Substituted pyrroles

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

 

The invention relates to substituted the pyrrole. Primarily, the invention relates to substituted the pyrrole of the formula

where R1and R1'independently mean hydrogen, (ness.)alkyl, (ness.)alkenyl or (ness.)quinil,

R2means hydrogen, nitro, cyano, halogen, (ness.)alkyl, (ness.)alkenyl, (ness.) quinil or (ness.)alkoxy, and

R2'means heteroaryl, heterocycle, ethyl, substituted by heteroaryl, or ethoxy, replaced by heteroaryl or heterocycle,

or their pharmaceutically acceptable salts.

Compounds according to the invention are used in the treatment or control of disorders of cell proliferation, primarily cancer, in particular in the treatment or control of solid tumors. First of all, the compounds according to the invention possess anti-proliferative activity, specifically, they inhibit cell division in G2/M-phase of the cell cycle.

Description of the invention

The invention relates to substituted the pyrrole. Primarily, the invention relates to substituted the pyrrole of the formula

where R1and R1'independently mean hydrogen, (ness.)alkyl, (ness.)alkenyl or (ness.)quinil;

R2means hydrogen, nitro, cyano, halogen, (ness.)alkyl, (ness.)alkenyl, (ness.)quinil or (ness.)alkoxy, and

R2'means heteroa is l, a heterocycle, ethyl, substituted by heteroaryl, or ethoxy, replaced by heteroaryl or heterocycle,

or their pharmaceutically acceptable salts.

The term "(ness.)alkyl"used in the text of the application, individually or in combination, signifies an alkyl group with straight or branched chain containing up to 3 carbon atoms, such as methyl, ethyl, propyl and isopropyl, which is unsubstituted or substituted by one or more of the following groups: hydroxy, (ness.)alkoxy, amino, halogen, thio(ness.)alkyl or (ness.)alkylsulfonyl. Examples (ness.)of alkyl, substituted by one or more halogen, include chloromethyl and trifluoromethyl.

The term "(ness.)alkoxy", used individually or in combination, means a group where the remainder (ness.)alkyl has the meanings specified above, such as methoxy, ethoxy, propoxy, isopropoxy etc.

The term "heteroaryl used individually or in combination, means a 5 - or 6-membered aromatic cycle containing 1 to 4 heteroatoms, which may be identical or different, and where the ring is unsubstituted or substituted by one or more of the following groups: halogen, (ness.)alkyl, hydroxy, carboxy, (ness.)alkoxy, nitro, amino or cyano. Heteroatom(s) selected from the group including nitrogen, sulfur and oxygen. Examples heteroa the La include furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazol, isothiazol, oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazin and triazine.

The term "heterocycle"used individually or in various combinations, means 4-7-membered nonaromatic cycle containing one or more heteroatoms, which may be identical or different, and where the ring is partially or fully saturated, and where the ring is unsubstituted or substituted by one or more of the following groups: halogen, (ness.)alkyl, hydroxy, carboxy, (ness.)alkoxy, nitro, amino or cyano. Heteroatom(s) selected from the group including nitrogen, sulfur and oxygen. Examples of unsubstituted heterocycle include pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, Piran, piperidine, dioxane, morpholine, Titian, thiomorpholine, piperazine and Titian.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "amino" means razmeshannuyu the amino group or amine substituted by one or more substituents selected from the group comprising alkyl, aryl, acyl, alkylsulfonyl or arylsulfonyl.

The term "alkenyl" means a hydrocarbon group of 2-5 carbon atoms, straight or branched chain, having at least one double bond.

The term "quinil" means a hydrocarbon group of up to 5 carbon atoms, straight or branched chain, having at least one triple bond.

In the above formula I is preferred if R1and R1'independently signify hydrogen, methyl or ethyl, unsubstituted or substituted (ness.)alkoxy, preferably methoxy or ethoxy. Most preferably, if at least one of R1and R1'means (ness.)alkyl, most preferred unsubstituted methyl.

Preferably, if R2means (ness.)alkoxy, this balance means methoxy, ethoxy preferred methoxy. Preferably, if R2means (ness.)alkyl, this balance means methyl or ethyl, which is unsubstituted or substituted by one or more group (ness.)alkoxy or halogen. Most preferably, if R2means (ness.)alkyl, this balance means methyl, which is unsubstituted or substituted by a methoxy group. In addition, R2preferably may mean halogenated, such as trifluoromethyl.

If R2'is heteroaryl, the remainder preferably means thiophenyl, furanyl, imidazolyl (unsubstituted or substituted (ness.)by alkyl), thiazolyl, pyrazolyl, which is unsubstituted or substituted (ness.)the alkyl, pyrimidinyl or isothiazole.

If R2'is a heterocycle, this residue is preferably of oznacza the t unsubstituted morpholine, the unsubstituted pyrrolidine, unsubstituted piperidine or piperazine, unsubstituted or substituted (ness.)the alkyl, (ness.)alkoxy or carboxy.

If R2'means ethyl, substituted by heteroaryl, heteroaryl preferably means imidazole. In addition, R2'may signify methyl or propyl, substituted by heteroaryl.

In addition to group ethoxy, replaced by heteroaryl or heterocycle, R2'it can also mean, methoxy or propoxy, replaced by heteroaryl or heterocycle.

In a preferred variant embodiment of the invention, where R2'means thiophenyl, R1and R1'both preferably means methyl, and R2means hydrogen or nitro.

In another preferred variant of embodiment of the invention, where R2'means furanyl, R1preferably means hydrogen, methyl, R1'means methyl, and R2means hydrogen or nitro.

In another preferred variant of embodiment of the invention, where R2'means imidazolyl, unsubstituted or substituted (ness.)by alkyl, preferably by stands, R1preferably means methyl, R1'means methyl, and R2means hydrogen, nitro, cyano, halogen or methoxy.

In another preferred variant of embodiment of the invention, where R2'means thiazolyl, preferably R1and Rsup> 1'both denote methyl, and R2means hydrogen or nitro.

In another preferred variant of embodiment of the invention, where R2'means pyrazolyl, unsubstituted or substituted (ness.)by alkyl, preferably by stands, R1and R1'both preferably means methyl, and R2means hydrogen, nitro or halogen.

In another preferred variant of embodiment of the invention, where R2'means pyrimidinyl, R1and R1'preferably means methyl, and R2means hydrogen or nitro.

In another preferred variant of embodiment of the invention, where R2'means isothiazol, R1and R1'preferably means methyl, and R2means hydrogen or nitro.

In another preferred variant of embodiment of the invention, where R2'means pyrrolidinyl, preferably, if R1means hydrogen or methyl, R1'means hydrogen, methyl or methoxymethyl, and R2means hydrogen, nitro, cyano, halogen, trifluoromethyl or methoxy.

In another preferred variant of embodiment of the invention, where R2'means piperidinyl, R1and R1'both preferably means methyl, and R2means hydrogen.

In another preferred variant of embodiment of the invention, where R2'means morpholinyl, R11'preferably means methyl, hydrogen or methoxymethyl, a R2means hydrogen, nitro, cyano, halogen, methyl, trifluoromethyl or methoxy.

In another preferred variant of embodiment of the invention, where R2'means ethoxy, replaced by heteroaryl or heterocycle, preferably heteroaryl, and more preferably imidazolium, R1and R1'both preferably means methyl, and R2means nitro.

The compounds of formula I receive, as described below.

The source material, the compound of formula 4 can be obtained according to the following scheme:

If R2'means a heterocycle or heteroaryl, and R1means (ness.)alkyl, compound 4 can be obtained according to scheme 1.

The compound of formula 2, where X is Br or I, was obtained by the known methods (see M.P. Moyer, Shiurba J.F., H. Rapoport, J. Org. Chem., 57, 5106 (1986)), and alkilirovanie known methods (NaH and alkylated in N,N-dimethylformamide (DMF) or tetrahydrofuran at a temperature from 0°With up to about 25° (C) to obtain the corresponding compounds of formula 3. In another embodiment, the alkylation can be carried out using dimethylcarbonate and grounds (such as2CO3) or catalyst (such as TAV) in DMF, boiling of the reaction mixture with the reverse was built in the ICOM (at temperatures above 90° C).

The compound of formula 3 interacts with heteroaryl, replaced by trialkylsilanes, in a solvent such as toluene or THF, in the presence of a base such as triethylamine, in a reaction catalyzed by palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), at temperatures from 50°to the temperature of reflux distilled, to obtain the corresponding compounds of formula 4 where R2'means heteroaryl.

In another embodiment, the compound of formula 3 is introduced into reaction with imidazole or substituted imidazole in the presence of cesium carbonate, 1,10-phenanthroline and dibenzylideneacetone catalyzed by complex triftorbyenzola copper(I):benzene, in a solvent such as xylene, at a temperature of 110-125°C, to obtain the corresponding compounds of formula 4 where R2'means imidazolyl attached to the indole cycle through the nitrogen atom, as described in article Kiyoori A., Marcoux J-F., Buchwald, S.L., Tetrahedron letters, 40, 2657 (1999).

If R2'means heterocyclic amine, such as pyrrolidinyl or morpholinyl, the compound of formula 4 can be obtained from compounds of formula 3 by reaction Buchwald (J.P. Wolfe, S.L. Buchwald, J. Org. Chem., 62, 6066 (1997)). The compound of formula C is introduced into the reaction with the heterocyclic amine, such as pyrrolidine, in the presence of tert-butoxide sodium 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 18-crown-, catalyzed by Tris(dibenzylideneacetone)dipalladium (0) in a solvent such as tetrahydrofuran, at temperatures from 25 to 65°With obtaining the compounds of formula 4.

If R2'means pyrimidinyl, the compound of formula 4 receive the following sequence of reactions. The compound of formula 3 is introduced into reaction with n-butyllithium at -78°in tetrahydrofuran, and then trialkylborane. The resulting product is treated with an aqueous methanol to obtain the compounds of formula 5. The compound of formula 5 is introduced into the reaction bromopyrimidine, tetrakis(triphenylphosphine)palladium (0) in the presence of a base such as sodium carbonate in dioxane at a temperature of 100-110°With obtaining the compounds of formula 4 where R2'means pyrimidinyl.

If R2'means ethoxy, substituted heterocycle or heteroaryl, such as 2-imidazol-1-ylethoxy, the compound of formula 4 can be obtained by the following sequence of reactions. The compound of formula 5 is introduced into reaction with hydrogen peroxide and sodium hydroxide to obtain compound 6. Treatment of compound 6 1-(2-hydroxyethyl)imidazole, triphenylphosphine and diethylazodicarboxylate leads to the production of the compounds of formula 4 where R2'mean 2-imidazol-1-ylethoxy.

The compound of formula 1 can be obtained according to scheme 2 in which slowey, what if R2and R1mean substituents that interact with anhydrides of acids, such as alkylamine, protect them suitable protective group.

The compound of formula 4 is introduced into the reaction oxalylamino in a solvent such as diethyl ether or diplomaten, at a temperature of from 0 to 25°C, to obtain the corresponding compounds of formula 7.

The compound of formula 7 is introduced into reaction with the compound of the formula 8, a known compound (see US patent No. 5057614) or a compound obtained by known methods, in the presence of a base such as triethylamine in dichloromethane at a temperature from 0 to 25°C. Then the obtained product is treated with acid, such as para-toluensulfonate acid or hydrochloric acid, in a solvent such as methylene chloride, methanol or THF, at temperatures from 25 to 65°C, to obtain the corresponding compounds of formula 1. If in reactions 7 or 8 is used protective group, it is removed at this stage by methods known in the art.

As shown in scheme 3, the compound of formula 4 is introduced into the reaction methylacetylene in a solvent such as diethyl ether or dichloromethane, or in the absence of solvent, at a temperature of from 0 to 25°With obtaining the compounds of formula 9. With the unity of formula 9 is introduced into the reaction hydrate hypophosphite sodium, catalyzed by palladium on charcoal, in a solvent such as dioxane at a temperature from 100 to 110°With obtaining the compounds of formula 10. The compound of formula 10 is introduced into reaction with ammonium hydroxide to obtain the corresponding compounds of formula 11.

The compound of formula 12 is introduced into the reaction methylacetylene in a solvent such as diethyl ether or dichloromethane, or in the absence of solvent, at a temperature of from 0 to 25°With obtaining the compounds of formula 13.

The compound of formula 11 is introduced into reaction with the compound of the formula 13 in the presence of a base, such as tert-piperonyl potassium in a solvent such as tetrahydrofuran, at temperatures from 0 to 25°C. the resulting product is treated with acid, such as hydrochloric acid, to obtain the compounds of formula 1.

As shown in scheme 4, the compound of formula 3 is introduced into the reaction oxalylamino in a solvent such as diethyl ether or methylene chloride, at a temperature of from 0 to 25°With obtaining the compounds of formula 14. The compound of formula 14 is introduced into reaction with the compound of the formula 8 in the presence of a base such as triethylamine in methylene chloride at a temperature of from 0°to 25°C. Then the obtained product is treated with acid, such as para-toluensulfonate acid or chlorine is estomatologia acid, in a solvent such as methylene chloride, methanol or THF, at temperatures from 25 to 65°C, to obtain the corresponding compounds of formula 15.

The compound of formula 15 is introduced into the reaction heteroaryl, replaced by trialkylamines or Bronevoy acid, such as 2-(tributylstannyl)thiophene or 2-(tributylstannyl)thiazole, thiophene-3-baronova acid, in the presence of a base such as triethylamine or sodium carbonate catalyzed by palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) or three(dibenzylideneacetone)dipalladium (0), in a solvent such as toluene, acetonitrile, tetrahydrofuran or dioxane, at a temperature of from 80 to 110°With obtaining the compounds of formula 1.

The transformation of the acid compounds of formula I in a pharmaceutically acceptable salt can be carried out by interaction with acceptable base by a known method. Acceptable salts are not only salts with inorganic bases, for example salts of sodium, potassium or calcium, salts of organic bases such as Ethylenediamine, monoethanolamine or diethanolamine. The transformation of the basic compounds of formula I, pharmaceutically acceptable salts can be carried out by interaction with acceptable acid by a known method. Acceptable salts are not only inorganic salts, for example hydrochlori is s, hydrobromide, phosphates or sulfates, and salts of organic acids, for example acetates, citrates, fumarate, tartratami, maleate, methanesulfonate or para-toluensulfonate.

Antiproliferative activity of the compounds according to the invention is given below. These results show that the compounds of the present invention can be used in the treatment of cancer, especially solid tumors, such as tumors of the breast and colon. Cell lines of epithelial breast carcinoma (MDAMB-435) were obtained from ATS (American Type Cell Culture Collection) and were cultured in the medium recommended by ATS. For the analysis of various compounds of formula I on the growth of these cells the cells were made in the wells of 96-well culture tablet (test plate) at a concentration of 1500 cells per well. A day after making the cells of the analyzed compounds were dissolved in 100% DMSO (dimethyl sulfoxide), receiving the original 10 mm solution. A solution of each compound was diluted with water to a final concentration of 1 mm and added to the first row of the control Board (the"master plate"), containing environment, three repeats for each connection, while the final concentration was 40 μm. Then there was a serial dilution of compounds in the environment control of the tablet. The diluted solution was transferred into a cultural tablets containing cells. In the row containing "counter the global cell", made DMSO. The final concentration of DMSO in each well was 0.1%. 5 days after adding compounds tablets were analyzed as described below.

To each well was added MTT (bromide 3-(4,5-methylthiazole-2-yl)-2,5-diphenyltetrazolium, thiazolyl blue) to a final concentration of 1 mg/ml Then the plates were incubated at 37°for 2.5-3 hours, the Medium containing MTT was removed and to each well was added 50 μl of 100% ethanol to dissolve formazan. Absorption was measured on an automatic reader tablet (company Biotek microplate reader). The value of the IC50was calculated by the equation reed, Munsa (see Reed, Munsch, Am. J. Hygiene, 27, 493-497 (1938)).

The results of in vitro experiments are shown below in table 1.

td align="left"> 0,01
Table 1
ExampleR1R2IC50(µm)
12gCH3CH3NO20,002
SCH3NNO20,002
DCH3NF0,003
12ECH3NCl<0,003
GCH3CH2OCH3NO20,02
14CH3CH3Br0,005
GCH3CH3Och30,04
SCH3CH3CF30,08
12KCH3CH3N0,06
15CH3CH3CN<0,01
12mCH3CH3N0,23
12ACH3CH3NO2 <0,01
11CH3CH3N0,02
13CH3CH3CN0,004
14aCH3CH3Och30,02
14bCH3CH3F0,03
]4BCH3CH3Cl0,002
14gCH3CH3Br0,003
DCH3CH3CF30,05
12BCH3CH3CH3<0,01
12VNCH3N0,07
3CH3CH3N0,04
5CH3CH3N0,04
2ZHCH3CH3N0,02
2iNCH3N0,03
2HCH3CH3NO20,01
4ACH3CH3N0,024
2BCH3CH3NO20,03
4BCH3CH3N0,06
4BCH3CH3NO20,02
4GCH3 CH3NO20,02
6CH3CH3NO20,04
1CH3CH3NO20,005
2ACH3CH3N0,05
2BCH3CH3Och30,06
2GCH3CH3NO20,12
2DCH3CH3N0,08
2sCH3CH3NO20,04
2ndCH3CH3NO20,02
7CH3CH 3N0,06
8ACH3CH3NO20,03
9CH3CH3Och3C0,06
10ACH3CH3Br0,025
10BCH3CH3CN0,03
8bCH3CH3NO20,25
8bCH3CH3NO20.02
8DCH3CH3N0,03
8CH3CH3Br0,025
2KCH3CH3O 20,2
2CH3CH3N0,25
2mCH3CH3Br0,07
17CH3CH3NO20,07
2HCH3CH3NO20,01
2CH3CH3N0,04
18CH3CH3NO20,05
19CH3CH3N0,08
12NCH3N0,08
14CH3CH3Cl
NCH3CH3Och2F0.17
12 ° CH3NF0,012
PCH3NN0,037
16CH3CH3CH3Och21,18
12LCH3CH3N3,41

Another variant embodiment of the invention relates to pharmaceutical compositions comprising at least one compound of formula I or its pharmaceutically acceptable salt.

These pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, pills, hard or soft gelatin capsules, solutions, emulsions or suspensions. In addition, they can be introduced rectally, for example in the form of suppositories. However, primarily, the compounds of the present invention suitable for parenteral administration, for example, in the form of injection races of the thieves.

The pharmaceutical compositions of the present invention, including the compounds of formula I, prodrugs of such compounds or their salts, can be prepared by known in this field, for example, using conventional methods of mixing, encapsulating, dissolving, granulating, emulsifying, inclusion in the polymer or gel, drazhirovanija or lyophilization. These pharmaceutical preparations can be recycled with therapeutically inert, inorganic or organic carriers. As such carriers in the manufacture of tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, starch grain and its derivatives, talc, stearic acid or its salts. Acceptable carriers for soft gelatin capsules include vegetable oils, waxes and fats. Depending on the nature of the active compounds in the case of soft gelatin capsules usually do not require any medium. Suitable carriers for the preparation of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oil, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid, polio the s.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer solutions, agents for covering the shell and antioxidants. In addition, they can contain other therapeutically valuable compounds, including additional active ingredients other than the compounds of formula I.

As mentioned above, the present invention relates also to a method for obtaining compounds of formula I, including

a) interaction of the compounds of formula 7 (scheme 2)

with a compound of formula 8 (scheme 2)

where R1and R1'independently mean hydrogen or (ness.)alkyl, (ness.)alkenyl or (ness.)quinil;

R2means hydrogen, nitro, cyano, halogen, (ness.)alkyl, (ness.)alkenyl, (ness.)quinil or (ness.)alkoxy;

and R2'means heteroaryl, heterocycle, ethyl, substituted by heteroaryl, or ethoxy, replaced by heteroaryl or heterocycle,

or its pharmaceutically acceptable salt,

b) interaction of the compounds of formula 11 (scheme 3)

with a compound of formula 13 (scheme 3)

where R1 and R1'independently mean hydrogen or (ness.)alkyl, (ness.)alkenyl or (ness.)quinil;

R2means hydrogen, nitro, cyano, halogen, (ness.)alkyl, (ness.)alkenyl, (ness.)quinil or (ness.)alkoxy, and

R2'means heteroaryl, heterocycle, ethyl, substituted by heteroaryl, or ethoxy, replaced by heteroaryl or heterocycle;

or its pharmaceutically acceptable salt, or

C) the interaction of the compounds of formula 15 (scheme 4)

where R1and R1'independently mean hydrogen or (ness.)alkyl, (ness.)alkenyl or (ness.)quinil;

R2means hydrogen, nitro, cyano, halogen, (ness.)alkyl, (ness.)alkenyl, (ness.)quinil or (ness.)alkoxy, and

R2'means heteroaryl, heterocycle, ethyl, substituted by heteroaryl, or ethoxy, replaced by heteroaryl or heterocycle;

or its pharmaceutically acceptable salt,

X is Br or I,

with heteroaryl, replaced by trialkylamines or Bronevoy acid, in the presence of base in the reaction catalyzed by palladium catalyst.

As mentioned above, the compounds of the present invention are used in the treatment or control of disorders of cell proliferation, primarily cancer. These compounds and compositions containing the above compounds, first always is, can be used in the treatment or control of solid tumors, such as tumors of the breast and colon.

Thus, the present invention includes the use of the above compounds to obtain drugs primarily for the treatment or control of disorders of cell proliferation, specifically cancer, for example for the treatment or control of solid tumors, such as tumors of the breast and colon. A therapeutically effective amount of the compounds of the present invention means the number of connections, which effectively prevents, mitigates or reduces the intensity of symptoms of disease or prolong the survival of the patient to be treated. Therapeutically effective amount is determined by a specialist.

Therapeutically effective amount or dosage of the compounds according to the invention can vary within a wide range and depends on the individual requirements in each particular case. Usually by oral or parenteral administration to adult weight of approximately 70 kg is sufficient daily dose from about 10 mg to about 10000 mg, preferably from about 200 mg to about 1000 mg, although when indicated upper limit can be offset is N. The daily dosage can be entered as a single dose or a single dose, or parenteral administration by continuous infusion.

Compounds of the present invention can be synthesized by known methods, for example, what the above on major schemes. Preferred methods of synthesis of compounds and methods of the present invention are illustrated by the following examples.

Example 1

3-[1-Methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2.5-dione

a) 6-Bromoindole (10.4 g, 53.1 mmole) (obtained as described in article M.P. Moyer, Shiurba J.F., H. Rapoport, J. Org. Chem., 51, 5106 (1986)) was added in small portions over 30 min to a stirred suspension of sodium hydride (2,96 g, 61,7 mmole, 50%suspension in mineral oil) in dry THF (120 ml) at 0°C. the Stirring was continued for another 30 min and then was added dropwise itmean (4,5 ml, 71.6 mmole). After 1 h the mixture was poured into ice water and was extracted with ether (3×200 ml). The combined organic extracts were washed with saline and dried (MgSO4). After evaporation of the solvent and chromatography of the resulting residue on silica gel using hexane was obtained 6-bromo-1-methyl-1H-indole (10.8 g, 97%).

b) a Solution of 6-bromo-1-methyl-1H-indole (6.2 g, to 29.5 mmole) in toluene was degirolami within 10-20 minutes, passing through the solution a current of argon was Then added Et 3N (8.2 ml, 59 mmol), tetrakis(triphenylphosphine)palladium (0) (681 mg, of 0.59 mmole) and 1-methyl-5-(tributylstannyl)imidazole (11.6 g, and 31.2 mmole) (see K. Gaare, Repstad T., T. Benneche, Undheim, K. Acta Chem. Scan.,47, 57 (1993)) in toluene (30 ml) and the mixture was heated at 120°C for 18 h before the appearance of black color Pd. The mixture is then cooled and filtered through a layer of silica gel, washed with EtOAc. The filtrate was evaporated, the residue was chromatographically on silica gel using 0.5-1% methanol in EtOAc, was obtained 1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (to 5.21 g, 84%) as a solid crystalline substance of white color.

C) 1-Methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (5.0 g, 23.7 mmole) was dissolved in CH2Cl2(25 ml) (dried over molecular sieves 3Å) at 0°C. Then added dropwise within 10 min the solution was added oxalicacid in CH2Cl2(2 M, with 23.7 ml, 47.4 mmole). The resulting mixture was stirred at 0°C for 2.5 h and evaporated. To the residue in the form of a solid substance was added ether (25 ml) and the mixture was stirred for 30 minutes resulting solid yellow substance was separated by filtration, washed with ether, and dried in vacuum for 30 minutes To solid yellow substance at 0°hydrochloride was added isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid (7,02 g, 22.5 mmole) and CH2Cl2(200 ml). Then on to plan for 10 min was added Et 3N (16,5 ml, 118,6 mmole) (dried over molecular sieves 3Å) and a mixture of orange-red color was stirred at room temperature overnight. The mixture was diluted with CHCl3and washed with an aqueous solution of Na2CO3. The aqueous layer was subjected to back extraction with CHCl3. The combined organic extracts were washed with saline, dried (K2CO3) and was evaporated. Then add Meon (150 ml) and .HCl (37%, 10 ml). The resulting mixture was boiled under reflux for 2 h, cooled, diluted with CHCl3and washed with an aqueous solution of Na2CO3. The aqueous layer was subjected to back extraction with CHCl3. The combined organic extracts were washed with saline and dried (K2CO3). The mixture was passed through a layer of silica gel (10×10 cm), which was washed with 10% methanol/EtOAc. After evaporation of the combined filtrates were obtained crude product in the form of a solid orange color. During crystallization of the product from EtOH/CHCl3received 3-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (5,65 g, 49%) as a solid orange color.

Example 2

The following compounds were obtained in the same way as described in example 1. The original materials were obtained in the same way as described in examples 1A) and 1B).

a) 3-(1-M the Teal-1H-indol-3-yl)-4-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione (391 mg, 45%) was obtained in the form of a solid orange color with 1-methyl-6-(3-methyl-ZN-imidazol-4-yl)-1H-indole (422 mg, 2 mmole) of the hydrochloride and isopropyl ether 1-methyl-3-indolinecarboxylic acid (530 mg, 2 mmole).

b) 3-(6-Methoxy-1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione (78 mg, 11%) was obtained in the form of a solid dark brown color using 1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (316 mg, 1.5 mmole) of the hydrochloride and isopropyl ether 2-(1-methyl-6-methoxy-1H-indol-3-yl)midinotate acid (445 mg, 1.5 mmole).

C) 3-[1-Methyl-6-(1-methyl-1H-imidazol-2-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (1.08 g, 34%) was obtained in the form of a solid orange color of 6-(1-methyl-1H-imidazol-2-yl)-1-methyl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid.

g) 3-[6-(1-Ethyl-1H-imidazol-2-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (155 mg, 38%) was obtained using 6-(1-ethyl-1H-imidazol-2-yl)-1-methyl-1H-indole (185 mg, of 0.82 mmole) of the hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid (256 mg, of 0.82 mmole).

e) 3-[6-(1H-Imidazol-2-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (37 mg, 14%) was obtained in the form of a solid orange color with 1-methyl-6-[1-(2-trimethy silanisation)-1H-imidazol-2-yl]-1H-indole (200 mg, to 0.61 mmole) of the hydrochloride and isopropyl ether 1-methyl-3-indolinecarboxylic acid (162 mg, and 0.61 mmole) followed by removal of protective groups 20% HCl in boiling EtOH.

e) of the Hydrochloride of 3-[6-(3H-imidazol-4-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (45 mg, 18%) was obtained from 1-methyl-6-[3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]-1H-indole (160 mg, of 0.49 mmole) and hydrochloride isopropyl ester of 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid (156 mg, 0.5 mmole) followed by removal of protective groups 20% HCl in boiling EtOH.

g) 3-(6-Furan-2-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (51 mg, 27%) was obtained in the form of a solid orange color with 6-furan-2-yl-1-methyl-1H-indole (100 mg, 0.5 mmole) of the hydrochloride and isopropyl ether 1-methyl-3-indolinecarboxylic acid (120 mg, 0.45 mmole).

C) 3-(6-Furan-2-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (70 mg, 40%) was obtained using 6-furan-2-yl-1-methyl-1H-indole (100 mg, 0.5 mmole) of the hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indole-3-yl)midinotate acid (117 mg, of 0.38 mmole).

3-(6-Furan-2-yl-1-methyl-1H-indol-3-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione was obtained from 6-furan-2-yl-1-methyl-1H-indole hydrochloride and isopropyl ether 2-[1-(2,2-dimethylpropyl)-1H-indol-3-yl]midinotate acid with the subsequent removal of the protective gr is PP NaOMe in methanol.

K) 3-[1-Methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid.

l) 3-(1-Methyl-1H-indol-3-yl)-4-[1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-yl]pyrrole-2,5-dione was obtained from 1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-1H-indol-3-yl)midinotate acid.

m) 3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-yl]pyrrole-2,5-dione was obtained from 1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indole hydrochloride and isopropyl ester of 2-(6-bromo-1-methyl-1H-indol-3-yl)midinotate acid.

h) 3-(6-Isothiazol-5-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 6-isothiazol-5-yl-1-methyl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid.

o) 3-(6-Isothiazol-5-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 6-isothiazol-5-yl-1-methyl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-1H-indol-3-yl)midinotate acid.

p) 3-[6-(1H-Imidazol-2-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methyl-6-[1-(2-trimethylsilylethynyl)-1H-imidazol-2-yl]-1H-indole hydrochloride and isopropyl E. the Ira 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid, followed by removal of protective groups hydrochloric acid in aqueous ethanol.

Example 3

3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophene-2-yl-1H-indol-3-yl)pyrrole-2,5-dione.

To a solution of 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione, obtained as described in example 2 (108 mg, 0.25 mmole), in dry THF (5 ml) was added tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmole), 2-(tributylstannyl)thiophene (0,12 ml, the 0.375 mmole) and triethylamine (0.10 ml, 0,70 mmole). The mixture is then boiled under reflux for three hours and cooled to room temperature. After evaporation of the solvent and chromatography of the crude product on silica gel using 30% EtOAc in hexane was obtained 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophene-2-yl-1H-indol-3-yl)pyrrole-2,5-dione (72 mg, 66%).

Example 4

The following compounds were obtained in the same way as described in example 3.

a) 3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-thiazol-2-yl-1H-indol-3-yl)pyrrole-2,5-dione (25 mg, 23%) was obtained from 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (108 mg, 0.25 to mmole) and 2-(tributylstannyl)thiazole (140 mg, the 0.375 mmole).

b) 3-(1-Methyl-1H-indol-3-yl)-4-[1-methyl-6-(1-methyl-1H-imidazol-2-yl)-1H-indol-3-yl]pyrrole-2,5-dione (46 mg, 38%) was obtained from 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole 2,5-dione (120 mg, of 0.28 mmole) and 1-methyl-2-(tributylstannyl)imidazole (0.8 ml, containing 50% 1-methylimidazole) (see Molloy HP, Waterfield R.S., M.F. Mahon, J. Organometallic. Chem., 365, 61 (1989)).

C) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiazol-2-yl-1H-indol-3-yl)pyrrole-2,5-dione (21 mg, 23%) was obtained from 3-(6-iodine-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole 2,5-dione (100 mg, to 0.19 mmole) and 2-(tributylstannyl)thiazole (0,107 ml).

g) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiophene-2-yl-1H-indol-3-yl)pyrrole-2,5-dione (180 mg, 37%) was obtained from 3-(6-iodine-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole 2,5-dione (525 mg, 1 mmol) and 2-(tributylstannyl)thiophene (0,98 ml, to 3.09 mmole).

Example 5

3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophene-3-yl-1H-indol-3-yl)pyrrole-2,5-dione.

Through a solution of 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (160 mg, 0.37 mmole) in dioxane (15 ml) for 10 min missed argon. Then added tetrakis(triphenylphosphine)palladium (0) (8.5 mg, 0,007 mmole), thiophene-3-Bronevoy acid (52 mg, 0,41 mmole) and an aqueous solution of Na2CO3(of 0.37 ml, 2 M). The mixture was boiled under reflux for 2 h, was added another portion of tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.01 mmole) and boiling under reflux was continued for 24 h Then the mixture was cooled and evaporated. The residue was chromatographically on silica gel using 50% EtOAc in hexane, was thus obtained 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophene-3-yl-1H-indol-3-yl)pyrrole-2,5-dione (117 mg, 72%).

Example 6

3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiophene-3-yl-1H and the Dol-3-yl)pyrrole-2,5-dione (11 mg, 12%) was obtained similarly as described in example 5, from 3-(6-iodine-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (100 mg, to 0.19 mmole) and thiophene-3-Bronevoy acid (49 mg, of 0.38 mmole).

Example 7

3-(6-Imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

a) kiln Dried ampoule Slanka was purged with argon. Then, the ampoule was placed complex triftorbyenzola copper(I):benzene (1.39 g, was 2.76 mmole), 1,10-phenanthroline (5,69 g of 31.6 mmole), dibenzylideneacetone (740 mg, and 3.16 mmole) and cesium carbonate (10 g, a 30.7 mmole), was added imidazole (3,23 g, 44,8 mmole), 6-iodine-1-methyl-1H-indole (8,13 g of 31.6 mmole) and xylene (16 ml)was purged with argon, the ampoule was sealed and heated with stirring at 160°C for 18 h Then the mixture was cooled to room temperature and distributed between CH2Cl2(35 ml) and saturated aqueous NH4Cl (5 ml). The organic layer was separated and washed with saline. Then the organic extract was dried over MgSO4, filtered and concentrated. The crude concentrate was filtered through a layer of silica gel and evaporated. The product was purified by the method GHUR, received 6-imidazol-1-yl-1-methyl-1H-indole in the form of a brown oil (3.1 g, 50%) (see Kiyoori A., Marcoux J-F., Buchwald, S.L., Tetrahedron Lett., 40, 2657 (1999)).

b) 6-Imidazol-1-yl-1-methyl-1H-indole (7.0 g, 35,5 mmole) was dissolved in CH2Cl2(100 ml), dried the hell molecular sieves 3Å ) at 0°C. Then added dropwise within 10 min the solution was added oxalicacid in CH2Cl2(2 M, of 35.5 ml, 71 mmol). The mixture was stirred at 0°C for 1.5 h and evaporated. The solid residue was added ether (100 ml)was stirred for 30 min, the resulting solid yellow substance was separated by filtration, washed with ether and dried in vacuum for 30 minutes To solid yellow substance at 0°hydrochloride was added isopropyl ether, 1-methyl-3-indolinecarboxylic acid (9.6 g, 36 mmol) and CH2Cl2(200 ml). Then dropwise within 10 min was added Et3N (dried over molecular sieves 3Å). The mixture of orange-red color was stirred at room temperature overnight. The mixture was diluted with CH2Cl2(300 ml), washed with an aqueous solution of Na2CO3(2×200 ml) and the aqueous layer was subjected to back extraction with CH2Cl2(100 ml). The combined organic extracts were washed with saline, dried (K2CO3) and was evaporated. Then add Meon (100 ml), .HCl (37%, 10 ml) and boiled under reflux for 2 hours, the Reaction mixture was cooled, diluted with water (200 ml) and EtOAc (200 ml), was podslushivaet hard To2CO3and was extracted with EtOAc (4×200 ml). The combined organic extracts were washed with an aqueous solution of Na2CO 3(2×200 ml), brine and dried (K2CO3). The mixture was passed through a layer of silica gel (10×10 cm), which was washed with 10% methanol in EtOAc. After evaporation of the combined eluates were obtained crude product in the form of a solid orange color. After recrystallization of the crude product using EtOAc, Meon and CHCl3received 3-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (5.0 g, 33%) as a solid orange color.

Example 8

The following compounds were obtained in the same way as described in example 7. The original materials were obtained in the same way as described in example 7.

a) 3-(6-Imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (ceiling of 5.60 g, 64%) was obtained from 6-imidazol-1-yl-1-methyl-lH-indole (3,70 g, to 18.7 mmole) of the hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indole-3-yl)midinotate acid (5,80 g, to 18.7 mmole).

b) 3-[1-Methyl-6-(2-Mei-1-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (23 mg, 5,5%) was obtained from 2-(1-methyl-6-(2-Mei-1-yl)-1H-indole (260 mg, 0.87 for mmole) of the hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid (271 mg, of 0.87 mmole).

C) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrazole-1-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methyl-6-pyrazole-1-yl-1H-indole and hydrochlor is Yes isopropyl ester of 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid.

g) 3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrazole-1-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methyl-6-pyrazole-1-yl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-1H-indol-3-yl)midinotate acid.

d) 3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrazole-1-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methyl-6-pyrazole-1-yl-1H-indole hydrochloride and isopropyl ester of 2-(6-bromo-1-methyl-1H-indol-3-yl)midinotate acid.

Example 9

3-(6-Imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

a) 6-Imidazol-1-yl-1-methyl-1H-indole (0,90 g, 4,56 mmole) was dissolved in CH2Cl2(2 ml) and cooled to 0°C. Then was added methylchlorosilanes (1.3 ml, 14 mmol), stirred at 0°C for 2 h and was added another portion of METHYLCHLOROSILANE (0.4 ml, 4.3 mmole). After 2 h the solvent was removed. The remainder in the form of solids carried in the ether, separated by filtration and thoroughly washed with ether, it was obtained the crude methyl ester (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)Glyoxylic acid (1.50 g).

b) the Crude methyl ester (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)Glyoxylic acid (1.40 g) in dioxane (100 ml) were placed in a round bottom flask of 250 ml, equipped with a reflux condenser and attached to the container with argon (through the top of the refrigerator). Through the system passed a current of argon, obavljale Pd/C (140 mg, 10%), hydrate hypophosphite sodium (7.2 g) in water (10 ml) and the mixture is boiled under reflux during the night. Added another portion of the hydrate hypophosphite sodium (3.0 g) in water (5 ml) and Pd/C (50 mg)was boiled under reflux for a further 5 h and cooled. The solvents are evaporated, the residue was diluted with EtOAc (100 ml). The solution is thoroughly washed in an aqueous solution of NaHCO3(2×100 ml). The combined aqueous layers were subjected to back extraction with EtOAc (2×200 ml). The combined organic extracts were filtered through a layer of silica gel and a layer of MgSO4located on a layer of silica gel, which was washed with 10% methanol in CH2Cl2. The combined filtrates were evaporated, the residue was chromatographically on silica gel using 1-6% methanol in CH2Cl2when this was obtained methyl ester (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)acetic acid (230 mg, 17%).

C) Methyl ester (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)acetic acid (230 mg, of 0.85 mmole) suspended in conc. NH4HE (5 ml) in a flask with a volume of 100 ml and stirred in a tightly closed flask for 24 hours After lyophilization was obtained the crude product, which was chromatographically on silica gel using 2-8% Meon in CH2Cl2when this was received (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)ndimethylacetamide (145 mg, 67%).

g) 6-Methoxy-1-methyl-1H-indole (1.0 g, to 6.19 mmole) dissolve the Yali in ether (10 ml) and cooled to 0° C. Then was added dropwise methylchlorosilanes (1,17 ml, 12.4 mmole) and stirred at 0°C for 6 hours the Mixture was filtered and thoroughly washed with ether, was obtained methyl ester (6-methoxy-1-methyl-1H-indol-3-yl)Glyoxylic acid (621 mg, 41%).

d) To a mixture of methyl ester (6-methoxy-1-methyl-1H-indol-3-yl)Glyoxylic acid (47 mg, of 0.18 mmole) and (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)ndimethylacetamide (46 mg, of 0.18 mmole) at 0°C was added dropwise a solution of tert-BuOK in THF (1 M, of 0.53 ml of 0.53 mmole). After 15 min the cooling bath was removed and the mixture was stirred at room temperature for 3 hours Then was added conc. hydrochloric acid (1 ml) and the mixture was stirred for 30 minutes and Then the mixture was podslushivaet aqueous solution of NaHCO3and was extracted with EtOAc (3×50 ml). The combined organic extracts were washed in an aqueous solution of NaHCO3and dried (K2CO3). The extracts were filtered through a layer of silica gel, which is washed with 5% Meon in EtOAc. The solvents are evaporated, the residue was chromatographically on silica gel using 70% EtOAc in hexane and then EtOAc, received 32 mg solid orange color, which was dissolved in MeOH/CH2Cl2(1:1.1 ml) and was diluted with ether (8 ml). The precipitate was separated by filtration and washed with ether/hexane (1:1, 8 ml), was thus obtained 3-(6-imidazol-1-yl-1-methyl-1H-ind the l-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (29 mg, 36%). (RO 28-4240) (see Faul M.M., Winneroski L.L., Krumrich S.A., J. Org. Chem. 63, 6053 (1998)).

Example 10

The following compounds were obtained in the same way as described in example 9. The original materials were obtained in the same way as described in example 9b) and 9 (g).

a) 3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (13 mg, 19%) was obtained from methyl ester (6-bromo-1-methyl-1H-indol-3)Glyoxylic acid (43 mg, of 0.14 mmole) and (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)ndimethylacetamide (50 mg, of 0.20 mmole).

b) 3-[4-(6-Imidazol-1-yl-1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1-methyl-1H-indole-6-carbonitrile (14 mg, 16%) was obtained from methyl ester (6-cyano-1-methyl-1H-indol-3)Glyoxylic acid (44 mg, of 0.18 mmole) and (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)ndimethylacetamide (46 mg, of 0.18 mmole).

Example 11

3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2.5-dione

a) the Flask, dried in a drying Cabinet, was purged with argon. Then the flask was placed 18-crown-6 (15 g, 56,7 mmole), 6-iodine-1-methyl-1H-indole (10.4 g, 40,46 mmole), morpholine (4.3 ml, 48.6 per mmole), tert-piperonyl sodium (5,42 g, 54,7 mmole), Tris(dibenzylideneacetone)dipalladium (0) (186 mg, of 0.20 mmole) and 2,2'-bis(diphenylphosphino)-1,1-binaphthyl (380 mg, and 0.61 mmole)was passed a current of argon for 10 min and added dry THF (80 ml). The mixture was stirred at room temperature for 5 h, then was diluted with ether and washed salt RAS is a thief. The organic layer was dried (MgSO4), was evaporated and the crude product was purified by chromatography on silica gel using 5-30% ether/hexane, 1-methyl-6-morpholine-4-yl-1H-indole (8,17 g, 94%) (see J.P. Wolfe, S.L. Buchwald, J. Org. Chem. 62, 6066 (1997)).

6-Iodine-1-methyl-1H-indole was obtained in the same way as described in example 1A).

b) a Solution of 1-methyl-6-morpholine-4-yl-1H-indole (0.50 g, 2,31 mmole) in CH2Cl2(5 ml) (dried over molecular sieves 3Å) was cooled to 0°C. Then dropwise over 5 min was added oxalicacid (0.4 ml, to 4.62 mmole), was stirred at 0°C for 4 h and evaporated. The solid residue triturated with ether, filtered, washed with ether and dried in vacuum for 30 minutes To the obtained solid substance is yellow at 0°hydrochloride was added isopropyl ether, 1-methyl-3-indolinecarboxylic acid (0,58 g of 2.20 mmole) and CH2Cl2(9 ml). Then dropwise within 10 min was added Et3N (1.8 ml) (dried over molecular sieves 3Å). The mixture of orange-red color was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 1 N. NaOH and the aqueous layer was subjected to back extraction with EtOAc. The combined organic extracts were washed with saline, dried (K2CO3) and was evaporated. The residue was dissolved in Meon (100 ml)containing TOH· H2O (3,30 g, a 17.3 mmole) and the mixture was stirred at room temperature for 4 h After removal of the solvents under reduced pressure the residue was diluted with EtOAc (500 ml) and podslushivaet aqueous solution of NaHCO3. The organic layers were separated and the aqueous layer was subjected to back extraction with EtOAc. The combined organic extracts were washed with saline, dried (MgSO4) and was evaporated. The residue was chromatographically on silica gel using 30-70% EtOAc/hexane, was obtained 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (0,30 g, 30%) as a solid orange color.

Example 12

The following compounds were obtained in the same way as described in example 11. The original materials were obtained in the same way as described in example 11a).

a) 3-(1-Methyl-6-morpholine-4-yl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (315 mg, 25%) was obtained from 1-methyl-6-morpholine-4-yl-1H-indole (0.56 g of 2.56 mmole) of the hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indole-3-yl)midinotate acid (0,81 g of 2.56 mmole).

b) 3-(1,6-Dimethyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1,6-dimethyl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)midinotate acid.

C) 3-(1H-Indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione floor is Ali from 1-methyl-6-morpholine-4-yl-1H-indole hydrochloride and isopropyl ether 2-[1-(2,2-dimethylpropyl)-1H-indol-3-yl]midinotate acid with the subsequent removal of the protective groups with sodium methoxide in methanol.

g) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (0.96 g, 28%) was obtained in the form of a solid dark brown color using 1-methyl-6-pyrrolidin-1-yl-1H-indole (1.60 g, 8 mmol) and hydrochloride isopropyl ester of 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid (2.24 g, 7.2 mmole).

d) 3-(6-Fluoro-1-methyl-1H-indol-3-yl)-4-(6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 6-pyrrolidin-1-yl-1H-indole hydrochloride and isopropyl ester of 2-(6-fluoro-1-methyl-1H-indol-3-yl)midinotate acid.

6-Pyrrolidin-1-yl-1H-indole was obtained as described below (stage D.-D.).

D.) a Mixture of 1-methyl-6-nitro-1H-indole (5.0 g, of 28.4 mmole) and 10% Pd/C (1.0 g) in ethanol (200 ml) and tetrahydrofuran (100 ml) was first made at atmospheric pressure for 14 hours, the Reaction mixture was filtered and concentrated, after crystallization from ether/hexane was obtained 1-methyl-6-amino-1H-indole (3.8 g, 80%).

D.) a Mixture of 1-methyl-6-amino-1H-indole (11 g, 83 mmole) and succinic anhydride (8,3 g, 83 mmole) in toluene (150 ml) was boiled under reflux for 1 h the Reaction mixture was cooled and evaporated, to receive solid (18,0). A mixture of the obtained solid (10.1 g) and sodium acetate (3,45 g, 42 mmole) in acetic anhydride (36 ml) was boiled under reflux for 15 minutes the Reaction mixture was cooled to room Tempe is atory, to the mixture was slowly added to ice water, stirred for 15 min and extracted with ethyl acetate/tetrahydrofuran. The combined organic extracts were washed with saline and dried over magnesium sulfate. The solvent is evaporated, to receive the crude product, which was purified by recrystallization from ethyl acetate/hexane, to receive (1-methyl-1H-indol-6-yl)pyrrolidin-2,5-dione (6.0 g).

D.) 1-(1-Methyl-1H-indol-6-yl)pyrrolidin-2,5-dione (3.8 g of 17.7 mmole) in tetrahydrofuran (75 ml) at room temperature was treated with lydialydia in tetrahydrofuran (88 ml, 1.0 M, 88 mmol) for 2 hours the Mixture was cooled, treated with an aqueous solution of sodium sulfate was extracted with ether, the organic layer was concentrated. The crude product was chromatographically on silica gel using 70% hexane/ethyl acetate, was obtained 6-pyrrolidin-1-yl-1H-indole in the form of a solid white color.

e) 3-(6-Chloro-1-methyl-1H-indol-3-yl)-4-(6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (1,2%) was obtained from 6-pyrrolidin-1-yl-1H-indole hydrochloride and isopropyl ester of 2-(6-chloro-1-methyl-1H-indol-3-yl)midinotate acid.

g) 3-(1-Methoxymethyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methoxymethyl-6-pyrrolidin-1-yl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-6-neither the ro-1H-indol-3-yl)midinotate acid.

1-Methoxymethyl-6-pyrrolidin-1-yl-1H-indole was obtained from 6-pyrrolidin-1-yl-1H-indole (example d) in the same way as described in example 1A), using as alkylating agent chloromethylmethylether ether.

C) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 3-(1-methoxymethyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (see above) boiling under reflux in a mixture of acetic acid and aqueous HCl. After treatment with water, the crude product was purified by chromatography on silica gel.

3-(1H-Indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained using 1-methyl-6-pyrrolidin-1-yl-1H-indole hydrochloride and isopropyl ether 2-[1-(2,2-dimethylpropyl)-1H-indol-3-yl]midinotate acid with the subsequent removal of the protective groups with sodium methoxide in methanol.

K) 3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (41 mg, 13%) was obtained using 1-methyl-6-pyrrolidin-1-yl-1H-indole (150 mg, 0.75 mmole) of the hydrochloride and isopropyl ether 1-methyl-3-indolinecarboxylic acid (200 mg, 0.75 mmole).

l) 3-(1-Methyl-1H-indol-3-yl)-4-[1-methyl-6-(4-methylpiperazin-1-yl)-1H-indol-3-yl]pyrrole-2,5-dione (256 mg, 67%) was obtained from 1-methyl-6-(4-methylpiperazin-1-yl)-1H-indole (192 mg, from 0.84 mmole), obtained as described in the ore 11a), and hydrochloride isopropyl ether 1-methyl-3-indolinecarboxylic acid (224 mg, from 0.84 mmole).

m) 3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-piperidine-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (56 mg, 28%) was obtained from 1-methyl-6-piperidine-1-yl-1H-indole (96 mg, 0.45 mmole) of the hydrochloride and isopropyl ether 1-methyl-3-indolinecarboxylic acid (120 mg, 0.45 mmole).

h) 3-(6-Fluoro-1-methyl-1H-indol-3-yl)-4-(1-methoxymethyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methoxymethyl-6-morpholine-4-yl-1H-indole hydrochloride and isopropyl ester of 2-(6-fluoro-1-methyl-1H-indol-3-yl)midinotate acid.

o) 3-(6-Fluoro-1-methyl-1H-indol-3-yl)-4-(6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(1-methoxymethyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione when removing protective groups by boiling with hydrochloric acid in THF, and then boiling in an aqueous solution of acetic acid.

p) 3-(1-Methyl-1H-indol-3-yl)-4-(6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-(4-methoxybenzyl)-6-morpholine-4-yl-1H-indole hydrochloride and isopropyl ether 1-methyl-3-indolinecarboxylic acid with the subsequent removal of the protective groups with sulfuric acid in triperoxonane acid.

Example 13

1-Methyl-3-[4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile

a) 1-Methyl-6-morpholine-4-yl-1H-indole (to 3.89 g, 18 mmol what th) was dissolved in CH 2Cl2(18 ml) and cooled to 0°C. Then was added methylchlorosilanes (2.4 ml, 26 mmol), there was observed a darkening of the solution, which was stirred at 0°C for 2 h and was added another portion of METHYLCHLOROSILANE (and 0.40 ml, 4.3 mmole). After 2 h the solvent is evaporated, the obtained solid was transferred into the ether, separated by filtration and thoroughly washed with ether, it was obtained the crude methyl ether (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)Glyoxylic acid (6 g).

b) the Crude methyl ether (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)Glyoxylic acid (6 g) in dioxane (300 ml) were placed in a round bottom flask with a volume of 500 ml, equipped with a reflux condenser and attached to the container with argon (through the top of the refrigerator). Through the system passed a current of argon, was added Pd/C (2 g, 10%), hydrate hypophosphite sodium (20 g) in water (50 ml) and boiled under reflux for 5 hours Then was added another portion of the hydrate hypophosphite sodium (10 g) in water (10 ml)was boiled under reflux for a further 3 h and cooled. A solid substance was separated by filtration and thoroughly washed with EtOAc. The filtrate was washed with saline and dried (MgSO4). After evaporation of the solvent and chromatography of the residue on silica gel using 20% EtOAc in hexane was obtained methyl ether (1-methyl-6-morpholin-yl-1H-indol-3-yl)acetic acid (2,79 g, 54%).

C) Methyl ether (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)acetic acid (2.67 g, 9,26 mmole) suspended in conc. NH4OH (20 ml) in a flask with a volume of 100 ml, flask was tightly closed and the mixture was stirred for 24 h the Mixture was transferred into a flask with a volume of 500 ml and was added another portion of NH4OH (80 ml). The flask is again tightly closed and stirred for another 24 hours Volatiles were removed under reduced pressure and after lyophilization received (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (2,39 g, 94%).

g) a Solution of tert-BuOK in THF (1 M, to 18.9 ml, 18.9 mmole) was added dropwise to a mixture of methyl ester (6-cyano-1-methyl-1H-indol-3-yl)Glyoxylic acid (1.85 g, of 7.64 mmole) and (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (1,74 g, 6,36 mmole) at 0°C. After 15 min the cooling bath was removed and the mixture was stirred at room temperature for 3 hours Then was added conc. hydrochloric acid (37%, 10 ml) and the reaction mixture was stirred for a further 30 minutes the Mixture was podslushivaet aqueous solution of NaHCO3and was extracted with CHCl3(3×500 ml). The combined organic extracts were washed with an aqueous solution of Na2CO3and dried (K2CO3). The extracts were filtered through a layer of silica gel, the solvent evaporated, the crude product was led from acetone/EtOAc, 1-methyl-3-[4-(1-methyl-6-morpholine-4-yl-1 is-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile (2,05 g, 69%) (see Faul M.M., Winneroski L.L., Krumrich S.A., J. Org. Chem., 63. 6053 (1998)).

Example 14

The following compounds were obtained in the same way as described in example 13. The original materials were obtained in the same way as described in the stages 13A), b) and C).

a) 3-(6-Methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (103 mg, 23%) was obtained from methyl ester (6-methoxy-1-methyl-1H-indol-3-yl)Glyoxylic acid (257 mg, the 1.04 mmole) and (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (259 mg, 0.95 mmole).

b) 3-(6-Fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (72 mg, 42%) was obtained from methyl ester (6-fluoro-1-methyl-1H-indol-3-yl)Glyoxylic acid (95 mg, 0.40 mmole) and (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (100 mg, 0.37 mmole).

C) 3-(6-Chloro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (96 mg, 83%) was obtained from methyl ester (6-chloro-1-methyl-4-1H-indol-3-yl)Glyoxylic acid (74 mg, 0.29 to mmole) and (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (67 mg, 0,245 mmole).

g) 3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (139 mg, 49%) was obtained from methyl ester (6-bromo-1-methyl-1H-indol-3-yl)Glyoxylic acid (190 mg, of 0.64 mmole) and (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (150 mg, 0.55 mmole).

d) 3-(1-Methyl-6-morpholine-4-yl-1H-indol-3-yl)-4-(1-methyl-6-trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione (11 mg, 54%) was obtained from methyl ester (1-methyl-6-trifluoromethyl-1H-indol-3-yl)Glyoxylic acid (172 mg, of 0.60 mol) and (1-methyl-6-morpholine-4-yl-1H-indol-3-yl)ndimethylacetamide (150 mg, 0.55 mmole).

e) 3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (49 mg, 46%) was obtained from methyl ester (6-bromo-1-methyl-1H-indol-3-yl)Glyoxylic acid (68 mg, 0,23 mmole) and (1-methyl-6-pyrrolidin-4-yl-1H-indol-3-yl)ndimethylacetamide (54 mg, of 0.21 mmole).

g) 3-(6-Methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (55 mg, 58%) was obtained from methyl ester (6-methoxy-1-methyl-1H-indol-3-yl)Glyoxylic acid (57 mg, 0,23 mmole) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)ndimethylacetamide (54 mg, of 0.21 mmole).

C) 3-(1-Methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-4-(1-methyl-6-trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione (67 mg, 35%) was obtained from methyl ester (1-methyl-6-trifluoromethyl-1H-indol-3-yl)Glyoxylic acid (111 mg, of 0.39 mmole) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)ndimethylacetamide (100 mg, of 0.39 mmole).

3-(6-Chloro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (70 mg, 37%) was obtained from methyl ester (6-chloro-1-methyl-1H-indol-3-yl)Glyoxylic acid (98 mg, of 0.39 mmole) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)ndimethylacetamide (100 mg, of 0.39 mmole).

Example 15

1-Methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile

a) M is tilby ether (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)acetic acid (360 mg, to 1.32 mmole) and NaOH (132 mg, 3.3 mmole) in methanol (8 ml) was boiled under reflux for 30 minutes, the Reaction mixture was cooled to 0°and acidified 1 N. HCl. The mixture was extracted with EtOAc (3×100 ml) and CH2Cl2(3×100 ml). The combined organic extracts were dried (MgSO4) and concentrated. After chromatography of the crude product on silica gel using 5-20% Meon in CH2Cl2received (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)acetic acid (241 mg, 71%).

Methyl ether (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)acetic acid was obtained in the same way as described in example 13 (a) and (b).

b) a Solution of oxalicacid in CH2Cl2(2 M, 1.6 ml, 3.2 mmole) was added dropwise to a solution of 6-cyano-1-methyl-1H-indole (360 mg, 2.3 mmole) in ether (5 ml). Stirring is continued at 0°C for 30 min, after which the cooling bath was removed. After 2 h was added another portion of 2 M solution of oxalicacid (0.2 ml, 0.4 mmole) and stirred at room temperature for a further 2 hours, the Solid was separated by filtration and was washed with ether, it was received (6-cyano-1-methyl-1H-indol-3-yl)Glyoxylic (450 mg, 79%) (see F. Troxler, Hamisch A., G. Bormann, F. Seemann, Szabo L., Helv. Chim. Acta, 51(1), 1616 (1968)).

C) 6-Cyano-1-methyl-1H-indol-3-Glyoxylic (260 mg, 1.05 mmole) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)acetic acid (241 mg, of 0.93 mmole) in CH Cl2(5 ml) was stirred at 0°C. Then was added triethylamine (0,41 ml, 2,95 mmole) and the mixture was stirred at room temperature for 16 hours the Solvent was removed in vacuo and to the residue was added toluene (10 ml) and napa-TsOH·N2O (0.35 g, of 1.84 mmole). After 2 h was added methanol (5 ml) and stirring continued until, until TLC (40% EtOAc/hexane) indicated the absence of starting material. The mixture was diluted with CH2Cl2(50 ml), washed with saturated solution of Na2CO3(3×50 ml). The aqueous layer was subjected to back extraction with CH2Cl2(2×50 ml). The combined organic extracts were dried (MgSO4) and evaporated, to receive 0,30 g solid purple color. After chromatography of the crude product on silica gel using 5%-20% EtOAc/hexane was obtained 1-methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydrofuran-3-yl]-1H-indole-6-carbonitrile (0,19 g, 45%) as a solid purple color.

g) 1-Methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydrofuran-3-yl]-1H-indole-6-carbonitrile (0.16 g, of 0.36 mmole) was dissolved in dry DMF (5 ml, dried over molecular sieves 3Å) in a round bottom flask with a volume of 50 ml To the mixture was added methanol (0.1 ml) and 1,1,1,3,3,3-hexamethyldisilazane (0.9 ml). The purple solution was stirred at room is the temperature during the night. Then added methanol (0,03 ml) and 1,1,1,3,3,3-hexamethyldisilazane (0,27 ml) and was stirred for 3 hours the Mixture was diluted with ethyl acetate (50 ml) and washed with saline. The aqueous layer was subjected to back extraction with ethyl acetate (2×50 ml). The combined organic extracts were diluted with an equal volume of hexane, dried (MgSO4) and was passed through a layer of silica gel. The silica gel was washed with ethyl acetate/hexane (1:1, 150 ml) and the filtrate was concentrated. After chromatography of the residue on silica gel using 25%-40% EtOAc/hexane was obtained 1-methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile (71 mg, 44%) as a solid purple color.

Example 16

3-(6-Methoxymethyl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 6-methoxymethyl-1-methyl-1H-indole and 1-methyl-6-morpholine-4-yl-1H-indole.

Example 17

3-[6-(2-Imidazol-1-ylethoxy)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione

a) a Solution of n-utility in hexane (1.6 M, 1.7 ml, to 27.2 mmole) was added to 6-bromo-1-methylindole (5.0 g, to 23.8 mmole) in dry THF (100 ml) at -78°C for 30 min in 30 min was added trimethylboron (2,93 g, 28.2 mmole) in dry THF (25 ml). Stirring was continued at -78°C for 30 minutes Then added methanol (12.5 ml) and water (12.5 ml) and the mixture was stirred at room the Oh temperature for 3 hours The mixture was diluted with ether (100 ml) and washed with sulfuric acid (1 ad, 2×100 ml) and water (2×100 ml). The aqueous layer was subjected to back extraction with ether (2×100 ml). The combined organic extracts were dried (MgSO4), filtered through a layer of silica gel, which was washed with ether (100 ml). The filtrate was concentrated and the crude product was chromatographically on silica gel using 10%-25% ethyl acetate/hexane, 1-methyl-1H-indole-6-Voronovo acid (2.6 g, 62.5 per cent).

b) 1-Methyl-1H-indole-6-Voronovo acid (1.4 g, 8.0 mmole) was dissolved in ether (25 ml). Then for 5 min was added hydrogen peroxide (15%solution, 6 ml) and the reaction mixture was stirred at room temperature for 1 h the Mixture was extracted with 1 N. NaOH (2×50 ml) and aqueous extracts were washed with ether (2×50 ml). The aqueous layers were cooled to 0°and acidified 6 N. HCl to pH 4.0. The mixture was extracted with ether (3×100 ml) and the organic extracts were washed with water. The organic extracts were dried (MgSO4), filtered through a layer of silica gel, which was washed with ether (100 ml). After concentration of the filtrate the residue was chromatographically on silica gel using 10%-20% ethyl acetate/hexane, 1-methyl-1H-indol-6-ol in the form of a solid yellow (0.56 g, 47%).

C) 1-Methyl-1H-indol-6-ol (0.36 g, of 2.45 mmole), 1-(2-hydroxyethyl)imidazole (0.35 g, 2,82 mmole) and triphenylphosphine (0,767 g of 2.92 mmole) was dissolved in dry THF in an argon atmosphere at -78°C. and Then for 2 min was added diethylazodicarboxylate (of 0.47 ml, 2,95 mmole) and the mixture was stirred at room temperature for 16 hours Then at -78°was added another portion of triphenylphosphine (0.7 g, to 2.67 mmole) and DEAD (to 0.47 ml, 2,95 mmole). The reaction mixture was stirred at room temperature for 24 h, diluted with ether (50 ml) and washed with water (2×50 ml). The aqueous layer was subjected to back extraction with ether (2×50 ml), the combined organic extracts were dried (MgSO4) and was evaporated. Crude oil red-orange color was passed through a layer of silica gel, which was washed with 10% methanol /methylene chloride (200 ml), to receive the oil red-brown color (3.15 g). After chromatography of the crude product on silica gel using 0-10% methanol/chloroform was obtained 6-(2-imidazol-1-ylethoxy)-1-methyl-1H-indole (0,19 g, 32%) as a thick brown oil.

g) 6-(2-Imidazol-1-ylethoxy)-1-methyl-1H-indole (185 mg, 0.77 mmole) was dissolved in CH2Cl2(2 ml) in an argon atmosphere at 0°C. To the solution was added oxalicacid (0,19 ml, 2.18 mmole) in CH2Cl2(2 ml). After stirring at 0°C for 4 h the mixture was evaporated and dried in vacuum for 2 hours To the obtained solid substance black is the hydrochloride was added isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid (239 mg, 0.77 mmole) and CH2Cl2(3 ml). To the mixture at 0°slowly added triethylamine (0,81 ml of 5.82 mmole) and stirred at room temperature for 16 hours the Mixture was evaporated to dryness and added methanol (5 ml) and 12 N. hydrochloric acid (1 ml). The mixture was heated at 80°C for 1 h After evaporation of the solvent was added ethyl acetate (50 ml) and the mixture is gently washed with 5%sodium bicarbonate solution (3×50 ml). The aqueous layer was subjected to back extraction with ethyl acetate (2×50 ml), the combined organic extracts were dried (MgSO4) and was filtered through a layer of silica gel, which was washed with 10% methanol/CH2Cl2(400 ml). The filtrate was concentrated and the crude product was chromatographically on silica gel using 1%-5% methanol/ethyl acetate, to receive a solid orange color. After further purification by dissolving the solid in hot CH2Cl2(3 ml) and precipitation in ether (20 ml) was obtained 3-[6-(2-imidazol-1-ylethoxy)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione in the form of a solid orange color (0,103 g, 26%).

Example 18

3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrimidine-5-yl-1H-indol-3-yl)pyrrole-2,5-dione

a) 1-Methyl-1H-indole-6-Voronovo acid (obtained as described in example 17B)) (0,86 g, 5 mmol) suspended in dry dioxane (20 m is) and was treated with 5-bromopyrimidine (1.0 g, 6.3 mmole), sodium carbonate (2.0 g) and tetrakis(triphenylphosphine)palladium (0) (120 mg, 0.10 mmole), the mixture was boiled under reflux for 16 h and cooled. Then the mixture was diluted with hexane (20 ml), filtered through celite and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate as solvent. 1-Methyl-6-pyrimidine-5-yl-1H-indole was led out of the ether.

b) 3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrimidine-5-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained from 1-methyl-6-pyrimidine-5-yl-1H-indole hydrochloride and isopropyl ether 2-(1-methyl-6-nitro-1H-indol-3-yl)midinotate acid.

Example 19

3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrimidine-5-yl-1H-indol-3-yl)pyrrole-2,5-dione was obtained as described in example 18, 1-methyl-6-pyrimidine-5-yl-1H-indole hydrochloride and isopropyl ether (1-methyl-3-indolinecarboxylic acid.

Example 20

The capsules are shown in table 2.

Table 2

No.Componentsmg/capsule
10 mg50 mg100 mg250 mg500 mg
1Example 12 g10,050,0100,0250,0500,0
2Water lactose154,0114,0148,042,082,0
3Starch 150025,025,040,040,070,0
4Talc10,010,010,015,020,0
5Magnesium stearate1,01,02,03,03,0
The total weight of the fillers200200300350675

Method get

1. Mix components 1, 2 and 3 in an appropriate mixer for 15 minutes

2. Skip the mixture obtained in stage 1, through the mill fitza low speed using sieves "00".

3. Add the adjusted number of components 4 and 5 and mix for 3 min in an appropriate mixer.

4. Fill in the powdery mixture obtained in stage 3, the capsules of the appropriate size.

Example 21

The composition of the tablets are shown in table 3.

Table 3

No.Componentsmg tablet
10 mg50 mg100 mg400 mg600 mg1000 mg
The core tablets
1Example 12 g10,050,0100,0400,0600,01000,0
2Anhydrous lactose177,0137,084,5279,579,5102,0
3Na+-crosscarmelose5,05,07,540,040,050,0
4Povidone K6,06,06,023,023,036,0
5Magnesium stearate2.02,02,07,57,5to 12.0
Mass of nucleus2002002007507501200
Film coating
6The hypromellose 6 cps-29103,03,03,06,09,0to 12.0
7Talc 1,51,51,53,04,56,0
8Titanium dioxide1,51,51,53,04,56,0
Total weight pills20620620675976824,0

Method get

1. Mix components 1, 2, 3 and 4 in the mixer with high shear for 5 minutes

2. To receive granules from a powder mixture obtained in stage 1, with purified water.

3. Dried granules obtained in stage 2, at 50°C.

4. To process the granules obtained in stage 3, the appropriate mill.

5. Add the adjusted quantity of the component 5 to the crushed granules obtained in stage 4, and mix for 5 minutes in a suitable mixer.

6. Compress the granules obtained in stage 5, on a suitable press.

7. Using appropriate air-spray system to cover core tablets obtained in stage 6, the suspension for film coating of the components 6, 7 and 8 in the treated water to the desired weight.

1. The compound of the formula

where

R1and R1'independently mean hydrogen or (ness.)and the keel, unsubstituted or substituted (ness.)alkoxy;

R2means hydrogen, nitro, cyano, halogen, (ness.)alkyl, unsubstituted or substituted with halogen, or (ness.)alkoxy,

R2'means thiazolyl, thiophenyl, isothiazolin, furanyl, pyrazolyl, which is unsubstituted or substituted (ness.)the alkyl, pyrimidinyl, the unsubstituted morpholinyl, the unsubstituted pyrrolidinyl, imidazolyl, which is unsubstituted or substituted (ness.)the alkyl, the unsubstituted piperidinyl or piperazinil, which is unsubstituted or substituted (ness.)the alkyl, or ethoxy, replaced by imidazolium; or

its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R2'means thiazolyl, thiophenyl, isothiazolin, furanyl, pyrimidinyl, imidazolyl, which is unsubstituted or substituted (ness.)the alkyl.

3. The compound according to claim 2, where at least one of R1and R1'means (ness.)alkyl.

4. The compound according to claim 3, where at least one of R1and R1'means methyl.

5. The compound according to claim 4, where R2'means thiophenyl.

6. The compound according to claim 5, selected from the group including

a) 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophene-2-yl-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophene-3-yl-1H-indol-3-yl)pyrrole-2,5-dione,

C) 3-(1-methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiophene-2-yl-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-1-methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiophene-3-yl-1H-indol-3-yl)pyrrole-2,5-dione.

7. The compound according to claim 4, where R2'means furanyl.

8. The connection according to claim 7, selected from the group including

a) 3-(6-furan-2-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(6-furan-2-yl-1-methyl-1H-indol-3-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione,

C) 3-(6-furan-2-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione.

9. The compound according to claim 4, where R2'means imidazolyl, unsubstituted or substituted (ness.)the alkyl.

10. The compound of claim 9 selected from the group including

a) 3-[1-methyl-6-(1-methyl-1H-imidazol-2-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(1-methyl-1H-imidazol-2-yl)-1H-indol-3-yl]pyrrole-2,5-dione,

C) 3-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-(1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione,

d) 3-(6-methoxy-1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione,

e) 3-[6-(1-ethyl-1H-imidazol-2-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-[6-(1H-imidazol-2-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione,

C) the hydrochloride of 3-[6-(3H-imidazol-4-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

3-(6-imidazol-1-yl-1-ethyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione,

K) 3-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

l) 3-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione,

m) 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione,

h) 3-[4-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1-methyl-1H-indole-6-carbonitrile,

o) 3-[1-methyl-6-(2-Mei-1-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

p) 3-[6-(1H-imidazol-2-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione.

11. The compound according to claim 4, where R2'means thiazolyl.

12. Connection claim 11, selected from the group including

a) 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiazol-2-yl-1H-indol-3-yl)pyrrole-2,5-dione and

b) 3-(1-methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiazol-2-yl-1H-indol-3-yl)pyrrole-2,5-dione.

13. The compound according to claim 4, where R2'means pyrazolyl, unsubstituted or substituted (ness.)the alkyl.

14. The connection 13, selected from the group including

a) 3-(1-methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrazole-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(1-Tawil-1H-indol-3-yl)-4-(1-methyl-6-pyrazole-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

C) 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrazole-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-[1-methyl-6-(2-methyl-2H-Piras the l-3-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

d) 3-(1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-yl]pyrrole-2,5-dione,

e) 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-yl] pyrrole-2,5-dione.

15. The compound according to claim 4, where R2'means pyrimidinyl.

16. The connection 15, selected from the group including

a) 3-(1-methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrimidine-5-yl-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrimidine-5-yl-1H-indol-3-yl)pyrrole-2,5-dione.

17. The compound according to claim 4, where R2'means isothiazolin.

18. The connection 17, selected from the group including

a) 3-(6-isothiazol-5-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(6-isothiazol-5-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione.

19. The compound according to claim 1, where R2'means the unsubstituted morpholinyl, the unsubstituted pyrrolidinyl, the unsubstituted piperidinyl or piperazinil, which is unsubstituted or substituted (ness.)the alkyl,

20. The connection according to claim 19, where at least one of R1and R1'means (ness.)alkyl.

21. Connection claim 20, where at least one of R1and R1'means methyl.

22. Connection item 21, where R2'means piperazine, unsubstituted or substituted (ness.)the alkyl.

23. Connection p.22, where R2'means 4-methylpiperazine.

24. Connection item 23, where the connection means 3-(1-methyl-1H-indol-3-yl)-4-[1-methyl-6-(4-methylpiperazin-1-yl)-1H-indol-3-yl]pyrrole-2,5-dione.

25. Connection item 21, where R2'means pyrrolidinyl.

26. Connection A.25 selected from the group including

a) 3-(1-methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(1-methyl-6-nitro-1H-indol-3-yl)-4-(6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

C) 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-(6-chloro-1-methyl-1H-indol-3-yl)-4-(6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

d) 3-(1-methoxymethyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

e) 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-(6-methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

C) 3-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-4-(1-methyl-6-trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione,

3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

K) 1-methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile,

l) 3-(1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione,

m) 3-(6-chloro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolic the n-1-yl-1H-indol-3-yl)pyrrole-2,5-dione.

27. Connection item 21, where R2'means piperidinyl.

28. Connection item 27 where the compound is 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-piperidine-1-yl-1H-indol-3-yl)pyrrole-2,5-dione.

29. Connection item 21, where R2'means morpholinyl.

30. The connection clause 29, selected from the group including

a) 3-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione,

b) 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

C) 1-methyl-3-[4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile,

g) 3-(6-methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

d) 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

e) 3-(6-chloro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

g) 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

C) 3-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)-4-(1-methyl-6-trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione,

3-(1,6-dimethyl-1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

K) 3-(1H-indol-3-yl)-4-(1-methyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

l) 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(1-methoxymethyl-6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

m) 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione,

h) 3-(1-methyl-1H-indol-3-yl)-4-(6-morpholine-4-yl-1H-indol-3-yl)pyrrole-2,5-dione.

31. The compound according to claim 1, where R2'means ethoxy, replaced by imidazolium.

32. Connection p, where at least one of R1and R1'means (ness.)alkyl.

33. Connection p, where at least one of R1and R1'means methyl.

34. Connection p, which is 3-[6-(2-imidazol-1-ylethoxy)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione.

35. The pharmaceutical composition inhibiting cell proliferation at the G2/M-phase, comprising as active ingredient an effective amount of a compound according to any one of claims 1 to 34 and a pharmaceutically acceptable carrier or excipient.

36. The pharmaceutical composition according p suitable for parenteral administration.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to derivatives of piperazine and piperidine of the formula (I): wherein ---Z represents =C or -N; Q means benzyl or 2-, 3- or 4-pyridylmethyl that can be substituted with one or more substitutes taken among group comprising halogen atom, cyano-group, (C1-C3)-alkoxy-group, CF3, OCF3, SCF3, (C1-C4)-alkyl, (C1-C3)-alkylsulfonyl and their salts, and to a method for their preparing also. It has been found that these compounds elicit valuable pharmacological properties owing to combination of (partial) agonism with respect to members of dopamine receptors subtype and affinity with respect to corresponding serotonin and/or noradrenergic receptors and can be useful in preparing compositions used in treatment of fear and/or depression or Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 3 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of azole of the formula:

wherein R1 represents (1) halogen atom; (2) nitrogen-containing 5- or 6-membered heterocyclic group comprising from 1 to 4 nitrogen atoms as atoms of ring system in addition to carbon atoms, and group with condensed rings comprising nitrogen-containing 5- or 6-membered heterocyclic group comprising 1-2 nitrogen atoms as atoms of ring system in addition to carbon atoms, and benzene ring wherein nitrogen-containing 5- or 6-membered heterocyclic group and group with condensed rings can comprise optionally from 1 to 3 substituted taken among group consisting of: (i) aliphatic hydrocarbon group comprising from 1 to 15 carbon atoms; (ii) (C6-C14)-aryl group, and (iii) carboxy-group that can be in form of group of (C1-C6)-alkyl ester wherein above indicated substitutes (i)-(iii) can have from 1 to 3 substituted additionally taken among group consisting of: (a) carboxyl group and (b) hydroxy-group; (3) (C1-C10)-alkylsulfanyl group that can be substituted with hydroxy-group; (4) heteroarylsulfanyl group taken among pyridylsulfanyl, imidazolylsulfanyl and pyrimidinylsulfanyl, or (5) amino-group that can be mono- or di-substituted optionally with substitutes(substitutes) among group consisting of: (i) (C1-C10)-alkyl group that can be substituted with hydroxy-group, and (ii) (C7-C10)-aralkyl group; Ab represents aryloxy-group that is substituted with alkyl group and can be substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl group, hydroxy-group or (C1-C6)-alkylcarbonyloxy-group additionally; B represents (C6-C14)-aryl group or thienyl group each of that can has optionally from 1 to 4 substitutes taken among halogen atom, (C1-C6)-alkoxy-group and (C1-C6)-alkyl group that can has optionally from 1 to 3 halogen atoms; Y represents saturated aliphatic bivalent group with direct or branched chain and having from 1 to 7 carbon atoms, or to its salt. Also, invention relates to a pharmaceutical composition that elicits activity for promoting production/secretion of neurotrophine, and to methods for prophylaxis and treatment based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used for prophylaxis and treatment of neuropathy.

EFFECT: improved and valuable medicinal properties of agent, improved methods for treatment.

19 cl, 1 dwg, 5 tbl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, chemical technology, explosive substances.

SUBSTANCE: invention relates to a method for preparing 4,4'-bis-[4-aminofurazan-3-yl-N(O)N-azoxy]-3,3'-azofurazane of the general formula (1):

that is a new thermostable explosive substance with improved exploitation indices. Method for preparing compound of the formula (1) involves treatment of 4,4'-diaminoazoxyfurazane with potassium bromate solution (KBrO3) in hydrochloric acid medium or its mixture with organic acid. Proposed compound can be used as a component of explosive compositions, solid rocket fuels and power-consuming compositions of different designations exploited at elevated temperatures (for example, in blast-hole drilling in depth mines).

EFFECT: improved preparing method, valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

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