RU1799382C - Method of substituted pyrrols or theirs pharmaceutically acceptable salts synthesis - Google Patents

Abstract

SUMMARY OF THE INVENTION: substituted pyrroles of formula I ... n 0 "N —O. d. R, Teg-g 3 1 N JYA-f W c, cng where RT- H, lower alkyl, possibly substituted with an OH group; R2 and Pz — H, halogen, lower alkyl, lower alkylthio group, NHa; - N.CH, R - CbH3, provided that Ri, R2, R3, R4-H, CH3, or - (CHg) p - X. p 2-6, X - H, OH, an azido group, halogen, aminocarbo- nyl, carboxyl, lower alkoxycarbonyl, lower alkylsulfonyloxy, CN, isothiocyanato, 1 - pyridinium, amidino. lower alkylsulfinyl, lower alkylsulfinyl, mercaptb, possibly substituted by lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, imidazol-2-yl, imidazolin-2-yl, 1-methyltetrazol-5-yl, pyridin-1-oxide -yl or amidine, or-NH2, possibly substituted 1-3 times with lower alkyl or 1 time with lower aminoalkyl, nitripyridin-2-yl, pyrmidin-2-yl, phenylsulfo, lower alkylsulfo, phenylcarbonyl, imidazol-1-yl -carbonyl, lower alkylcarbonyl, aminocarbonyl, amidino, (4-benzyloxyphenyl) iminocarbonyl,. (4-hydroxyphenyl) iminocarbonyl, amino nitroiminocarbonyl, aminothiocarbonyl, amino cyaniminocarbonyl, methylamino cyaniminocarbonyl, dimethylaminocyaniminocarbonyl, methyl and animocarbonyl, - 1-amino-2-nitro-2-nitro-1-1-nitro. rovinyl group, or their pharmaceutical. sky acceptable salts. Reagent 1: compound I, where O is contained in cycle A instead of N. Reagent 2: MH 3 or (CHabSlfcNH in methanol. Reaction conditions: respectively, under pressure in DMF and water or in toluene or chloroform. If necessary, the product is transferred to the corresponding modified; derivative and isolated in its free form or in the form of salt. 2 tab.

Description

The invention relates to organic chemistry, and in particular to a method for producing substituted pyrroles of the general formula I

 n

R ° GYY ° 23SU

T.

H

CH2R,

where Ri is hydrogen or lower alkyl, which may be substituted by a hydroxyl group; .

R2 and Ra are independently hydrogen, halogen, lower alkyl, lower alkylthio or amino; R4 is hydrogen or methyl; R is phenyl, provided that Ri, R2, R3 and R-i are hydrogen. or methyl, or a linear methylene chain - (CH2) p-X, in which n is 2-6; X is hydrogen, hydroxyl group, azido group, halogen, aminocarbonyl group, carboxyl group, lower alkoxycarbonyl group, lower alkylsulfonyloxy group, cyano group, and zothiocmanato corpus, 1-pyridine group, amidino group, lower alkyl alkylsulfopyl Tpyrtna, a mer capto group which may be substituted with lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl group, imidazol-2-yl group, imidazolin-2-yl group, 1-methyltetrazol-5-yl group, pyridine - 1 -oxide-2- a single group or an amidino group, or means an amino group which can be substituted up to three times with lower alkyl or once substituted with a lower aminoalkyl group, a nitropyridin-2-yl group, a pyrimidin-2-yl group, a phenylsulfo group, a lower alkylsulfo group , a phenylcarbonyl group, an imidazol-1-ylcarbonyl group, a lower alkylcarbonyl group, an aminocarbonyl group, an amidino group, (4-benzyloxyphenyl) iminocarbonyl group, (4-hydroxyphenyl) iminocarbonyl group, aminonitriminocarbonyl g uppa, an aminothiocarbonyl group, an amino-cyaniminocarbonyl group, a methylamino-cyaniminocarbonyl group, a dimethylaminocyaniminocarbonyl group, a methylthiocyaniminocarbonyl group, a 1-amino-2-nitrovinyl group or a 1-methylthio-2-nitrovinyl group, and also a pharmaceutically acceptable salt thereof ability to inhibit protein kinase and can be used in medicine.

It is known to use 3,4-bis (3-indolyl) -1H-pyrrole-2,5-dione (1) to inhibit protein kinase, however, its activity is not high enough.

The aim of the invention is to develop an affordable method for producing compounds I, which consists in the fact that

an,

Oj

4Ri

where R, Ri, R2, R3 and R take the indicated values, and X in the composition of R is hydrogen, a hydroxyl group, a carboxy group, an azido group, an alkoxycarbonyl group

5 10 15 20 25 30 35 40

45

fifty

55

or (tert.-butyloxycarbonyl) alkylamino group, treated with ammonia under pressure in dimethylformamide-water or hexamethyldisalazane and methanol in toluene or chloroform, and the desired product is isolated in free form or in the form of a salt or, if necessary, functional modification is carried out substituent X within the indicated values and provided that RI does not contain a hydroxy group and R2 and Pz are not an amino group, by alkylating the carboxyl group, reducing the azido group, sulfonylating the hydroxy group or exchanging it and a halogen, pyridinium or an aminoalkylamino group with the isolation of the obtained compounds in free form or in the form of salts, or, if necessary, further modifying the substituent X within the above values by exchanging the sulfonyloxy group for a dialkylamino group, trialkylammonium group, cyano group, imidazol-2-ylthio group, 1-methyltetrazol-5-ylthio group, pyridin-1-oxide-2-ylthio group, amidinothio group, alkylthio group or acylthio group, or by acylation of an amino group, sulfonylation of an amino group, or rotating it into an isothiocyanato group, or by replacing a hydrogen atom of an amino group with an amidino group, an aminonitroiminocarbonyl group, a 1-methylthio-2-nitro-vinyl group, a nitropyridin-2-yl group, a pyrimidin-2-yl group, (4-benzyloxyphenyl) iminocarbonyl group or methylthiocyanimino group with the isolation of the obtained compounds in free form or in the form of salts, or, if necessary, further modification

. substituent X within the above values by oxidizing the alkylthio group to an alkylsulfinyl or alkylsulfonyl group, aminating the cyano group, formylating the yzothiocyanato group, hydro. lysis of the (4-benzyloxyphenyl) iminocarbonyl group, ammonolysis of the imidazol-1-ylcarbonyl group, 1-methylthio-2-nitrovinyl group or methylthiocyanimino group with ammonia or the corresponding amine and isolation. we eat the obtained compounds in free form or in the form of salts,

The invention is illustrated by the following examples.

Example 1. 0.4 g 3- (1-methyl-3-indolyl) - 4- (1-methyl l-5-nitro-3-y-share l) -fu ran-2,5-dione is treated with 3 ml of DMF and 20 ml of a 33% aqueous ammonia solution and the mixture is heated for 3.5 hours at 140 ° C in a closed vessel. The cooled mixture is filtered and the residue washed with water and dried with obrzovanie 0.29 g of 3- (1-methyl-3-indolyl) -4- {1-methyl-5-nitro-3-indolyl) -1 H-pyrrole- 2,5-dione. so pl. 282-284 ° C.

The furandionic starting material is prepared as follows:, ...

0.7 g of 1-methyl-5-nitroindol-3-glyoxylyl chloride in 20 ml of dichloromethane is treated with 0.85 ml of triethylamine and 0.5 g of 1-methyl-indol-3-yl-acetic acid. The mixture was allowed to stand at room temperature for 16 hours and then concentrated. The residue was chromatographed on silica gel, eluting with 50% ethyl acetate in petroleum ether to give 0.42 g of furandione, mp. 220-221 ° C.

PRI me R 2. 3- (1-Methyl-3-indolyl) -4- (1-naphthyl) furan-2,5-dione (56 mg) is treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia and the resulting mixture was heated for 5 hours at 130 ° C. in a closed vessel. The precipitate formed is filtered off, washed with water and dried to obtain 53 gZ- (1-methyl-3-indolyl) -4 - (1-naphthyl} -1H-pyrrole-2,5-dione, mp 258- 26 (fC.

Furandione starting material is prepared as follows.

To 1.1 g of 1-methylindole-3-glyoxylyl chloride in 30 ml of dichloromethane, 1.65 ml of triethylamine was added, and then a solution of 0.93 g of 1-naphthylacetic acid in 20 ml of dichloromethane was added. After stirring for 16 hours, the mixture was concentrated and the residue was purified on silica gel with dichloromethane to give 295 mg of furandione, m.p. 217 - 219 ° C.

Example 3.0.3 g of 3- (1-methyl-3-indolyl) - 4- (3-methylphenyl) furan-2,5-dione are treated with 8 ml of DMF and 60 ml of a 33% aqueous ammonia solution and then heated at 150 ° C for 5 hours, after which the mixture was allowed to cool. The precipitate formed is filtered off, washed with water and dried to give 162 mg of 3- (1-methyl-3-indolyl) -4- (3-methylphenyl) -1 N-pyrrole-2,5-dione, mp . 243 ° C.

The furandione starting compound is prepared as follows.

1.5 g of 1-methylindr-3-glyoxyl chloride in 30 ml of dichloromethane at 0 ° C are treated with 2.17 ml of triethylamine and 1.02 g of 3-methyl-phenyl-acetic acid. The mixture was allowed to warm to room temperature and was stirred overnight. Silica was added and the solvent was evaporated. Silicon oxide and adsorbed products are purified on silica gel using a system of 20% ethyl acetate - in petroleum ether to form 307 mg of furandion, so pl. 158-160 ° C.

Example 4. 160 mg of 3-0 benzothiophen-3-yl) -4- (1-methyl-3-indolyl) furan-2,5-dione is treated with 2 ml of DMF and 20 ml of a 33% aqueous ammonia solution and the resulting mixture heated for 5 hours at 40 ° C. The cooled mixture was filtered and the residue washed with water and dried. The solid is purified on silica gel with a mixture of 50% ethyl acetate in petroleum ether to give 20 mg of 3- (1-benzothiophen-3-yl} -4- {1-methyl-3-indolyl) -1H-pyrrole-2,5-dione , mp 250-255 ° C.

The furandione starting compound is prepared as follows.

1 g of 1-methylindole-3-glyoxyl chloride in 20 ml of dichloromethane is treated with 1.6 ml of triethylamine and a solution of 0.87 g of 1-benzothiophene-3-yl-acetic acid in dichloromethane. After standing at room temperature for 16 hours, the mixture was concentrated and the residue was chromatographed on silica gel with a mixture of 50% ethyl acetate in hexane to give 0.33 g of furandione, mp. 165 ° C.

PRI me R 5. 0.28 g of 3- {1-methyl-3-indole and l 4- {3-thienne and l) fu n-2,5-d ion and the sample is 10 ml of DMF and 40 ml of a 33% aqueous ammonia solution are added. The mixture is heated for 4 hours at 140RS. The cooled solution is poured into 150 ml of water and the resulting precipitate is filtered off and dried to give 0.15 g of 3- (1-methyl-3-indolyl} -4- (3-thienyl) -1H-pyrrole-2.5 dione, mp 211-212 ° C.

The starting furandion is prepared as follows.

1.1 g of 1-methylindole-3-glyoxyl chloride in 10 ml of dichloromethane is treated with 1.65 ml of triethylamine and a solution of 0.71 g of 3-thiophenacetic acid in dichloromethane. After stirring for 2 hours at room temperature, the mixture was concentrated and the residue was purified on silica gel with dichloromethane to give 0.42 g of furandione, mp. 162-164 ° C.

Example 6, 0.17 g of 3- (5-amino-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) furan-2,5-dione was treated with 4 ml of DMF and 30 ml of a 33% aqueous ammonia solution and the resulting mixture was heated for 4 hours at 140 ° C. The cooled solution is filtered off and the residue washed with water to form 0.08 g of PM5-amino-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) -1 N-pyrrol-2,5-dione, t .pl. 254-256 ° C.

The starting furandion is prepared as follows.

0.2 g of 3- (1-methyl-3-indolyl) -4- (1-methyl-5-nitro-3-indolyl) furan-2,5-dione in 50 ml of THF is hydrogenated over 0.2 g of 10% Pd / C for 23 hours. The resulting mixture was filtered and the solvent was evaporated, yielding 0.17 g of furandione, mp. 130-134 ° C.

Example 7.0.05 g of the product from Example 6 was treated with 10 ml of acetic anhydride at room temperature for 1 hour. The excess of acetic anhydride was evaporated to give 0.039 g of 3- (5-acetamido-1-methyl-3-indolyl) -4- 0-methyl-3-indolyl U-1 Н-pyrrole.b-dione, mp 276-279 ° С. Mr. Example. 0.058 g of 3- {5-hydroxy-1-methyl-3-indrilyl) -4- {1-methyl-3-indolyl) furaM-.-2.5-dione is treated with 1.5 ml of DMF in 20 ml of 33% aqueous ammonia solution and the resulting mixture is heated for 3 hours at 140 ° C in a closed vessel. The solvent was removed from the cooled solution and the residue was treated with water. The resulting solid was filtered and dried to give 0.018 g of 3- (5-hydroxy-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, mp, 284-287 ° C.

The starting furandion is prepared as follows.

7.85 g of 5-methiCi-1-methylindole-3-glyoxyl chloride in 100 ml of dichloromethane are treated with 10.8 g of triethylamine, after which 5.86 g of 1-methylindol-3-yl-acetic acid is treated. After 16 hours, the mixture was concentrated and the residue was chromatographed on silica gel using a mixture of 1% methanol in dichloromethane. .-.- .. ..0.1 g of the obtained 3- (5-methoxy-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) furan-2.5-dione (mp. 234-237 ° C) is treated with 3 ml of pyridine and 0.4 g of pyridine hydrochloride and the resulting mixture is heated at 220 ° C for 3 hours. The mixture is partitioned between dichloromethane and water, and the organic phase is washed with water and then with a 0.5 M hydrochloric acid solution . The organic phase is dried and concentrated. The residue was subjected to chromatographic chromatography on silica gel with 1% methanol in dichloromethane. The result is 0.058 g of furandion, so pl. 128-132 ° C.

Example 9. A solution of 800 mg of 3- (1-methyl-3-indolyl) -4- (1-methyl-2-pyrrolyl) furan-2D-dione in 6 ml of DMF and 50 ml of a 33% aqueous ammonia solution are heated for 3 hours at 130 ° C in a closed vessel. The precipitate was filtered off and dried, yielding 400 mg of 3- (1-methyl-3-indolyl) -4- (1-methyl-2-pyrrolyl) -1 N-pyrrole-2,5-dione; mp. 248 - 250 ° C.

The starting furandion is prepared as follows.

To 6.4 g of 1-methylindole-3-glyoxyl chloride in 120 ml of dichloromethane and 8.0 ml of triethylamine 4 g of 1-methylpyrrole-2-acetic acid was added under nitrogen. After stirring for 1.6 hours, the solvent was evaporated. The residue was purified on silica gel using ethyl acetate-petroleum ether (1: 2) to give 800 mg of furandion, mp. 163-165 ° C.

Example 10 1.4 ml of acetaldehyde dimethyl acetate and 10 mg of p-toluenesulfonic acid are added to a solution of 250 mg of 3,4-bis (3-indolyl) -1H-pyrrole-2,5-dione in 40 ml of chloroform. The resulting mixture was heated to reflux for 18 hours under nitrogen. The resulting solution

5 was evaporated and the residue was purified on silica gel with an ethyl acetate / petroleum ether system (1: 2). Recrystallization from chloroform / hexane gives 165 mg of 3,4-bis / 1- (1-methoxyethyl) -3-indolyl / -1H-pyr

0 roll-2,5-dione, mp 222-224 ° C.

Example 11. 220 mg of thiophenol and 1. A drop of concentrated hydrochloric acid was added to a solution of 150 ml of the product of example 10 and in 40 ml of dichloromethane. The resulting solution was stirred for 2 hours under nitrogen. The solvent was evaporated and the residue was recrystallized from diethyl ether / hexane to give 190 mg of 3,4-bis / 1- (1-phenylthioeethyl) -3-indolyl / -1H-pyrrole-2,5-dione, mp . 102N05 ° C.

PRI me R 12. 20 ml of a 1 M solution of CAlNd in diethyl ether was added to a solution of 1 g of 3,4-bis (3-indolyl) -1 N-pyrrole-2,5-dione in

5 140 ml of TTF. The resulting mixture was stirred for 18 hours under nitrogen. The mixture was cooled to 0 ° C, 50 ml of water was added, then acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate.

0 The organic extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was purified on silica gel with 5-10% methanol in dichloromethane. The first eluted product was treated with ethyl acetate / hexane to give 175 mg of 3,4-bis (3-indolyl) -3-pyrrolin-2-one, mp. 290-293 ° C (decomposition). The second eluted product was recrystallized from ethyl acetate tat / hexane to give 490 mg 5-hydroxy-3,4-bis (3-indolyl) -3-pyrrolin-2-one, m.p. above 250 ° C (decomposition).

The starting pyrrolidone was prepared as follows.

5 A solution of 18.72 g of indole in 240 ml of benzene was treated with 48 ml of a 3 M solution of methylmagnesium iodide in diethyl ether and stirred under a nitrogen atmosphere for 0.5 h. 10.2 g of dibromomaleimide were added and the half-heated mixture was heated for 65 h with

refluxed, cooled and then evaporated. . The residue was partitioned between dichloromethane and a 2 M hydrochloric acid solution and the insoluble matter was filtered off. The dichloromethane extract was separated and dried, and the solvent was evaporated. The product was purified on silica gel using a mixture of ethyl acetate / petroleum ether to obtain 6.0 g of pyrrolidone, so pl. 252-253 ° C after precipitation from methanol / water.

Example 13. 820 mg of Lzesson's reagent is added to a solution of 330 mg of 3,4-bis (3-indolyl) -1 N-pyrrole-2,5-dione in 50 ml of dimethoxyethane and the resulting mixture is heated for 1 h with reflux. Then, 410 mg of Lawesson's reagent was added and the mixture was heated to reflux for another 1 hour. The solvent was evaporated and the residue was purified on silica gel with ethyl acetate / hexane (1: 4). Recrystallization from diethyl ether / hexane gives 30 mg of 5-thioxo-3,4-bis (3-indolyl) 3-pyrrolin-2-one, m.p. 254-257 ° C.

Example 14. A solution of 804 mg of 3- (1-methyl-3-indolyl) -4- / 1-methyl-2- (methylthio) -3-indolylfuran-2,5-dione in 12 ml of DMF and 5-0 ml of a 33% aqueous ammonia solution is heated for 2 hours at 130 ° C. The product is filtered off and dried to give 675 mg of 3- (1-methyl-3-indolyl) -4- / 1-methyl-2 - (- methyl thio) -3-indolyl / -1 H-pyrrole-2.5 dione, mp 281-283 ° C.

The starting furandion is prepared as follows. .

1.4 g of oxalyl chloride are added to a solution of 1.77 g of 1-methyl-2-methylthioindole in 45 ml of dichloromethane at 0 ° C. The resulting solution was warmed to room temperature and the solvent was evaporated. To a solution of the product in dichloromethane was added 2.02 g of triethylamine and 1.89 g of 1-methylindol-3-yl-acetic acid in a nitrogen atmosphere. After stirring for 18 hours, the solvent was evaporated. The residue was purified on silica gel using ethyl acetate / hexane to give 1.32 g of furan-2,5-dione, mp. 230-232 ° C, after recrystallization from a mixture of dichloromethane / hexane.

Example 15. 270 mg of m-chloroperbenzoic acid was added to a stirred solution of 500 mg of the product of Example 14 in 250 ml of dichloromethane at 0 ° C. The solution was stirred at 0 ° C for 1 hour and then washed with a saturated solution of sodium bicarbonate in water. The resulting solution was dried. The residue is treated with methanol to give 505 mg of 3- (1-methyl-3-indolyl) 4/1-methyl-2- (methyl-sulfinyl) -3-indolyl / -1 N-pyrrole-2,5-dione, t. pl. 300 ° C.

Example 1b A solution of 200 mg of 3- / CZ-acetoxypropyl) -3-indolyl / -4- (1-methyl-3-indolyl) furan-2,5-dione in 1 ml of DMF and 2 ml of a 3.3% aqueous ammonia solution are heated in for 2 hours at 100 ° C. 50 ml of water was added and the resulting solid was filtered off, dried and recrystallized from ethyl acetate to give 85 mg of 3- / 1- (3-hydroxypropyl) -3-indolyl / -4- (1-methyl-3-indolyl ) -1H-pyr of roll-2,5-dione, mp 185-187 ° C.

The starting furandion is prepared as follows.

367 µl of oxalyl chloride was added to a solution of 868 mg of 1- (3-acetoxypropyl) indole in 10 ml of dichloromethane at OOC. The resulting solution was stirred for 3 hours and then the solvent was evaporated. The residue was dissolved in dichloromethane and triethylamine and 756 mg of 1-methyl-dol-3-yl-acetic acid were added under nitrogen atmosphere. After stirring for 18 hours, the solvent was evaporated and the residue was purified on silica gel using an ethyl acetate / petroleum ether system. Recrystallization from ethyl acetate / hexane gave 290 mg of furandione, mp. 94-96 ° C.

Example 17. A solution of 200 mg of 3- / 1- {2-methoxycarbonylethyl) -3-indolyl / -4 (1-methyl-3-indolyl) furan-2,5-dione in 1 ml of DMF and 2 ml of 33% aqueous ammonia is heated for 0.75 hours at 100 ° C. 30 ml of ethyl acetate was added to the cooled solution, and the organic phase was separated and washed with saturated sodium bicarbonate solution. The organic phase is dried and the solvent is evaporated. Recrystallization from ethyl acetate / petroleum ether gave 40 mg of 3- / 1- (2-carbamoylethyl) -3-indolyl / -4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione , mp 243-247 ° C.

The starting furandion is prepared as follows.

A solution of 622 μl of oxzlil chloride and 1.5 g of 1- / 2- (methoxycarbonyl) ethyl / indole in 20 ml of dichloromethane was stirred for 10 minutes at 0 ° C and then for 2 hours at room temperature, after which the solvent was evaporated. The residue was dissolved in dichloromethane and 2.03 ml of triethylamine and 1.4 g of 1-methyl-dol-3-yl-acetic acid were added under nitrogen atmosphere. After stirring for 18 hours, the solvent was evaporated and the residue was purified on silica gel with dichloromethane and then with ethyl acetate / petroleum ether. Recrystallization from a mixture of egilece

tat / petroleum ether receive 590 mg of the mixture for 2 hours and then the solvent of the radion, so pl. 150-152 ° C. evaporated. The residue was dissolved in dichloro Example 18. A solution of 150 mg of 3- / 1- {2-methane and treated with 17.4 ml of diisopropycarbroxyethyl) -3-indolyl / -4- (1-methyl-3-in - ethylamino 9.45 g topped up) furan-2,5-dione in 1 ml of DMF and 2 ml of 5 1-methylindol-3-yl-acetic acid, in an at- 33% aqueous solution of ammonia is heated in a nitrogen atmosphere. After stirring for 1 h at 100 ° C. After cooling for 3 days, the solvent was evaporated and evaporated and the residue was recrystallized. The residue was purified on silica gel using ethyl acetate / petroleum dichloromethane. Recrystallization from ether to give 90 mg of a 3- / 1- (2-carboxy-ethyl acetate / petroleum mixture. Ether polytyl) -3-indolyl / -4- (1-methyl-3-indolyl) -1 N- 09 g 3- (1- (3-bromopropyl) -3-indolyl) pyrrole-2,5-dione, mp, 256 258 ° С. 4- (1-methyl-3-indolyl) furan-2,5-dione, mp

The starting furandion receive the following - 168-170 ° C. c. A solution of 2.8 g of the product from step b) c

A solution of 200 mg of 3- / 1- (2-methoxycarboni- 15 50 ml of DMF is stirred for 2 hours with ethyl) -3-indolyl-4- (1-methyl-3-indolyl) fur- at room temperature and then for - 2,5-dione in .4. ml of ethanol is heated for 2 hours at 60 ° C in the presence of 1.2.5 g of azide for 1 hour under reflux in sodium. The solvent was evaporated and the residue was present in the presence of 180 mg KOH. The solvent was partitioned between dichloromethane and evaporated, and the residue was acidified with 2 M solution of 20 milks. The organic phase is washed with water, hydrochloric acid, rum, and dried and evaporated. Recrystallization was extracted with dichloromethane. Organically from ethyl acetate, 2.5 g of the desired phase are obtained, separated, dried and evaporated. furandiona, so pl. 154-156 ° C. The residue is treated with ethyl acetate with a saw-Example 21. A) A solution of 1.9 g of the product by the study of 170 mg of furandione. 222-224 ° C. 25 of Example 20 in 300 ml of ethyl acetate hydri Example 19 A solution of 40 mg of the product was triturated with 190 mg of 10% Pd / C for 3 days, of example 18 in 5 ml of methanol was heated to the resulting solution, and it was filtered under reflux for 4 hours. concentrated by evaporation, in the absence of 10 mg of p-toluenesulfonic acid. The resultant precipitate was filtered off and the residue 30 was removed and dried to give 1.57 g of 3- / 1- recrystallized from ethyl acetate with (3-aminopropyl) -3-indolyl / 4- (1-methyl-3- yielding 25 mgЗ- / 1- (2-methoxycarbonodolyl) -1H-pyrrol-2.5-dione, mp 195-ethyl) -3-indyll / 4- (1-methyl-3-in, dol) - 197 ° C. 1H-pyrrole-2,5-dione; mp. 209-211 ° C. B) 1.3 g of the product from step a) transfer

EXAMPLE 20. A solution of 2.50 g3- / 1- (3-azi-35 in 500 ml of acetate and treated with saturated dopropyl) -3-indolyl / 4- (1-methyl-3-indolyl) hydrogen chloride solution in ethifuran-2,5-dione, in 13 ml of DMF and 18 ml of 33% acetate, the mixture is heated to precipitate until the evolution of aqueous ammonia ceases. This mixture was stirred for 4 hours at 140 ° C. The product is filtered off for 2 hours and then filtered to obtain 1.5 g of the cooled mixture to obtain 2.27 g of 40 3- / 1- (3-aminopropyl) -3-indolyl / 4- (1-methyl- 3- / 1 - (3-azidopropyl) -3-indolyl / -4- {1-methyl-3-indolyl) -1H-pyrrole-2,5-dione hydrochloro-3-indolyl) -1H-pyrrole-2,5-dione, so pl. reed, so pl. 215-220 ° C. 222-224 ° C. ...... PRI me R 22. 40 mg 60% suspension

The starting furandion is obtained following sodium hydride in mineral oil in an additional way ... 45 poured to a solution of 327 mg of 3,4-bis- (3-indolyl) a) To a solution of 23.4 g of indole in 200 ml of 1H-pyrrole-2,5-dione in 5 ml of DMF at 0 ° C in DMF, cooled to 10 ° C, a nitrogen atmosphere is added. After 0.5 hours, the mixture was cooled to 22.4 g of potassium hydroxide and 101 g of 1,3-dibromo to -20 ° C and 108 mg of ropan chloride was added. The resulting mixture was stirred in trimethylsilyl. The mixture was allowed to warm for 3 days under a nitrogen atmosphere, at 50 ° C, then the solid was cooled, filtered off to 0 ° C, then another 80 mg of hydride was added and the filtrate was evaporated. Residue sodium.

chromatographically purified After 0.5 h at 0 ° C, 116 mg of silica gel was added in the presence of 5% propylene diethyl oxide and the resulting transester mixture in petroleum ether to give 55 was stirred overnight. 5 ml of 14.7 g of 1- (3-bromopropyl) indole are added. water and the mixture is extracted with dichloromethane.

b) 4.2 ml of oxalyl chloride are added. The organic phase is dried and evaporated, to a solution of 11.75 g of 1- (3-bromopropyl) indole in the residue, the residue is purified on silica gel with a system of 125 ml of dichloromethane at 0 ° C. The resulting ethyl acetate / petroleum ether. The cross-solution is stirred at room crystallization from a diethyl mixture.

ether / petroleum ether is obtained. 3 mg of 3,4-bis / 1- (2 hydroxypropyl) 3-indolyl / -1H-pyrrole-2,5-dione; mp. 133-135 ° C.

Example 23. 3,4-bis (1-methoxymethyl-3-indolyl) -1 H-pyrrole-2,5-dione; mp. 172- is prepared by a method similar to that described in Example 10, Example 24. According to the method described in Example I or II, the following compounds are prepared:

3,4-bis / 1- / 1- (1-hydroxyethylthio) ethyl /

-3-indolyl / -1H-pyrrole-2,5-dione, t, pl. 191 - 194 ° C, 3,4-bis / 1- / 1- (2-mercaptoethylthio) ethyl /

-3-indolyl / -1H-pyrrole-2,5-dione; mp. 97-99 ° C. and 3.4-6is / 1- / 1- (carboxymethylthio) ethyl /

-3-indolyl / -1H-pyrrole-2,5-dione; mp. 111 - 114 ° C.

Example 25. According to the method described in Example 14, the following compounds are prepared:.

3,4-bis (1-methyl-Zshndolil) -1 N-pyrrole

-2,5-dione, mp 355 ° C

3- {4-methoxy-1-methyl-3-indolyl} -4- (1-methyl-3-indolyl) -1 H-pyrrole 2,5-dione,

so pl. 288-290 ° C,

3- (1-methyl-5-methylthio-3-indolyl) -4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp

260 ° C

3-Sb-methoxy-L-methyl-3-indolyl) -methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp 267 ° С,

3- (7-methoxy-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) -1 N-pyrrole-2,5-dione, 35 mp 255 ° C,

3,4-bis (1-benzyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp 108 ° C, 3- (5-chloro-1-methyl-3-indol yl} -4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp 270- 40

271 ° C ..; .- -

PRI me R 26. 3- (1-methyl-5-methylsulphinyl-3-indolyl) -4- (1-methyl-3-indolyl) -1 Y-pyrrole-2,5-dione, t .pl. 292 ° C. is obtained by a method similar to that described in Example 45.

PRI me R 27, According to a method similar to that described in example 16 receive the following substances:

3- / 1- (4-hydroxybutyl) -3-indolyl / -4- (1 50 -methyl-3-indolyl) -1 H-pyrrole-2,5-dione, m.p. 185-188 ° C,

3- (1-alpha-0-glucopyranosyl-3-indol-yl) -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, mp 210-215 ° C, 55

3,4-bis / 1- (4-hydroxybutyl-3-indolyl) / -1 H-pyrrole-2,5-dione, mp 192-193 ° C, and

3- / 1- (5-hydroxypentyl) -3-indolyl / -4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp 179-181 ° C.

5

10

fifteen ,

0

5

0

5

0

5

0

5

Example 28. 3- / 1- {4-carbamoylbutyl) - 3-indolyl / -4- 1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione; mp. 247-249 ° C. Obtained according to a method similar to that described in example 17.

Example 29. According to a method similar to that described in example 18, the following compounds are prepared:

3- / 1- (3-carboxypropyl) -3-indolyl-4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp 238-240 ° C, and

3- / 1- (4-carboxybutyl} -3-indolyl / -4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp 234-238 ° C.

Example 30. According to a method similar to that described in example 19, the following compounds are prepared:

3- / 1-3 (methoxycarbrnyl) propyl / -3-yn tolyl / -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 208-210RS, and

3- / 1- / 4- (methoxycarbonyl) butyl / -3-indolyl - / - 4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, mp 138-140 ° C.

Example 31. According to a method similar to that described in example 20, the following compounds are prepared:

3- / 1- (4-Azidobutyl) -3-indolyl / -4- {1-methyl-3-indolyl) -1H-pyrrole-2.5-dione, m.p. 196-198 ° C, and

3- / 1- (5-azidopentyl) -3-indolyl / -4- (1-methyl-3-indolyl) -1 H-pyrrole-2.5-dione, mp 170-172 ° C.

Example 32. According to a method similar to that described in example 1, the following compounds are prepared:

a) 3- (1-benzyl-3-indolyl} -4- (1-methyl-3: - indolyl) -1H-pyrrole-2,5-dione, mp 261-262 ° С,

b) 3- (5-methoxy-1-methyl-3-indolyl) -4- {1-methyl-3-indolyl} -1 H-pyrrole-2,5-dione, so pl. 240-245 ° C,

c) 3- (5-benzoyloxy-1-methyl-3-indolyl} - 4- {1 - methyl-3-indolyl) -1 H-pyrrole-2,5-dione, m.p. 215-218 ° C,

d) 3- (1-methyl-3-indolyl) -4- (1-methyl-7-nitro-3-indolyl} -1 H-pyrrole-2,5-dione, mp 264-266 ° С ,

d) 3- (1-methyl-3-indolyl) -4- (1-methyl-6-nitro-3-indolyl) -1 H-pyrrole-2,5-dione, mp 285-287 ° C1

e) 3- {1-methyl-3-indolyl) -4- (1,5-dimethyl-3-indrlyl) -1H-pyrrole-2,5-dione, so pl. 283-285 ° C.

g) 3- (1,7-dimethyl-3-indolyl) -4; (1-methyl-3-indo-yl) -1H-pyrrole-2,5-dione. so pl. 300 ° C.

h) 3- (6-chloro-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 280-282 ° C,

i) 3- {1-methyl-3-imdolyl) -4- (1-methyl-4-nitro-3-indolyl} -1H-pyrrole-2,5-dione, so pl.

315-316X and

j) 3- (T, 4-dimethyl-3-indolyl) -4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, m.p. 292--293 ° С .. .... . .: ..

The above pyrroldione d) and d) can also be prepared as described in the following reference examples 41 and 49 by reacting the corresponding furadione with hexamethyldisilazane and methanol in toluene or chloroform.

Example 33 In accordance with a method similar to that described in example 3, the following compounds are prepared:

3- (1-methyl-3-indolyl) 4-phenyl-1H-pyrr-ol-2,5-dione, m.p. 243 ° C (decomposition),

3 4-methoxyphenyl) -4- (1-methyl-3-yn tolyl) - N-pyrrole-2,5-dyon, m.p. 262 ° C

3- (4-chlorophenyl) -4- (1-methyl-3-indolyl} - 1H-pyrrole-2,5-dione, mp 2b8-270 ° С.

3- (1-methyl-3-indolyl) -4- / 4- (methylthio) phenyl / -1H-pyrrole-2,5-dione, m.p. 266-2b7 ° C,

3- (1-methyl-3-indolyl) -4- (2-nitrophenyl)

t-pyrrole-2; 5-dione, mp 230-231 ° C,

3- (4-aminophenyl) -4- (1-methyl-3-indolyl)

-1H-pyrrole-2,5-dione; mp. 297 ° C

3- (1-methyl-3-indolyl) -4- (3-nitrophenyl)

-1H-pyrrole-2,5-dione; 248 ° C

3- (3-chlorophenyl) -4- (1-methyl-3-indolyl) 1H-pyrrole-2, 5-dione, mp 224-225 ° C,

3- (1-methyl-3-indolyl) -4- (2-methylphenyl)

-1H-pyrrole-2,5-dione; mp. 245-247 ° C,

3- (3-bromophenyl) -4- {1-methyl-3-indolyl) -1H-pyrrole-2,5-dioy. so pl. 219-220 ° C,

3- (2,5-dimethylphenyl) -4- (1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione; mp. 2b2-2bZ ° C,

3- (2-chlorophenyl) -4- (1-methyl-3-indolyl) - 1H-pyrrl-2,5-dione, mp 238-239 ° C,

3- (1-methyl-3-indolyl) -4- (2-trifluoromethylphenyl) -1 N-pyrrole-2.5-dione, mp 237--238 ° С,:

3- (1-methyl-3-indolyl) -4- (3-trifluoromethylphenyl) -1 H-pyrrole-2,5-dibn; 187 - 188 ° C ...

Example 34. 3- (1-methyl-3-indolyl) -4- {2-naphthyl) -1H-pyrrole-2,5-dione, mp. 289 C (decomposition) was obtained according to a method similar to that described in example 2.

Example 35.3- (1-methyl-3-indolyl) -4H (2-thieni) -1H-pyrrole-2.5-dione, mp 244-246 ° C. was obtained according to a method similar to that described in the example 5.

PRI me R 36. According to a method similar to that described in example 6, get 3- (7-aminr-1-methyl-3-indolyl) - 4- (1-methyl-3

-indolyl) -1 H-pyrrole-2,5-dione, mp 300 ° C, 3- (b-amino-1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) -1H-pyrrole-2.5-dione; mp. 264-2b7 ° C, and

3- (3-aminophenyl) -4- (1-methyl-3-indolyl)

-1H-pyrrole-2,5-dione; mp, 2590C.

Example 37. According to a method similar to that described in example 7, the following compounds are prepared:

3- (7-acetamido-1-methyl-3-indolyl) -4- (1

-methyl-3-indolyl) -1Y-pyrrole-2,5-dione, mp 300 ° C, and

3- {6-acetamido-1-methyl-3-indolyl) -4- (1 0-methyl-3 indolyl) -1 H-pyrrole-2,5-dione, mp 300 ° С.

Example 38. According to a method similar to that described in Example 15, the following compounds are prepared:

5 3- (1-methyl-3-indolyl) -4- / 4- (methylsulphonyl) phenyl - / - 1H-pyrrole-2,5-dione, m.p. 265 ° C, and

3- (1-methyl-3-indolyl) -4- / 4- (methylsulphinyl) phenyl-1H-pyrrole-2,5-dione, so pl. 0 256-258 ° C;

Example 39. According to a method similar to that described in example 1, the following compounds are prepared:

3- (1-methyl-Z-in topped) -4- (1-dimethyl-Z 5 -indolyl) -1H-pyrrole-2,5-dione, so pl. 305-306 ° C, and

3- (1-methyl-2-indolyl) -4- (1-methyl-3-in tolyl) -1H-pyrrl-2,5-dione, mp 300 ° C.

Example 40. According to a method similar to that described in Example 3, the following compounds are prepared:

3- (1-methyl-3-indolyl) -4- (2,3-dimethyl-) -1H-pyrrole-2,5-dione, m.p. 275-276 ° C. 3- (3,5-dichlorophenyl) -4- (1-methyl-3-indo-5 lyl) -1 H-pyrrole-2,5-dione; mp. 197-200 ° C,

3- (2,3,6-trichloro rfe ni) -4- (1-methyl-3-and n-tolyl) -1H-pyrrole-2,5-dione, mp 306-309 ° C, and.

3- (2,6-dichlorophenyl) -4- (1-methyl-3-indo (0 lyl) -1 H-pyrrole-2,5-dione, mp 285-286 ° C.

Example 41. A mixture of 163 mg of 3- (1-indolyl) -4- (1-methyl-3-indolyl) furan-2,5-dione, 2.6 g of hexamethyldisilazane, 0.6 g of methanol and 50 ml of toluene is stirred for 1 5 h at 40 ° C and then for 1 h at 110 ° C. The resulting mixture is evaporated and the residue is chromatographed on silica gel, eluting with 10% methanol in dichloromethane to give 0 75 mg 3- ( 1-indolyl) - 4- {1-methyl-3-indolyl) -1H-pyrrole-2,5-dione, mp. 235-2360C.

The starting furandibn is prepared as follows.

876 mg of d-Chl-acetic acid in 50 5 ml of dichloromethane is first treated with 1.65 ml of diisopropylethylamine and then with a solution of 1.10 g of 1-methylindole-3-glyoxyl chloride in 50 ml of dichloromethane. The resulting mixture was stirred for 3 hours and then concentrated. The residue was chromatographed on silica gel with dichloromethane to give 430 mg of furandione, mp. 164-166 ° C.

Example 42. 3- (3-Benzofuranyl} -4- {1-methyl-3-indolyl) -1 H-pyrrole-2,5-dione, mp. 183-185 ° C was obtained by a method similar to that described in example 41.

Example 43. 200 mg of the product of Example 21 b) in 10 ml of dimethylformamide was treated with a solution of 85 mg of 1,1-thiocarbrnildiimidazole in 2 ml of tetrahydrofuran and the mixture was stirred for 16 hours. Then the solvents are evaporated and the residue is chromatographed on silica gel with 10% methanol in dichloromethane to give 129 mg of 3- {1- / 3-isothiocyanatopropyl / -3-indolyl-4- / 1-methyl-3-indolyl / - 1H pyrrole-2,5-dione; melting point 219-221 ° C.

Example 44. A solution of 100 mg of the product of Example 21 b) in 10 ml of dimethylformamide is treated with a solution of 40 mg of 1,1-carbonyldiimidazole in 2 mg of tetrahydrofuran. The mixture was stirred for 16 hours. The solvents were evaporated and the residue was chromatographed on silica gel with a mixture of chloroform / methanol / acetic acid / water 60: 18: 2: 3 / to obtain 90 mg of 3-1-3- (1-imide zolyl carboxamido (p ro-3-indolyl-4- (1-methyl-3-indolyl) -1H-pyrrl-2,5-dione; mp: 145-148 ° C.

Example 45. A suspension of 500 mg of the product of Example 21 b) in 100 ml of ethanol was added to a mixture of 116 mg of sodium carbonate and 177 mg of dimethylcyanodithioiminocarbonate. After 16 hours, 160 mg of dimethyl M-cyanodithioiminocarbonate was added and stirring was continued for an additional 2 days, the solvent was evaporated, and the residue was chromatographed on silica gel, first with dichloromethane and then with ethyl acetate, to give 120 mg of 3-1- / 3-cyano-2 -methyl zotioureido / propyl-3-ind6lyl / -4- [1-methyl-3-indolyl] -1 H-pyrrole-2,5-dione; melting point 236-238 ° C.

Example 46, A solution of 200 mg of the product of example 21 b) in 10 ml of dimethylformamide was treated with a solution of 83 mg of 1,1-bis / methylthio / -2-nitroethylene in 10 ml of acetonitrile and the mixture was heated at 85 ° C for 3 days . Evaporation of the solvent and chromatography of the residue on silica gel with 10% methanol in dichloromethane afforded 154 mg of 3- (1-methyl-3-indolyl / -4-1-3-3- (methylthio / t2-) nitrovinyl-amino propyl -3-indolyl -1 H-pyrrole-2,5-dione; melting point 144-146 ° C.

Example 47, A solution of 175 mg of the product of example 44 in 10 ml of dimethylformamide was treated with 10 ml of ethanol ammonia.

The mixture was stirred for 3 hours and then the solvents were evaporated. The residue is crystallized from ethanol to give a solid, which is purified on silica gel with 1-20%

methanol in dichloromethane to give 43 mg of 3- / 1-methyl-3-indolyl / -4- {1- / 3-ureidopropyl / -3-indolyl -1H-pyrrol-2,5-dione, melting point 248- 250 ° C.

Example 48. A solution of 150 mg of 3,5-dimel-tylpyrazole-1-carboxamidine nitrate in 10 ml of ethanol was treated with 200 mg of the product of Example 21 b) and the mixture was refluxed for 3 days. The solvent was evaporated and the residue was chromatographed on silica gel using a mixture of dichloromethane / methanol / acetic acid / water / 60: 18: 2: 3 / to give 53 mg of 3- {1- / 3-guanidinopropyl / -3-indolyl-4- / 1-met. IL-3-INDOLYL / -1H-pyrrole-2,5-dione nitrate, melting point 179-181 ° C.

Example 49. A solution of 0.4111 gZ-1-3 / acetoxypropyl / -3-indolyl-4- / 2-nitrophenyl / furan-2,5-dione in 50 ml of chloroform is treated with a mixture of 1.53 g of 1.1 , 1,3,3,3-hex5 of methyldisilazane and 0.3 g of methanol and the mixture is heated at 60 ° C for 1 h. An additional 1.53 g of hexamethyldisilazane and 0.3 g of methanol are added and heating is continued for nights after which again

0 1.53 g of hexamethyldisilzane and 0.3 g of methanol are added. The mixture is further heated for 1 h. The solvents are removed under reduced pressure and the residue is chromatographed on silica gel using

5 5% methanol in dichloromethane to give 130 mg of 3- 1- (3-acetoxypropyl) -3-indolyl-4- (2-nitrophenyl) -1H-pyrrole-2,5-dione; melting point 77-78 ° C.

The starting material of furandion is prepared as follows.

3.2 g of oxalyl chloride are added to a solution of 5.0 g of 1- / 3-acetoxypropyl / indole in 100 ml of dichloromethane at 0 ° C. The mixture was brought to room temperature and stirred for 3 hours before evaporation. The resulting solid was treated with dichloromethane and 5.5 g of triethylamine, followed by 3.9 g of 2-nitrophenylacetic acid. The mixture was stirred for 16 hours and the solvents were evaporated. The residue was chromatographed on silica gel using ethyl acetate to give the desired furandion.

PRI me R 50. A solution of 40 mg of hydroxide

5 sodium in 5 ml of ethanol is added to a solution of 400 mg of the product of example 49 in 10 ml of ethanol. After stirring for 3 hours, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel using 10% methanol in dichlorome. 191799382 20

tane to give 190 ml of 3- 1- (3-hydroxyptio / propyl-3-indolyl} -1H-pyrrole-2,5-diroropyl / -3-indolyl -4- / 2-nitrophenyl / -1H -one, melting point 170-173 ° C. .pyrrole-2,5-dione, melting point Example 56, By the method of Example 53, 193-195 ° C. outcome of 25 mg of 2-mercaptopopyrimidine and

Example 51. A solution of 128 mg of product 5 100 mg of the product of example 52 receive 45 mg of example 46 in 30 ml of ethanol; 10 3- / 1-methyl-3-indolyl / -4- 1- {3- / 2-pyrimide-ml saturated solution of ammonia in ethanoynylthio / propyl-3-indolyl-1H-pyrrole and the mixture is heated at 80 ° C for 3 h. 2,5-dione, m.p. 125- The solvent was evaporated under reduced 127 ° C.

pressure and the residue is chromatographed on a si 10 PRI me R 57. To a solution of ligagel methoxide using 10% methanol in sodium, obtained from 51 mg sodium and 20 dichloromethane to obtain 39 mg 3- {1- 3- / 1- ml of methanol, 315 mg of 2-mercapto-amino-2-nitrovinylamino / propyl} -3-indo-pyridine-M-oxide is added and 200 mg of the product are exemplified by l-4- / 1-methyl-3-indolyl / -1H- pyrrole-2.5-PA 52. The mixture was heated at 55 ° C for dione, melting point 206 209 ° C 15 16 hours. The solvent was removed under reduced (decomposition) pressure and the residue was triturated with this Example 52. Suspension SOmgproduct - lace atom. The resulting solid of that of Example 43 in 10 ml of ethanol is treated with washed with 2 normal hydroxide, 4 ml of dimethylformamide and then 10 ml of sulfur and then with water. Chromatography on a silica solution of ammonia in ethanol. A mixture of 20 kagels using 1% methanol was allowed to stand at room temperature in edichloromethane to give 49 mg in 1 hour and then the solvent was evaporated. 2- 3- 3- {3- / 1-methyl-3-indolyl / -2,5-dioxo- The residue is crystallized from ethanol to give 1H-pyrrol-4-yl -1-indolyl propylthio with a dose of 18 mg 3 - (1-methyl-3-indolyl) -4- 1- [3-ridine 1-oxide, melting point thioureidopropyl / -3-indolyl -1H-pyrrole-25 165-167 ° C.

2,5-dione, melting point 166-Example 58. YuOm product of example 168 ° C (decomposition). 45 is heated with 30 ml of ethanol, 2 ml of dimethyl Example 53.190 mg of methanesulfonic formamide and 40 ml of a saturated solution of anhydride were added to a solution of 399 mg of ammonia in ethanol at 100 ° C over 16 duct of Example 16 and 1 ml of pyridine in 40 ml 30 h. Solvents removed under reduced dichloromethane. After 2 hours, an additional pressure was added and the residue was chromatographed on 40 mg of silica gel methanesulfonic anhydride using 1% methanol in 1 ml of pyridine and stirring with prodichloromethane to give 10 mg 3-1 / 2-pressed for 16 hours. The mixture was washed with water, cyanoguanidino / propyl-3-indolyl-4- / 1 - dried and evaporated. Crystallization from 35-methyl-3-indolyl / -1H-pyrrole-2,5-dione, ethyl acetate / hexane, gave a half-melting point of 168-170 ° C. the study of 350 mg of 3- / 1-methyl-3-indolyl / -4- 1-PRI me R 59. A solution of 100 mgZ- 1- / 3- 3- / methylsulfonyloxy / propyl-3-aminopropyl / 3-indolyl -4- {1-methyl-3-yn - / indolyl -1 N-pyrrole-2,5-dione, topped up) - N-pyrrole-2,5-dione acetate, melting point 202-204 ° С . 40 g of oversized equivalent amount of refiner EXAMPLE 54. 7 mg of a 80% dispersion of acetic acid, in 10 ml of sodium hydride in mineral oil, dimethyl sulfoxide (DMSO) is treated to a cooled solution 23 mg 2-measure 35 mg sodium bicarbonate and 36 mg of 2-chloro-captoimidazole in 10 ml of dimethylformamide. 3-nitropyridine. The mixture is heated at. The mixture is stirred for 0.5 h at 45-60 ° C for 1 h and at 100 ° C for 2 cooling, 100 mg of the product of example 52 d. The solution is allowed to cool, add and the mixture is stirred when cooled, the water is filtered off and the precipitate is chromatographed for an additional 2 hours. The mixture is then chromatographed on silica gel. Using it, it is brought to room temperature and 1-5% methanol in dichloromethane. The product is stirred overnight. The solvents are removed - 50 are further purified by crystallization, poured under reduced pressure, and the residue from hexane / ethyl acetate is chromatographed on silica gel using 60 mg of 3- / 1-methyl 3 Indolyl / -4- {1- 3- / 3-nit - eat 10% methanol in dichloromethane to give ro-2 pyridylamino / propyl-3-indolyl - 20 mg 3- {1- {3- / 2-imidazolylthio / propyl} -3-yn-1 H-pyrrole-2,5 dione, temperature topped up N; (1 methyl-3-indolyl) -1 H-pyrrole-2.5-55 m.p. 218-220 ° C. dione, melting point 130-132 ° C.

Example 55. By the method of example 53, Example 60. By the method of example 56, the starting point is 27 mg of 2-mercaptothiazoline and. 100 starting from 100 mg of the product of example 26 a) and mg of the product of example 52 receive 18 mg3- / 1- 36 mg of 2-chloro-5-nitropyridine receive 45 methyl-3-indolyl / -4- {1- {3- / 2- thiazolyl-2-yl - 3- / 1-methyl-3-indolyl- / 4- 1- 3- / 5-nitro2-pyridylamino / propyl-3-indolyl -1 H-pyrrole-2,5-dione, melting point 245-247 ° C.

EXAMPLE 61. A mixture of 100 mg of 3- 1- / 3-aminopropyl / -3-indolyl-4- / 1-methyl-3-indolyl / TN-pyrrole-2,5-dione acetate containing an excessively equivalent amount of acetic acid, 75 mg of 2-chloropyrimidine and 100 mg of sodium carbonate in LL ml of DMSO are heated at 80 ° C for 2 hours. 50 ml of water are added to the cooled solution and the precipitate is filtered off and chromatographed on silica gel using 5% methanol in dichloromethane to give 60 mg of 3- (1-methyl-3-indolyl) -4-1,3- (2-pyrimidinylamino) propyl-3-indolyl -1H-pyrrole-2,5-dione, melting point 214-215 ° C.

Example 62. A solution of 560 mg of the product of Example 21 a) containing two equivalents of acetic acid in 20 ml of dimethylformamide was treated with 180 mg of sodium bicarbonate and 300 mg of methyl 4-benzyl. Sibenzimidate hydrochloride at room temperature for 24 h. The solvent was evaporated and the residue was chromatographed on silica gel using 1-10% methanol in dichloromethane to give 275 mg.

3- 1- 3- / 4-benzyloxy-a-iminobenzylamino / propyl-3-indolyl-4- / 1-methyl-3-indolyl / -1Н- p. Pyrrole-2,5-dione hydrochloride, temperature melting point 254-256 ° C.

Methyl 4-benzyloxybenzimidate hydrochloride used above is prepared as follows:

Rartvor 560 mg of 4-benzyloxybenzonitrile in 16 ml of tetrahydrofuran-and 0.2 ml of methanol, cooled to 0 ° C, saturated with hydrogen chloride and maintained at 4 ° C for 16 hours. The precipitate was filtered off, washed with diethyl ether and dried to give 357 mg methyl.

Hydrochloride 4-benzyloxybenzimidate. Melting point 179-180 ° C.

Example 63. 93 mg of methanesulfonic anhydride was added to a solution of 0.46 mmol of the product of Example 50 in 25 ml of dichloromethane. 0.5 ml of pyridine was added and the mixture was stirred for 0.5 h, then washed with water, dried and concentrated. Chromatography of the residue on silica gel using 10% methanol in dichloromethane affords 160 mg 3-1- (methyl eul phonyloxy) propyl-3-indolyl-4- (2-nitrophenyl) -1 H-pyrrole -2,5-dione, melting point 177-178 ° C.

Example 64. 50 mg of thiourea are added to a solution refluxing from 150 mg of the product of Example 60 in 15 ml of ethanol. The mixture was heated for 1 h and then the solvent was evaporated. The remainder

chromatographic on silica gel using 20% methanol in dichloromethane to give 10 mg of 3- {1- {3- / amidinothio / propyl-3 Indolyl} - 4- / 2-nitrophenyl / -1H-pyrrole-2,5-dione meta nsulfonate, melting point 164-165 ° C .:

Example 65. 150 mg of 3- [1-methyl-3-indolyl / -4- / 1-phenyl-3-indolyl / furan-2,5-dione are treated with 3 ml of dimethylphosphamide and 10 ml of 33% aqueous ammonia at 80 ° C for 4 hours. The mixture was cooled and extracted with ethyl acetate. The ethyl acetate extract was dried and concentrated, the residue was crystallized with bt hexane to give 120 mg / 3- [1-methyl-3-yn dolyl / -4- / 1-phenyl-3-indolyl / -1H-pyrrole-2,5-dione, melting point 135-T37 ° C.

The starting furandion is prepared as follows.

0.7. g of oxalyl chloride is added to a solution of 1 g of 1-phenylindole in 50 ml of dichloromethane at 0 ° C. After warming to room temperature and stirring for 16 hours, the solvent was removed under reduced pressure. The resulting resin was treated with 50 ml of dichloromethane, 1.4 g of triethylamine and 1.0 g of 1-methylindol-3-yl-acetic acid and the mixture was stirred for 4 hours. The solvent was evaporated and the residue was chromatographed on silica gel using an ethyl acetate / hexane mixture to give 190 mg furandione, melting point 94-96 ° C,

PRI me R 66. A solution of 50 mg of the product of example 45 in 10 ml of dimethylformamide is treated with 4 ml of a 33% solution of methylamine in ethanol. The mixture was stirred for 16 hours and the solvents were then removed under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate to give 46 mg .3- / 2-cyano-3-methylguanidino / propyl-3-indolyl-4/1-methyl-3-indolyl / -1 H-pyrrol-2, 5-dione, melting point 190-193 ° C.

Example 67, 100 mg of the product of Example 45 was treated with 10 ml of ethanol, 10 ml of dimethylformamide and 20 ml of 40% aqueous diethylamine for 16 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel using 10% methanol. in dichloromethane to give 53 mg 3: 1- 3- / 2- cyano-3,3-dimethylguanidino / propyl-3-in-lilyl-4- / 1-methyl-3-indolyl / -1 H-pyrrol-2, 5-dione, melting point 150-153 ° C.

PRI me R 68. A solution of 107 mg of the product of example 59 in 30 ml of ethanol is treated with 10 mg of 10% palladium on charcoal and shaken

at 1 atm of hydrogen for 16 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using 1-10% methanol in dichloromethane. The resulting product was purified by dissolving in methanol, filtering, concentrating the filtrate by trituration of the residue with ethyl acetate, filtering and drying the filtered residue to obtain 22 mg of 3- 1- 3- / 4-hydroxy-a - iminobenzylamino / propyl-3-in tol -1 - N-pyrrole-2,5-dione, melting point 300 ° C.

Example 69. 150 mg of the product of Example 52 and 50 mg of 2-imidazolidinedione are boiled under reflux for 5 hours in 5 ml of ethanol. The solvent was evaporated and the residue was chromatographed on silica gel using 10-25% methanol in dichloromethane to give 50 mg of 3- / 2-imidazolin-2-ylthio / propyl-3-indo-lyl-1 H-pyrrole-2,5-dione methanesulfonate, melting point 134 136 ° C.

Example 70. 0.5 g of 3- 1- / 3-aminopropyl / -3-indolyl-4- / 1-methyl-3-indolyl / -1 H-pyrrole-2,5-dione acetate, 110 mg sodium bicarbonate and 242 mg 3, 5-dimethyl-N-nitro-1-pyrazrl-1-carboxyamidine was heated under reflux in 25 ml of ethanol for 4 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using 1-5% methanol in dichloromethane to give 500 mg of 3- / 1-methyl-3-indolyl / -4- 1- 3- (2-nitroguanidino) propyl-3-indolyl - 1H-pyrrole-2,5-dione, melting point 268- 270 ° G (decomposition).

Example 71. 0.5 ml of pyridine and 115 mg of methanesulfonyl chloride were added to a solution of 50 mg of the product of Example 21 a) in 35 ml of dichloromethane-a. The resulting solution was stirred overnight. Then 2 ml of pyridine was added and the reaction mixture was refluxed for 8 hours. The cooled reaction mixture was washed with 2 molar hydrochloric acid, saturated sodium bicarbonate solution and water. The solution was dried and evaporated to give a solid which was recrystallized from dichloromethane / diethyl ether / hexane. 40 mg of 3- (1-methyl-3-indolyl) -4-1,3- (methylsulfonamido) propyl-3-indolyl -1 H-pyrrole-2,5-dione are obtained, melting point 135-138 ° C. .

Example 72. 3- 1- 3- / Benzenesulfonamido-propyl-3-indolyl-4- / 1-methyl-3- indolyl / -1 N-pyrrole-2,5-dione, temperature melting point 125-128 ° C. receive according to the method of example 68.

P r and. Mer 73. 30 µl of benzyl chloride was added to a solution of 50 mg of the product of Example 20 a) in 40 ml of dichloromethane. 200 μl of pyridine is then added to this mixture and the mixture

stirred for 5 hours. Then the mixture was washed with 2 molar acid and saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from ethyl acetate / petroleum ether

0 results in 45 mg of 3- 1- / 3-benzamidopropyl / -3-indolyl-4- (1-methyl-3-indolyl) -1 N-pyrrole-2,5-dione, melting point 138 -140 ° C.

Example 74. 102 mg of acetic anhydride 5 was added to a solution of 50 mg of the product of Example 20 a) in 40 ml of dichloromethane. The resulting solution was stirred for 1 hour. The mixture was washed with 2 molar hydrochloric acid and saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from dichloromethane / hexane gives 45 mg of 3- 1- / 3-acetamidopropyl-3-indolyl - 4: / 1-methyl-3-indolyl / -1H-pyrrole-2,5-dio5, melting point 132-136 ° C.

Example 75. A mixture of 300 mg of the product of Example 52 and 2 ml of a 33% solution of dimethylamine in ethanol is heated at 90 ° C. for 1.4. The mixture is evaporated, the residue

0 was dissolved in 50 ml of ethyl acetate, the solution was washed with a saturated solution of sodium bicarbonate and treated with 10 ml of hydrochloric acid in ethyl acetate. The solvent was evaporated and the residue was purified on silica 5 Le using a mixture of dichloromethane / methanol / acetic acid / water (60: 18: 2: 3). Crystallization from methanol / ethyl acetate gives 40 mg of 3-1-3- (dimethylamino) propyl-3-indolyl-4- (1-metho-yl-3-indolyl) -1H-pyrrole-2, 5-dione hydrochloride, mp 268-270 ° C.

Example 76. A mixture of 173 mg of the product of example 52 and 2 ml of a 33% solution of trimethyl 5 min in ethanol was heated at 90 ° C for 3 h. The solvent was evaporated and the residue was purified on silica gel using a mixture of dichloromethane / methanol / acetic acid / water (60: 18: 2: 3). Grinding with

0 ethyl acetate gives 75 mg of trimethyl 3- 3- 3- (1-methyl-3-indolyl) -2,5-dioxo-3-pyrrolin-4-yl. 1-indole yl-propyl ammonium methyl sulfonate, melting point 180-185 ° C.

5 PRI me R 77. A solution of 500 mg / tert-butoxycarbonyl / - / methyl / amino - propyl-3-indolyl - 4- / 1-methyl-3-indolyl / -furan-2,5- dione in 1. ml of dimethylformamide and 2 ml of a 33% aqueous solution of ammonia are heated to 140 ° C for 4 hours.

The solvent was evaporated and the residue was dissolved in 30 ml of ethyl acetate. The insoluble material was filtered off and a saturated solution of hydrogen chloride in ethyl acetate was added to the filtrate. The solvent was evaporated and the residue was chromatographed on silica gel using a mixture of dichloromethane / methanol / acetic acid / water (60: 18: 2: 3). Crystallization from a methanol / ethyl acetate mixture affords 75 mg of 3- (1-methyl-3-indolyl) -4-1-3- (methylaminol / prpril-3-indolyl -1 H-pyrrole-2.5 dione hydrochloride, melting point 273-275 ° C.

The starting furandion is prepared as follows.

 a) 3 g of 1- / 3-bromopropyl / indole is treated with a 33% solution of methylamine in ethanol. The resulting solution was stirred for 6 hours. The solvent was evaporated and the residue was dissolved in 50 ml of dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried and evaporated to give 2.30 g of 1- / 3-methylaminopropyl / indole.

b) 2.67 g of di- / tert-butyl / dicarbonate and 1.24 g of triethylamine are added to a solution of 2.3 g of 1- / 3-methylaminopropyl / indole in 40 ml of dichloromethane at 0 ° C. After 4 hours, the mixture was washed with saturated sodium bicarbonate solution, dried and evaporated. obtaining 3.68 g of 1- {3- (trit-butoxycarbonyl) methyl) amino propyl indole.

c) 1.14 ml of oxalyl chloride are added to a solution of 3.6 g of product b) in 40 ml of diethyl ether at 0 ° C. The resulting solution was stirred at 0 ° C for 1 h, and the solvent was then evaporated. The residue was dissolved in 120 ml of dichloromethane and treated with 3.44 ml of triethylamine and 2.36 t of T-methylindol-3-yl-acetic acid. After stirring at room temperature for 1.8 hours, the solvent was evaporated and the residue was purified on silica gel using ethyl acetate / petroleum ether (1: 2). Evaporation of the solvents afforded 1.4 g of the desired product of furandione, melting point 73-80 ° C.

Example 78. 75 mg of methanesulfonyl chloride was added to a solution of 170 mg of the product of Example 16 in 8 ml of pyridine. The resulting solution was stirred for 4 hours and the solvent was then evaporated. The residue was purified on silica gel using ethyl acetate / petroleum ether (1: 1). Recrystallization from ethyl acetate / hexane afforded 40 mg / 3-chloropropyl / -3-indolyl-4- / 1-methyl-3-indolyl / -1H-pyrrole-2.5-dione, melting point 254-256 ° C .

Example 79- By the method of example 21 receive

3- 1- / 2-aminoethyl / -3-indolyl-4- / 1-methyl-3-indolyl / 1 H-pyrrole-2,5-dione hydrochloride, melting point 245-247 ° C,

3- T- / 4-aminobutyl / -3-indolyl-4- / 1-methyl-TIL-3-INDOLI. L / -1 H-pyrrole-2,5-dione hydrochloride, melting point 190-192 ° C; and

3- 1- (5-aminopentyl) -3-indolyl-4- (1- methyl-3-indolyl) -1 H-pyrrole-2,5-dione, melting point 180-182 ° C.

 -

PRI me R 80. A solution of 1.6 g-1- / 2-acetoxyethyl / -3-indolyl-4- / 1-methyl-3-indol yl / furan-2,5-dione in 4 ml of dimethylform - mida and 8 ml of a 33% aqueous ammonia solution are heated to 160 ° C. for 4 hours. The precipitate is filtered off and dried to obtain 1.04 g of 3- 1- / 2-hydroxyethyl / -3-indolyl-4- / 1-me TIL-3-INDOLYL / -1 H-pyrrole-2,5-dione, melting point 250-252 ° C.

The starting furandion is prepared as follows.

a) 11.7 g of indole in 500 ml of dimethylformamide are treated with 4 g of sodium nitride dispersed in mineral oil. After 1 hour, the mixture was cooled in an ice bath and 10 ml of ethylene oxide was added. The mixture was allowed to warm to room temperature) and then stirred for 2 hours. The solvent was evaporated and the residue was taken up in 50 ml of water and neutralized with 2 molar hydrochloric acid. The product was extracted into dichloromethane, the solvent was evaporated, and the residue was chromatographed using ethyl acetate / petroleum ether to give 7.6 g of 1- / 2-hydroxyethyl / indole.

b) an ice-cooled solution of 4.6 g of 1- / 2-hydroxyethyl / indole in 10 ml of diethyl ether is treated with 1 ml of pyridine and 4 ml of acetic anhydride. After 2 hours, 50 ml of water were added, the mixture was extracted with 100 ml of dichloromethane and the dichloromethane extract was dried. The solvent was evaporated to give 5.7 g of 1- / 2-acetoxyethyl / indole.

c) 2.57 ml of oxalyl chloride is added to a solution of 5.7 g of 1- / 2-acetoxyethyl / indole in 70 ml of dichloromethane at 0 ° C. A solution is obtained, stirred for 2 hours and then the solvent is evaporated. To the residue dissolved in 210 ml of dichloromethane. 7.7 ml of triethylamine and 5.29 g of 1-methylindole-3-acetic acid are added under nitrogen. After stirring for 18 hours, the solvent was evaporated and the residue was purified on silica gel using an ethyl acetate / petroleum ether mixture (1: 2). Crystallization from see all ethyl acetate / hexane

271799382 28

yields 1.87 g of 3- {1- / 2-acetr-, treated at 0 ° C with a solution of 837 mg of siethyl / -3-indolyl-4- / 1-methyl-3-indolyl-1-methylindole-3-glyoxyl chloride in 25 ml of furan-2,5-dione, the melting point of dichloromethane and then 975 mg of diisopropyl 198-199 ° C. tilamine. The mixture is allowed to warm to

PRI me R 81. 200 mg of 3- / 1-methyl: 3-yn-5 at room temperature and then stirred / -4- / 4-pyridyl / furan-2,5-dione was twisted for 22 h. After concentration, work up in 5 ml of dimethylformamide and 5 ni and chromatograph the residue by ml of 33% aqueous ammonia. Obtaining silica gel using a mixture of ethyl acetate solution is heated at 140 °. Sweattat / hexane (1: 1) obtain 540 mg 3-1- / benzene 17 hours. After cooling, a suspension of 10 l sulfonyl / -3-pyrrolyl 4- / 1-methyl-3-yn is diluted with water. The product was filtered off-topped / furan-2,5-dione. They are washed, washed with water and dried to obtain b) 255 mg of the product a) in 10 ml of ethanol, 144 mg of 3- / 1-methyl-3-indolyl / -4- / 4-pyri- are treated with 2.5 ml of 2.5 M aqueous hydroxide (-1H-pyrrole-2,5-dione, sodium bis temperature). The solution was allowed to stand at melting 332-334 ° C. 15 room temperature for 17 hours

. The starting furandion was prepared as follows. After dilution with 10 ml of water, the mixture was extracted with diethyl ether. Water

5 g of 4-pyridyl-acetic acid hydrochloride was acidified with concentrated cochloride, IZ, 72 g of diisopropylethylamine hydrochloric acid and extracted with ethyl acetate; ml of dichloromethane was treated at 0 ° C for 20 volumes. The ethyl acetate extracts were dried and, first, 6.37 g of 1-methyl-indole: 3-glyoxylil was concentrated to give 140 mg of target chloride in 50 ml of dichloromethane and then 7.5 g of furandione, t / e 292 (M,}. Diisopropylethylamine. The mixture allows Example 84.1.455 g of the product of the example to warm to room temperature and, in 45 ml of ethanol, is treated with 364 mg of thiomethane and stirred for 65 hours. The solution is 25 urea and the mixture is heated under reflux. pressure by refrigerator for 18 hours. After cooling, the residue is dissolved in dichloromethane and by cooling the precipitate is otfil It is washed and washed by silica gel using ethanol and diethyl ether. Solid ethyl acetate. The fractions containing the substance are dried to obtain 1.33 g of a 3-1- {3- product, concentrated. indolylZ-4- / 1-from ethyl acetate / hexane mixture leads to polytyl-3-indolyl / -1H-pyrrole-2,5-dione meta-teaching 940 mg of 3- / 1-methyl-3-indolyl / -4- / 4- nsulfonate, melting point 236-pyridip / furan-2,5-dione, temperature 238 ° C (decomposition), melting point 217-219 ° C. Example 85. By the method of example 81

Example 82. By the method of Example 78 35, 3- 1- 2- (amidinthio) -ethyl-3-indo is obtained; methyl-3-indolyl / -1H-pyrrole-2,5-DIL / -1 H-pyrrole-2,5-dione, temperature dione methsulfonate, melting point 278-279 ° С, melting point 238-240 ° С (decomposition) .

3- / 1-methyl-3-indolyl / -4- / 2-pyridyl / 3-1-4- / amidinthio / butyl-3-indolyl -1H-pyrrole-2,5-dione, melting point 40 4 - / 1-methyl-3-indolyl / -1H-pyrrole-2,5-dione 242-244 ° С. methanesulfonate, melting point

PRI me R 83. 135 mg 3- / 1-methyl-3-in-150 ° C (decomposition), and

topped up / -4- / 3-pyrrolyl / -furan-2,5-dione ob-3-1-5- / amidinthio / pentyl-3-indolyl with 5 ml of dimethylformamide and 5 ml of -4- / 1-methyl-3 -indolyl / -1H-pyrrole-2,5-di- 33% aqueous ammonia. The solution is 45-methanesulfonate; the melting temperature is heated at 140 ° C for 4 hours. Cool-130 ° C (decomposition).

the solution was diluted with water, IP R and Mp 86. 450 mg of the product of the example was extracted with dichloromethane. Extracts 52 in 20 ml of treated dichloromethane dimethyl sulfoxide are dried and concentrated. 116 mg of sodium cyanide are chromed. The mixture was heated by chromatography of the residue on silica gel with 50 at 50 ° C for 8 hours, then it was cooled and poured into water with ethyl acetate / hexane (1: 1). The mixture was extracted with ethyl followed by crystallization from the mixture with cetate and the extracts dried. Concentrated ethyl acetate / hexane gave 50% and chromatography on silica gel with 3- / 1-methyl-3-indolyl / -4- / 3-pyrrolyl / - using a mixture of toluene / acetic acid-TH-pyrrole-2.5 -dione, melting point 55 ta (9: 1) leads to the production of a solid vein 240-241 ° C. substance that is rubbed with diethyl

The starting furandion is obtained following ether, filtered off and dried. 69 mg of 3- {1- / 3-cyanopropyl / -tindolyl a) 1 g of 1- / benzenesulfonyl / -3-pyrroli-4- / 1-methyl-3-indolyl / -1 H-pyrrole - acetic acid in 25 ml of dichloromethane

2,5-dione, melting point 245-247 ° C.

Example 87.3- 1- / 4-cyanobutyl / -3-indolyl-4- / 1-methyl-3-indolyl / -1H-pyrrole-2,5-dione, melting point 195-198 ° C, obtained by the method Example 83

PRI me R 88.100 mg of the product of example

83 in 20 ml of ethanol is treated with hydrogen chloride gas until a saturated solution is obtained. After 6 hours, the solvent was evaporated and the residue was dissolved in 50 ml of ethanol. The solution was cooled to 0 C, saturated with gaseous ammonia and then allowed to warm to room temperature. After 17 hours of settling, the solvent was evaporated. The residue was dissolved in water and extracted with ethyl acetate. The aqueous solution was lyophilized to give

84 mg of 3- 1- / 3-amidinoprolyl / 3-indolyl} -4- / 1-methyl-3-indolyl / -1H-pyrrole-2,5-dione hydrochloride, m.p. 175-177 ° C. . .

Example 89. 100 mg of the product of Example 52 in TO ml of dimethyl sulfoxide was treated with 12.0 mg of 5-mercapto-1-methyltetrazole sodium salt. The solution was heated at 55 ° C for 6 hours, then cooled and poured into water. The aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts were dried and concentrated. Chromatography on silica gel using a mixture of dichloromethane / ethyl acetate (4: 1) gives 48 mg 3- / 1-methyl-3-indolyl / -4-1,3- / 1-methyl-5-tetrazolothio- / propyl - 3-indolyl -1H-p, irrol-2,5-dione, melting point 95-97 ° C.

PRI me R 90. 600 mg of the product of example 16 in 60 ml of dichloromethane are treated with 237 mg of pyridine. The mixture was added at 5-10 ° C to a solution of 855 mg trifluoromethanesulfonic anhydride in 15 ml of dichloromethane. After 1 h at 5-10 ° C, the mixture was added to. 944 mg of 1,2-diaminoethane in 20 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes and then washed with sodium bicarbonate solution. The dichloromethane solution was dried and concentrated. Chromatography of the residue on silica gel using a mixture of chloroform / methanol / acetic acid / water (60: 18: 2: 3) gives a gum which is dissolved in 50 ml of ethanol. The solution was treated with 25 ml of 1 M hydrochloric acid and concentrated. The residue was triturated with diethyl ether, filtered and dried to give 221 mg of 3- 1- 3- / 2-aminoethylamino / propyl - / 3-indolyl-4- / 1-methyl-3-indolyl / - 1H-pyrrole-2 5-dione, melting point 190-193 ° C.

Example 91. 100 mg of the product of Example 52 in 5 ml of dimethyl sulfoxide were treated with 30 mg of sodium methanethiolate. The solution was stirred for 30 minutes and then diluted with water. The precipitate was filtered off, washed with water and dried to obtain 52 mg of 3- (1-methyl-3-indolyl) -4-1-3 - / - methylthio / propyl} -3-indolyl -1 H-pyrrole-2.5-dione melting point 222-224 ° C.

Example 92. 116m g of the product of example

88 in 5 ml of dichloromethane is treated at 0 ° C. with 60 mg of 85% metachloroperbenzoic acid in 5 ml of dichloromethane. The solution was allowed to warm to room temperature and then stirred for 1 hour. The solution was washed with aqueous sodium bicarbonate and dried. The solution was concentrated and the residue was crystallized from ethyl acetate / hexane to give 84 mg of rac-3- / 1-methyl-3-indolyl / -4-1- / 3-methylsulfinylpropylAZ-indolyl-1H-pyrrole-2 5-dione, melting point 140 ° C.

PRI me R 93. 90 mg of the product of example

89 in 5 ml of dichloromethane are treated with 60 mg of 85% metachloroperbenzoic acid in 5 ml of dichloromethane. The solution was stirred for 2 hours and then washed with aqueous sodium bicarbonate. The solution was dried and concentrated. Chromatography of the residue on silica gel using a dichloromethane / ethyl acetate (1: 1) mixture and recrystallization from ethyl acetate / hexane afforded 25 mg of 3- / 1-methyl-3-indolyl / -4- 1- / 3- methylsulfonyl l propyl / 3-indolyl -1H-pyrrole-2,5-dione; melting point 225-227 ° C.

Example 94, 838 mg of the product of Example 52 in 15 ml of dimethyl sulfoxide was treated with 600 mg of potassium thiol acetate. The solution was stirred for 3 hours and then diluted with water. The solution was extracted with ethyl acetate and the ethyl acetate extracts dried. Concentration and chromatography on silica gel with ethyl acetate afforded 723 mg of 3-1-3- (acetylthio) progyl-3-indblyl-4- (1-methyl-3-indolyl / -1 H-pyrrole 2,5-dione, melting point 210-213 ° C.

Example 95. 350 mg of the product of example 91 in 20 ml of 50% methanol in dimethylformamide is treated with 0.5 ml of 33% aqueous ammonia. The mixture was stirred for 17 hours, then diluted with 20 ml of sodium chloride solution and extracted with ethyl acetate. The ethyl acetate extracts were dried and evaporated. Chromatography of the residue on silica gel using ethyl acetate / hexane (3: 1) gave 266 mg of 3- 1- / 3-mercaptopropyl / -3-indolyl-4- / 1-methyl-3

-indolyl / -1H-pyrrole-2,5-dione; melting point 155-1570 ° C.

Example 96. 0.71 g of trifluoromethanesulfonate anhydride was added to a solution of 0.5 of the product of Example 16 in 10 ml of pyridine at 0 ° C. The mixture was stirred at room temperature for 3 days and then evaporated. The residue was chromatographed on silica gel using 10% methanol in dichloromethane to give 0.11 g of 3- / 1-methyl-3-indolyl / -4- {1- {3- / 1-pyridino / propyl-3-indolyl - 1H-pyrrole-2,5-dione trifluoromethanesulfonate, melting point 8788 ° C. ;. - ..; .; -. . .

Example 97 Chromatography of the free base of Example 21 a) on silica gel. Using a mixture of dichloromethane / methanol / acetic acid / water (60: 18: 2: 3), the corresponding acetate used as the starting material in Example 56.58 and 67 are obtained.

Pyrroles of formula 1 and their pharmaceutically acceptable salts are protein kinase inhibitors; they inhibit cellular processes, for example, cell proliferation, and can be used to treat and prevent diseases, for example, inflammatory disorders such as arthritis, immune diseases, together with organ transplants, as well as in oncology. They inhibit the infection of cells with the human immunodeficiency virus and, thus, may be useful in the treatment of AIDS.

These substances also inhibit smooth muscle contraction and therefore can be used to treat cardiovascular and pulmonary bronchial disorders. In addition to this, they are also used in the treatment of asthma.

The activity of the compounds of the present invention in inhibiting protein kinase C can be demonstrated using an in vitro assay system described, for example, in BBBC 19 (1979) 1218.

The IGso values shown in the following table are those concentrations of the test compound that reduce the protein kinase-induced P incorporation of N - - P / ATP into histone by 50% (Tables 1 and 2).

Claims (1)

The claims The method of obtaining substituted pyrroles of General formula v " Oh, N -P where RI is hydrogen or lower alkyl, which may be substituted by a hydroxyl group; R2 and RS are each independently hydrogen, halogen, lower alkyl, lower alkylthio or amino; R4 is hydrogen or methyl; R-phenyl, provided that Ri-R4 is hydrogen or methyl, or the linear methylene chain is (CH2) p-X, where p is 2-6, X is hydrogen, hydroxyl group, azido group, halogen, aminocarbonyl group, carboxyl group a lower alkoxycarbonyl group, a lower alkylsulfonyloxy group, a cyano group, an isothiocyanato group, a 1-pyridinium group, an amidino group, a lower alkylsulfinyl group, a mercapto group which may be substituted with a lower alkyl, oxynyl-lower alkyl carbamide - th group, imidazolin-2-yl a group, a 1-methyltetrazol-5-yl group, a pyridin-1-oxide-2-yl group or an amino group, or means an amino group which may be substituted up to three times by lower alkyl or once substituted by a lower aminoalkyl group, nitropyl a ridin-2-yl group, a pyrimidin-2-yl group, a phenyl sulfo group, a lower alkyl sulfo group, a phenylcarbonyl group, an imidazol-1-ylcarbonyl group, a lower alkylcarbonyl group, an aminocarbonyl group, an amidino group, (4-benzyloxyphenyl) (4-hydroxyphenyl) and a multinocarbonyl group, an aminonitroiminocarbonyl group, an aminothiocarbonyl group, an aminocyaniminocarbonyl group, a methylamino cyaniminocarbonyl group, a methylthiocyaniminocarbonyl group, a methylthiocyaniminocarbonyl group, a 1-amino-2-nitro-2-nitro-nitro-2-nitro-nitrile-nitro-nitro-2-nitro-nitro-nitro-nitro-2-nitro-nitro-amino-nitro group t l and h - and with the fact that the compound of General formula O  - .1 J-C © (Щ, , t OQ) N o ... ni, where R, RI, R2, Iz and R4 are as defined herein; X in R represents hydrogen, a hydroxyl group, a carboxyl group, an azido group, an alkoxycarbonyl group or a (tert-butyloxycarbonyl) alkylamino group, is treated with ammonia under pressure in a medium of dimethylformamide water or. hexamethyldisalazane and methanol in toluene or chloroform and the desired product is isolated in the free form or in the form of a salt, or, if necessary, functional modification of the substituent X is carried out within the indicated values and provided that RI does not contain a hydroxy group, a R2 and RS do not an amino group, by alkylating the carboxyl group of the reduction of the azido group, sulfonylating the hydroxy group or exchanging it for a halogen, pyridinium or aminoalkyl group, releasing the obtained compounds in free form or in the form of salts, or, if necessary, by further modification of the substituent X within the limits of the indicated values by exchange of the sulfonyloxy group for a dialkylamino group, trialkylammonium group, cyano group, imidazol-2-ylthio group, 1-methyltetrazol-5-ylthio group, pyridin-1-oxide-2-ylthiog- , an amidinthio group, an alkylthio group or an acylthio group, either by acylating an amino group, sulfonylating an amino group, or by converting it to an isothiocyanato group, or by replacing an atom hydrogen of the amino group by an amidino group, an aminonitroiminarcarbonyl group, a 1-methylthio-2-nitrovinium group, a nitropyridin-2-yl group, and pyrimidin-2-yl group, (4-benzyloxyphenyl) iminocarbonyl group or methylthiocyanimino group with the isolation of the obtained compounds in free form or in the form of salts, or, if necessary, further modification substituent X within the indicated values by oxidation of the alkylthio group to an alkyl sulfinyl or alkyl sulfonyl group, amination of the cyano group, formyls of the anhydrcyano group, hydrolysis (4-benzyloxyphenyl) iminocarbonyl group, ammonolysis of the imidazol-1-ylcarbonyl group, 1-methylthio-2-nitrovinyl group or methylthiocyanimino group with ammonia or the corresponding amine and isolation of the obtained compounds in free form or in the form of salts. j Tables 1 Compound (2 carbamoylethyl) -3-indolyl / -4- (1-methyl-3 indolyl) -1H-pyrrole-2.5 dione i 3 (5 amino-1-methyl 3 indolyl) -4- (1-methyl-3) indolyl} -1H-pyrrole-2, 3 (1-methyl-3-indolyl) -k- (3-methylphenyl) -1H-pyrrole-2,5-dione (amDmnRthio) pr ° saw (3 indolyl) (1-methyl-3-indolyl) - 1H-pyrrole-2,5-dione 3 (1-Methyl-3 indolyl) -4- 1- / 3- (2-nitroguanidino) propyl / -3- INDOLYL / -1H-pyrrole-2,5-dion3- / 1- (3-isothiocyanatopropyl) - 3 indolyl / - (1-methyl-3-indolyl) - 1 H-pyrrole-2,5-dione Example | 211 24 J25 T26 J29a 1C SO 0.5 μM 0.6 μM 1.0 μM 0.010 μM 0.025 μM 0.008 μM T a 6 and u a 2