Substituted pyrrole

 

(57) Abstract:

Describes the new substituted pyrrole General formula I

< / BR>
in which R1represents lower alkyl, lower cycloalkyl, aryl or lower aralkyl; R2represents hydrogen, aryl or lower alkyl; m and n are equal to 1 or 2, and their pharmaceutically acceptable salts that can be used for treatment or prevention of diseases, especially for the treatment or prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological or cardiovascular disorders, for the treatment of asthma, AIDS or diabetes complications, or to stimulate hair growth. 2 C. and 7 C.p. f-crystals.

The present invention relates to new substituted the pyrrole General formula I

< / BR>
in which R1represents lower alkyl, lower cycloalkyl, aryl or lower aralkyl, R2represents hydrogen, aryl or lower alkyl, m and n is 1 or 2, and pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids and medications, for example, the pharmaceutical compositions based on them.

In the EP 0384349 A1, 040490 A1 describe the uly I and their aforementioned salts, proposed according to the present invention show higher activity compared to, for example, described a similar - 3-[8-(aminomethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]- 4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (compound A), for example, in experiments on anti-inflammatory activity in animals.

Thus, the invention relates to compounds of General formula I and their aforementioned salts, both in itself and as therapeutically active substances, as well as medical drugs with the action of protein kinases, in particular protein kinase C.

The above compounds and their salts can be used for treatment or prevention of diseases, in particular for the treatment or prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for the treatment of asthma, AIDS or diabetes complications, or to stimulate hair growth, or for the production of drugs against inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, or asthma, AIDS or diabetes complications, or to stimulate hair growth.

The compounds of formula I contain two chiral carbon atom and can therefore exist in racemic or optically active forms. The present invention includes in its scope not only racemic compounds but also the optically active isomers.

In the compounds of the formula I R1in the preferred embodiment, is a lower alkyl, particularly lower alkyl containing 1-3 carbon atoms. R2in the preferred embodiment, represents lower alkyl, in particular methyl. In a preferred embodiment, m is 1 and n is 2.

Especially preferred compounds of formula I are the following:

3-[8(S)-[1(R or S)-aminopropyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione; and

3-[8(S)-[1(S)-amino-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione.

Other predpochtitel]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione,

3-[8(R or S)-1(R or S)-aminopropyl]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione,

3-[8(R or S)-1(R or S)-aminobutyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione, and

3-[8(R or S)-1(R or S)-amino-2-methylpropyl]-6,7,8,9 - tetrahydropyrido[1,2-a]-indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione.

Below are also preferred compounds described by formula I:

3-[8(S)-1(R)-amino-2-methylpropyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione,

3-[8(R or S)- [alpha - (R or S)-aminobenzyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione,

3-[8(S)- [(R or S)-(amino)(cyclopentyl)methyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione,

3-[2(R or S)-[1(R or S)-amino-2-methylpropyl]-2,3-dihydro - 1H-pyrrolo[1,2-a]indol-9-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5 - dione,

3-[8(RS)-[1(RS)-amino-2-methylpropyl] -7,8,9,10-tetrahydro-6H - azepino[1,2-a]indol-11-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5 - dione,

3-[7(RS)-[1(RS)-amino-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-9-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione, and

3-[8(S)-[1(S)-amino-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)-1H - pyrrole-2,5-teamname salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, produced by cleavage of the protective group R3in the compound of General formula II

< / BR>
in which R1, R2, m and n have the meanings defined above, and R3represents urlencoding group

and, if necessary, modify chemically active substituents of the radical R2in the compound of formula I thus obtained, and also, if necessary, you can implement the transformation of the acid compounds of formula I in a pharmaceutically acceptable salt with a base or the transformation of the basic compounds of formula I in a pharmaceutically acceptable salt with acid.

Urlencoding group, denoted by R3in the General formula II is in the preferred embodiment, the lower alkoxycarbonyl, in particular, tert-butoxycarbonyl or lower alkoxycarbonyl, in particular, benzyloxycarbonyl.

Cleavage of the protective group R3the compounds of formula II can be carried out using known in this technical field techniques. For example, when R3represents the lowest alkoxycarbonyl, cleavage may be effected by treatment with a mineral acid, such as hydrochloric acid, in an inert organic solvent, such as simple is irah, such as ethyl acetate or a halogenated, in particular chlorinated hydrocarbons, e.g. dichloromethane, or processing triperoxonane acid. When R3represents alcoxycarbenium group, removal is carried out by hydrogenolysis by means known in this technical field procedures; for example, using hydrogen in the presence of a catalyst such as palladium/charcoal.

Functional modification of reactive substituent contained in R2in the resulting compound of formula I, may include esterification of carboxypropyl in the lower alkoxycarbonyl group, hydrolysis of alloctype in oxygraph or turning a lower alkoxycarbonyl group in carboxypropyl. All these modifications can be carried out in accordance with techniques which are known in this technical field.

The transformation of the acid compounds of formula I in a pharmaceutically acceptable salt can be carried out by treatment of the corresponding basis using methods known in this technical field. The corresponding salts are salts that get not only from inorganic bases, such as, for example, salts of sodium, potassium, salts of CA is their such salts. The transformation of the basic compounds of formula I in a pharmaceutically acceptable salt can be carried out by treatment of the corresponding acid using procedures that are known in this technical field. The corresponding salts are salts that get not only from inorganic acids, such as, for example, chlorhydrate, bromhidrosis, phosphates, sulfates, etc., but also from organic acids, for example acetates, citrates, fumarate, tartratami, maleate, methanesulfonate, p-toluensulfonate etc.

The initial products of the formula II, above, are novel and also form an object of the present invention. They can be obtained, for example:

(a) the interaction of compounds of General formula III

< / BR>
in which R1, R3, m and n are defined above, with oxalylamino, condensation of the resulting activated glyoxylate General formula IV

< / BR>
in which R1, R3, m and n are previously defined, with imitator General formula V

< / BR>
in which R2defined previously, a R4represents lower alkyl, in the presence of a strong base, followed by hydrolysis and dehydration resulting from oxopyrrolidin General formula VI

< / BR>
< / BR>
in which R2previously defined,

in the presence of a strong base, and converting the resulting substituted furandione General formula VIII

< / BR>
in which R1, R2, R3, m and n are previously defined in the corresponding imide of formula II.

The reaction of the compound of formula III with oxalylamino is usually carried out in the presence of an inert organic solvent, for example, halogenated aliphatic hydrocarbons, such as dichloromethane. This reaction can also be carried out at a temperature of about 0oC.

Condensation of activated glyoxylate formula IV with imitator formula V, which is a known compound or an analogue of a known compound, is usually carried out in an inert organic solvent. Appropriate bases are, for example, tertiary amines such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-ethylmorpholine and 1,4-diazabicyclo[2.2.2] octane, and pyridine. Appropriate solvents are, for example, halogenated aliphatic hydrocarbons, such as dichloromethane and chloroform, but not necessarily halog rostie acyclic ethers, such as dimethoxyethane, simple tert-butyl methyl ether and tetrahydrofuran, formamide, such as dimethylformamide, esters such as ethyl acetate and NITRILES, such as acetonitrile. Condensation in the preferred embodiment, is carried out at a temperature from about 0oC to 40oC, in particular at room temperature. In addition it is possible that condensation to carry out in situ.

The hydrolysis and dehydration of oxopyrrolidin formula VI to obtain the compounds of formula II are usually carried out by treatment with a mineral acid, such as hydrochloric acid or sulfuric acid, or organic acid, such as methanesulfonate acid or p-toluensulfonate, or processing allermuir reagent, such as triperoxonane anhydride and an appropriate base, such as pyridine, typically at about room temperature. Oxopyrrolidin formula VI in a preferred embodiment, hydrolyzing and subjected to dehydration in situ.

The reaction of activated glyoxylate formula IV with indolylacetic acid of the formula VII, which is a known compound or an analogue of a known compound, is usually carried out similarly to the above, condensate the formula VIII in the original imide of formula II can be usually carried out by treatment with hexamethyldisilazane in the presence of alkanol, such as methanol, in an inert organic solvent. Appropriate solvents are, for example, halogenated aliphatic hydrocarbons, such as dichloromethane and chloroform, optionally halogenated aromatic hydrocarbons such as benzene, toluene and chlorobenzene, a simple cyclic ethers and simple acyclic ethers, such as dimethoxyethane, simple tert-butyl methyl ether and tetrahydrofuran, or formamide, such as dimethylformamide. The reaction in the preferred embodiment, is carried out in the range from about room temperature to 100oC, in particular at a temperature of about 50oC.

The compounds of formula III above can be obtained, for example, as shown in the reaction scheme I, in which R1, m and n are previously defined.

Shown in scheme stage I can be carried out in accordance with known techniques. In the first stage, complex ethyl ester of formula IX, which is a known compound or an analogue of a known compound, is subjected to saponification to the corresponding acid of formula X using, for example, a solution of hydrate of sodium oxide. Then the resulting acid lidiruyut, for example, vzaimodei formula XI is converted into a nitrile of the formula XII, using, for example, triperoxonane anhydride. Then the nitrile of formula XII interacts with the Grignard reagent of formula R1-Mg-X, where R1previously defined, and X represents a halogen, preferably chlorine, and the resulting Imin formula XIII restore using a complex metal hydride, for example, alumoweld lithium, primary amine of the formula XIV. Such reversal is preferably carried out in situ. The primary amine of formula XIV is converted into a compound of formula III, for example, the interaction with chloroformiate formula R3Cl or anhydride of the formula R3OR3in which R3has the value that was previously defined, in the presence of a base such as triethylamine.

Homochiral compounds of formula III, denoted in the future through IIIA can be obtained, for example, as shown in the reaction scheme II, in which R1, m and n have already been defined above, and R5represents lower alkyl.

A separate synthesis step, represented in the reaction scheme II can be carried out in accordance with techniques which are known in this technical field. In the first stage, complex metalowy ether of the formula XV, which is known soedinenii sulfuric acid, to the corresponding carboxylic acid of formula XVI. This acid is then condensed with N,O-dimethylhydroxylamine, and the resulting N-methoxy-N-methylcarbamic formula XVII interacts with the Grignard reagent of formula R1-Mg-X, in which R1has the meaning previously defined, and X represents a halogen, preferably chlorine, to obtain a ketone of formula XVIII. The reaction of this ketone with a hydroxylamine of the formula H2N-OR5in which R5was defined above, gives the oxime of formula XIX, which restores using complex metal hydride, such as alumalite lithium, primary amine of formula XX. Last connection, then, turns into a homochiral the original compound of formula IIIA by acylation in the same way as described in reaction scheme I for the conversion of compounds of formula XIV to a compound of formula III.

A reaction scheme III illustrates an alternative way of obtaining homochiral starting compounds of the formula IIIA. In this reaction scheme, R1, m and n have been defined above, a Ms is methanesulfonyl.

Indicated in scheme III stage of the synthesis can be carried out using known methods. First of all, the alcohol of formula XXI evaluation of ONAT formula XXII make using sodium cyanide in the nitrile of formula XXIII. The latter is subjected to hydrolysis, for example using a solution of hydrate of sodium oxide, into the corresponding carboxylic acid of formula XXIV, which was identified in, for example, using methanol in the presence of concentrated sulfuric acid in methyl ester of formula XXV. Reaction of the latter with a halide of formula R1-X, in which R1and X have been defined above, in the presence of a strong base, such as diisopropylamide lithium, followed by treatment with a solution of hydrate of sodium oxide, gives a carboxylic acid of formula XXVI. The latter interacts with diphenylphosphorylacetate to obtain isocyanate of formula XXVII, which is converted into the primary amine of formula XX by treatment with hydrochloric acid. The conversion of the primary amine of formula XX in homochiral compound of formula IIIA carried out by acylation according to the same scheme that was described in the case of reaction scheme I.

The compounds of formula I and their pharmaceutically acceptable salts are inhibitors of protein kinases; they inhibit cellular processes such as proliferation and secretion, and can be used to treat and prevent diseases, for example, for the treatment or prevention of inflammatory resstr is also in Oncology. They inhibit infection of cells by human immunodeficiency virus or virus of Epstein-Barr and therefore can be used in the treatment of AIDS and infectious mononucleosis. Compounds and salts of this invention also inhibit smooth muscle contraction and can therefore be used in the treatment of cardiovascular and bronchopulmonary disorders. In addition, they can also be used in the treatment of asthma. The proposed compounds and salts inhibit the aggregation of platelets and can be used to treat and prevent thrombosis. In addition, they inhibit the release of mediators from activated neutrophils and therefore can be used for the treatment of ischemic diseases, such as heart or brain. In addition, they inhibit the neurotoxicity caused by increased concentrations of glucose and therefore can be used for the treatment of diabetic complications. Finally, the proposed compounds and salts stimulate hair growth and can therefore be used to prevent hair loss or restore hairline.

The proposed activity of the compounds in the inhibition of protein kinase C can be illustrated by the written Takai et al., BBRC 19, 1218, (1979). The reaction mixture (100 μl) containing 10 μm [-32P] ATP, 0.2 mg/ml (approximately 15 microns) enriched lysine of histone, 0.5 mm CaCl2and 40 μg/ml phosphatidylserine in 25 mm Tris HCl, 5 mm MgNO3(pH 7.5) buffer. The enzyme protein kinase C isolated from the brain of a rat in accordance with the method of Kikkawa et al., J. Biol. Chem. 257, 13341 (1982).

The reaction starts with the addition of the enzyme is carried out at a temperature of 30oC for 10 minutes and then stop, using 1 ml ice trichloroacetic acid. The precipitated acid protein was collected by filtration on disks made of fiberglass. Then these discs are washed with 5% trichloroacetic acid containing 20 mm sodium pyrophosphate (to remove unreacted ATP), and then ethanol. The discs are dried and analyzed on the counter. Calculations on each disk, showing the inclusion of32P [-32P] ATP into histone. The degree of locking of the enzyme for each concentration of the test compounds are calculated according to the formula

Pulses/min to enable + tested.connection + enzyme/ Impulses/min for inclusion - tested.connection + enzyme 100%

IC50- value is the concentration of test compound which reduces by 50% caused proteinkinase test for some representatives of the compounds of formula I, listed in tab. I. PL. II shows the test results of a number of compounds in vivo obtained by the method indicated below.

Induction of paw edema rat line AHH/R2 caused 12,13-dibutyrate of phorbol

Method:

Females rats AHH/R2 was administered orally (10 ml/kg) test compound one hour before induction of edema induced by injection of 12,13-dibutyrate of phorbol (Dbuf) in the right hind paw with 0.1 ml of 10-3M). The volume of edema was detected by plethysmography combined with 0.5, 1, 2, 3, 4, and 6 hours after dosing.

Test compounds are prepared in Sanitaria (destruction of biological material) in 10% succinylamino gelatin for 3 minutes, followed by dilution required filler. Dbuf prepared by dissolving 10 mg in 1 ml ethanol and 1 ml of saline solution, obtaining a solution of 10-2M. This solution is then diluted in saline to a concentration of 10-3M with a view to its use in this experiment.

The compounds of formula I and their aforementioned salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. These pharmaceutical preparations can be used for oral administration, for example, in the form of the. However, they can be used rectally (e.g. in the form of a suppository), or parenteral (for example, in the form of solutions for injection).

To obtain pharmaceutical preparations of the compounds of formula I and their aforementioned salts can be used therapeutically inert, inorganic or organic carriers. As such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, maize starch or its derivatives, talc, stearic acid or its salts, etc., Appropriate carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc., depending on the nature of the active material carriers, however, usually are not required when using soft gelatin capsules. Appropriate media to obtain solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc., Appropriate carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc., Appropriate carriers for suppositories are, for example, natural or thickened oil, varvarousa agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, flavoring agents, coloring agents, flavouring agents, salts for varying the osmotic pressure, buffers, covering agents or antioxidants. They can also contain other therapeutically acceptable substances. Medicaments containing a compound of formula I or its salt, which were defined above and a therapeutically inert carrier, and the method of obtaining such drugs, are also targets of the present invention. This method allows the conversion of the compounds of formula I or its corresponding salt, in herbal form, together with a therapeutically inert carrier and, if necessary, with one or more other therapeutically active substances.

As mentioned above, the compounds of formula I and their aforementioned salts can be used for the treatment or prevention of diseases, in particular for the treatment or prevention of inflammatory, immunological, bronchopulmonary, dermatological and cardiovascular diseases, for the treatment of asthma, AIDS or diabetes complications, or to stimulate hair growth. The dosage may vary Shi is the case for oral use for adult patients, the daily dose varies from about 5 mg to about 500 mg, although the upper limit may be higher, if necessary. The daily dose can be applied in a single dose or multiple doses.

The following examples illustrate the present invention.

Example 1

A solution of 1.25 g (2,32 mmole) of 3-[8(R or S)-[1(R or S)-tert - butoxybenzoate] -6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]- 4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in 10 ml of acetate was treated with 30 ml of a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 18 hours. The obtained solid material was separated by filtration and dried to obtain 1.0 g of the hydrochloride of 3-[8(R or S)-[1(R or S)-amino-ethyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1 - methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 324-325oC.

3-[8(R or S)-[1(R or S)-tert-butoxybenzoate]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) used as starting product was received as follows:

(1) Stirring a suspension of 27 g (126 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a] indole-8-carboxylic acid in 30 ml of water and 450 ml of acetone was cooled to 0oC and processed 6.3 ml 0,880 ammonia and stirring continued for 1 hour. The solvent was removed under reduced pressure and the residue triturated with aqueous ethanol. The product was separated by filtration and dried to obtain 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide as a white solid with a melting point 165-168oC.

(2) of 25.7 g (126 mmol) triperoxonane anhydride was added dropwise to stirred suspension of 26.5 g (123 mmole) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide and 23.4 g (300 mmol) of pyridine in 500 ml of dry dioxane at a temperature of 10oC. After completion of the addition the solvent was removed under reduced pressure and the residue was led from methanol to obtain 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(RS)-carbonitrile as svetlozheltogo brown solid with a melting point of 106-109oC.

(3) a Solution of 1.4 g (7.2 mmole) of 6,7,8,9-tetrahydropyrido[1,2-a]- indole-8(RS)-carbonitrile in 400 ml of dry toluene was treated with 7 ml (21 mmol) of a 3M solution of chloride Metalmania in tetrahydrofuran and the resulting solution was heated at the boil under reflux in nitrogen atmosphere for 0.5 hours. Then this solution was added 17 ml (17 mmol) of 1M solution of lithium aluminum hydride in tetrahydrofuran. The resulting solution was heated at cibacen what letricia and washed with 100 ml of ethyl acetate, and connected to the filtrate and washing liquid evaporated under reduced pressure to obtain 1.55 g of light brown oil.

This oil was dissolved in 70 ml of dry dichloromethane and treated with 1.5 g (15 mmol) of triethylamine, and then 1.8 g (7.4 mmole) dicret-BUTYLCARBAMATE at 0oC in nitrogen atmosphere. Stir the solution was allowed to warm to room temperature and stirring continued for 1 hour. The solvent was removed under reduced pressure and the product was subjected to purification using flash chromatography on silica gel, using a simple diethyl ether/petroleum ether (1: 2) for the elution to obtain 925 mg of tert-butyl[1(R or S)-(6,7,8,9 - tetrahydropyrido[1,2-a]indole - 8(R or S)-yl)ethyl] carbamate as a mixture of diastereoisomers in the form of a white solid with a melting point 114-117oC.

(4) Mix a solution of 3.0 g (to 9.57 mmole) of tert-butyl[1(R or S)-(6,7,8,9-tetrahydropyrido[1,2-a]indole - 8(R or S)-yl)ethyl]carbamate in 150 ml of dichloromethane was treated dropwise at 0oC 1.28 g (10.3 mmole) of oxalicacid. After 5 minutes the solvent was removed under reduced pressure, and the residue was dissolved in 150 ml of dichloromethane and treated 2,94 g (11 mmol) of the hydrochloride isopropyl-1-met the first temperature, the solution was stirred 24 hours, washed with water and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was dissolved in 30 ml of pyridine. This mixed solution was cooled to the temperature of the ice bath and treated dropwise 1.5 ml (10.8 mmol) triperoxonane anhydride. After 15 minutes the solvent was removed under reduced pressure, and the residue was divided between 200 ml ethyl acetate and 200 ml of 0.2 M hydrochloric acid. The organic layer was washed with 50 ml of sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was subjected to purification using flash chromatography on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to obtain 1.35 g of 3-[8(R or S)-[1(R or S)- tert-butoxybenzoate] -6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 255-257oC. Further elution gives to 1.38 g of diastereoisomer B in the form of a red solid with a melting point 230-233oC.

Example 2

By analogy with the procedure that was described in the first paragraph of Example 1, to 1.38 g of 3-[8(R or S)-[1(R or S)- tert-butoxybenzoate]-6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl]-4-g of the hydrochloride of 3-[8(R or S)-[1(R or S)-amino-ethyl]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole - 2,5-dione (diastereoisomer B) as a red solid with a melting point 254-258oC.

Example 3

Using a procedure analogous to that described in the first paragraph of Example 1, 180 mg of 3-[8(R or S)-[1(R or S)- tert-butoxypropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) received 115 mg of the hydrochloride of 3-[8(R or S)-[1(R or S)-aminopropyl]- 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 321-323oC.

3- [8(R or S)-[1(R or S)-tert-butoxypropyl]- 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione (diastereoisomer A) used as starting product was received as follows:

(1) using a procedure similar to that described in Example 1(3), 500 mg (2.5 mmole) of 6,7,8,9 - tetrahydropyrido[1,2-a]indole-8(RS)-carbonitrile and 2.5 ml (5 mmol) of a 2M solution of bromide of etermine in tetrahydrofuran were obtained 480 mg of tert-butyl[1(R or S)-6,7,8,9-tetrahydropyrido[1,2-a] indole - 8(R or S)-yl)propyl] carbamate as a mixture of diastereoisomers in the form of a white solid with a melting point 153-156oC.

(2) using a procedure analogous to that described in Example 1(4), 440 mg (1,34 mmol is whether S)- tert-butoxypropyl]-6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red resin. Further elution gave 130 mg of diastereoisomer B in the form of a red resin.

Example 4

Using a procedure analogous to that described in the first paragraph of Example 1, from 130 mg of 3-[8(R or S)- 1(R or S)- tert-butoxypropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrol-2,5-Dion [the diastereoisomer B, obtained as described in Example 3(2)] received 65 mg of the hydrochloride of 3-[8(R or S)-[1(R or S)-aminopropyl]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl - 3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) as a red solid with a melting point 245-249oC.

Example 5

Using a procedure analogous to that described in the first paragraph of Example 1, 400 mg (0.7 mmole) of 3-[8(R or S)- [1(R or S)-tert-butoxypropyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1 - methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) was obtained 310 mg of the hydrochloride of 3-[8(R or S)-[1(R or S)-aminobutyl]-6,7,8,9-tetrahydropyrido- [1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 237-241oC.

3-[8(R or S)-[1(R or S)-tert-butoxypropyl]- 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-direcetory, similar to what was described in Example 1(3) and (4), 1.0 g (5 mmol) of 6,7,8,9-tetrahydropyrido- [1,2-a]indole-8(RS)-carbonitrile and 5.0 ml (10 mmol) of a 2M solution of chloride of n-Propylamine in simple diethyl ether was received 470 mg of 3-[8(R or S)-[1(R or S)-tertbutoxycarbonyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 227-229oC. Further elution gave 285 mg of diastereoisomer B in the form of a red solid with a melting point 169-172oC.

Example 6

Using a procedure analogous to that described in the first paragraph of Example 1, 270 mg (0.48 mmole) of 3-[8(R or S)-[1(R or S)-tert-butoxypropyl] -6,7,8,9-tetrahydropyrido[1,2-a] - indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B), obtained as described in the second paragraph of Example 5, received 210 mg of the hydrochloride of 3-[8(R or S)-[1(R or S)-aminobutyl]- 6,7,8,9-tetrahydropyrido[1,2-a]indol-10 - yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) as a red solid with a melting point 235-238oC.

Example 7

Using a procedure analogous to that described in the first paragraph of Example 1, 400 mg (0.7 mmole) 3-is)-1H - pyrrole-2,5-dione (diastereoisomer A) received 300 mg of the hydrochloride of 3- [8 (R or S)-[1(R or S)-amino-2-methylpropyl]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 254-256oC.

3-[8(R or S)-[1(R or S)-tert-butoxypropan-2-methylpropyl] - 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) used as starting product was received as follows:

(1) a Solution of 2.0 g (10 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]- indole-8(RS)-carbonitrile in 150 ml of dry toluene was treated with 10 ml (20 mmol) of a 2M solution of chloride Isopropylamine in tetrahydrofuran and the resulting solution was heated at the boil under reflux for 20 minutes. The solution was cooled and treated dropwise 24 ml (24 mmole) of 1M solution of lithium aluminum hydride in tetrahydrofuran. The resulting solution was stirred at room temperature for 1.5 hours, cooled and the aqueous phase was treated with about 20 ml of water. The precipitate was separated by filtration, washed with 100 ml of dichloromethane, and the United filtrates evaporated under reduced pressure to obtain 7.2 g of a pale-brown oil. This oil was dissolved in 100 ml of dry dichloromethane and treated 2,34 g (23.4 mmole) of triethylamine, and then 2.8 g (of 11.6 mmole) dicret-BUTYLCARBAMATE at a temperature of 0oC in nitrogen atmosphere. Stir the solution was allowed to warm to room temperature and stirring was continued for 70 hours. Rafii on silica gel, using a simple diethyl ether/petroleum ether (1:2) for the elution to obtain 800 mg of tert-butyl[1(R or S)-[6,7,8,9-tetrahydropyrido[1,2-a]- indole-8(R or S)-yl] -2-methylpropyl]carbamate (diastereoisomer A) in the form of a white solid with a melting point 118-119oC. Further elution gave 420 mg of diastereoisomer B in the form of a white solid with a melting point 128-129oC.

(2) Mix a solution of 770 mg (2.25 mmole) of tert-butyl [1(R or S)-[6,7,8,9-tetrahydropyrido[1,2-a] indole-8(R or S)- yl]-2-methylpropyl]carbamate (diastereoisomer A) in 30 ml dichloromethane at 0oC was treated dropwise 287 mg (2.4 mmole) of oxalicacid. After 5 minutes the solvent was removed under reduced pressure, and the residue was dissolved in 30 ml dichloromethane and treated 686 mg (to 2.57 mmole) of the hydrochloride isopropyl-1-methyl-3-indoleacetate and of 1.02 g (10 mmol) of triethylamine at 0oC in nitrogen atmosphere. After heating to room temperature, the solution was stirred for 18 hours, washed with 50 ml water and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was dissolved in 10 ml of pyridine. Stir the solution was cooled to the temperature of the ice bath and was treated dropwise 664 μl (4.8 mmole) triperoxonane dioxide is slotow, was dried over magnesium sulfate and evaporated until dry. The residue was subjected to purification using flash chromatography on silica gel using ethyl acetate/petroleum ether (1: 2) for the elution to obtain 460 mg of 3-[8(R or S)- [1(R or S)-tert-butoxypropan-2-methylpropyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) as a red solid with a melting point p.223-224oC.

Example 8

Using a procedure analogous to that described in the first paragraph of Example 1, 270 mg (0.48 mmole) of 3-[8(R or S)- [1(R or S)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer B) received 180 mg of the hydrochloride of 3-[8(R or S)-[1(R or S)-amino-2-methylpropyl]-6,7,8,9 - tetrahydropyrido[1.2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole - 2,5-dione (diastereoisomer B) as a red solid with a melting point 248-250oC.

3-[8(R or S)-[1(R or S)-tert-butoxypropan-2 - methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1 - methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) used as starting product was received as follows:

Using procedures similar the 2-methylpropyl] carbamate (diastereoisomer B) obtained as described in Example 7(1), was obtained 270 mg 3-[8(R or S)- [1(R or S)-tert-butoxypropan - 2-methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl] -4- (1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) in the form of a red resin.

Example 9

Using a procedure analogous to that described in the first paragraph of Example 1, 1.2 g (2,17 mmole) of 3-[8(S)-[1(R or S)-tert-butoxypropyl] -6,7,8,9-tetrahydropyrido[1,2-a] - indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) received 850 mg of the hydrochloride of 3-[8(S)-[1(R or S)- aminopropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl] -4-(1-methyl - 3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 304-308oC.

3-[8(S)-[1(R or S)-tert.-butoxypropyl]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole - 2,5-dione (diastereoisomer A) used as starting product was received as follows:

(1) Chilled with ice a solution of 50.0 g (248 mmol) 8(S)-oxymethyl-6,7,8,9-tetrahydropyrido[1,2-a] indole in 500 ml of dichloromethane was treated with 50 ml (358 mmol) of triethylamine and with 52.0 g (298 mmol) of anhydride methanesulfonic acid for 20 minutes. After 2 hours was added 250 ml of water and the organic phase primevals phase was dried over magnesium sulfate and evaporated. The residual solid is triturated with simple ether, separated by filtration and dried in vacuum to obtain of 65.4 g [6,7,8,9-tetrahydropyrido- [1,2-a] indole-8(S)-yl]methyl-methanesulfonate in the form of a pale pink solid with a melting point 114-115oC;

[]2D0= -39,7o(c = 1%, CH2Cl2).

(2) 18.0 g (367 mmol) of sodium cyanide was added to a solution of 65.0 g (233 mmole) (6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)- yl)methyl-methanesulfonate in 500 ml of dimethylformamide and the mixture was heated to 70oC for 24 hours. This mixture was divided between 1000 ml of water and 600 ml of ethyl acetate. The aqueous phase was extracted twice each time with 700 ml of ethyl acetate and combined extracts were washed twice with 500 ml of water each time, dried over magnesium sulfate and evaporated. The obtained brown solid was dissolved in ethyl acetate, and the solution was filtered through a layer of silica gel. The solvent was removed in vacuo and the residue was led from methanol to obtain and 25.8 g of 6,7,8,9-tetrahydropyrido[1,2-a] - indole-8(S)-acetonitrile as a pale brown solid with a melting point 100-101oC;

[]2D0= -40,6o(c = 0,84%, CH2Cl2).

(3) a Solution of 27.0 g (129 mmol) of 6.7, evali boiling under reflux for 4 hours. Was added 400 ml of ethyl acetate and the organic phase is washed successively with 500 ml of water, 150 ml of 2M hydrochloric acid and three portions of 500 ml of water, dried over magnesium sulfate and evaporated to obtain 29 g 8(S)-(6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid as a pale pink solid with a melting point 118-120oC.

(4) a Solution of 29 g (127 mmol) 8(S)-(6,7,8,9-tetrahydropyrido- [1,2-a] indolyl)acetic acid and 5 ml of concentrated sulfuric acid in 500 ml of methanol was heated at the boil under reflux for 1 hour. This mixture was concentrated under reduced pressure and the product was separated by filtration and dried to obtain 28.4 g of methyl-[8(S)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl]acetate as a pale pink solid with a melting point 84-87oC.

(5) 10 g (100 mmol) of Diisopropylamine in 60 ml of dry tetrahydrofuran was treated at 0oC in nitrogen atmosphere 63 ml (100 mmol) of 1.6 M solution of n-utility in hexane and stirred for 15 minutes. The resulting solution was cooled to -78oC and a solution of 14.9 g (61,3 mmole) of methyl-[8(S)-6,7,8,9-tetrahydropyrido[1,2-a] indolyl] - acetate in 60 ml of tetrahydrofuran was added dropwise. After 30 minutes, was added 15.6 g (100 mmol) of Atilio anatoy temperature for about 1 hour. This mixture was divided between 300 ml simple diethyl ether and 20 ml of 2M hydrochloric acid. The organic phase is washed three times with 300 ml of water each time), dried over magnesium sulfate and evaporated to obtain 17 g of a pale orange oil. The sample was led from methanol to obtain methyl-alpha(R or S)-ethyl-6,7,8,9 - tetrahydropyrido [1,2-a]indole-8(S)-acetate (diastereomers A+B) as a pale pink solid with a melting point 87-90oC.

(6) a Solution of 17 g (63 mmole) of methyl-alpha(R or S)-ethyl - 6,7,8,9-tetrahydropyrido[1,2-a] indole-8(S)-acetate (diastereomers A+B) in 150 ml of methanol was treated with 130 ml of a 2M solution of hydrate of sodium oxide and heated at the boil under reflux for 18 hours. The cooled solution was added 150 ml of 4M hydrochloric acid and the resulting precipitate was filtered and divided between 200 ml of dichloromethane and 100 ml of water. The organic phase was separated, dried over magnesium sulfate and evaporated to obtain 15 g alpha(R or S)-6,7,8,9 - tetrahydropyrido[1,2-a]indole-8(S)-acetic acid (diastereomers A+B) as a pale pink solid.

(7) Mixed solution of 15 g (58,4 mmole) of alpha-(R or S)- 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetic who foyleside at room temperature in a nitrogen atmosphere. After 1 hour at room temperature the mixture was heated at the boil under reflux for 0.5 hours, cooled and the solvent was removed under reduced pressure. The residue was subjected to purification using flash chromatography on silica gel, using a simple diethyl ether/petroleum ether (1:3) for the elution to obtain 14 g of the isocyanate as a colorless oil. This oil was dissolved in 400 ml of dioxane and 150 ml of 2M hydrochloric acid and the resulting solution was stirred at room temperature for 18 hours. The solution was concentrated and separated between 300 ml of ethyl acetate and 2M solution of hydrate of sodium oxide. The aqueous layer was extracted with 100 ml ethyl acetate and the combined organic solutions were washed twice with 400 ml of water each time), dried over magnesium sulfate and evaporated to the dry state to obtain 7.7 g of cream-colored foam.

This foam 200 ml of dry dichloromethane was treated with 7.6 g (75 mmol) of triethylamine and 10.9 g (50 mmol) dicret-BUTYLCARBAMATE and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was subjected to flash chromatography on silica gel, using a simple diethyl ether/petroleum ether (1:2) for the elution to get the CSO solids with a melting point 152-158oC.

(8) using a procedure similar to that described in example 1(4), 4.3 g (13.1 mmol) of tert-butyl[1(R or S)- [6,7,8,9-tetrahydropyrido[1,2-a] indole-8(S)-yl] propyl]carbamate (diastereomers A+B) was obtained 1.2 g of 3-[8(S)-[1(R or S)- tert-butoxypropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol - 10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) and 2.0 g of diastereoisomer B, both in the form of a red solid.

Example 10

Using a procedure similar to that described in the first paragraph of example 1, 2.0 g (3,62 mmole) of 3-[8(S)-[1(R or S)- tert-butoxypropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B), obtained as described in Example 9, received 1.28 g of the hydrochloride of 3-[8(S)-[1(R or S)-aminopropyl]-6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) as a red solid with a melting point 247-253oC.

Example 11

Using a procedure analogous to that described in the first paragraph of Example 1, of 1.46 g of 3-[8(S)-[1(S)- tert-butoxypropan-2-methylpropyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione was obtained 1.29 g of the hydrochloride of 3-[8(S)-[1(S)- amino-2-methylpropyl] -6,7 is the melting temperature 253-256oC.

3-[8(S)-[1(S)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione used as starting product was received as follows:

(1) To 40 g (114 mmol) of complex 1-mentolovogo ether 6,7,8,9-tetrahydropyrido[1,2-a] indole-8(S)-carboxylic acid was added 50 ml of concentrated sulfuric acid and the resulting mixture was stirred until then, until all starting material did not dissolve (approximately 20 minutes). The solution was carefully poured into 1500 ml of a mixture of ice-water and the resulting precipitate was separated by filtration, washed with petroleum ether/toluene (3:1) and dried to obtain 24.2 g 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-carboxylic acid as a white solid with a melting point 251-253oC.

(2) Stir the suspension of the 24,0 g (111 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-carboxylic acid in 500 ml of dichloromethane was treated sequentially at 0oC 24 ml (138 mmol) of diisopropylethylamine, 13,24 g (136 mmol) of the hydrochloride of N,O-dimethylhydroxylamine, 10 mg dimethylaminopyridine and 23,04 g (112 mmol) of dicyclohexylcarbodiimide. The resulting mixture was stirred at room temperature for 18 hours and filtered, and Titania, and the residue was subjected to purification using flash chromatography on silica gel using ethyl acetate/petroleum ether (1: 3) for the elution to get to 22.6 g of a white solid. The sample was rubbed with a simple ether/petroleum ether, to obtain 6,7,8,9-tetrahydro-N-methoxy-N-methylpyridin[1,2-a] indole-8(S)- carboxamide in the form of a white solid with a melting point 78-80oC.

(3) Mix a solution of 10.0 g (38.7 mmol) of 6,7,8,9-tetrahydro-N-methoxy-N-methylpyridin[1,2-a]indole - 8(S)-carboxamide in 250 ml of tetrahydrofuran was treated dropwise at 0oC 60 ml (120 mmol) of a 2M solution of isopropylacrylamide in tetrahydrofuran. This mixture was stirred at room temperature for 18 hours and poured into 250 ml of saturated solution of ammonium chloride. The aqueous phase was washed 4 times with 100 ml of a simple diethyl ether each time, and the United ethereal extracts were washed with 200 ml brine, dried over magnesium sulfate and evaporated until dry. The product was subjected to purification using flash chromatography on silica gel using ethyl acetate/petroleum ether (1:3) for the elution to obtain 4.4 g isopropyl - 6,7,8,9-tetrahydropyrido[1,2-a] indole-8(S)-Ilkeston in the form of a white solid with pace] indole-8(S)-Ilkeston in 120 ml of ethanol was treated with a solution of 2.30 g (33 mmole) of hydroxylamine hydrochloride and 1.0 g (25 mmol) of hydrate of sodium oxide in 20 ml of water. The resulting mixture was heated at the boil under reflux for 3.5 hours, cooled and filtered. The obtained solid was dried to obtain of 3.54 g of the oxime as a white solid.

This oxime was dissolved in 150 ml of dry tetrahydrofuran and treated with 12.5 ml (12.5 mmole) of 1M solution of lithium aluminum hydride in tetrahydrofuran. The resulting solution was heated at the boil under reflux for 3 hours in nitrogen atmosphere, cooled and carefully treated with 150 ml of water. The mixture was extracted with 200 ml of ethyl acetate, and then the two portions of 150 ml of ethyl acetate and the combined organic extracts were dried over magnesium sulfate and evaporated until dry. The residue was dissolved in 150 ml of dichloromethane and the resulting solution was treated with 3 ml (21.5 mmole) of triethylamine and 3.4 g (15.6 mmole) dicret-BUTYLCARBAMATE and stirred 18 hours. This mixture was washed with 150 ml of saturated solution of ammonium chloride, dried over magnesium sulfate and evaporated under reduced pressure. After cleaning with rapid chromatography on silica gel, using a simple diethyl ether/petroleum ether (1: 3) for the elution, were obtained 1.4 g of tert-butyl[1(R)-[6,7,8,9-tetrahydropyrido[1,2-a] indole-8(S)- yl] -2-methylpropyl]carbamate is 1.1 g of tert-butyl[1(S)-[6,7,8,9-tetrahydropyrido- [1,2-a] indole-8(S)-yl]-2-methylpropyl]carbamate in the form of a white solid with a melting point 154-155oC.

(5) using a procedure similar to that described in Example 1(4), 1.1 g of tert-butyl[1(S)-[6,7,8,9 - tetrahydropyrido[1,2-a]indole-8(S)-yl]-2-methylpropyl] carbamate was obtained of 1.46 g of 3-[8(S)-[1(8)-tert-butoxypropan-2-methylpropyl] - 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione as a red foam.

Example 12

Using a procedure similar to that described in the first paragraph of Example 1, 0.5 g (0,88 mmole) of 3-[8(S)-[1(R)- tert-butoxypropan-2-methylpropyl] -6,7,8,9-tetrahydropyrido- [1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione was obtained 0,41 g of the hydrochloride of 3-[8(S)-[1(R)-amino-2-methylpropyl] - 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione as a red solid with a melting point 235-242oC.

3-[8(S)-[1(R)-tert. -butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole - 2,5-dione used as starting product was received as follows:

Using a procedure similar to that described in Example 1(4), from 0,94 g of tert-butyl[1(R)-[6,7,8,9-tetrahydropyrido- [1,2-a]indole-8(S)-yl]-2-methylpropyl] carbamate obtained as described in Example 11 (1)-(4) were of 1.05 g of 3-[8(S)-[1(R)-tert-butoxide the th foam.

Example 13

Using a procedure analogous to that described in the first paragraph of Example 1, 100 mg 3-[8(R or S)-[alpha - (R or S)- tert-butoxyethanol] -6,7,8,9-tetrahydropyrido[1,2-a] indol - 10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) received 50 mg of the hydrochloride of 3-[8(R or S)-[alpha - (R or S)-aminobenzyl]- 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl] -4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 234-237oC.

3-[8(R or S)-[alpha - (R or S)-tert-butoxyethanol]- 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione (diastereoisomer A) used as starting product was received as follows:

(1) using a procedure analogous to that described in Example 1(3), of 1.0 g (5.1 mmole) of 6,7,8,9-tetrahydropyrido- [1,2-a]indole-8(RS)-carbonitrile and 3.7 ml (11 mmol) of a 3M solution of phenylmagnesium in tetrahydrofuran was obtained 0.9 g of tert-butyl-[alpha - (R or S)-(6,7,8,9-tetrahydropyrido[1,2-a]indole - 8(R or S)-yl)benzyl]carbamate as a mixture of diastereoisomers in the form of a white solid with a melting point of 160-165oC.

(2) using a procedure analogous to that described in Example 1(4), 800 mg 3-[8(R or S)-[alpha - (R or S)- tert-butoxyethanol]-6,7,8,9-tetrahydropyrido[1,2-a]indol - 10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red resin. Further elution gave 280 mg of diastereoisomer In a red resin.

Example 14

Using a procedure analogous to that described in the first paragraph of Example 1, from 200 mg 3-[8(R or S)-[alpha - (R or S)- tert-butoxyethanol] - 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione (diastereoisomer B), obtained as described in Example 13(2), received 70 mg of the hydrochloride of 3-[8(R or S)-[alpha - (R or S)-aminobenzyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] - 4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) as a red solid with a melting point 226-233oC.

Example 15

Using a procedure analogous to that described in the first paragraph of Example 1, from 200 mg 3-[8(S)-[(R or S)- (tert-butoxyphenyl)(cyclopentyl)methyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) received 150 mg of the hydrochloride of 3-[8(S)-[(R or S)-(amino)(cyclopentyl)methyl]-6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 236-241oC.

3-[8(S)-[(R or S)-(tert-butoxyphenyl)(cyclopentyl)methyl]- 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-IU (1) using the procedures similar to what was described in Example 11(3), 2.0 g (of 7.75 mmole) 6,7,8,9-tetrahydro-N-methoxy - N-methylpyridin[1,2-a]indole-8(S)-carboxamide and 15 ml (30 mmol) of a 2M solution of chloride cyclopentylamine in simple diethyl ether there was obtained 1.1 g of cyclopentyl-6,7,8,9-tetrahydropyrido[1,2-a] indole - 8(S)-Ilkeston in the form of a pale yellow solid with a melting point 69oC.

(2) using a procedure analogous to that described in Example 11(4), of 1.05 g (3.9 mmole) cyclopentyl-6,7,8,9 - tetrahydropyrido[1,2-a] indole-8(S)-Ilkeston received 330 mg, 8(S)-[(R or S)-tert.-butoxypropyl)(cyclopentyl)methyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indole (diastereoisomer A) in the form of a white solid with a melting point 140-143oC. further elution was obtained 430 mg of diastereoisomer In the form of a white solid with a melting point 58-63oC.

(3) using a procedure analogous to that described in Example 1(4), 300 mg, 8(S)-[(R or S)- tert-butoxyphenyl)(cyclopentyl)methyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indole (diastereoisomer A) received 200 mg 3-[8(S)-[(R or S)-(tert-butoxyphenyl)(cyclopentyl)methyl]- 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3 - indolyl)-1H-pyrrole-2,5-dione as a red resin.

oC.

3-[8(S)-[(R or S)-(tert. -butoxypropyl)(cyclopentyl)methyl] - 6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione used as starting product was received as follows:

Using a procedure analogous to that described in Example 1(4), 400 mg 8(S)-[(R or S)-(tert-butoxyphenyl)(cyclopentyl)methyl] -6,7,8,9-tetrahydropyrido[1,2-a] indole (diastereoisomer B) were obtained as described in Example 15 (1)- (2), 250 mg 3-[8(S)-[(R or S)-(tert-butoxyphenyl)(cyclopentyl)methyl] - 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione as a red resin.

Example 17

Using a procedure analogous to that described in the first paragraph of Example 1, 40 mg of 3-[2(R or S)- [1(R or S)- tert-butoxypropan-2-methylpropyl] -2,3-dihydro-1H-pyrrolo- [1,2-a]indol-9-yl]-4- (1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) received 20 mg of the hydrochloride of 3-[2(R or S)-[1(R or S)-amino-2 - methylpropyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl] -4-(1 - methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer A) in the form of a red solid with a melting point 224-230oC.

3-[2(R or S)-[1(R or S)-tert-butoxypropan-2-methylpropyl]- 2,3-dihydro-1H-pyrrolo[1,2-a] indol-9-yl]-4-(1-methyl-3-Indore 8.0 g (35 mmol) of ethyl-2,3-dihydro-1H - pyrrolo[1,2-a]indol-2(RS)-carboxylate in 100 ml ethanol and 100 ml of water was treated with 3.0 g (75 mmol) hydrate of sodium oxide. This mixture was heated at the boil under reflux for 15 minutes, then cooled and acidified with 60 ml (120 mmol) of 2M hydrochloric acid. The suspension was filtered and the solid is washed with 50 ml water, and then dried to obtain 5.9 g of 2,3-dihydro-1H - pyrrolo[1,2-a] indol-2(RS)-carboxylic acid as a white solid with a melting point 171-173oC.

(2) using a procedure analogous to that described in Example 11(2) of 4.0 g (20 mmol) of 2,3-dihydro-1H-pyrrolo[1,2-a]- indole-2(RS)-carboxylic acid was obtained 2.35 g of 2,3-dihydro-N - methoxy-N-methyl-1H-pyrrolo[1,2-a] indol-2(RS)-carboxamide as a white solid with a melting point 87-88oC.

(3) Suspension of 840 mg (35 mg atom) of magnesium turnings in 60 ml of tetrahydrofuran was treated dropwise with a solution of 4.4 g (37 mmol) of 2-bromopropane in 10 ml of tetrahydrofuran. This mixture was heated at the boil under reflux for another 30 minutes, then was cooled to 0oC and was added at this temperature a solution of 2.3 g (9.4 mmole) of 2,3-dihydro-N-methoxy-N-methyl-1H-pyrrolo[1,2-a] - indole-2(RS)-carboxamide in 50 ml of tetrahydrofuran. After stirring at 0oC for 30 minutes, the mixture was poured into 200 ml of a saturated aqueous solution of chloride of MMA. the donkey adding petroleum ether (boiling point 40-60oC) was obtained precipitate, which was separated by filtration and dried to obtain 1.6 g of a white solid. This solid substance was dissolved in 100 ml of ethanol and subjected to hydrogenation over 200 mg of 10% palladium/coal at atmospheric pressure for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure until, until the start of crystallization. The product was separated by filtration and dried to obtain 1.55 g isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a] indol-2(RS)-Ilkeston in the form of a white solid with a melting point 104-105oC.

(4) using a procedure analogous to that described in Example 11(4), 1.5 g of isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol - 2(RS)-Ilkeston received 830 mg of tert-butyl[1(R or S)-[2,3-dihydro - 1H-pyrrolo[1,2-a]indol-2(R or S)-yl] -2-methylpropyl]carbamate as a mixture of diastereoisomers. This mixture was stirred in 20 ml of ethyl acetate saturated with hydrogen chloride for 2 hours. The obtained solid substance was separated by filtration and subjected to purification using fast chromatography on silica gel using methanol/dichloromethane (1: 10) for elution to obtain 150 mg gargiulo substances. The subsequent elution received 150 mg of diastereoisomer In the form of a white solid.

(5) a Solution of 100 mg (range 0.38 mmole) of the hydrochloride of 2(R or S)-[1(R or S)-amino-2-methylpropyl] -2,3-dihydro-1H-pyrrolo[1,2-a] indole (diastereoisomer A) in 30 ml of dichloromethane was treated with 110 mg (0.5 mmole) dicret-BUTYLCARBAMATE and 100 mg (1 mmol) of triethylamine and stirred for 72 hours. This solution was washed successively with 30 ml of 1M hydrochloric acid and 30 ml of saturated aqueous sodium bicarbonate, and then dried over magnesium sulfate. After filtration, concentration of the filtrate under reduced pressure and purification of the residue by means of fast chromatography, using a simple diethyl ether/petroleum ether (boiling point 40-60oC) (1:2) for the elution, received 100 mg of tert-butyl[1(R or S)- [2,3-dihydro-1H - pyrrolo[1,2-a]indol-2(R or S)-yl]-2-methylpropyl]carbamate (diastereoisomer A) in the form of butter.

(6) using a procedure analogous to that described in the first paragraph of Example 1, 55 mg of tert-butyl[I(R or S)- [2,3-dihydro-1H-pyrrolo[1,2-a] indol-2(R or S)-yl] -2 - methylpropyl]carbamate (diastereoisomer A) received 40 mg of 3-[2(R or S)-[1(R or S)-tert-butoxypropan-2-methylpropyl] -2,3 - dihydro-1H-pyrrolo[1,2-a] indol-9-yl] -4-(1-methyl-3-indolyl)-1 is the had been described in the first paragraph of Example 1, 80 mg of 3-[2(R or S)-[1(R or S)- tert-butoxypropan-2-methylpropyl] -2,3-dihydro-1H-pyrrolo- [1,2-a] indol-9-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) received 40 mg of the hydrochloride of 3-[2(R or 8)-amino - 2-methylpropyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl]-4-(1 - methyl-3-indolyl)-1H-pyrrole-2,5-dione (diastereoisomer B) as a red solid with a melting point 220-225oC.

3-[2(R or S)-[1(R or S)-tert-butoxypropan-2-methylpropyl]- 2,3-dihydro-1H-pyrrolo[1,2-a] indol-9-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione used as starting product was received as follows:

(1) using a procedure analogous to that described in Example 17(5), 90 mg (0,34 mmole) of the hydrochloride of 2(R or S)-[1(R or S)-amino-2-methylpropyl] -2,3-dihydro-1H-pyrrolo[1,2-a] indole (diastereoisomer B), obtained as described in Example 17(4), received 100 mg of tert-butyl[1(R or S)-[2,3-dihydro-1H-pyrrolo- [1,2-a]indol-2(R or S)-yl]-2-methylpropyl]carbamate (diastereoisomer B) in the form of butter.

(2) using a procedure similar to that described in Example 1(4), 100 mg of tert-butyl[1(R or S)-[2,3-dihydro - 1H-pyrrolo[1,2-a]indol-2(R or S)-yl] -2-methylpropyl] carbamate was obtained 80 mg of 3-[2(R or S)-[1(R or S)-tert-butoxypropan - 2-methylpropyl]-2,3-dihydro-1H-pyrrolo is Edery, similar to what was described in the first paragraph of Example 1, from 320 mg of 3-[8(RS)-[1(RS)- tert-butoxypropan-2-methylpropyl] -7,8,9,10-tetrahydro-6H - azepino[1,2-a] indol-11-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione was obtained 220 mg of the hydrochloride of 3-[8(RS)-[1(RS)-amino-2-methylpropyl] - 7,8,9,10-tetrahydro-6H-azepino[1,2-a] indol-11-yl] -4-(1-methyl-3 - indolyl)-1H-pyrrole-2,5-dione as a red solid with a melting point 248-256oC.

3-[8(RS)-[1(RS)-tert-butoxypropan-2-methylpropyl] -7,8,9,10 - tetrahydro-6H-azepino[1,2-a]indol-11-yl]-4-(1-methyl-3-indolyl)- 1H-pyrrole-2,5-dione used as starting product was received as follows:

(1) using a procedure analogous to that described in Example 11(2), 1.0 g (4.4 mmole) 7,8,9,10-tetrahydro-6H-azepino- [1,2-a]indole-8(RS)-carboxylic acid was obtained 0.8 g 7,8,9,10-tetrahydro-N-methoxy-N-methyl-6H-azepino[1,2-a] indole - 8(RS)-carboxamide as a white solid with a melting point 134-135oC.

(2) using a procedure analogous to that described in Example 17(3), 0.8 g (2.9 mmole) 7,8,9,10-tetrahydro-N-methoxy - N-methyl-6H-azepino[1,2-a] indole-8(RS)-carboxamide was obtained 0.56 g isopropyl-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-8(RS)-Ilkeston in the form of a white solid with tempera is 4), from 0.56 g (2.2 mmole) isopropyl-7,8,9,10-tetrahydro - 6H-azepino[1,2-a] indole-8(RS)-Ilkeston were obtained 330 mg of tert-butyl[1(RS)-[7,8,9,10-tetrahydro-6H-azepino[1,2-a] indole - 8(RS)-yl]-2-methylpropyl]carbamate as a mixture of diastereoisomers in the form of a white solid with a melting point 152-153oC.

(4) using a procedure analogous to that described in Example 1(4), from 300 mg of tert-butyl[1(RS)-[7,8,9,10-tetrahydro - 6H-azepino[1,2-a] indole-8(RS)-yl] -2-methylpropyl] carbamate was obtained 350 mg 3-[8(RS)-[1(RS)-tert-butoxypropan-2-methylpropyl] -7,8,9,10 - tetrahydro-6H-azepino[1,2-a] indol-11-yl] -4-(1-methyl-3 - indolyl)-1H-pyrrole-2,5-dione as a red oil.

Example 20

Using a procedure analogous to that described in the first paragraph of Example 1, from 800 mg of 3-[7(RS)-[1(RS)-tert-butoxypropan - 2-methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione were obtained 480 mg of the hydrochloride of 3-[7(RS)-[1(RS)-amino-2-methylpropyl] -6,7,8,9-tetrahydropyrido- [1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione as a red solid with a melting point 238-244oC.

3-[7(RS)-[1(RS)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole - 2,5-dione used in kachestvena in Example 11(2), from 2.0 g (9.3 mmole) of 6,7,8,9-tetrahydropyrido[1,2-a]- indol-7(RS)-carboxylic acid was obtained 1.6 g 6,7,8,9-tetrahydro-N - methoxy-N-methylpyridin[1,2-a]indole-7(RS)-carboxamide as a pale yellow oil.

(2) using a procedure analogous to that described in Example 17(3), out of 1.6 g of 6,7,8,9-tetrahydro-N-methoxy-N-methylpyridin- [1,2-a]indole-7(RS)-carboxamide was obtained 1,05 g isopropyl-6,7,8,9 - tetrahydropyrido[1,2-a] indole-7(RS)-Ilkeston in the form of a brown-reddish solid substance with a melting point 43-44oC.

(3) using a procedure analogous to that described in Example 11(4), 1.0 g of isopropyl-6,7,8,9-tetrahydropyrido- [1,2-a]indole-7(RS)-Ilkeston received 800 mg of tert-butyl[1(RS)- [6,7,8,9-tetrahydropyrido[1,2-a] indole-7(RS)-yl] -2 - methylpropyl]carbamate as a white solid with a melting point 55-57oC (in the form of a mixture of diastereomers).

(4) using a procedure analogous to that described in Example 1(4), from 700 mg of tert.-butyl-[1(RS)-[6,7,8,9 - tetrahydropyrido[1,2-a]indole - 7(RS)-yl] -2-methylpropyl] carbamate received 800 mg of 3-[7(RS)-[1(RS)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl] -4-(1-methyl-3-indolyl)-1H - pyrrole-2,5-dione as a red resin.

Example 21

By means of the procedure, l]-6,7,8,9-tetrahydropyrido- [1,2-a] indol-10-yl] -4-(1-phenyl-3-indolyl)-1H-pyrrole-2,5-dione was obtained 1.12 g of the hydrochloride of 3-[8(S)-[1(S)-amino-2-methylpropyl] - 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)- 1H-pyrrole-2,5-dione as a red solid with a melting point 235-245oC.

3-[8(S)-[1(S)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-phenyl-3-indolyl)-1H - pyrrole-2,5-dione used as starting product was received as follows:

(1) Chilled with ice, a solution of 10 g (51.8 mmole) of 1-phenylindole in 100 ml of anhydrous simple diethyl ether was treated dropwise over 5 minutes a solution of 6 ml (68,8 mmole) of oxalicacid in 20 ml of anhydrous simple diethyl ether. This mixture was stirred for 3 hours under ice cooling, and then was treated with 25 ml of ethanol in one piece. After stirring for 10 minutes the solvent was removed under reduced pressure and the residual solid was led from 60 ml of ethanol to obtain 12,38 g ethyl-1-phenylindol-3-glyoxylate in the form of a pale yellow solid with a melting point 109-110oC.

(2) a Mixture of 10 g (34.1 mmole) ethyl-1-phenylindol-3-glyoxylate and about 25 g of Raney Nickel in 350 ml of ethanol and 150 ml of water was heated at the boil under reflux for 6 hours. The suspension was filtered through filter paper, and is the ut. The filtrate was concentrated under reduced pressure, and the residue was subjected to purification using flash chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. Received 6,38 g ethyl-1-phenylindol-3-acetate as a yellow oil.

(3) a Solution of 6.3 g (22,6 mmole) ethyl-1-phenylindol-3-acetate in 20 ml of ethanol was treated with 20 ml (40 mmol) of a 2M solution of hydrate of sodium oxide and kept at room temperature for 17 hours. The ethanol was removed under reduced pressure and the aqueous solution was washed with two 20 ml portions of simple diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid, and the resulting suspension was kept at 0oC for 2 hours. The suspension was filtered and the solid was led from methanol/water (2:1) to obtain 5.6 g of 1-phenylindole-3-acetic acid in the form of bluish-gray solid with a melting point 131-135oC.

(4) Cooled with ice, a solution of 3 g (8,77 mmole) of tert-butyl[1(S)-[6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-yl]-2 - methylpropyl]carbamate obtained as described in Example 11(4), in 50 ml of anhydrous simple diethyl ether was treated dropwise under nitrogen atmosphere for 5 minutes a solution of 0.85 ml (9,74 manigandan pressure, and the residue was dissolved in 50 ml of dry dichloromethane. The solution was added dropwise at 0oC stir in a mixture of 2.2 g (8,77 mmole) 1-phenylindol-3-acetic acid and the 3.65 ml (26,3 mmole) of triethylamine in 50 ml of dry dichloromethane. The mixture was stirred for 17 hours, then the solvent was removed under reduced pressure. After purification using flash chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution, followed by crystallization from ethyl acetate/hexane was obtained 1.6 g of 3-[8(S)-[1(S)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-phenyl-3-indolyl)-furan - 2,5-dione as an orange solid substance with a melting point 148-150oC.

(5) a Solution of 1.6 g (of 2.54 mmole) of 3-[8(S)-[1(S)-tert-butoxypropan-2-methylpropyl] -6,7,8,9 - tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)-furan - 2,5-dione in 20 ml of dry N,N-dimethylformamide was treated to 5.35 ml (25.4 mmole) hexamethyldisilazane and 0.41 g (12.8 mmole) of methanol. The solution was heated to 50oC 3 hours, and then treated yet to 5.35 ml (24.8 mmole) hexamethyldisilazane and 0.41 g (12.8 mmole) of methanol. After only 6 hours, the solvent is evaporated under reduced pressure and the residue is again evaporated to 20 ml of methanol. In the flash chromatography of lamido-2 - methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]-4-(1 - phenyl-3-indolyl)-1H-pyrrole-2,5-dione as a red solid with a melting point 165-168oC.

The following examples illustrate the General pharmaceutical compositions containing compounds that are the subject of the present invention.

An example of a

Tablets containing the following ingredients can be obtained using a known method.

Ingredient - a tablet

The compound of formula I - 5,0 mg

Lactose - 125,0 mg

Maize starch is 75.0 mg

Talc - 4.0 mg

Magnesium stearate 1.0 mg

Mass of tablets: 210,0 mg

Example B

Capsules containing the following ingredients can be obtained using a known method.

Ingredient - On capsule

The compound of formula I - 10.0 mg

Lactose - 165,0 mg

Maize starch - 20.0 mg

Talc - 5.0 mg

The weight of the filled capsules: 200,0 MSU

1. Substituted pyrrole General formula I

< / BR>
in which R1represents lower alkyl, lower cycloalkyl, aryl or lower aralkyl;

R2represents hydrogen, aryl or lower alkyl;

m and n is 1 or 2,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, wherein R1represents lower alkyl, in particular lower alkyl, coderay a lower alkyl.

4. Compounds according to any one of paragraphs.1 to 3, characterized in that m = 1 and n = 2.

5. Connection on p. 1, characterized in that it is a 3-[8(S)-[1(R or S)-aminopropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

6. Connection on p. 1, characterized in that it is a 3-[8(S)-[1(S)-amino-2-methylpropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

7. Connection on p. 1, selected from the following group: 3-[8(R or S)-1(R or S)-amino-ethyl] -6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[8(R or S)-1(R or S)-aminopropyl]-6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[8(R or S)-1(R or S)-aminobutyl]-6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione and 3-[8(R or S)-1(R or S)-amino-2-methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

8. Connection on p. 1, selected from the following group: 3-[8(S)-1(R)-amino-2-methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[8(R or S)-[alpha - (R or S)-aminobenzyl]-6,7,8,9-tetrahydropyrido[1,2-a] indol-10-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[8(S)-[(R or S)-(amino)(cyclopentylpropionyl]-2,3-dihydro-1H-pyrrolo[1,2-a] indol-9-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[8(RS)-1(RS)-amino-2-methylpropyl] -7,8,9,10-tetrahydro-6N-azepino[1,2-a] indol-11-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 3-[7(RS)-[1(RS)-amino-2-methylpropyl]-6,7,8,9-tetrahydropyrido[1,2-a] indol-9-yl] -4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione and 3-[8(S)-[1(S)-amino-2-methylpropyl] -6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)-1H-pyrrole-2,5-dione.

9. Substituted pyrrole General formula I on p. 1, inhibiting the protein kinase C.

Priority points:

10.05.93 on PP.1 to 7 and 9.

21.02.94 on p. 8.

 

Same patents:

The invention relates to new imidazolidinedione intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of 1,2,4-triazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical compositions containing them, and method of inhibiting seizures

The invention relates to compounds and their pharmaceutically acceptable salts, having the ability to inhibit matrix metalloprotease, in particular interstitial collagenase, and therefore suitable for the treatment of painful conditions in mammals, facilitated by the inhibition of such matrix metalloprotease

The invention relates to the field of organic chemistry, namely to new individual compounds of class imidazopyridines, method of production thereof, which exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to new N-substituted azabicycloalkanes

The invention relates to a compound of formula I and pharmaceutically acceptable acid additive salts, where: a Is N or CH; b is-NR1R2-NHCHR1R2, -OCHR1R2
Up!