII are either commercially available or can be obtained by methods known in the art, such as described in L. Fieser aniem following scheme of reactions:

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Compounds of formula IX can be obtained by reaction of a compound with formula XI, where A, W, X, Y, Z, R2, R3, R4and R5defined above, with chlorine, bromine or iodine in a suitable solvent in the presence of a suitable base. Preferred is the reaction with bromine. Suitable solvents include C1-C6-alcohols, methylene chloride, chloroform, or carbon tetrachloride. The preferred solvent is methanol. Suitable bases include triethylamine, pyridine, sodium carbonate and acid sodium carbonate. The preferred base is acidic sodium carbonate. The reaction is carried out at a temperature of from about 0oC to about 65oC, preferably at approximately 25oC.

Connection with formula IV can be obtained by reaction of compounds of formula IX, where A, W, X, Y, Z, R2, R3, R4, R5and R14defined above, with an acid chloride or symmetrical anhydride of the acid of formula R15CO2H in a suitable solvent in the presence of a suitable base. The preferred acid chloride or acid anhydride is the anhydride triperoxonane acid. Suitable solvents include globpattern solvent is methylene chloride. Suitable bases include triethylamine, pyridine and acid sodium carbonate. The preferred base is pyridine. The reaction is carried out at a temperature of from about 0oC to about 65oC, preferably approximately 25oC.

Compounds of formula XI can be obtained using methods known in the art, such as described in European patent application, publication N 0438230 A2.

Compounds of formula IX, where W is oxygen, X and Z is nitrogen and Y is carbon, can also be obtained by the reaction between the compounds of formula XII

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and formula XIII

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where

A, R4, R12defined above,

R17- C1-C6is alkyl or aryl,

in an inert solvent in the presence of a base [P. Sauerberg, et al., J. Med. Chem., 687 (1991), G. A. Showell, J. Med., Chem., 1086 (1991) and European patent application, publication N 0438230 A2. Suitable solvents include ethers, such as tetrahydrofuran, 1,4-dioxane and diethyl ether, and methylene chloride, chloroform, carbon tetrachloride and C1-C6-alcohols. The preferred solvent is tetrahydrofuran. Suitable bases include sodium metal, sodium hydride, potassium hydride and Tr is Colo 0oC to 101oC, preferably at about 66oC.

Compounds of formula XII, if they are not commercially available, can be obtained by reaction of compounds of formula XIV

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where

A and R17defined above,

with chlorine, bromine or iodine in a suitable solvent in the presence of a suitable base. Preferred is the reaction with bromine. Suitable solvents include C1-C6- alcohols, methylene chloride, chloroform or carbon tetrachloride. The preferred solvent is methanol. Suitable bases include triethylamine, pyridine, sodium carbonate and acid sodium carbonate. The preferred base is acidic sodium carbonate. The reaction is carried out at a temperature of from about 0oC to about 65oC, most preferably at about 25oC.

Compounds of formula XIII can be obtained by methods known in the art, such as described in C. L. Bell et al., J. Org. Chem., 2873 (1964).

Compounds of formula XIV are either commercially available or can be obtained using methods known in the art, such as described in E. Ferber, et al., Chem. Ber., 839 (1939).

Connection with formula I, which is and inorganic and organic acids. Although such salts must be pharmaceutically acceptable for application to animals, in practice, often it is preferable to select a compound with the formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter back to the free base by treatment with an alkaline reagent, and then to turn the free base in a pharmaceutically acceptable salt with an acid. Salts with acids the major compounds in this invention are easily obtained by treating the major compounds substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. With careful evaporation of the solvent is obtained the desired solid salt.

The acid used to obtain pharmaceutically acceptable salts of basic compounds of this invention form non-toxic salts, i.e. salts containing pharmacologically 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, fumariaceae with formula I, which by nature are also acidic, i.e. if R2contains carboxyl, can form basic salts with various pharmacologically acceptable cations. Examples of such salts include salts with alkali and alkaline earth metals, in particular sodium and potassium salts. All these salts receive by conventional methods. The chemical bases that are used as reagents for producing pharmaceutically acceptable basic salts of this invention are those which form non-toxic basic salts described here, the acidic compounds with formula I. These non-toxic basic salts include derivatives pharmacologically 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, followed by evaporation of the resulting solution to dryness, preferably under reduced pressure. They can also be obtained in an alternative way, by mixing solutions of the acidic compounds and the desired alkoxide of an alkali metal in a lower alcohols with subsequent evaporation of the resulting solution to dryness so to ensure complete reaction with the maximum yield of the desired end product.

Connection with formula I and their pharmaceutically acceptable salts (hereinafter also referred to as the active compounds according to the invention) can be used as a psychotherapeutic tool, have a potential affinity for serotonin (5-HT1) and can be used in the treatment of depression, anxiety, disorders in feeding behavior, obesity, substance abuse, "histamine" headache, migraine, chronic paroxysmal of hemicrania and headache associated with vascular disorders, pain and other diseases caused by the lack of serotonergic neurotransmission. Connections can also be used as antihypertensive and vasodilator Central action. Evaluation of the active compounds according to the invention as anti-migraine can be carried out by determining the degree of masking them sumatriptan in contact with an isolated stretch of saphenous vein of the dog [P. P. A. Humphrey et al., Br.J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked by methiothepin known antagonist of serotonin. It is known that sumatriptan is used to treat migraine and causes a selective increase in carotid vascular resistance in the shot of the dog. Was wiscasset, associated with affinity to serotonin 5-HT1can be measured in tests on binding to the receptor in vitro as described for receptor 5-HT1Ausing as the source of the receptor to the cortex of the rat and [3H]-8-OH-DPAT as radioligand [D. Hoyer et al., Eur. J. Pharm., vol. 118, 13 (1985)] and as described for receptor 5-HT1Dusing bovine caudate as a source of receptor and [3H] serotonin as radioligand [R. E. Heuring and S. J. Peroutka, J. Neuroscience, vol. 7, 894 (1987)]. Activity associated with affinity for 5-HT1when any test for binding, is determined by the agents with values of affinity (IC50) 250 nm or less.

The compositions of the present invention can be prepared in the usual manner using one or more pharmaceutically acceptable carrier. Thus, the active compounds according to the invention can be adapted for oral, oral, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for application by inhalation or insufflation.

For oral administration the pharmaceutical compositions may take the form, napraxine as binding agents (for example, prezentatsionnyy corn starch, polyvinylpyrrolidone or hydroxyhydrocinnamate); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g. magnesium stearate, talc or silica); agents that cause disintegration (e.g., potato starch or sodium salt starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets can be well-known methods of the coating. Liquid preparations for oral administration can be, for example, in the form of solutions, syrups or suspensions, or they may be in the form of a dry product intended for mixing with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means and can contain pharmaceutically acceptable additives such as suspendresume agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or Arabian gum); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol) and preservatives (e.g. methyl or propylhydroxybenzoate or Sorb is prepared in the usual way.

The active compounds according to the invention can be prepared in a form for parenteral administration by injection, including conventional technique catheterizable or infusion. Compositions for injection can be accommodated in the form of unit doses, for example in ampoules or in mnogochasovykh packages with added stabilizer. The composition can be in such forms as suspensions, solutions or emulsions in oily or aqueous medium, and may contain such composite agents, as suspendida, stabilizing and/or dispersing agents. In alternative cases, the active ingredient may be in powder form, designed to create a drug with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The active compounds according to the invention can also be in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppozitornoj bases such as cocoa butter or other glycerides.

The active compounds according to the invention, intranasal or use by inhalation convenient to serve in the form of a solution or suspension of the spray container that is squeezed or pokachivaetsya using a suitable dispersant, for example DICHLORODIFLUOROMETHANE, triptoreline, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure, the unit dose can be set by providing a supply valve it metered. Pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may contain a powdery mixture of compounds according to the invention and a suitable powder base such as lactose or starch.

A proposed dose of the active compounds according to the invention for oral, parenteral or oral application for an average adult human for the treatment of the aforementioned conditions (e.g., migraine) is 0.1 to 200 mg of active ingredient in a unit dose, which can be used, for example, 1 to 4 times a day.

Aerosol composition for the treatment of the aforementioned conditions (e.g., migraine) for the average adult human are preferably so that each metered dose or "exhaust" of aerosol contains from 20 to 1000 μg of the compounds according to the invention. The total is 2, 3, 4, or 8 times, with submission, for example, 1, 2 or 3 doses each time.

The following examples illustrate the formation of compounds of the present invention. The melting temperature is given without correction. Data of NMR are given in millions of shares (), and is referred to Lok signal deuterium from the solvent of the sample. The specific rotation was measured at room temperature using the D line of sodium (589 nm). Unless otherwise noted, all mass spectra were measured under conditions of electron impact (E1, 70 eV).

Sales reagents were used without additional purification. Chromatography refers to column chromatography, which was performed on a 32 - 63 µm silica gel and was conducted under conditions of nitrogen pressure (flash chromatography). Room temperature refers to 20 - 25oC.

Example 1. General methods hydride recovery 3-(N-benzyloxy-carbonyl-pyrrolidin-2-ylmethyl)-1H-indoles to form a 3-(N-methylpyrrolidine-2-ylmethyl)-1H-indoles.

To a stirred solution of sociallyengaged (0.152 g, 4.00 mmol, 2 EQ. ) in anhydrous tetrahydrofuran (10 ml) at 0oC was rapidly added a solution of 3-(N-benzyloxycarbonyl-pyrrolidin-2-ylmethyl)-1H-indole (2.00 mmol) in anhydrous tetrahydrofuran (5 ml). Recip is whether and sequentially added water (0.25 ml), 15% aqueous sodium hydroxide solution (0.25 ml) and again water (0.75 ml). The resulting mixture was stirred at 25oC for 30 minutes, filtered and the filtrate evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (approximately 50 g) and elution with a solution of methylene chloride : methanol : ammonium hydroxide [9:1:0,1] or other appropriate solvent system; the result is the corresponding 3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole.

By this technique were obtained the following compounds:

A. (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole.

Used (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N - benzyloxycarbonylamino-2-ylmethyl)-1H-indole. Chromatography using 5% solution of triethylamine in ethyl acetate obtained a named connection (71%) as white solids:

so pl. 146,0 - 148,0oC;13With NMR (CDCl3) 169,8, 157,1, 139,3, 137,3, 129,2, 128,5, 128,0, 126,4, 125,7, 123,2, 121,2, 117,6, 114,8, 113,2, 111,5, 66,6, 57,5, 40,8, 38,1, 31,4, 29,6, 21,9;

ICSD (mass spectroscopy low-resolution m/z, relative intensity) 387 (M+, 4), 303(34), 155(30), 147(17), 115(18), 85(63), 84(100), 83(57); []25= + 68o(CHCl3c = 1,0).

Analysis: calculated Gladiator-5-yl)-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole.

Used (R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(N - benzyloxycarbonylamino-2-ylmethyl)-1H-indole. Column chromatography as described above, obtained a named connection (34%) as a yellowish brown solid:1H NMR (CDCl3) 8,48 (s, 1H) at 8.36 (s, 1H), to $ 7.91 (DD, J = 8 and 2 Hz, 1H), 7,43 - 7,25 (m, 6H), 7,12 (s, 1H), 4,13 (s, 2H), 3,28 is 3.15 (m, 2H), 2.77 - to of 2.68 (m, 1H), 2,53 (m, 1H), 2,46 (s, 3H), 2.26 and (K, J = 8 Hz, 1H), 1,92 - of 1.74 (m, 2H), 1,74 - and 1.54 (m, 2H); SVR (mass spectroscopy high resolution) calculated for C23H24N4O 372.1945 found 372.1978.

C. (R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl-methyl-3-(N - methylpyrrolidine-2-ylmethyl)-1H-indole.

Used (R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3- (N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole. Column chromatography as described above, obtained a named connection (24%) as a beige resin:1H NMR (CDCl3) 8,10 (sh.s, 1H), 7,47 (C. 1H), 7,34 - to 7.18 (m, 6H), was 7.08 (DD, J = 8 and 2 Hz, 1H),? 7.04 baby mortality (sh.s, 1H), 4,25 (s, 2H), 4,01 (s, 2H), 3,22 - of 3.07 (m, 2H), 2,66 is 2.55 (m, 1H), 2,54 is 2.43 (m, 1H), 2,42 (s, 3H), 2,24 (K, J = 8 Hz, 1H), 1,86 was 1.69 (m, 2H), 1,68 of 1.50 (m, 2H); msvr calculated for C24H26N4O 386.2070 found 386.2074.

Example 2. General methodology for catalytic reduction of 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indoles with obrazovanie mmol) and 10% palladium on coal (0.20 g) in absolute ethanol (15 ml) was shaken in a hydrogen atmosphere (3 ATM) for 4 24 hours depending on the substrate. The reaction mixture was filtered through kieselguhr and the filtrate evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (approximately 10 g) and elution with a solution of methylene chloride : methanol: ammonium hydroxide [8:2:0,2] or other appropriate solvent system, get the corresponding 3-(pyrrolidin-2-ylmethyl)-1H-indole

By this technique were obtained the following compounds:

A. (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(pyrrolidin-2-yl-methyl)- 1H-indole.

Used (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N - benzyloxycarbonylamino-2-ylmethyl)-1H-indole, and the reaction mixture was heated at 40oC for 24 hours. Chromatography using a mixture of methylene chloride : methanol : ammonium hydroxide [9:1:0,1] obtained a named connection (12%) as amorphous solids:1H NMR (CDCl3) 9,1 (Shir. s, NH indole), 8,17 (d, J = 1.4 Hz, 1H), 7,74 (DD, J = 1.6 and 8.5 Hz, 1H),7,35 - 7,21 (m, 6H), 7,02 (s, 1H), to 6.67 (s, 1H), 4,22 (s, 2H), 3,5 (Shir. s, NH), 3,41 - 3,29 (m, 1H), 3,03 - by 2.73 (m, 4H), 1,94 - to 1.61 (m, 3H), 1,49 - to 1.38 (m, 1H);13With NMR(CDCl3) 169,9, 157,0, 139,2, 137,4, 129,2, 128,5, 127,7, 126,4, 125,5, 123,8, 121,2, 117,3, 114,3, 113,3, 111,7, 59,2, 46,0, 38,1, 31,5, 31,1, 24,9; SVR: calculated for C23H23N3S 374.1615, the tins through catalyzed by palladium the cyclization of 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-halogenfree)- N-triptoreline)-propanol.

A mixture of 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2 - halogenfree)-N-triptoreline)propene (2.00 mmol), tetrabutylammonium chloride (2.00 mmol) and palladium (II) acetate (0,089 g, 0.40 mmol, 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). The ethyl acetate layer was removed and carried out the extraction of the aqueous layer with ethyl acetate (25 ml). The organic extracts were combined, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (approximately 50 g) and elution of 40% solution of ethyl acetate in hexane or a suitable solvent system; obtained the corresponding 3-(N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole.

By this technique were obtained the following compounds:

A. (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-benzyloxycarbonylamino-2 - ylmethyl)-1H-indole.

Was used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3- (N-(2-bromo-4-(4-benzyl-1,3-thiazol-2-yl)phenyl)-N - triptoreline)propene. Chromate is trained for a named connection (58%) as a pale yellow foamy substance; ICSD with the Belarusian library Association (mass spectroscopy low-resolution fast atom bombardment, m/z, relative intensity): 509 (MH+, 37), 508 (M+, 100), 462 (5), 372 (8), 304 (33); SVR with the Belarusian library Association: calculated for [C31H30N3O3S H]+509.2139 found 509.2106. Elemental analysis: calculated for C31H30N3O2S 1/2 C4H8O2the ethyl acetate : C 71,71; H 6,20; N 7,60. Found: C 71,55; H Of 5.82; N 7,664.

B. (R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(N - benzyloxycarbonylamino-2-ylmethyl)-1H-indole.

Was used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N- (2-bromo-4-(3-benzyl-1,2,4-oxadiazol-5-yl)phenyl)-N-triptoreline)propene.

Column chromatography using the system described above solvents obtained the named substance (74%) as a pale yellow resin: Rf= 0,41 (hexane - EtOAc 50: 50); SVR - calculated for C30H29N4O3493.2288 found 493.2240.

C. (R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3- (N-benzyloxycarbonylamino-2-ylmethyl)-1H-indole.

Was used (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N- (2-bromo-4-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)phenyl)-N - triptoreline)propene. Column chromatography using the UB> = 0,063 (hexane-EtOAc 50:50); SVR: calculated for C31H31N4O3507.2396 found 507.2387.

Example 4. A common technique to obtain 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-2-halogenfree)-N - triptoreline)propanol the reaction mix Mitsunobu 2-halogen-N-triptoreline with 1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropane.

To a stirred solution of 1-(N-benzyloxycarbonylamino-2 - yl)-3-hydroxypropane (form R or S or a racemate, 2.00 mmol), 2-halogen-N-triptorelin (2.5 mmol, 1.25 EQ.) and triphenylphosphine (0,655 g of 2.50 mmol, 1.25 EQ.) in anhydrous tetrahydrofuran (15 ml) at 0oC in an atmosphere of nitrogen was added dropwise diethylazodicarboxylate (of 0.39 ml, 2.48 mmol, 1.25 equiv. ). The reaction solution was slowly heated to 25oC for 2 hours and then further stirred at 25oC in nitrogen atmosphere for 12 hours. The resulting reaction solution was evaporated under reduced pressure and the residue was subjected to column chromatography using silica gel (approximately 150 g) and elution with a suitable solvent system; obtained 1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-halogenfree)-N - triptoreline)propene.

By Dan(4-benzyl-1,3-thiazol-2-yl)phenyl)-N-triptoreline)propene.

Used 4-(4-benzyl-1,3-thiazol-2-yl)-2-bromo-1 - triftoratsetofenona and (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan. Chromatography with elution solution of ether in methylene chloride gradient concentration 1 - 5% received a named connection (97%) as a white foamy substance; ICSD with the Belarusian library Association (m/z, relative intensity): 686 ( MN+2, 100), 685 (MH+, 60), 684 (M+, 90), 640(23), 578(15), 441(17), 371(20); SVR with the Belarusian library Association: calculated for [C33H29BrF3N3O3S H]+[with79Br and32S] 684.1145 found 684.1157.

B. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-bromo-4- (3-benzyl-1,2,4-oxadiazol-5-yl)phenyl)-N-triptoreline)propene.

Used 4-(3-benzyl-1,2,4-oxadiazol-5-yl)-2-bromo-1 - triftoratsetofenona and (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-hydroxypropan. Chromatography using elution with 5% solution of ether in methylene chloride obtained a named connection (88%) as a thick yellow oil; Rf= 0,32 (CHCl3); ICSD (m/z, relative intensity): 669 (M+, 25).

C. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3-(N-(2-bromo-4-( 3-benzyl-1,2,4-oxadiazol-5-ylmethyl)phenyl)-N-triptoreline)propene.

IP is irreligion-2 - yl)-3-hydroxypropan. Chromatography with elution with 5% solution of ether in methylene chloride obtained above compound (90%) as a thick yellow oil: Rf= 0,75 (CHCl3-CH3OH 20:1); ICSD (m/z, relative intensity): 683 (M+, 18).

Example 5. (R)-1-(N-benzyloxycarbonylamino-2-yl)-3 - hydroxypropan.

To a stirred solution of ethyl ester of (R)-3-(N-benzyloxycarbonylamino-2-yl)-2-propionic acid (3.03 g, 10,00 mmol) in anhydrous tetrahydrofuran (75 ml) at -78oC in an atmosphere of nitrogen was added dropwise a solution of diisobutylaluminium (1.0 M in hexano, 22,0 ml of 22.0 mmol, 2.2 EQ. ). The resulting solution was stirred at -78oC in nitrogen atmosphere for 30 minutes. Then the reaction solution was heated to room temperature within 24 hours. Was added a saturated solution of acid sodium carbonate (50 ml) and the aqueous mixture was extracted with ethyl acetate (3 50 ml). The extracts were combined, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to column chromatography using a mixture of diethyl ether - hexane [1:1]; received the named compound as a clear colorless oil (1,41 g, 5.40 mmol, 54%).1H NMR (CDCl3) 7,40 - 7,25 (m, 5H), 5,75 - of 5.53 (m, 2H), 5,20 - 5, Asciano for C15H19NO3261.1365 found 261.1356.

Example 6. Ethyl ester of (R)-3-(N-benzyloxycarbonylamino-2-yl)-2-propionic acid.

To a stirred solution of N-carbobenzoxy-2-carboxaldehyde (1,17 g, 5.00 mmol) in anhydrous tetrahydrofuran at -78oC portions in the form of a solid substance was added (carletonville)-triphenylphosphorane (2,09 g, 6,00 mmol, 1.2 EQ.). The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours and then was heated under reflux in nitrogen atmosphere for 1 hour. The reaction mixture is evaporated under reduced pressure and the residue was subjected to column chromatography using silica gel (approximately 100 g) and elution 20% solution of diethyl ether in hexano; received the named compound as a clear colorless oil (1,11 g, 3.65 mmol, 73%). 1H NMR (CDCl3): 7,34 - 7,25 (m, 5H), 6.89 in - 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 (K, J = 7,1 Hz, 2H), 3,55 is 3.40 (m, 2H), 2,11 - 2,00 (m, 1H), 1,90 -1,75 (m, 3H), of 1.28 (t, J = 7,1 Hz, 3H);13With NMR (CDCl3) [note: due to slow nitrogen inversion in NMR spectroscopy shows two conformer products]: 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�openonline with anhydride triperoxonane acid.

To a stirred solution of 2-halogenation (2.00 mmol) and pyridine (of 0.18 ml, 2.22 mmol, 1.1 EQ.) in anhydrous methylene chloride (10 ml) at 0oC in an atmosphere of nitrogen was added dropwise to the anhydride triperoxonane acid (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 acid sodium carbonate (15 ml) and the aqueous mixture was extracted with ethyl acetate (3 15 ml). The extracts were combined, dried (MgSO4) and evaporated under reduced pressure. If necessary, the residue was subjected to column chromatography using silica gel (approximately 50 g) and elution with a solution of ethyl acetate in hexano with a concentration gradient; get the corresponding 2-halo-N-trifurcation.

Under this procedure there were obtained the following compounds:

A. 4-(4-benzyl-1,3-thiazol-1-yl)-2-bromo-1-triftoratsetofenona

Used 4-(4-benzyl-1,3-thiazol-2-yl)-2-bromaniline. The residue after extraction was ground in a mixture of diethyl ether:hexane 1:1, 10 ml and got a named connection (92%) as a white powder: so pl. 102,0 - 104,0oC;13With NMR (CDCl3) 164,9, 158,0, 138,7, 134,1, 132,6, 130,1, 129,1, 128,6, 126,8, 126,6, 121,8, 115,2, 114,4, 38,0. E is S="ptx2">

B. 4-(3-benzyl-1,2,4-oxadiazol-5-yl)-2-bromo-1 - triftoratsetofenona.

Used 4-(3-benzyl-1,2,4-oxadiazol-5-yl)-2-bromaniline. Column chromatography in the above conditions of the titled compound (81%) as a white solid: so pl. to 152.0 - 153,0oC;1H NMR (CDCl3) 8,64 (Shir. s, 1H), 8,53 (d, J = 8 Hz, 1H), scored 8.38 (d, J = 2 Hz, 1H), 8,13 (DD, J = 8 and 2 Hz, 1H), 7,40 - 7,26 (m, 5H), 4,14 (s, 2H); ICSD (m/z, relative intensity) 426 (M+, 85).

Century 4-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromo-1 - triftoratsetofenona.

Used 4-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-2 - bromaniline. Column chromatography in the above conditions of the titled compound (90%) as a yellow resin:1H NMR (CDCl3) 8,59 (Shir. s, 1H), at 8.36 (Shir. s, 1H), they were 8.22 (d, J = 8 Hz, 1H), 7,42 (s, 1H), 7.24 to to 7.32 (m, 5H), 4,10 (s, 2H), 4,01 (s, 2H); ICSD (m/z, relative intensity) 440 (M+, 90).

Example 8. 4-(4-benzyl-1,3-thiazol-2-yl)-2-bromaniline.

A mixture of 4-amino-3-brombenzene (1.66 g, 7,18 mmol) and 1-chloro-3-phenylacetone [Tarhouni, R. et al., Tetrahedron Letters, 835 (1984)] (1,36 g, 8,07 mmol, 1.1 EQ.) in absolute ethanol (18 ml) was heated under reflux in nitrogen atmosphere for 2.5 hours. The reaction mixture is evaporated under lowered the ml). An ethyl acetate layer was removed, and carried out the extraction of the aqueous layer with ethyl acetate (2 20 ml). The organic extracts were combined, dried (MgSO4) and evaporated under reduced pressure. The remaining solid was chromatographically using silica gel (approximately 175 g) and elution with a solution of ethyl acetate in hexano with concentration gradient from 1:4 to 1:1]; obtained a named connection (68%) as a pale yellow solid: so pl. 110 - 115oC;13With NMR (CDCl3) 166,8, 157,1, 145,6, 139,1, 130,7, 129,1, 128,6, 126,9, 126,4, 125,4, 115,3, 113,2, 109,2, 38,0. Elemental analysis: Calculated for C16H13BrN2S : C 55,66; H 3,79; N 8,11. Found: C 55,36; H 3,71; N 7,92.

Example 9. 4-Amino-3-brombenzene

Stir a solution of 4-amino-3-bromobenzonitrile (6,92 g of 35.1 mmol) and diethyldithiophosphate (17,7 ml, 105 mmol, 3 EQ.) in absolute ethanol (160 ml) at 0oC was treated with gaseous hydrogen chloride supplied at a moderate speed for 30 minutes. The resulting reaction mixture was stirred at room temperature for 12 hours, after which the solvent was removed by evaporation of the mixture under reduced pressure. The residue is suspended in a saturated solution of acid sodium carbonate (25 ml) and about the O4) and evaporated under reduced pressure. The residue was chromatographically using silica gel (approximately 300 g) with elution with a solution of acetone in methylene chloride with a concentration gradient [from 1:50 to 1:20]; received the named substance (1,02 g, 25%) as amorphous yellow solid:1H NMR (DMSO-d8) 9,41 (Shir. s, NH), 9,13 (Shir. s, NH), 8,11 (d, J = 2.1 Hz, 1H), 7,78 (DD, J = 2.1 and 8.6 Hz, 1H), 6,72 (d, J= 8.7 Hz, 1H), 6,03 (s, 2NH); TCX: R Bf0,15 [1% solution of diethyl ether in methylene chloride].

Example 10. A General method of obtaining 2-halogen-4-(1,2,4-oxadiazol-5-yl)anilines or 2-halogen-4-(1,2,4-oxadiazol-5-ylmethyl)anilines by condensation of the corresponding alilovic esters of 4-amino-3-halogenating acids or alilovic esters of 2-(4-amino-3-halogenfree)acetic acid, respectively, of the oxime of phenylacetamide.

To a stirred solution of oxime of phenylacetamide (0.33 g, 2.2 mmol, 1.1 EQ. ) in anhydrous THF (10 ml) was added sodium hydride (87 mg, 60% oil dispersion, 2 mmol) C. L. Bell, et al., J. Org. Chem., 2873 (1964)], and the resulting reaction mixture was heated under reflux for 30 minutes. Then solution was added Olkiluoto ether 4-amino-3-halogenating acid or alkylboron ether 2-(4-amino-3-halogenfree 2 hours. The mixture was left to cool to room temperature before adding water (10 ml). From the resulting aqueous mixture was made extraction with dichloromethane (3 25 ml). The extracts were combined, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to chromatographicaliy using silica gel (20 g) and elution with chloroform; obtained the corresponding 2-halogen-4-(1,2,4-oxadiazol-5-yl)aniline or 2-halogen-4-(1,2,4-oxadiazol-5-ylmethyl)aniline.

On this procedure, there were obtained the following compounds:

A. 4-(3-benzyl-1,2,4-oxadiazol-5-yl)-2-bromaniline.

Used the methyl ester of 4-amino-3-bromobenzoyl acid. Column chromatography in the above conditions of the titled compound (33%) as a yellow-brown solid; T. pl. 144 - 145oC;1H NMR (CDCl3) 8,18 (d, J = 2 Hz, 1H), 7,82 (DD, J = 8 and 2 Hz, 1H), 7,39 - 7,25 (m, 5H), 6,77 (d, J = 8 Hz, 1H), 4.09 to (s, 2H); ICSD (m/z, relative intensity) 330 (M+, 90).

B. 4-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromaniline

Used the ethyl ester of 2-(4-amino-3-bromophenyl)acetic acid. Column chromatography in the above conditions of the titled compound (41%) as a yellow resin;1H NMR (CDCl3, 15).

Example 11. General methods of synthesized anilines with obtaining 2-bromoaniline

To a stirred mixture of aniline (2.00 mmol) and acid sodium carbonate (0.21 g, of 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 reaction mixture is then stirred at 25oC for 30 minutes. It is then evaporated under reduced pressure and the residue was placed in a saturated solution of acid sodium carbonate (10 ml). From this aqueous mixture was made to extraction with ethyl acetate (3 15 ml). The extracts were combined, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (approximately 50 g) and elution with a suitable solvent system; obtained the corresponding 2-bromaniline.

According to this method were obtained the following compounds:

A. 4-amino-3-bromobenzonitrile.

Used 4-aminobenzonitrile. Chromatography with elution by ethyl acetate solution in hexano with the concentration gradient [from 1:5 to 1:3] obtained a named connection (71%) as white solids:1H NMR (CDCl3) the 7.65 (d, J = 2.1 Hz, 1H), 7,34 (DD, J = 2.1 and 8.1 Hz, 1H), of 6.71 (d, J = 8.0 Hz, 1H), 4,6 (W is lots

Used the methyl ester of 4-aminobenzoic acid. Chromatography with elution by ethyl acetate solution in hexano [1:4] obtained a named connection (36%) as an orange oil.1H NMR (CDCl3) of 8.09 (d, J = 2 Hz, 1H), of 7.75 (DD, J = 9 and 2 Hz, 1H), of 6.71 (d, J = 9 Hz, 1H), 4,49 (Shir. s, 2H), of 3.84 (s, 3H), ICSD (m/z, relative intensity) 230 (M+, 100).

C. Ethyl ester 2-(4-amino-3-bromophenyl)acetic acid.

Used the ethyl ester of 2-(4-AMINOPHENYL)acetic acid. Chromatography with elution by ethyl acetate solution in hexano [1:4] obtained a named connection (25%) as a light brown oil:1H NMR (CDCl3) 7,33 (d, J = 2 Hz, 1H), 7,02 (DD, J = 8 and 2 Hz, 1H), 6,76 (DD, J = 8 Hz, 1H), 4,11 (K, J = 7 Hz, 2H), 3.45 points (s, 2H), 1,23 (t, J = 7 Hz, 3H); ICSD (m/z, relative intensity) 258 (M+, 100).

1. Derivatives of indole of General formula I

< / BR>
where A is a direct bond or C1-C4-alkyl;

R1is hydrogen or C1-C6-alkyl;

W, X, Y, Z each independently represent oxygen, sulfur, nitrogen or carbon provided that at least one of W, X, Y, or Z is nitrogen, one of R2, R3, R4and R5represents C1-C6-alkyl, phenyl, C1-C3-alkylphenyl, and the other is syrupy, by hydroxyl,

or its pharmaceutically acceptable salt.

2. Derived under item 1, representing a compound of formula I

< / BR>
where the values of A, R1, R2, R3, R4, W, X, Y and Z indicated in paragraph 1.

3. Derived under item 2, representing zisapel.

4. Derived under item 1, where R1is hydrogen or C1-C4-alkyl, Z is nitrogen, Y is carbon, W and X each independently represents oxygen, sulfur, nitrogen or carbon.

5. Derived under item 4, representing a compound of formula I

< / BR>
where the values of A, R1- R5W and X are specified in paragraph 4.

6. Derived under item 5, representing zisapel.

7. Derived under item 1, representing a compound selected from ( R )-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole, ( R )-5-(4-benzyl-1,3-thiazol-2-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole, ( R )-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole, ( R )-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole, ( R )-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole and ( R )-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole.

8. Pharmaceutical composition having Akti is the lasting themes as the active ingredient it contains an effective amount of the compounds under item 1.

9. The derived formulas II

< / BR>
where A is a direct bond or C1-C4-alkyl;

W, X, Y and Z each independently represents oxygen, sulfur, nitrogen or carbon provided that at least one of W, X, Y, or Z is nitrogen, one of R2- R5- C1-C6-alkyl, phenyl, C1-C3-alkylphenyl, and the other is hydrogen;

R13- alkylphenyl, and specified phenyl possibly substituted C1-C4-alkyl, halogen, C1-C4-alkoxygroup, hydroxyl.

10. Derived by p. 9, representing a compound of formula II

< / BR>
where the values A, R2- R5, R13, W, X, Y and Z are specified in paragraph 9.

11. Derived under item 10, which represents zisapel.

12. Derived by p. 9, where Z is nitrogen, Y is carbon, W and X each independently represents oxygen, sulfur, nitrogen or carbon.

13. Proizvodnje under item 12, which represents a compound of formula II

< / BR>
where the values of A, R2- R5, R13W and X are listed in paragraph 12.

14. Derived by p. 13, which represents zisapel.

15. The derivative of indole accessible formula III

the ru, nitrogen or carbon, provided that at least one of W, X, Y, or Z is nitrogen, one of R2- R5- C1-C6-alkyl, phenyl, C1-C3-alkylphenyl, and the other is hydrogen;

R13- alkylphenyl;

R14- halogen;

R15is COCF3.

16. Derived by p. 15, representing a compound of formula III

< / BR>
where the values of A, R2- R5, R13- R15, W, X, Y and Z are specified in paragraph 15.

17. Derived by p. 16, representing zisapel.

18. Derived under item 15, where Z is nitrogen, Y is carbon, W and X each independently represents oxygen, sulfur, nitrogen or carbon.

19. Derived under item 18, which represents a compound of formula III

< / BR>
where the values A, R2- R5, R13- R15W and X are specified in paragraph 18.

20. Derived under item 19, which represents zisapel.

 

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< / BR>
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< / BR>
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< / BR>
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