Indeliberately derivatives of sugars, containing pharmaceutical composition and method of inhibiting the growth of tumors

 

(57) Abstract:

This invention relates to new indeliberately derivatives of sugars General formula I, where R1and R1Adenote hydrogen or a group hexose formula, provided that one of R1and R1Adenotes hydrogen and the other is not hydrogen; R2and R'2independently represent hydrogen, HE; R3and R'3independently represent hydrogen, HE; R4and R'4independently represent hydrogen, HE, azido, NH2halogen; R5, R'5, R5independently represent H, HE, azido, NR9R10, halogen, C(O)Ra, SR, OSO2Rc, or, or together form =O, provided that R2, R3, R4, R5and R'2, R'3, R'4, R'5and R5all are not simultaneously hydrogen, R represents hydrogen, C1-7alkyl, heterocyclic 6-membered ring containing 1 or 2 nitrogen atom as heteroatoms, and specified WITH1-7the alkyl may be substituted by phenyl; Ra represents IT; Rc denotes a1-7alkyl; R6denotes hydrogen, C1-7alkyl, HE, NH2and specified WITH1-7the alkyl may be substituted by phenyl, which in turn may be substituted WITH1-71X'1, X2and X'2independently denote H, halogen, -CN, -C(O)Ra, provided that X'1, X2and X'2are not 1,11-dichloro, and provided that when X2and X'2indicates each H, X1and X'1each independently denotes H or halogen, R1means hexose, R7and R8together represent About each of R2, R5and R4IT denotes, R'2, R'3, R'4, R'5and R5each denotes H, Q indicates NH, and then each of R3and R6is not NH2and R3is not methoxy when R6represents H; W represents S; Q represents NH, O or S; or its pharmaceutically acceptable salt. The compounds of formula I exhibit activity against topoisomerase-1 and is suitable for inhibiting the proliferation of tumor cells, showing anti-tumor effect is also described pharmaceutical composition and method of inhibiting tumor growth. 3 C. and 15 C.p. f-crystals, 5 PL.

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I. the Scope of the invention

II. Description of the prior art

Indolo[2,3-a] carbazole alkaloids, such as rebeccamycin (U.S. patent N 4487925 and 4552842) and its water-soluble clinically active analogue, 6-(2-detramental)rebeccamycin (1) (U.S. patent N 4785085) are effective antitumor agents acting on DNA.

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Topoisomerases are viable nuclear fragments that solve topological dilemmas in DNA, such as neokrashivanija, twisting and education chains, which typically occur during replication, transcription, and possibly other processes in DNA. These enzymes allow the DNA to relaksiruet through the formation of filament breaks with enzyme bridges, which act as an unstable passages or main points for the passage of other DNA strands. Drugs that act on topoisomerase affect this reaction gap connection in DNA topoisomerases. In the presence of active towards the topoisomerase agents intermediate product called "rapeutic to cell death. Therefore, expansion of the active towards the topoisomerase I agents provides a new approach in therapeutic Arsenal used in the clinic for cancer treatment. In an article in Cancer Chemother. Pharmacol (1994), 34 (suppl): S 41 - S 45 discusses active against topoisomerase I compounds studied in clinical studies discovered that these agents are effective clinical anticancer agents. Structurally these clinical agents belong to camptothecin alkaloids (2)

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Camptothecin

In European patent documents 0545195 B1, published on November 22, 1995, and 0602597 A2, published on 22 June 1994, and in articles in Cancer Research 1993, 53, 490-494 and 1995, 55, 1310-1315 described indolo[2,3-a]carbazole derivatives (3) belonging to the class rebeccamycin with antitumor activity; however, the main mechanism of action may be different from the action of camptothecin. Camptothecin operate on the mechanism of topoisomerase 1. In the application WO 95/30682 also described indolocarbazole, related to the connection (3) and with antitumor activity.

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Hudkins, etc. in WO 96/11933, published on 25 April 1996, and in the corresponding U.S. patent N 5475110 described a number skondensirovavshajasja (HUT), about the inhibition of some compounds of protein kinase C (PKC). In U.S. patent N 5468849 describes some analogues Torrevecchia useful as anticancer agents, as well as the way they are received by feeding the analog percription strain of Saccharothrix aerocolonigenes, preferably Saccharothrix aerocolonigenes C38,383-RK2 (ATCC 39243), producing rebeccamycin.

Glicksman and others in the U.S. patent N 5468872 described indolocarbazole alkaloids, which differ in structure from the compounds of the formula I according to this invention.

Kojiri and others in WO 96/04293, published February 15, 1996, described indeliberately containing disaccharide glycosides Deputy, which differs from our aminosilane sugars.

In the prior art and the above sources give no information about the new the cytotoxic amino sugar and other indeliberately derivatives of sugars, some of which are active with respect to the topoisomerase-I, described in this invention.

The invention

The purpose of this invention is to create a new indeliberately derivatives of sugars that inhibit the proliferation of tumor cells, some of these derivatives have is her invention relates to new antitumor compounds of General formula I or their pharmaceutically acceptable salts

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where R1and R1adenote hydrogen or a group hexose formula (B)

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provided that one of R1and R1adenotes hydrogen and the other is not hydrogen;

R2and R'2independently represent hydrogen, OH;

R3and R'3independently represent hydrogen, OH;

R4and R'4independently represent hydrogen, OH, azido, NH2, halogen;

R5, R'5, R5independently represent H, OH, azido, NR9R10, halogen, C(O)Ra, SR, OSO2Rc, Or, or together form =O;

provided that R2, R3, R4, R5and R'2, R'3, R'4, R'5and R5all are not simultaneously hydrogen,

R denotes hydrogen, C1-7alkyl, heterocyclic 6-membered ring containing 1 or 2 nitrogen atom as heteroatoms, with the specified C1-7the alkyl may be substituted by phenyl;

Rarepresents OH;

Rcrepresents C1-7alkyl;

R6denotes hydrogen, C1-7alkyl, OH, NH2and the specified C1-7the alkyl may be substituted by phenyl, which in turn may be substituted C1-7by alkyl;

R7and R8together represent O;

R9T cyclic 6-membered non-aromatic ring, containing one or two heteroatoms selected from the group N, O;

X1X'1X2and X'2independently denote H, halogen, -CN, -C(O)Raprovided that X'1X2and X'2are not 1,11-dichloro, and provided that when X2and X'2indicates each H, X1and X'1each independently denotes H or halogen, R1means hexose, R7and R8together represent O, and each of R2, R5and R4represents OH, R'2, R'3, R'4, R'5and R5each denotes H, Q indicates NH, and then each of R3and R6is not NH2and R3is not methoxy when R6denotes H.

W represents C;

Q represents NH, O or S;

or its pharmaceutically acceptable salt.

Another aspect of the present invention relates to a method of inhibiting the growth of tumors in a mammal which consists in the introduction of the latest inhibiting tumor growth in the number of compounds of formula I.

Another aspect of the invention provides a pharmaceutical composition, which comprises an antitumor effective amount of the compounds of formula I in combination with odnim">

Detailed description of the invention

This invention provides a new amino sugar and related derivatives introperative and their salts, some of which are agents with respect to the topoisomerase-I. These compounds suitable for inhibiting the proliferation of tumor cells and antineoplastic action.

In this description, unless otherwise specified and are not meant to be used the following definitions. The numbers in the index refer to the carbon atom C denote the number of carbon atoms, which may contain specific group. For example, C1-6means a linear or branched saturated carbon chain containing from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert. butyl, n-pentyl, Deut.pencil, isopentyl and n-hexyl. Depending on the context, C1-6may also refer to C1-6alkylene that connects two groups; examples include propane-1,3-diyl, butane-1,4-diyl, 2-methyl-butane-1,4-diyl etc. C2-6alkenyl means a linear or branched carbon chain containing at least one carbon-carbon double bond and containing the l and hexenyl. Depending on the context2-6alkenyl may also refer to C2-6alcindoro connecting two groups; examples include ethylene-1,2-diyl (vinile), 2-methyl-butene-1,4-diyl, 2-hexene-1,6-diyl etc. C2-6quinil means a linear or branched carbon chain containing at least one carbon-carbon triple bond and containing from two to six carbon atoms; examples include ethinyl, PROPYNYL, butynyl and hexenyl.

"Aryl" means an aromatic hydrocarbon radical containing six to ten carbon atoms; examples include phenyl and naphthyl. "Substituted aryl" means aryl, an independent substituted by one to five (preferably one to three) groups selected from C1-6alkanoyloxy, hydroxy, halogen, C1-6of alkyl, trifloromethyl, C1-6alkoxy, aryl, C2-6alkenyl, C1-6alkanoyl, nitro, amine, cyano, azido, C1-6alkylamino, di-C1-6alkylamino and aminogroup. "Halogen" denotes fluorine, chlorine, bromine and iodine; fluorine is preferred.

"Heteroaryl" means a five - or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples gelil, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazini etc.

Compounds according to the present invention have the General formula

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where R1refers to a group of hexose formula (B)

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Preferred compounds of formula I are compounds in which R1or R1aall the substituents denote H, in addition to R2, R3and R4each represents OH, and R5denotes NR9R10.

Other preferred compounds of formula I are compounds in which R1or R1aall the substituents denote H, in addition to R2, R3and R5each represents OH and R4denotes NH2.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R2, R3and R4, each of which denotes OH, and R5denotes halogen.

Other preferred compounds of formula I are those in which R7and R8taken together, represent o

Other preferred compounds of formula I Java preferred compounds of formula I are compounds, have the specified halogen is fluorine.

Other preferred compounds of formula I are those in which Q denotes O, S or NH.

Other preferred compounds of formula I are those in which R2, R3and R5each represents OH; and R4denotes NH2, halogen or N3.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R5, R3and R4, each of which denotes OH and R2denotes halogen.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R2and R3, each of which represents OH; R5denotes halogen; and R4indicates azido, NH2or OH.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R2and R3, each of which represents OH; R5denotes halogen and R4denotes halogen or H.

Other preferred compounds of formula I are connected denotes hydrogen or hydroxy; R4denotes hydrogen, halogen or azido; and R5denotes hydroxy, azido, halogen or NR9R10.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R3and R4, each of which denotes hydrogen or hydroxy; R2denotes hydrogen and R5denotes hydroxy, azido, halogen or NR9R10.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R3and R5, each of which denotes hydrogen or hydroxy; R2denotes hydrogen, and R4denotes hydroxy, azido, halogen or NH2.

Other preferred compounds of formula I are those, in which R1or R1aall the substituents denote H, in addition to R2and R4, each of which denotes hydrogen or hydroxy; R3denotes hydrogen and R5denotes hydroxy, azido, halogen or NR9R10.

Pharmaceutically acceptable salt and/or solvate of the compounds of formula I are also covered by this invention which also includes STI formula I, and anomers, which are formed due to the stoichiometry of R1.

Compounds according to this invention can exist in the form of pharmaceutically acceptable salts. These salts include the salts of the accession of inorganic acids such as hydrochloric and sulfuric acids, and organic acids such as acetic, citric, methansulfonate acid, toluensulfonate acid, tartaric and maleic acid. In addition, the compounds according to the invention contain an acidic group, the latter can exist in the form of salts of alkali metals, for example, potassium salt and sodium salt; salts of alkaline earth metals such as magnesium salt and calcium salt; and salts with organic bases, for example, ethylammonium salt and arginine salt.

Compounds according to this invention are useful pharmacological agents with antitumor properties. In recent years there have been numerous reports in which it is assumed that the role of drugs acting on the topoisomerase-I, consists in the stabilization of the covalent complex with DNA-topoisomerase-I by getting involved with enzyme admonitive DNA fragments. From a pharmacological point of view, there are advantages of Vlatko assumes independence of its functions from the growth rate of cells and secondly, active in relation to the topoisomerase-I agents can be effective in the process of slow growth and proliferation of tumor cells. It has been shown that cells from tumors of the colon contain a higher intracellular concentration of topoisomerase-I than normal mucosal cells, suggesting the possibility of selective cytotoxic advantages. Thus, the inhibition of proliferation of tumor cells by compounds of the formula I originally was shown by the effective inhibition of topoisomerase-I. Selective compounds of formula I, usually have EC50 values less than 10 μm in the analysis of topoisomerase-I, were also tested in the inhibition of proliferation of tumor cells in human/mouse. Compounds according to the invention were studied for their therapeutic effect in vivo on tumor (P388) in mice, the results are shown in the following examples, pharmacological test (table 1).

In vivo antitumor efficacy

The vivo tests started with implantation mice (BDF1 or CDF1) leukemia cells 10(6) P388 intraperitoneally. Treatment was started one day after implantation by intraperitoneal administration of a certain dose of one ray, which was administered the same dose, parallel control groups of patients with leukemia mice were eight to ten mice. Assessment activity carried out on the basis of comparisons of the mean survival time (MST) mice, which were injected medication (T) with a mean survival time of control mice (C). Activity was determined as % T/C > or = 125%, was calculated by equation MST(T)/MST(C) 100 = % T/C

The activity of topoisomerase I (in vitro)

The activity of topoisomerase I, was defined as follows. The method of determination included the formation of single-stranded fragments in DNA induced by topoisomerase I, which is described Hsiang and others, J. Biol. Chem. 260: 14873-14878 (1985). The samples were dissolved in 100% DMSO, receiving or 10 μm, or 10 mg/ml solutions, if not otherwise stated, which was diluted in Tris-EDTA buffer. Marine bacteriophage PM2 DHK (Boehringer Mannheim) was also diluted in Tris-EDTA buffer to a concentration of 0.02 μg/μl. Various solutions of the test compounds was mixed with the diluted DNA and the mixture was added to 1000 units (one unit of enzyme activity represents the amount that can relaksiruet 100 ng overspilling DNA in approximately 30 min at 37oC) aliquot samples of purified human topoisomerase I (Topogen) 2X reaction buffer for the beginning of the reaction. Gernam solution containing sodium dodecyl sulphate and proteinase K (Sigma). This mixture was kept at 37oC for another 10 min, after which the mixture was removed from the water bath and were extracted with a mixture of 24: 1 chloroform/isoamyl alcohol. After centrifugation an aliquot of the aqueous phase is placed in the wells of 0.9% agarose (Sea Kem) gel in Tris-borate buffer containing 0.5 µg/ml of ethidium bromide and subjected to electrophorese for 15 hours to separate the different topological isomers and "nicks" and DNA fragments. After bleaching gel in water, the reaction products of the DNA bromide stained by ethidium, were subjected to imaging irradiation of the gel with UV light. Negatives of photographs of the irradiated gels were scanned by a densitometer and determined the area under the peaks in order to obtain the formation of single-stranded DNA fragments in percent for each sample. For each compound was determined by the mean effective concentration (EC50) by interpolating between the points obtained dose - efficiency curve, which determines the potency of the compound for its effect on the formation of single-stranded DNA fragments mediated by topoisomerase I.

The activity of selected compounds according to the invention in relation to the topoisomerase I is shown in table II.

the, is provided in table II, show excellent activity against topoisomerase-I, even in submicromolar range of concentrations. However, a priori this activity is unexpected and unpredictable for professionals, because a small change in the structure of substitution leads to a completely unexpected change of activity. This is illustrated by the different values of the compounds obtained in examples 18 and 19, with respect to the topoisomerase-I. Connection example 19 is an effective antitumor agent with submicromolar activity against Toro-I, while the compound from example 18 does not detect activity against Toro-I at a concentration of, even exceeding 100 micromol. The only difference between the compounds in examples 18 and 19 is that in the connection example 18 X1and X'1denote 2,10-debtor and R6denotes the amino group, and the compound from example 19 X1and X'1means 3,9-debtor and R6denotes hydrogen. Moreover, rebeccamycin, in which X1and X'1means 1,11-dichloro, R4denotes methoxy, and R5denotes hydroxy, is also not active against Toro-I.

Oprean line of human colon were defined as follows.

Cytotoxicity was determined in HCT116 cells carcinoma human colon using Templ (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] -2H - tetrazole hydroxide, as described in the literature, Scudiero DA, Shoemaker RH, Paul, KD, Monks, A, Tiermey, S, Nofziger, TH, Currens, MJ, Seniff, D, and Boyd, MR. Evaluation of the effect of soluble tetrazole/formosana on cell growth and sensitivity to medications in culture using cell line human tumor and other tumors was conducted in accordance with the procedure described in Cancer Res. 48: 4827-4833, 1988. Cells in the amount of 4000 cells/well were placed into tablets with a 96-well plate and after 24 hours, add drugs and diluted. Cells were cultured at 37oC for 72 h, then was added tetrazolium dye Templ containing finishingtouches. The enzyme dehydrogenase in viable cells restores Templ to a form that absorbs light at 450 nm, which can be quantified by spectrophotometry. The greater the absorbance, the greater the number of viable cells. The results are expressed as IC50, the concentration of drug required to inhibit cell proliferation (i.e., the absorbance at a wavelength of 450 nm) by 50% compared with control cells.

Respect the present invention relates to compounds of formula I or its pharmaceutically acceptable salt or MES to a mammal, which implanted tumors or prone to cancer. In General, the connection will be injected dose in the range of from about 0.01 mg/kg to about MTD (maximum tolerated dose). Although the dose, mode and frequency of introduction of the compounds of formula I in each case should be carefully selected taking into account the skills of the physician and the patient's age, weight and condition, the route of administration and the nature or the extent of spread of cancer. The term "system introduction" used in this description, refers to oral sublingual, Transbaikalia, transnasal, transdermal, rectal, nutrientrelated, vnutriobolochechnoe and subcutaneous methods of introduction. In accordance with clinical practice, preferably compounds in such amounts that will ensure the effective beneficial effects without causing harmful or unwanted side effects.

Description of the specific forms of embodiment of the invention

Method of producing compounds of the formula I is shown in Scheme I, and retrieving key/intermediate compounds in Scheme II.

In Schemes I and II, R2-R6X1X2X'1X'2and Q above. PQ denotes si is, for example, acyl group such as acetyl, or trifluoracetyl arylalkyl group, such as benzyl, etc., are Appropriate "protective" or "blocking" groups used in organic synthesis well known in the art and described in the literature. See, for example, Theodora Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York. The original substances in Scheme I are dihaloalkanes derivative (II), such as 3,4-dibromomalonamide; and the corresponding indole derivatives of the formula III. Adding derivatives of indole III (R = H or Ar) to maleimide II in the presence of a base, such as ethylmagnesium or etc., in the environment of organic solvents such as THF (tetrahydrofuran), benzene or toluene or mixtures thereof at temperatures from -20oC to temperature phlegmy leads to the formation of mono - and besprovodnyh V and IV respectively. The number of reagents can be changed by varying the ratio of V to IV in any direction. The intermediate compound VI can then be turned into intolorable compound VI in conditions of oxidative cyclization, such as dicyandiamide (DDQ)/acid/heat or palladium acetate/acid or iodine, light, etc., Glycosylation VI reactive proizvoditeli and others, in the presence of an appropriate base, such as diisopropylethylamine, hexamethyldisilazide, with the formation of mono - or di - or trunion indiaparenting compounds VI in an organic solvent type, THF, DMF (dimethylformamide), dioxane, benzene, dimethyl ether (i.e dimethoxyethane) results in a fully protected derivative VIII. In addition, more preferably glycosylation by reacting 1-hydroxycodone corresponding protected derivative of sugar from a structure VI in a well-known reaction conditions, Mitsunobu [PPh3] /dialkyldithiocarbamate] in the environment of the ether solvent type THF or chlorinated solvent type CH2Cl2. The corresponding derived sugar for glycosylation can be obtained by selective modification of the various hydroxyl groups using known methods. For example, in an article in J. Carbohydrate Chemistry (1995), 14, p. 1279-94 described derivative of 6-halogen-6-deoxyglucose. Another method of obtaining compounds VIII includes glycosylation of monoadduct first, in the conditions described above, with the formation of intermediate compounds VII and subsequent dehydrohalogenation and cyclization as described the Council of the solution VII in solvents such as dioxane, ethanol or a mixture of solvents. Compound VIII is protected form the compounds of formula I. the Choice of protective groups in the Sahara allows selective manipulation of the primary hydroxyl group. For example, when the primary 6'-hydroxyl group is protected p-methoxybenzyl protecting group (PMB), and the remaining hydroxyl was protected only by a simple benzyl group (Bn), specialists can remove the PMB group without removal of the protecting benzyl groups. Thus, the primary 6'-hydroxyl group is oxidized to form the corresponding acid and its ester and amide derivatives. Further, under controlled oxidation conditions using reagent dess-Martin or similar, the 6-hydroxyl group is oxidized to the corresponding aldehyde. Treatment of the aldehyde is well known fluorinating reagent type DAST led to a 6-deformational derived. Similarly, other modified hydroxyl group. For example, the 4-hydroxyl group derived galactose (exony sugar in the pyranose form, in which the 4-hydroxyl directs axial position) can be used to modify the 4-position. Oxidation of the 4-hydroxyl group is protected properly pray derivatives, including 4-ftoroproizvodnykh, using known methods. If the 4-hydroxyl group is activated, for example, in the case of 4-nelfinavir, it can undergo nucleophilic substitution agents, for example, azide (e.g. sodium azide) to obtain 4-azido derived. On the other hand, when sugar derived from unprotected 4-hydroxyl group is treated fluorinating agent, DAST, receive a 4-ftoroproizvodnykh. In this way also selectively modified other hydroxyl group. For example, modification by known literature methods allows you to enter a fluorine atom at the 2-position of the sugar (Bioorg. Med. Chem., vol. 5, N 3, p. 497-500 (1997)). This is shown in example 90. Simple manipulation with a protective group, such as hydrogenation or transfer hydrogenation in the presence of a catalyst Perlman, for removal of the benzyl protective groups in fragments of sugar or, if necessary, hydrolysis of KOH or NaOH group protecting the nitrogen maleimide, obtaining anhydride after treatment with acid, followed by heating with the appropriate amine will lead to the desired compound of formula Ia with the correct structure replacement. Selective derivatization of each hydroxyl group in fragments sugar soedineniya hydroxyl, in the presence of groups, protecting the secondary hydroxyl group. For example, when the compound of the formula Ia in glucopyranosyloxy form (namely, hexose formula (B)), where all the hydroxyl groups of sugar free, processed silyl reagent type trimethylsilyl or tert.butyl diphenylsilane or, preferably, tert.butyl-dimethylacrylate in the presence of a base in a solvent of the type CH2Cl2or THF in the cold or at room temperature, to obtain a derivative in which the 3 - and 6-positions are protected in the form of cyrilovich esters. Selective removal protection 6-salelologa ether can be achieved in controlled conditions in the presence of aqueous mineral or organic acid, for example, a mixture triperoxonane acid and water as a solvent at low temperature, for example, in the range from -25oC and 0oC during the period of time from 30 minutes to 3 hours or until until the reaction is complete as evidenced by thin layer chromatography. This intermediate compound is subjected to further derivatization at the 6-position to activate the 6-hydroxyl in tsepliaeva group, type nelfinavir or halide. Otherwise, selective metilirovanie primary 6-hydroxyl group of mo is the Achar is not protected, in pyridine and in the presence of methylchloride in pyridine at 0oC.

Nucleophilic substitution of the corresponding amine or other nucleophilic agents type of azide to amine will produce the desired compounds of formula I, such as 6'-amino sugar Ib. In this way there was obtained 6-methylsulfone derived with the use of sodium salt Colnago derived or thiol and substrate type K2CO3in DMF or organic amine type triethylamine or cause Gunga at temperatures varying from room temperature up to 150oC. 6-alkylsulfate, for example, 6-metilsulfate, then oxidized known oxidants type Oksana or m-chloroperbenzoic acid or, preferably, magnesium salt monoperoxyphthalic acid (MMPP) to their sulfide and sulfone in controlled conditions. Like the other hydroxyl group can be derivateservlet, if this is desirable. Another modification of the compounds of formula I leads to N-maleimide substituted (namely, R6) indeliberately derived Ic. For example, the anhydride obtained by hydrolysis using a base suitably protected forms of compounds of formula I, can be subjected to wsimages the Hema II, N-substituted maleimide derivative can be obtained either directly from dialogmessage anhydride and its processing corresponding amino derivatives, or halogenoalkanes of maleimide with subsequent alkylation. Source indole derivatives having no substituents in 2-position, can be obtained by the known methods and 2-arylindole can be obtained from arylmethylidene by a well-known method of Fischer obtain indoles.

Compounds that constitute this invention and their methods of obtaining will become more clear from the following examples which are given for illustration only and in no way limit the scope of the invention.

Some of the intermediate compounds, as well as other conventional raw materials, for example, II, III and IX, is used to obtain the final products of formula I are usually industrially available. Examples of some of the final compounds of formula I (where R1all substituents are hydrogen unless otherwise specified) is shown below. Also described methods of synthesis of some intermediate compounds, for example, in examples 1-11, 14, 91-96, 98-102, 104, and 105.

All reactions carried out in the absence of water, Pravoberezhnaya solvents. Column chromatography was performed using silica gel 60 (E M Science, 230-400 mesh mesh.) and the above-mentioned solvents as the eluent. Thin-layer chromatography was performed on silikagelevye plates Anatech GFLH or Whatman MK6F. The melting points were determined in open capillary tube with the help of the device Thomas-Hoover to determine the melting temperature, unless otherwise specified, and are not corrected. Infrared spectra were taken using a spectrophotometer Perkin-Elmer 1800 Fourier in the form of thin films or KBr pellets.1H NMR spectra and13C NMR spectra were recorded on instruments Bruker AM-300 or JEOL 300 or Bruker AC-300 or 500 Megahertz devices, spectra are given in parts per million (ppm or using the aforementioned solvent as an internal standard. Constant interaction is expressed in Hertz and the signals displayed as the observed singlet (s), triplet (t), Quartet (q), multiplet (m) and broad (br). Mass spectra of low-grade resolution was determined by mass spectrometer Finnigan Model 4500 Quadrapole by direct chemical ionization (DCI) with the use of isobutane as a positive CI gas, Finnigan instrument Model SSQ-70000 (the negative. or position. ESI), or on a Kratos MS-25, or on the device Finnigan TSQ-70 (FAB). Mass spectra of high degree whom I in glycerol as a reference or device Finnigan MAT-900 using electrospray ionization with polypropylenglycol as a reference.

Example 1

3,4-Dibromomalonamide (II; R6= H, y = Br).

To stir magnetic stirrer, the solution maleimide (25,0 g, 0,258 mol) in deionized water (250 ml) was quickly added bromine (100 g, 0,626 mol) and then benzoyl peroxide (300 mg). The reaction mixture is heated at 50oC for 6.5 hours and then stirred at room temperature for 11.5 hours. The reaction mixture is cooled in a bath with a mixture of ice/water for 45 min and separated solid precipitate is filtered off, washed with water and dried in air to obtain 36,35 g (55.4 per cent) of the above compound as a white solid, 75 MHz13C NMR (acetone-d6): 165,08, 130,73; FAB mass spectrum, m/e 253 (M+); Anal. Calc. C4HBr2NO2: C, 38,30; H, Is 2.05; N, 4,06; Br, 46,32. Found: C, 38,28; H, 2.06 To; N 4,07; Br, 46,24.

Example 2

1-(tert. Butylbenzyl)-3,4-dibromomalonamide (II; R6= tert.butylbenzyl, y = Br).

To stir magnetic stirrer, a solution of 3,4-dibromomalonamide (20,0 g, 78.5 per mmol) in acetone (1200 ml) is added potassium carbonate (132 g, 0,954 mol). 4-(tert. Butyl)benzylbromide (24,98 g, 20.2 ml, 110 mmol) is added slowly over 15 min and then the reaction mixture was stirred in the dark for 6 hours. The reaction mixture was filtered through a layer of celite and probabililty network of 22.5 g (71,5%) of the above compound as a white solid. 300 MHz1H NMR (CDCl3): 7,45-7,25 (m, 4H), and 4.75 (s, 2H), 1,32 (s, 9H); DCl mass spectrum, m/e 399 (M+); Anal. Calc. C15H15Br2NO2: C, 44,92; H, OF 3.77; N, 3,49. Found: C, For 45.04; H, 3,81; N, 3,38.

Example 3

2-(2-Benzo[b] thienyl)-5-fluoro-1H-indole (III: X1-5F; X2= H; R" = 2-benzo[b]thienyl, R' = H)

n-Utility in hexane (1,6 M, 255 ml of 0.41 mol) is added in portions of 5 ml to a chilled (4oC) the solution tianeptine (of 47.8 g of 0.36 mol) in a mixture of dry tetrahydrofuran/diethyl ether (1:1, 400 ml) in a nitrogen atmosphere. Alkylate add such a rate that the internal reaction temperature did not exceed 8oC. After the addition, the reaction mixture is brought to room temperature and stirred for 1 hour, then cooled to 4oC and carefully treated with a solution of acetaldehyde (50 ml) in dry tetrahydrofuran (50 ml). The mixture is brought to room temperature for 0.5 hours and then quenched with water and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried and concentrated. The aqueous phase is extracted twice with ethyl acetate and combined with the previous organic extract for further processing. Purification of the obtained residue flash chromatography on silica gel (starting elution with 7% e-yellow solid, which is directly used in the future. Alcohol (29,15 g of 0.16 mol) dissolved in anhydrous dichloromethane (800 ml) and the reaction mixture is treated with telicom (36 g), pyridine chlorochromate (35 g). After one hour at room temperature, add dichloromethane (400 ml), celite (36 g) and PCC (35 g). The mixture is then stirred additionally for 1 hour at room temperature and then diluted with ether (1 l), filtered with suction through a layer of silica gel and concentrated. Isolate the ketone (27,6 g, 96%) as a pure white solid. To a stirred suspension of the hydrochloride of 4-forfamilies (32,98 g of 0.20 mol) and ketone (27.5 g, 0,156 mol) in absolute ethanol (150 ml) is added in one portion anhydrous sodium acetate (16.6 g, of 0.20 mol). The mixture is refluxed for 2 hours, then cooled, diluted with dichloromethane and washed with saturated solution of sodium bicarbonate, 1N hydrochloric acid and brine. The subsequent drying and removing the solvent, recrystallization of the residue from hot ethanol leads to pure hydrazone (40,08 g, 90%) as a yellow solid. The hydrazone (18,3 g, 64,4 mmol) is placed in a round bottom odnogolosy flask of 500 ml equipped with a reflux condenser), kotou bath (180oC). After 1 hour the temperature of the oil bath was adjusted to a temperature of 140oC and then into the flask gently add absolute ethanol. The mixture is refluxed for 6 hours, cooled, diluted with ethyl acetate and washed with 1N hydrochloric acid and brine, then dried and concentrated to 1/3 volume. Filtration with suction leads to the above-mentioned product (22,4 g, 65%) as a white solid, so pl. 263-264oC;1H NMR (300 MHz, DMSO-d6): 11,91 (s, 1H), 7,99-of 7.96 (m, 1H), 7,89-7,86 (m, 2H), 7,83 (s, 1H), 7,43-7,29 (series m, 4H), 7.03 is-of 6.96 (m, 1H), for 6.81 (d, J = 1.5 Hz, 1H);13C NMR (75 MHz, DMSO-d6): ppm 158,79, 155,72, 140,01, 138,35, 134,92, 133,92, 133,79, 128,64, 128,50, 124,93, 124,79, 123,70, 122,44, 119,73, 112,35, 112,22, 110,76, 110,41, 104,90, 104,59, 100,90, 100,84; IR (KBr, cm-1) 3421, 1625, 1586, 1567, 1501, 1448, 1412, 1286, 1201, 1188, 1128, 862,825, 783, 744, 725, 559, 515; MS (negative. ESI, M-H) m/z 266. Anal. Calc. C16H10FPS: C, 71,89; H, OF 3.77; N, 5,24. Found: C, 71,82; H, 3,76; N, 5,13.

Example 4

(E)-4-fluoro-2-nitro-dimethylaminostyryl.

A mixture of 4-fluoro-2-nitrotoluene (to 185.0 g, 1,19 mol) and dimethylacetal N,N-dimethylformamide (500 ml, of 3.77 mol) in dry dimethylformamide is refluxed for 2 hours in nitrogen atmosphere with the previous azeotropic distillation of methanol from the reaction mixture. At the same time carried the CSO solids (hardens when cooled), which is pure enough for further transformations. Distillation with a glass nozzle (tube with glass beads) leads to the above-mentioned compound (analytically pure for the purposes of characteristics) in the form of a dark-red crystalline substance, so pl. 54-55oC; 1H NMR (300 MHz, DMSO-d6): 7,72 to 7.62 (m, 2H), 7,37-7,32 (m, 1H), 7,33 (d, J = a 13.4 Hz, 1H), 5,58 (d, J = a 13.4 Hz, 1H), 2,58 (s, 6H);13C NMR (75 MHz, DMSO-d6): ppm 158,19, 154,99, 146,16, 143,13, 143,02, 132,57, 132,54, 126,14, 126,04, 120,98, 120,69, 111,41, 111,07, 88,23; IR (KBr, cm-1) 3446, 1622, 1570, 1508, 1386, 1270, 1092, 940, 822, 798; MS (MH+) m/z 211. Anal. Calc. C10H11FN2O2: C 57,14; H, 5,27; N, 13,33. Found: C, 57,09; H, 5,16; N, 13,46.

Example 5

6-Florinda (III: X1= F, X2= R" = R' = H).

(E)-4-fluoro-2-nitro-dimethylaminostyryl (120 g of 0.5 mol) dissolved in tetrahydrofuran (1 l) and subjected to hydrogenation according to Parr (Parr hydrogenation) 50 psi (H2, room temperature, 24 h) using 10% palladium on coal (30 g). The mixture is filtered through celite (washed with THF, methanol and methylene chloride) and concentrate to dryness. This reaction is carried out optionally in three steps in order to process source material, mentioned above. Steam distillation results in the above-mentioned compounds (192,6 d,1H), 7,16 (dd, J = 10,1, 2.3 Hz, 1H), 6.87 in-to 6.80 (m, 1H), to 6.43-6,41 (m, 1H);13C NMR (75 MHz, DMSO-d6): ppm 160,26, 157,16, 135,79, 135,63, 125,94, 125,89, 124,42, 120,97, 120,83, 107,43, 107,10, 101,17, 97,47, 97,13; IR (KBr, cm-1) 3392, 3072, 1626, 1508, 1448, 1342, 1144, 954, 846, 802, 728, 508; MS (MH+) m/z 136. Anal. Calc. C8H6FN: C, 71,10; H, TO 4.47%; N, 10,36. Found: C, 71,28; H, 4,69; N, 10,24.

Example 6

3,4-bis(5-fluoro-1H-indol-3-yl)-N-[4-(tert. butyl)benzyl] -pyrrole-2,5-dione (IV: X1= F; X2= R" = R' = H; R6= 4-(tert.butyl)benzyl).

To stir magnetic stirrer, a solution of 5-farindola (7.0 g, to 51.8 mmol) in anhydrous benzene (125 ml) is added under argon with stirring Metalmania iodide (3.0 M in ether; 18,0 ml of 54.0 mmol). The mixture is stirred at room temperature for 30 min and then the solution was added via syringe over 10 min to a vigorously stirred solution of N-[4-(tert. butyl)benzyl] -3,4-dibromomalonamide (6.50 g, 16.2 mmol) in anhydrous benzene (60 ml). The obtained dark purple solution was stirred at room temperature under argon for 16 h and poured into a mixture of 20% aqueous citric acid (350 ml) and ethyl acetate (500 ml). The organic layer was washed with water (200 ml) and brine (200 ml) and dried (Na2SO4). Evaporation in vacuum with subsequent flash chromatography on silica gel with ispne in the form of a red solid. 300 MHz1H NMR (CDCl3): 8,63 (br s, 2H), 7,87 (d, J = 2,9 Hz, 2H), 7,46-7,34 (m, 4H), 7.23 percent (dd, 2H, J = 8,9, and 4.4 Hz), 6,79 (ddd, 2H, J = 9,1, the 8.9 and 2.5 Hz), 6.48 in (dd, 2H, J = 10,2, 2,5 Hz), a 4.83 (s, 2H), of 1.30 (s, 9H); 75 MHz13C NMR (CDCl3): 172,15 (s), 157,73 (d, J = 235 Hz), 150,82 (s), 133,79 (s), 132,27 (s), 129,92 (s), 128,32 (s), 127,14 (s), 126,16 (d, J = 10.4 Hz), 125,72 (s), 112,19 (d, J = 9.8 Hz), 111,10 (d, J = 26,6 Hz) 106,95 (d, J = 4.3 Hz), 106,43 (d, J = 25,l Hz), 41,68 (s), 34,55 (s), 31,33 (s); FAB mass spectrum, m/e 509 (M+).

Example 7

3-Bromo-4-(6-fluoro-indol-3-yl) -pyrrole-2,5-dione (V: X1= 6F; R' = R" = R6= H; y = Br) and 3,4-bis(6-fluoro-indol-3-yl) -pyrrole-2,5-dione (IV: X1= F; X2= R' = R" = R6= H).

To a solution of 6-farindola (50.0 g, and 0.37 mol) in anhydrous benzene (1 l) under nitrogen atmosphere added with a syringe, etimani bromide (3 M, 130 ml of 0.43 mol) at such a speed that the temperature inside the support between 45-50oC. the mixture is Then heated at 50-55oC for 0.5 hour, after which the reaction mixture is make a suspension of 2,3-dibromomalonamide (24,9 g, 0,093 mol) in anhydrous benzene. The mixture is refluxed for 22 hours, cooled, diluted with ethyl acetate and acidified to pH 1 using 1N HCl. Then the organic phase is separated, washed with brine, dried and concentrated. The aqueous phase is diluted once with ethyl acetate and separated. The organic phase about before chromatography. Cleaning consolidated balance flash chromatography on silica gel (starting elution with 10% ethyl acetate in hexane and then 40% ethyl acetate in hexane) results in two main products. The above-mentioned compound of the formula V (12,31 g, 21.5 percent) was isolated in the form of a brick-red solid substance and the above-mentioned compound of the formula IV (31,5 g, 41%) was isolated as a reddish-orange foam.

For the above-mentioned compounds of formula V: so pl. 73-75oC;1H NMR (300 MHz, DMSO-d6): 11,14 (br s, 1H), 7,51 (dd, J = 8,6, and 5.5 Hz, 1H), 7,32 (t, J = 2,9 Hz, 1H), 7,16 (dd, J = 10,1, 2.3 Hz, 1H), 6.87 in-to 6.80 (m, 1H), to 6.43-6,41 (m, 1H);13C NMR (75 MHz, DMSO-d6): ppm 160,26, 157,16, 135,79, 135,63, 125,94, 125,89, 124,42, 120,97, 120,83, 107,43, 107,10, 101,17, 97,47, 97,13; IR (KBr, cm-1) 3392, 3072, 1626, 1508, 1448, 1342, 1144, 954, 846, 802, 728, 508; MS (MH+) m/z 136. Anal. Calc. C8H6FN: C, 71,10; H, TO 4.47%; N, 10,36. Found: C, 71,28; H, 4,69; N, 10,24.

For the above-mentioned compounds of formula IV: so pl. 207-208oC (decomp.);1H NMR (300 MHz, DMSO-d6): 12,10 (s, 1H), 11,37 (s, 1H), 8,03 (d, J = 2,9 Hz, 1H), 7,86 (dd, J = 8,9, 5,4, 2.3 Hz, 1H), 7,28 (dd, J = 9,6, and 2.3 Hz, 1H), 7,00 (t, J = 9,3, 2.3 Hz, 1H);13C NMR (75 MHz, DMSO-d6): ppm 170,12, 167,35, 160,70, 157,56, 137,65, 136,62, 136,45, 131,58, 131,56, 123,51, 123,38, 121,27, 115,40, 109,03, 108,70, 103,89, 98,47, 98,14; IR (KBr, cm-1) 3328, 3222, 1726, 1604, 1450, 1338, 1240, 1192, 1148, 840, 794; MS (MH+) m/z 309, 311. Anal. Calc. C12H6VL[2,3-a]pyrrole[3,4-c]carbazole-5,7(6-N-[4-(tert. butyl)benzyl] )-dione (VI: X1= X'1= F; X2= X'2= R' = H; R6= 4-(tert.butyl)benzyl; Q = NH).

To stir magnetic stirrer, a solution of the product from example 6 (11.6 g, of 22.8 mmol) in anhydrous benzene (1700 ml) is added under argon with stirring monohydrate p-toluenesulfonic acid (170 mg) and DDQ (10,9 g, 48,0 mmol). The mixture is refluxed in an argon atmosphere with stirring for 1 hour and stirred at room temperature for 16 hours. The obtained dark solid precipitate was separated by filtration, washed with cold ethyl acetate (50-70 ml) and dried in vacuum for 1-2 hours with obtaining 12,80 g (94%) of the above compound as a yellow-brown solid (monotinicity complex by proton NMR; further drying in a vacuum it is possible to reduce the content of ethyl acetate from half to two thirds). Recrystallization from a mixture of THF/ethyl acetate gives analytically pure product as a pale yellow solid (monotinicity complex by proton NMR). 300 MHz1H NMR (DMSO-d6): 11,83 (br s, 2H), 8,46 (dd, 2H, J = 9,7, and 2.6 Hz), 7,69 (dd, 2H, J = 8,9, and 4.6 Hz), was 7.36 (ddd, 2H, J = 9,l, 8,9, and 2.6 Hz), 7,34 - 7,22 (m, 4H), 4,63 (s, 2H), 1,22 (s, 9H); FAB mass spectrum, m/e 507 (M+). Anal. Calc. C31H23F2
2,10-Debtor-12,13-dihydro-5-indole[2,3-a] pyrrole[3,4-c] carbazole-5,7(6)-dione (VI: X1= X'1= F; X2= X'2= R' = R6= H; Q = NH).

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (15,81 g to 0.70 mol) is added in one portion to a stirred suspension of 3,4-bis(6-fluoro-1-indol-3-yl)-1-pyrrole-2,5-dione (11.5g, to 0.032 mol) and toluenesulfonic acid monohydrate (0,44 g) in benzene (1 l) under nitrogen atmosphere and the mixture is refluxed for 2 hours, after which it is cooled, stand at room temperature for 16 hours and filtered with suction through a porous glass filter. The precipitate is washed thoroughly with benzene, ethyl acetate and ether until the filtrate becomes colorless. Parallel conduct other reaction by 20.0 g using such quantitative ratios of the reagents in the first reaction. After the unification produce the above compound (15,51 g, 40%) as a yellowish green solid substance, so pl. >305oC; 1H NMR (300 MHz, DMSO-d6): 11,67 (br s, 2H), of 10.93 (br s, 1H), 8,84 (dd, J = 8,8, 5.8 Hz, 2H), 7,55 (dd, J = 10,0, 2,3 Hz, 2H), 7,11 (dt, J = 9,2, 2.3 Hz, 1H), 2,00 (q, J = 7,l Hz, 2H), 1,96 (s, 3H);13C NMR (75 MHz, DMSO-d6): ppm 171,09, 170,32, 163,27, 160,08, 141,00, 140,83, 129,25, 125,69, 125,55, 119,54, 118,23, 115,09, 108,51, 108,19, 98,64, 98,28, 59,74, 20,74, 14,07; IR (KBr, cm-1) 3320, 1748, 1690, 1572, 1404,4; N, 9,31. Found: C, 64,12; H, 3,76; N, Of 9.55.

Example 10

3,9-Debtor-12,13-dihydro-13-[3,4,6-Tris-O-(phenylmethyl) -- D-glyukopiranozil] -5-indole[2,3-a] pyrrole[3,4-c] carbazole-5,7(6-N-[4- (tert. butyl)benzyl] )-dione (VIII: X1= X'1= F; X2= X'2= R' = R"' = H; R6= 4-(tert.butyl)benzyl; Q = NH, PG = benzyl).

To stir magnetic stirrer suspension of the substance from example 8 (of 9.50 g of 17.7 mmol) in anhydrous THF (450 ml) is added over 5-10 min under argon with stirring bis(trimethylsilyl)amide, sodium (1.0 M in THF; 50,0 ml, 2.82 from EQ. ). The obtained dark red solution was stirred at room temperature for 45 min, carefully treated with syringe chlorotrimethylsilane (of 5.06 ml, 40.0 mmol) and stirred at room temperature for another 1 hour. Then the reaction mixture is refluxed and supporting boiling, add a solution of 1,2-anhydrosugar IX (13.5 g, and 31.2 mmol; see J. Org. Chem. 1993, 58, 343-349) in anhydrous THF (200 ml) for 3.5 hour via an addition funnel. After adding the reaction is refluxed for 10 hours in an argon atmosphere, is treated with a solution of 1,2-anhydrosugar IX (800 mg) in anhydrous THF (40 ml) and refluxed for 2.5 hours. SME. The mixture is distributed between ethyl acetate (2000 ml) and 0.5 N HCl (600 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (300 ml), water (350 ml) and brine (400 ml). The initial aqueous acid layer is extracted with fresh ethyl acetate (600 ml), then washed with water (100 ml) and brine (150 ml). The combined organic extract is dried (Na2SO4) and evaporated in a rotary evaporator to a volume of about 300 ml, obtained as a yellow solid residue is separated by filtration, washed with ethyl acetate (300 ml) and dried in vacuum to obtain 3.00 g (31,6% returned in its original, unadulterated product. The filtrate was concentrated in vacuo, dissolved in a mixture of methylene chloride/hexane and purified flash chromatography on silica gel using 5-10% ethyl acetate in hexane. The yellow fractions containing the least polar spots, evaporated to a volume of approximately 300 ml and left overnight, getting 625 mg (3.8 percent) beautiful yellow prisms N12,N13-double-glycosylated product (structure defined X-RAY crystallography). Additional 380 mg (2.3% of the same product is recovered from the mother liquor. Further elution using 10-15% ethyl acetate in hexane gives 9,23 g (55,5%, 81%, taking into account the unreacted source product) Ana who MSO-d6): 10,85 (br s, 1H), 8,84 (dd, 1H, J = a 9.6, 2.7 Hz), the rate of 8.75 (dd, 1H, J = 9,6, 2,5 Hz), 7,54 (ddd, 1H, J = 9,1, to 9.1 and 2.7 Hz), 7,42-to 7.18 (m, 21H), to 6.43 (d, 1H, J = 8,8 Hz), 5,38 (d, 1H, J = 6.3 Hz, 2'OH), 4,94-4,56 (m, 8H), 4,30-to 4.15 (m, 2H), 3,98-and 3.72 (m, 4H), 1,24 (s, 9H); FAB mass spectrum, m/e 939 (M+). Anal. Calc. C58H51F2N3O7: C, 74,11; H, 5,47; F, ANDROID 4.04; N, 4,47. Found: C, 73,89; H, 5,51; F, Of 3.77; N, 4.26 Deaths.

Example 11

2,10-Debtor-12,13-dihydro-13-[3,4,6-Tris-O-(phenylmethyl) -- D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 Dion (A = VIII: X1= X'1= F; X2= X'2= R6= R"' = H; Q = NH, PG = benzyl) and 2.10-Debtor-12,13-dihydro-13-[2-O-3,4,6-Tris-O-(phenylmethyl) - D-glyukopiranozil] -3,4,6-Tris-O-(phenylmethyl) -- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c] carbazole-5,7 Dion (B = VIII: X1= X'1= F; X2= X'2= R6= H; Q = NH, PG = benzyl; R"' = 3,4,6-Tris-O-(phenylmethyl) - D-glyukopiranozil).

A solution of bis(trimethylsilyl)amide, sodium (1M, and 9.1 ml, 3.3 EQ.) in tetrahydrofuran added via syringe to a solution of 2.10-debtor-12,13 indole[2,3-a] pyrrole[3,4-c]carbazole-5,7 Dion (11,17 g, 32,38 mmol) in anhydrous tetrahydrofuran (600 ml) at room temperature. After 25 min the reaction mixture was added dropwise a solution of epoxide (24,27 g, 56,11 mmol, 1.7 EQ.) in anhydrous THF (50 ml). The mixture is refluxed for 6 h, then treated with n is Saul, dried and evaporated. Purification of the residue flash-chromatography on silica gel (starting elution with 15% of tetrahydrofuran in hexane and further 40% of tetrahydrofuran in hexane) results of the aforementioned compounds And formula VIII (6,1 g, 30%) as a yellow foam, unreacted source aglycone (4,00 g) and bis-sugar product (10,9 g, 34%; MS(M+) calc. for C14H66F2N3O121226, 4615, viewers. 1226, 4566) as a yellow foam, which is converted directly into the above-mentioned compound A of formula VIII, as described below. For the main compounds of formula A = VIII: So pl. 140-147oC;1H NMR (300 MHz, CDCl3): 10,50 (s, 1H), 8,79-a total of 8.74 (dd, J = 8,8, 5.8 Hz, 1H), 8,21 (dd, J = 8,8, 5.6 Hz, 2H), to 7.59-7,33 (m, 11H), 7,28-7,12 (2m, 11H), 7,06-7,00 (m, 1H), for 6.81 (dd, J = 9,1, 2.2 Hz, 1H), 6,61 return of 6.58 (m, 1H), of 5.83 (d, J = 9.0 Hz, 1H), 5,12 (d, J = 5.3 Hz, 1H), 5,08 (d, J = 5,2 Hz, 1H), 5,01-to 4.98 (m, 1H), around 4.85 (d, J = 10,8 Hz, 1H), 4,73-4,72 (m, 1H), 4,55 is 4.35 (m, 4H), 4,07-3,93 (m, 3H), 3,76-and 3.72 (m, 1H);13C NMR (75 MHz, CDCl3): ppm 169,55, 169,10, 164,43, 164,25, 161,18, 161,00, 143,00, 140,83, 142,83, 141,68, 141,50, 137,69, 137,59, 136,32, 130,45, 128,91, 128,74, 128,63, 128,56, 128,43, 128,06, 127,02, 126,89, 126,15, 126,01, 120,00, 119,01, 118,44, 118,17, 118,09, 110,33, 110,02, 109,48, 109,16, 98,04, 97,70, 97,34, 85,89, 85,62, 76,35, 75,36, 75,05, 74,09, 73,74, 66,75; IR (KBr, cm-1) 3430, 3334, 2914, 2870, 1752, 1702, 1580, 1452, 1328, 1232, 1140, 1062, 698; MS (MH+) calc. for C47H38F2N3O7794,2678, viewers. 794,2687. The N, 5,10; H2O, 0,4.

Compound B is converted into a compound A stirring solution of 2.10-debtor-12,13-dihydro-13-[2-O-3,4,6-Tris-O-(phenylmethyl) - D-glyukopiranozil] -3,4,6-Tris-O-(phenylmethyl) -- D glyukopiranozil] --indole[2,3-a] pyrrole[3,4-c] carbazole-5,7 Dion (10,9 g, 8,89 mmol) in dry ethyl acetate (25 ml) and treated with a solution of anhydrous methanolic hydrogen chloride (8M, 500 ml) in a closed flask for 96 hours at room temperature. Then evaporated the solvent(s) in vacuum and the resulting residue diluted with ethyl acetate and tetrahydrofuran and neutralized to pH 8 with saturated sodium bicarbonate solution. The organic phase is separated and washed with brine, and then dried and concentrated solvent. Purification of the residue flash-chromatography on silica gel (as described above) gives the above-mentioned compound A of the formula VIII (5.7 g, 81%) as a yellow foam, as well as the original aglionby product (0.7 g).

Example 12

3,9-Debtor-12,13-dihydro-13 -[- D-glyukopiranozil]- indol[2,3-a]pyrrole[3,4-c] carbazole-5,7(6-N-[4-(tert.butyl)benzyl]-)-dione (la: X1= X'1= F; X2= X'2= H; R6= 4-(tert.butyl)benzyl; Q = NH, R2= R5= OH). To stir magnetic stirrer, a solution of the product from example 10 (2,10 g of 2.23 mmol) in 95% ethanol (450 is m in nitrogen atmosphere with vigorous stirring for 20 hours. The mixture is filtered hot through celite and washed with methanol. The filtrate was concentrated in vacuo and purified flash chromatography on silica gel using 3-5% methanol in methylene chloride, to obtain 1.35 g (90%) of the net above-mentioned compound as a yellow-orange solid. An analytical sample, one stripped off from ethyl acetate, dried under vacuum, provided in the form of complex 1/2 EtOAc molecule. 300 MHz1H NMR (DMSO-d6): 11,81 (br s, 1H), 8,84 (dd, 1H, J = 9,7, 2.7 Hz), 8,76 (dd, 1H, J = 9,7, and 2.6 Hz), of 8.04 (dd, 1H, J = 9,3, 4,4 Hz), of 7.70 (dd, 1H, J = 8,9, and 4.6 Hz), 7,55-7,46 (m, 2H), 7,40-7,33 (m, 4H), of 6.31 (d, 1H, J = 8,9 Hz), 6,12 (br s, 1H), 5,43 (d, 1H, J = 4.4 Hz), to 5.17 (d, 1H, J = 5.5 Hz), 4,39 (d, 1H, J = 5.4 Hz), the 4.90 (s, 2H), 4,13-4,07 (m, 1H), 4,00-of 3.96 (m, 2H), a 3.87-of 3.80 (m, 1H), 3,63-of 3.46 (m, 2H), 1,24 (s, 9H); FAB mass spectrum, m/e 669 (M+). Anal. Calc.37H33F2N3O71/2C4H8O2: C, 65,63; H, 5,22; F, 5,32; N, OF 5.89. Found: C, 65,04; H, 5,20; F, 5,32; N, 5,91.

Example 13

2,10-Debtor-12,13-dihydro-13 -[- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c]carbazole-5,7 Dion (Ia: X1= X'1= F; X2= X'2= R6= H; Q = NH, R2= R5= OH)

A solution of 2.10-debtor-12,13-dihydro-13-[3,4,6-Tris-O-(phenylmethyl) -- D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 Dion (4,36 g, 5,49 mmol) in a mixture of ethanol and ethyl acetate (1:1, 100 ml) is subjected to hydrogenation according to Parr (His utilizator. After filtration with suction through celite, the filtrate concentrated to dryness to obtain an orange-yellow solid residue, which is purified by chromatography on a column of silica gel (elution with 50% tetrahydrofuran in hexane) to give the above compound (2,33 g, 77%) as a yellow solid, so pl. 255-260oC;1H NMR (300 MHz, DMSO-d6): 11,77 (s, 1H), 11,19 (s, 1H), 9,14-9,03 (m, 2H), 7,89 (dd, J = 11,0, 2.0 Hz, 1H), 7,41 (dd, J = 9,8, and 2.3 Hz, 1H), 7,27-7,19 (m, 2H), of 6.26 (d, J = 8,9 Hz, 1H), 6,14-6,12 (m, 1H), 5,43 (d, J = 4.0 Hz, 1H), 5,17 (d, J = 5.5 Hz, 1H), to 4.98 (d, J = 5.5 Hz, 1H), 4,24-of 3.94 (m, 3H), 3,83-3,81 (m, 1H), 3,59 is 3.57 (m, 1H), 3,50-of 3.42 (m, 1H);13C NMR (75 MHz, DMSO-d6): ppm 170,99, 170,91, 163,43, 160,24, 143,12, 141,63, 130,09, 128,74, 126,02, 120,90, 119,35, 118,22, 118,14, 117,74, 116,54, 108,78, 108,57, 98,77, 98,55, 98,20, 84,64, 78,56, 76,44, 73,06, 67,51, 58,29; IR (KBr, cm-1) 3326, 1744, 1700, 1578, 1452, 1328, 1232, 1114, 1074, 828; MS (MH+) m/z 523. Anal. Calc. C26H19F2N3O70,25 EtOAc 0,40 H2O: C, 58,68; H, 3,98; N, 7,60; H2O, 1,30. Found: C, 58,55; H, 4,18; N, 7,38; H2O, 1,20.

Example 14

2,10-Debtor-12,13-dihydro-13-[2-O-(triethylsilyl)-3,4,6-Tris - O-(phenylmethyl) -- D-glyukopiranozil] -6-triethylsilyl indole[2,3-a]pyrrole[3,4-c] carbazole-5,7 Dion (A = VIII: X1= X'1- F; X2= X'2= H; R6= R"' = triethylsilyl; Q = NH, PG = benzyl) and 2.10-debtor-12,13-dihydro-13-[2-O-(triethylsilyl)-3,4,6-Tris - O-(fenil R6= H; R"' = triethylsilyl; Q = NH, PG = benzyl).

Triethylsilyl triflate (9.0 ml, 40.0 mmol, 20 EQ.) add one portion to a solution of 2.10-debtor-12,13-dihydro-13-[3,4,6-Tris - O-(phenylmethyl) -- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c]carbazole-5,7 Dion (1.60 g, 2.0 mmol) in dry pyridine (100 ml). The mixture is stirred in a closed flask at room temperature for 48 hours and then add absolute ethanol (5 ml). After 10 min the solvent is removed in vacuum at room temperature. The residue is then diluted with ethyl acetate and tetrahydrofuran and acidified with 0.1 N hydrochloric acid until acidic. Next, separate the organic phase, the organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification of the residue flash chromatography (2) on silica gel (elution with 10% tetrahydrofuran in hexane for the first time and 40% ether in hexane for the second time) lead to the above-mentioned compound A (1.4 g) as a yellow foam containing a small admixture. The admixture is B. the Complete transformation of A to B can be done by dissolving A (1.4 g, 1.37 mmol) in absolute ethanol (20 ml) and the processing solution of ammonium acetate (0.11 g, of 1.40 mmol) at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and tsewa. The above product B (1.19 g, 96% isolated in the form of a yellow foam.

For A: So pl. 77-79oC;1H NMR (300 MHz, CDCl3): at 10.64 (s, 1H), 9,29 (dd, J = 8,8, 5.8 Hz, 1H), 9,23-9,20 (m, 1H), 7,33-7,20 (m, 15H), 7,13? 7.04 baby mortality (m, 4H), 5,77 (d, J = 8,8 Hz, 1H), of 5.05 (d, J = ll,6 Hz, 1H), 4,89-rate 4.79 (m, 2H), 4,67-4,63 (m, 2H), 4,54 (d, J = 12,4 Hz, 1H), 4,28 (m, 1H), 4,16 (m, 1H), 3,97 (m, 2H), 3,79 is 3.76 (m, 2H), 1,23-of 1.16 (m, 6H), 1,11-of 1.06 (m, 9H), 0,24 (t, J = 8.0 Hz, 9H), -0.29 to(-0,50) (m, 6H);13C NMR (75 MHz, CDCl3): ppm 175,34, 142,70, 141,88, 138,08, 137,40, 136,28, 128,72, 128,56, 128,27, 128,13, 128,05, 127,52, 127,40, 127,17, 126,73, 121,40, 118,12, 109,84, 109,53, 109,21, 98,26, 97,52, 86,12, 77,71, 77,44, 77,01, 76,72, 76,59, 75,53, 75,25, 74,26, 66,82, 6,91, 6,12, 4,03, 3,95; IR (KBr, cm-1) 3458, 3334, 2954, 2876, 1692, 1454, 1328, 1330, 1116, 1072, 732, 696; MS (M+) calc. for C59H66F2N3O7Si21022, 4407, viewers. 1022, 4377.

For B: So pl. not determined;1H NMR (300 MHz, CDCl3): 10,65 (s, 1H), 9,25-which 9.22 (m, 1H), 9,14 (dd, J = 8,8, 5.6 Hz, 1H), 7,72 (s, 1H), 7,33-7,21 (m, 14H), 7,16-7,03 (m, 4H), 5,77 (d, J = 8,8 Hz, 1H), of 5.05 (d, J = 11.5 Hz, 1H), 4,87-4,78 (m, 2H), 4,69-4,63 (m, 2H), 4,59-4,51 (m, 1H), 4,28 (t, J = 8,8 Hz, 1H), 4,15 (t, J = 8,8 Hz, 1H), was 4.02-3,91 (m, 2H), 3,79-to 3.73 (m, 2H), 0,23 (t, J = 8.0 Hz, 9H), -0.28 and-(-0,52) (m, 6H);13C NMR (75 MHz, CDCl3): ppm 169,70, 169,66, 164,39, 161,18, 142,80, 142,64, 142,16, 141,99, 138,05, 137,37, 136,26, 130,65, 130,65-126,71 (11 signals, olefin. ), 121,11, 119,48, 119,11, 118,93, 118,68, 118,44, 110,04, 109,74, 109,44, 98,39, 98,04, 97,63, 97,26, 86,11, 86,06, 77,76, 77,21, 76,74, 75,52, 75,25, 74,30, 66,86, 6,10, 4,03; IR (KBr, cm-1) 3434, 2876, 1754, 1718, 1624, 1582, 1454, 1326, 1116, 1086, 738; MS (FAB, MH+tor-12,13-dihydro-13-[6--(methylsulphonyl)-a-D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (Ib: X1= X'1= F; X2= X'2= R6= H; R2= R4= OH; R5= Mesilate)

To stir magnetic stirrer, a solution of 3,9-debtor-12,13-dihydro-13 -[- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c]carbazole-5,7 Dion (330 mg, 0,630 mmol) in anhydrous pyridine (8 ml) atoC in an atmosphere of nitrogen was added via syringe methanesulfonyl chloride (80 μl, of 1.03 mmol). The reaction mixture was stirred at 0oC for 3.25 hours and controlled by TLC on silica gel (eluent EtOAc) spots appearance of a new product with higher Rfcompared with the original material. Add additional methanesulfonyl chloride (20 μl, 0.26 mmol) and the reaction stirred at 0oC for 1.25 hours, then treated with EtOAc (350 ml) and saturated aqueous copper sulfate (II) (100 ml). An ethyl acetate layer was washed with saturated aqueous copper sulfate (II) (3 x 150 ml) of 0.1 N HCl (200 ml), water (200 ml), brine (200 ml) and dried (Na2SO4). Evaporation in vacuum and subsequent flash chromatography on silica gel using 4% to 6% methanol in dichloromethane gives 146 mg (39%) of the above compound as a yellow solid: 500 MHz COSY1H NMR (CD3COCD3) the 10.40 (s, 1H), 10,00 (br s, 1H), 8,97-8,86 (m, 2H), 8,02-of 7.96 (m, 2H), 7,42-7,33 (m, 2H), to 6.43 (d, 1H, ; AB mass spectrum, m/e 601 (M+).

Example 16

2,10-Debtor-12,13-dihydro-13-[6-deoxy-6-(1,3-dihydro-1,3 - dioxo-2-ethenolysis) -- D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 Dion (A = Ib: X1= X'1= F; X2= X'2= R2= R6= H; R2= R4= OH; R5= phthalimid)

Phthalimide potassium (0.45 g, 2,43 mmol) added in one portion to a stirred solution of 2.10-debtor-12,13-dihydro-13-[6--(methylsulphonyl)-a-D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (200 mg, 0.33 mmol) in anhydrous dimethylformamide (10 ml) and the mixture is then heated at 130oC for 3 h, cooled to room temperature and after the night was concentrated in vacuo. The residue is treated with ethyl acetate (add a little tetrahydrofuran (THF) and washed with 0, 1N hydrochloric acid and brine. Subsequent drying and concentration of the solvent, purification of the residue flash-chromatography on silica gel (elution with 7% methanol in chloroform) to give the above compound (46 mg, 21%) as a yellow solid.

So pl. >300oC;1H NMR (500 MHz, DMSO-d6): 11,21 (m) 10,80 (s), 9,15-9,13 (m), 9,07-9,02 (m) of 7.97 (d, J = 8,8 Hz, 1H), 7,86 (d, J = 11,1 Hz, 1H), 7,47-7,69 (m), 7,40 (d, J = 10.3 Hz, 1H), 7,31-of 7.23 (m), 7,20-7,17 (m) 6,09 (d, J = 9,l Hz, 1H), 5,73 (m), 5,64 (m), and 5.30 and 5,26 (2m), 4,99 (m), 4,36-4,27 (m), 4,21 (51.

Example 17

13-[6-(Azido-6-deoxy -- D-glyukopiranozil)-2,10-debtor-12,13-dihydro indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (Ib: X1= X'1= F; X2= X'2= R6= H; R2= R4= OH; R5= N3).

Sodium azide (0,29 mg, 0.44 mmol) is added in one portion to a stirred solution of 2.10-debtor-12,13-dihydro-13-[6 (methylsulphonyl)-a-D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (132 mg, 0.22 mmol) and make the molecular sieve 4E (4 Angstrom) (50 mg) in anhydrous dimethylformamide (3 ml), after which the mixture is heated at 60oC for 6 h, cooled to room temperature, diluted with ethyl acetate (add a little tetrahydrofuran (THF) and washed with saturated sodium bicarbonate solution and brine. Subsequent drying and concentration of the solvent, purification of the residue flash-chromatography on silica gel (elution with 10% methanol in chloroform) to give the above compound (40 mg, 33%) as a yellow solid, Razlog. if 256oC;1H NMR (500 MHz, DMSO-d6): 11,89 (br s, 1H), 11,21 (br s, 1H), 11,14 (br s, 1H), was 10.82 (s, 1H), 9,19 (dd, J = 8,8 Hz, 1H), 9,13-9,06 (m, 3H), of 7.90 (dd, J = 10,8, and 2.1 Hz, 1H), 7,71 (dd, J = 10,5, and 2.1 Hz, 1H), 7,49 (dd, J = a 9.6, 2.1 Hz, 1H), 7,35 (dd, J = 9A, 2.3 Hz, 1H), 7,30-7,22 (m, 4H), 6,33 (d, J = 8.7 Hz, 1H), 6,27 (d, J = 8.6 Hz, 1H), 5,72 (d, J = 5,2 Hz, 1H), 5,61 (d, J = 4,9 Hz, 1, 110, 1740, 1700, 1622, 1580, 1450, 1381, 1329, 1231, 1170, 1115, 1074, 828, 763; HRMS (negative. ESI, M-H-calc. for C26H17F2N6O6547,1256, viewers. 547,1199.

Example 18

6-Amino-13-(6-amino-6-deoxy -- D-glyukopiranozil)-2,10-debtor-12,13-dihydro indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (Ic: X1= X'1= F; X2= X'2= H; R2= R4= OH; R5= NH2= R6).

Hydrazinehydrate (2 ml) are added to 2,10-debtor-12,13-dihydro-13-[6-deoxy-6-(1,3-dihydro-1,3-dioxo-2 - ethenolysis) -- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c] carbazole-5,7 the dione (19 mg, 0,029 mmol) and the mixture is stirred at room temperature for 1 hour and at 50oC for 1 h, then concentrated in vacuo for 24 hours. Purification of the residue by HPLC (HPLC) on a column with C18YMC Pack ODS (30% isocratic flow (isocratic flow) using methanol/water/0.1% of triperoxonane acid) leads to the above-mentioned compound (10 mg, 27%) as an orange-yellow solid, so pl. >300oC;1H NMR (500 MHz, DMSO-d6/D2O): 8,49-8,89 (2m), 8,81 (m), 8,68 (m), to 7.93 (m) of 7.82 (d, J = 10.0 Hz, 1H), 7,73 (d, J = 10,2 Hz, 1H), 7,39 (d, J = 9.5 Hz, 1H), 7,12-7,11 (m), 6,93 (m), of 6.20 (d, J = 8,9 Hz, 1H), 6,09 (d, J = 7.7 Hz, 1H), 4,22 (m), 4,16-4,12 (m), 4,14 (t, J = 8,9 Hz, 1H), 3,79 (t, J = 8,9 Hz, 1H), 3.75 to to 3.73 (m), 3,61-to 3.52 (m), 3,40-3,34 (m), 3,31-3,27 SUB>2
N5O6536,1460, viewers. 536,1349.

Example 19

13-[6-Amino-6-deoxy -- D-glyukopiranozil] -3,9-debtor-12,13-dihydro indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (Ib: X1= X'1= F; X2= X'2= R6= H; R2-R4= OH, R5= NH2).

To a solution of compounds 13-[6-(Azido-6-deoxy - D-glyukopiranozil)-2,10-debtor-12,13-dihydro indole[2,3-a]pyrrole[3,4-c]carbazole-5,7 Dion accounted for 98.9 mg, 0,180 mmol) in absolute methanol (125 ml) in a nitrogen atmosphere in the device Parr (Parr) is added palladium chloride (II) (90 mg, 0.51 mmol). The mixture was exposed to ultrasound for 10 min and then placed in a shaker (shaking) Parr (Parr shaker) at a pressure of 70 psi hydrogen for 45 hours. The mixture is filtered through a small layer of celite, washed with methanol and concentrated in vacuo. Purification on a column of Sephadex LH 20 chromatography with methanol (flow rate of 0.4-0.5 ml/min) gives to 69.6 mg (70%) of the above compound as a yellow-orange solid: 500 MHz COSY1H NMR (DMSO-d6): 11,20 (brs, 1H), of 8.92 (dd, 1H, J = 9,7, and 2.6 Hz), 8,81 (dd, 1H, J = 9,7, and 2.6 Hz), with 8.05 (dd, 1H, J = 9,0, 4.6 Hz), 7,95 (brs, 3H), 7,88 (dd, 1H, J = 8,9, and 4.6 Hz), of 7.48 (ddd, 1H, J = 2,5, 8,9, and 9.1 Hz), 7,41 (ddd, 1H, J = 2,5, 8,9, 9.1 Hz), 6,41 (d, 1H, J = 8,8 Hz, 1'H), 5,70 (brs, 1H), are 5.36 (brd, 2H, 2', 3'OH), 4,23-4,19 (m, 1H, 5'H), 4,06-was 4.02 (m, 1H, 2'H), 3,89-a-3.84 (m, 1H, 3'H), of 3.56 (t, 1H, J = 8,9 Hz, 4'H), 3,32-of 3.25 (m, 1H,1-methyl pyrrole-2,5-dione (V: X1= 5F; X2= H = R':R6= Me; R ' = benzo[b]thienyl; y = Cl).

To a solution of 2-(2-benzo[b] thienyl-5-farindola (10.0 g, of 0.37 mol) in anhydrous tetrahydrofuran (250 ml) under nitrogen atmosphere was added when using the syringe etimani bromide (3M, 13,1 ml to 0.39 mmol) with such speed that the reaction temperature was maintained between 45-50oC. the Mixture was then heated at 50-55oC for 0.5 hour and cooled to room temperature and then added dropwise into the reaction mixture a solution of 3,4-dichloro-1-methylmaleimide (7,41 g of 0.41 mol) in anhydrous tetrahydrofuran. The mixture is refluxed for 2 hours, cooled, diluted with ethyl acetate, washed with a saturated solution of ammonium chloride and brine, then dried and concentrated solvent to 1/4 volume. Filtration with suction resulting suspension leads to the above-mentioned compound (12,65 g, 82% in the form of a red-violet solid, so pl. 250-251oC;1H NMR (300 MHz, DMSO-d6): 12,50 (s, 1H), 8,03-7,79 (m, 1H), 7,93-7,89 (m, 1H), 7,83 (s, 1H), 7,52 (dd, J = 8,9, and 4.4 Hz, 1H), 7,46 and 7.36 (m, 2H), 7,29 (dd, J = a 9.9, 2.5 Hz, 1H), 7,16-to 7.09 (m, 1H), 3,37 (s, 3H);13C NMR (75 MHz, DMSO-d6): ppm 167,71, 165,34, 159,10, 156,00, 139,48, 134,18, 133,76, 133,19, 133,06, 132,66, 127,41, 127,27, 125,20, 125,02, 124,22, 123,64, 122,55, 113,23, 113,10, 111,89, 111,54, 105,40, 105,07, 100,56, 24,61; IR (KBr, cm-12
O2S: C, 61,39; H, TO 2.94; N, 6,82. Found: C, 61,08; H, Is 2.88; N, 6,62.

Example 21

3-Fluoro-6-methyl-benzo[b] thienyl[2,3-a]-pyrrole[3,4-c]carbazole-5,7-dione (VI:1= F; X2= X'1= X'2= R' = H; Q = S; R6= Me).

The suspension containing 4-[2-(benzo[b]Tien-2-yl)-5-fluoro indol-3-yl] -3-chloro-1-methyl pyrrole-2,5-dione (12,6 g, 30.7 mmol) in a mixture of dry absolute ethanol/dioxane (60%, 1 l) placed in a 2 l flask made of Pyrex, equipped with a reflux condenser. The mixture is stirred and irradiated (mercury lamp, medium pressure Hanovia, 450 W) for 14 h, then cooled to room temperature and additional leave in the fridge for 24 hours in 5oC. Filtration with suction suspension leads to the above-mentioned compound (12.7 g, 95% in the form of fluorescent yellow-green, similar to fibrous glass, solids, so pl. >305oC;1H NMR (500 MHz, DMSO-d6): 9,50 (d, J = 7.8 Hz, 1H), 8,39 (d, J = 9.7 Hz, 1H), with 8.05 (d, J = 7.8 Hz, 1H), 7,55-7,47 (m, 3H), 7,33-7,29 (m, 1H), 3,55 (s, 0,3 H dioxane, 3H), 2,96 (s, 3H);13C NMR (125 MHz, DMSO-d6when 40oC): ppm 168,99, 168,73, 158,05, 138,98, 138,93, 137,97, 134,13, 129,91, 127,73, 127,07, 126,59, 125,40, 125,22, 122,99, 121,18, 118,50, 115,75, 115,55, 114,81, 112,85, 112,78, 109,87, 109,67, 66,45 (dioxane), 23,66; IR (KBr, cm-1) 3263, 1756, 1702, 1694, 1629, 1494, 1455, 1374, 1291, 1256, 1222, 1168, 1156, 1110, 982, 869, 806, 755, 745, 704, 613; MS (s>2
O, 0,89. Found: C, 65,86; H, 3.43 points; N, 6,68; H2O, 0,56.

Example 22

3-Fluoro-6-methyl-13-[2,3,4,6-Tetra-O-(phenylmethyl) -- D-glyukopiranozil benzo[b] thienyl[2,3-a]-pyrrole[3,4-c]carbazole-5,7 Dion (VIII: X1= F; X2= X'1= X'2= H; Q = S; R6= Me; PG = R' = benzyl).

Aminobutiramida azodicarboxylate (4.6 ml of 24.0 mmol, 4.5 EQ.) added dropwise to a cooled (0oC) a light suspension of 3-fluoro-6-methyl-benzo[b] thienyl[2,3-a] -pyrrole[3,4-c]carbazole-5,7-dione (2.0 g, of 5.34 mmol), 2,3,4,6-Tetra-O-benzyl-In-glucopyranose (8,67 g, 16,03 mmol, 3.0 EQ.) and triphenylphosphine (of 6.31 g of 24.0 mmol, 4.5 EQ.) in anhydrous tetrahydrofuran (200 ml). The mixture was stirred at 0oC for 1 h, and then diluted with ethyl acetate and washed with 0.1 N hydrochloric acid and brine. Subsequent drying and concentration of the solvent, purification of the residue flash-chromatography on silica gel (elution with 10% ethyl acetate in hexane and then 15% ethyl acetate in hexane) to give the above compound (4,60 g, 96%) as a yellow foam, so pl. 64-70oC;1H NMR (500 MHz, DMSO-d6the mixture is rotary (conformational) isomers 1: 1): 9,87 and 9,78 (2m, 1H), 9,00-8,99 and cent to 8.85-8,83 (2m, 1H), 8,11-8,02 (2m, 1,5 H), 7,73 (d, J = 7.2 Hz, 1H), 7,58-rate of 7.54 (m, 2,5 H), 7,38-of 7.23 (m, 15H), 7,18 (d, J = 7.9 Hz, 1H), 6,84 (t, J = 7,4 Hz, 0.5 H), of 6.78-6.75 in (m, 0.5 H), to 6.67 (t, J = 7,6 Hz, 1H), 6,55 (t, J = 7,5 Hz-4,20 (m, 0.5 H), 4,14 (br s, 0.5 H), 4,11-4,00 (m, 3H), 3,93 (d, J = 10,6 Hz, 0.5 H), a 3.87 (br s, 1H), 3,18 (s, 3H); IR (KBr, cm-1) 3423, 2920, 2866, 1759, 1699, 1622, 1481, 1453, 1380, 1283, 1255, 1213, 1180, 1160, 1089, 744, 697; MS (FAB, M+), m/z 896.

Example 23

3-Fluoro-6-methyl-13 -[- D-glyukopiranozil benzo[b]thienyl[2,3-a] -pyrrole[3,4-c] carbazole-5,7 Dion (Ia: X1= F; X2= X'1= X'2= H; Q = S; R6= Me; R2-R5= OH).

To a cooled (0oC), stirred solution of 3-fluoro-6-methyl-13-[2,3,4,6-Tetra-O-(phenylmethyl) -- D-glyukopiranozil benzo[b]-thienyl[2,3-a] -pyrrole[3,4-c]carbazole-5,7 dione (4.5 g, 5,02 mmol) in ethanthiol (30 ml) is added a cold (0oC) apirat boron TRIFLUORIDE (6,36 ml of 50.2 mmol). The mixture was stirred at 0oC for 1 hour, and then continue stirring at room temperature during 48 hours. Add additional apirat boron TRIFLUORIDE (3.2 ml) in 12 hour and 24 hour. The solvent is removed in vacuum and the remaining residue is treated with a mixture of ethyl acetate/tetrahydrofuran and washed with 1N hydrochloric acid and brine, then dried and concentrated solvent. Purification of the residue flash-chromatography on silica gel (elution with 10% methanol in chloroform and then 15% methanol in chloroform) to give the above compound (2,53 g, 94%) as a yellow solid, (H), to 7.99 (dd, J = 9,0, 4.5 Hz, 0,75 H), to 7.61-7,41 (3m, 3H), 6,26 and 6,09 (2d, J = 8.8 and 9.3 Hz, 1H), are 5.36-5,33 (3H), 4,84-4,72 (m, 1,5 H), 4.04 the-3,98 (m, 1H), 3,92-3,86 (m, 1,75 H), 3,76-3,68 (m, 2H), 3,63-of 3.54 (m, 1,75 H), and 3.16 (s, 3H);13C NMR (125 MHz, DMSO-d6): ppm 169,34, 169,19, 169,04, 158,81, 156,95, 140,06, 138,48, 137,05, 133,12, 131,70, 131,49, 130,85, 129,75, 128,36, 127,40, 127,20, 126,52, 125,78, 125,71, 125,39, 122,80, 122,66, 122,35, 119,81, 116,33, 116,08, 115,94, 115,74, 110,70, 110,50, 105,28, 87,77, 81,36, 77,72, 70,89, 69,86, 61,28, 24,33; IR (KBr, cm-1) 3428, 1756, 1694, 1622, 1481, 1460, 1448, 1384, 1084, 745; MS (negative. ESI M-H-) m/z 535.

Example 24

3-Fluoro-13 -[- D-glyukopiranozil benzo[b] thienyl[2,3-a]-pyrrole[3,4-c] carbazole-5,7 Dion (Ia: R2-R5= OH; R6= X2= X'1= X'2= H; Q = S).

3-Fluoro-6-methyl-13 -[- D-glyukopiranozil benzo[b]thienyl[2,3-a] -pyrrole[3,4-c] carbazole-5,7 dione (0.2 g, and 0.37 mmol) are suspended in an aqueous 10% solution of potassium hydroxide (30 ml) under nitrogen atmosphere. The mixture is gently refluxed for 3 hours and then titrated with concentrated HCl until a dense precipitate. The precipitate is treated with a mixture of ethyl acetate/tetrahydrofuran and washed with 1N hydrochloric acid and brine, then dried and concentrated solvent. The residue is dissolved in absolute ethanol (1 ml) and add solid ammonium acetate (3.0 g). The mixture is melted at 150oC for 3 h, then cooled, diluted with a mixture of et the ka of this residue to flash chromatography on silica gel (elution 30% tetrahydrofuran in chloroform and then 50% tetrahydrofuran in chloroform) to give the above compound (69,5 mg, 36%) as a yellow solid, so pl. >305oC;1H NMR (500 MHz, DMSO-d6): 11,67 (s, 0,25 H), 11,53 and 11,51 (2s, 1H), 9,95-to 9.93 and to 9.91-9,89 (2m, 1H), 9,02 and 8,97 (2dd, J = 9,8, 2,7 and 9.7, 2.8 Hz, 1H), 8,24-8,23 and 8,18-8,16 (2m, 1H), 8,08 and 8,01 (2dd, J = 9,4, to 4.4 and 9.1, 4.6 Hz, 1H), 7,69-7,63 (m, 2H), 7,54-of 7.48 (m, 1H), 6,34 and 6,09 (2d, J = 8,9 and 9.4 Hz, 1H), lower than the 5.37 to 5.35 (m, 1H), 5,28 and 5,22 (2br m, 2H), 4.75 V (br m, 0,75 H) of 4.04 and a 3.87-3.75 to (2m, 3H), 3,68-to 3.58 (m, 2H), 3,55-to 3.52 (m, 2H);13C NMR (125 MHz, DMSO-d6): ppm 170,39, 170,16, 158,76, 156,89, 140,05, 138,34, 136,87, 133,09, 131,76, 128,32, 127,28, 126,62, 125,64, 122,64, 120,60, 116,16, 115,95, 115,84, 110,76, 110,56, 107,35, 87,71, 81,13, 77,45, 70,74, 69,79, 67,01, 61,23; IR (KBr, cm-1) 3392, 1747, 1705, 1625, 1481, 1462, 1430, 1326, 1284, 1262, 1180, 1087, 804, 758, 747; HRMS (negative. ESI M-H-) calc. for C26H18FN2O7S 521,0897, viewers. 521,0802.

Example 25

3,9-Debtor-12,13-dihydro-13-[3,6-O-(tert. butyldimethylsilyl) -- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c] carbazole-5,7(6-N-[4-(tert.butyl)benzyl] -)-dione (Ib: X1= X'1= F; X2= X'2= H; R6= 4-(tert.butyl)benzyl; Q = NH, R2= R4= OH; R3= R5= tert.butyldimethylsilyloxy).

To stir magnetic stirrer, a solution of the product from example 12 (750 mg, 1.12 mmol) and imidazole (1.9 g, 28 mmol) in anhydrous DMF (14 ml) in an atmosphere of N2with stirring using a syringe tert.butyldimethylsilyl triftorbyenzola (2,96 g, ml). The mixture is diluted with ethyl acetate (150 ml) and washed with water (6 x 100 ml), brine (100 ml) and dried (Na2SO4). This product is used directly in the next stage without additional purification. Analytically pure sample of the purified flash chromatography on silica gel with hexane/methylene chloride: 300 MHz1H NMR (CDCl3): 10,06 (br s, 1H), 9,12 (dd, 1H, J = 9,2, 2.7 Hz), 7,88-7,81 (m, 1H), 7,72 (dd, 1H, J = 9,2, 3,9 Hz), 7,41 (ddd, 1H, J = 8,9, 8,9, and 2.6 Hz), 7,25 (dd, 1H, J = 9,0, 4,1 Hz), 7,20-6,99 (m, 4H), of 6.99 (ddd, 1H, J = 8,7, 8,7, the 2.4 Hz), 5,97 (d, 1H, J = 8,9 Hz), 4,58-3,90 (m, 8H), of 1.18 (s, 9H), of 0.91 (s, 9H), or 0.83 (s, 9H), or 0.27 (s, 3H), of 0.10 (s, 3H), of 0.05 (s, 3H), -0,02 (s, 3H); FAB mass spectrum, m/e 897 (M+).

Example 26

3,9-Debtor-12,13-dihydro-13-[3-O-(tert.butyldimethylsilyl) -- D-glyukopiranozil] indole[2,3-a] pyrrole[3,4-c] carbazole-5,7(6-N-[4-(tert. butyl)benzyl] -)-dione (Ib: X1= X'1= F; X2= X'2= H; R6= 4-(tert.butyl)benzyl; Q = NH, R2= R4= OH; R3= tert.butyldimethylsilyloxy).

To stir magnetic stirrer, a solution of the crude product from example 25 when -5oC add the mixture triperoxonane acid: water 9:1, pre-cooled to -5oC. the Reaction was stirred at -5oC for 45 min, diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (-chromatography on silica gel with a mixture of 1-10% methanol in methylene chloride to give 59 mg (6%) of the original product (cf. the compound of example 25), 78 mg (10% fully desilusionado product (cf. the compound of example 12)and 585 mg (74%) of net above-named product as a yellow solid: 500 MHz COSY1H NMR (DMSO-d6) 11,80 (brs, 1H), 8,82 (dd, 1H, J = a 9.6, 2.7 Hz), 8,76 (dd, 1H, J = 9,7, 2.7 Hz), 8,03 (dd, 1H, J = 9,2, 4,4 Hz), to 7.68 (dd, 1H, J = 8,9, and 4.5 Hz), 7,51 was 7.45 (m, 2H), 7,38-7,31 (m, 4H), 6,28 (d, 1H, J = 9.1 Hz, 1'H), between 6.08 (t, 1H, J = 3,9 Hz, 6'OH), to 5.35 (d, 1H, J = 6,8 Hz, 4'OH), 4,88 (s, 2H), to 4.81 (d, 1H, J = 6,8 Hz, 2'OH), 4,12-4,08 (m, 1H, 6'H), 3,98-3,93 (m, 1H, 5'H), 3,93-3,90 (m, 1H, 4'H), 3,86-3,82 (m, 1H, 6'H), to 3.73 (t, 1H, J = 8,8 Hz, 3'H), 3,39 (ddd, 1H, J = 9,1, 8,8, 6,8 Hz, 2'H), of 1.23 (s, 9H), 0.76 to (s, 9H), of 0.07 (s, 3H), -0,03 (s, 3H); FAB mass spectrum, m/e 783 (M+).

Example 27

3,9-Debtor-12,13-dihydro-13-[3-O-(tert. butyldimethylsilyl)-6 - O-(methanesulfonyl) -- D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7(6-N-[4-(tert. butyl)benzyl] -)-dione (Ib: X1= X'1= F; X2= X'2= H; R6= 4-(tert.butyl)benzyl; Q = NH, R2= R4= OH; R3= tert.butyldimethylsilyloxy; R5= methansulfonate).

To stir magnetic stirrer, the solution of the pure product from example 26 (403 mg, 0,514 mmol) in anhydrous pyridine (7 ml) at -10oC under argon added via syringe over 1 min methanesulfonyl chloride (46 μl, 0,594 mmol). After 70 min at -10oC select an aliquot, add to the mixture ethyl acetate in methylene chloride. Determine the presence of mostly original material with a small amount of product with higherf. Add additional methanesulfonyl chloride (32 μl), and the reaction is performed for 1 hour at -10oC. at intervals of 30 min the reaction process in the following portions methanesulfonyl chloride (33 μl, 31 μl, 31 ml and 24 ml). Later on the whole 5 hours at -10oC TLC shows the main spot of the product and a little of the original substance with a lower Rf. After another 1.5 hours, the reaction temperature allowed to rise to -1oC -10oC. the Reaction mixture was quenched by adding 200 ál of absolute ethanol, stirred for 5 min and distributed between ethyl acetate (600 ml) and saturated aqueous copper sulfate (II) (250 ml). The organic layer was washed with saturated aqueous copper sulfate (II) (200 ml), water (200 ml) and brine (200 ml) and dried (Na2SO4). Evaporation in vacuum and subsequent flash chromatography on silica gel with 1% methanol in methylene chloride to give 404 mg (91%) net of the above product and 40 mg returned in the original substance: 300 MHz1H NMR (CDCl3): 9,83 (brs, 1H), remaining 9.08 (dd, 1H), 7,80-7,71 (m, 1H), 7,68 (dd, 1H), 7,52 (dd, 1H), 7,40 (ddd, 1H), 7,21-7,13 (m, 2H), 7.03 is of 6.68 (m, 3H), 5,94 (d, 1H), 5,15-to 3.92 (m, 10H), to 3.02 (s, 3H), 1,19 (s, 9H), from 0.84 (s, 9H), to 0.23 (s, 3H), -0,01 (s, 3H); FAB mass glucopyranosyl] indole[2,3-a] pyrrole[3,4-c] carbazole-5,7(6-N-[4-(tert. butyl)benzyl]-)-dione (Ib: X1= X'1= F; X2= X'2= H; R6= 4-(tert.butyl)benzyl; Q = NH, R2= R4= OH; R3= tert.butyldimethylsilyloxy; R5= morpholine).

To stir magnetic stirrer, the solution of the pure product from example 27 (193 mg, 0,224 mmol) in anhydrous DMSO (5 ml) under nitrogen was added morpholine (210 μl, to 2.41 mmol). Received the red reaction mixture is stirred for 69 hours at 47oC and distributed between ethyl acetate (350 ml) and saturated aqueous sodium bicarbonate (75 ml). The organic layer was washed with water (4 x 70 ml) and brine (75 ml) and dried (Na2SO4). Evaporation in vacuum and subsequent flash chromatography on silica gel 20-25% ethyl acetate in methylene chloride to give 9 mg (5% who returned the initial substance and then 102 mg (53%; 56% for returning the source material) net above-named product as a yellow solid: 300 MHz1H NMR (CDCl3): there is a 10.03 (brs, 1H), which is 9.09 (dd, 1H), 8,02-of 7.96 (m, 1H), 7,69 (dd, 1H), 7,39 (ddd, 1H), 7,30-of 7.23 (m, 1H), 7,21-7,17 (m, 2H), 7,07-of 6.96 (m, 3H), 5,96 (d, 1H), 4.53-in-3,93 (m, 6H), 3.72 points is 3.57 (m, 4H), 3,19 are 2.98 (m, 2H), 2,82-a 2.71 (m, 2H), 2,68-of 2.58 (m, 2H), 1,19 (s, 9H), to 0.88 (s, 9H), or 0.27 (s, 3H), and 0.08 (s, 3H); ESI (negative.) mass spectrum, m/e 851 (M-H-).

Example 29

3,9-Debtor-12,13-dihydro-13-[6-(4N-morpholine) -- D-glyukopiranozil]6 = H; R5= 4N-morpholine; Q = NH, R2= R4= OH).

To stir magnetic stirrer, the solution of the pure product from example 28 (205 mg, 0,240 mmol) in absolute ethanol (160 ml) is added aqueous potassium hydroxide (4.45 M, 42 ml, 187 mmol). The obtained dark red solution is heated in an open flask until all the ethanol has evaporated and will remain solid viscous substance (approximately 1.5 hours). The mixture is cooled in a stream of nitrogen and add concentrated HCL (12N; 17 ml, 204 mmol). The mixture is stirred for 5 min and add absolute ethanol (90 ml) and then solid ammonium acetate (85 g). The mixture is heated with stirring in an open flask until almost boiling for 2.5-3 h, then 180oC (internal temperature of melting) in about 2 hours. The mixture is then heated further to 200oC for 10-15 min, quickly cooled in a stream of nitrogen to 50-60oC and treated with water (200 ml), saturated aqueous sodium bicarbonate (200 ml) and ethyl acetate (800 ml). The organic layer was washed with brine (200 ml), the combined aqueous layers extracted with fresh ethyl acetate (300 ml) and the extract washed with brine (100 ml). The combined organic extract is dried (Na2SO4) and evaporated in vacuo. The crude product is dissolved in IU the Ute at room temperature for 15 hours. The solvent is evaporated in vacuum, the residue is again dissolved in methanol (250 ml), treated with 1N HCL (15 ml) and evaporated in vacuo. The residue is dissolved in absolute ethanol (500 ml), evaporated in vacuum and the process is repeated again. Recrystallization from 95% ethanol gives to 79.6 mg (53%, 2 servings) net above-mentioned compounds in the form of its HCl-salt: 500 MHz COSY1H NMR (DMSO-d6): 12,67 (brs, 1H), 11,19 (s, 1H), of 8.92 (dd, 1H, J = 9,7, and 2.6 Hz), 8,79 (dd, 1H, J = 9,8, and 2.3 Hz), with 8.05 (dd, 1H, J = 9,0, 4.5 Hz), 7,94 (dd, 1H, J = 8,7, and 4.5 Hz), 7,46 (ddd, 1H, J = 2,5, 8,9, and 9.0 Hz), 7,41 (ddd, 1H, J = 2,6, 9,0, 9.1 Hz), is 6.61 (d, 1H, J = 8.6 Hz, 1'H), of 3.97 (t, 1H, J = 8,8 Hz, 2'H), 3,91-and 3.16 (m, 13H).

Example 30

3,9-Debtor-12,13-dihydro-13-[6-azido -- D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7(6-hydroxy)-dione (Ic).

To stir magnetic stirrer, a solution of pure 3,9-debtor-12,13-dihydro-13-[6-azido -- D-glyukopiranozil] indole-[2,3-a] pyrrole[3,4-c] carbazole-5,7[6(4-tert. butylbenzyl)] -dione (20 mg, 0,029 mmol) in absolute ethanol (5 ml) is added aqueous potassium hydroxide (4.45 M, 1.1 ml, 4.9 mmol). The obtained dark red solution is heated in an open flask until all the ethanol has evaporated and will remain solid viscous substance (approximately 1.5 hours). The mixture is cooled in a stream of nitrogen and add absolute ethanol (5 ml) and then hydroxylamine hydrochloride (685 the morning melting point after as the evaporated solvent) for about 3 hours. The mixture is cooled in a stream of nitrogen to room temperature and treated with 1N HCl (80 ml) and ethyl acetate (400 ml). The organic layer was washed with 1N HCl (3 x 50 ml), water (2 x 50 ml) and brine (100 ml) and dried (Na2SO4). Evaporation in vacuum and subsequent cleaning on a column with Sephadex LH 20 chromatography with methanol (flow rate of 0.4-0.5 ml/min) to give 4.3 mg (27%) of the above product in the form of a yellow-red solid: IR (KBr) 2114 cm-1; 500 MHz COSY1H NMR (CD3OD) 8,53 (dd, 1H, J = a 9.6, 2.1 Hz), at 8.36 (dd, 1H, J = 9,5, 1.9 Hz), to 7.68 (dd, 1H, J = 8,8, and 3.7 Hz), was 7.36 (dd, 1H, J = 8,8, 4,2 Hz), 7,24 (ddd, 1H, J = 8,7, to 8.7, 2.0 Hz), 7,14 (ddd, 1H, J = 8,9, of 8.8, 2.3 Hz), 5,98 (d, 1H, J = 9,0 Hz, 1'H), 4,47 (d, 1H, J = 12.1 Hz, 6'H), 4,28 (d, 1H, J = 12.1 Hz, 6 H), 4,11 (d, 1H, J = 9.4 Hz, 5'H), 3,91 (t, 1H, J = 9.4 Hz, 4'H), 3,61 (t, 1H, J = 9.0 Hz, 2'H), of 3.46 (dd, 1H, J = 9,4, 9,0 Hz, 5'H); FAB mass spectrum, m/e 564 (M+).

Example 31

3,9-Debtor-12,13-dihydro-13-[6-amino-a-D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7(6-hydroxy)-dione (Ic).

To a solution of the product from example 30 (3.0 mg, 0,0053 mmol) in absolute methanol (2 ml) in nitrogen atmosphere in the device Parr (Parr) add palladium (II) chloride (15 mg, 0.09 mmol). The mixture was exposed to ultrasound for 10 min and placed in a shaker (shaking) Parr (Parr shaker) at a hydrogen pressure of 65 psi is of 2 mg (66%) of the above compound as a yellow-orange solid: FAB mass spectrum, m/e 538 (M+).

Additional examples of compounds of the formula I, which can be synthesized by modifications of previous synthetic methods presented in the following table IV, where the substituents are the same as in example 29, unless otherwise noted.

Analytical data for some of the samples shown in table IV, are given below.

Example 32: IR (KBr) 2110 cm-1; 500 MHz COSY1H NMR (CD3OD): 8,81-8,79 (m, 2H), 7,68 (dd, 1H, J = 9,1, 4.0 Hz), 7,56 (dd, 1H, J = 8,8, 4,2 Hz), 7,38-7,25 (m, 6H), equal to 6.05 (d, 1H, J = 8.5 Hz, 1'H), and 4.75 (s, 2H), 4,29 (d, 1H, J = 12,8 Hz, 6'H), 4,17-4,06 (m, 2H, 5'H, 6"H), of 4.00 (t, 1H, J = 8,9 Hz, 4'H), 3,70-the 3.65 (m, 2H, 2'H, 3'H), of 1.27 (s, 9H); FAB mass spectrum, m/e 694 (M+).

Example 33: yellow solid: IR (KBr) 2112, 1750, 1700 cm-1; 500 MHz COSY1H NMR (CD3OD) 8,78-8,72 (m, 2H), to 7.77 (dd, 1H, J = 9,1, 4,1 Hz), 7,55 (dd, 1H, J = 8,8, 4,2 Hz), 7,33-7,26 (m, 2H), 6,12 (d, 1H, J = 8.5 Hz, 1'H), 4,27 (d, 1H, J = 11.5 Hz, 6'H), 4,15-4,07 (m, 2H, 5'H, 6"H) to 4.01 (t, 1H, J = 8.7 Hz, 4'H), 3,74-to 3.67 (m, 2H, 2'H, 3'H); FAB mass spectrum, m/e 548 (M+).

Example 34: a yellow-orange solid: 500 MHz COSY1H NMR (CD3OD) 8,81-8,61 (m, 2H), 7,88? 7.04 baby mortality (m, 7H), 6,32 (d, 1H, J = 8,9 Hz, 1'H), 4,20-3,30 (m, 6H); FAB mass spectrum, m/e 574 (M+).

Example 35: yellow solid: FAB mass spectrum, m/e 605 (M+).

Example 36: yellow solid, so pl. 257-273oC:1H NMR (500 MHz, DMSO-d6): , H), 2,99-to 2.57 (series m, 4H); IR (KBr, cm-1) 3412, 2924, 2800, 1706, 1653, 1602, 1567, 1481, 1463, 1425, 1321, 1301, 1198, 1110, 1067, 916, 804, 764, 742; MS (+ESI, M+H+m/z 610.

Example 37

12-[6-Amino-6-deoxy -- D-glyukopiranozil] -3-fluoro benzo[b] thienyl[2,3-a]pyrrole[3,4-c]carbazole-5,7 Dion.

Triphenylphosphine (107 mg, 0.41 mmol) is added in one portion to a stirred solution of 12-[6-azido-6-deoxy -- D-glyukopiranozil]-3-fluoro benzo[b]thienyl[2,3-a]pyrrole[3,4-c]carbazole-5,7 dione (75 mg, 0.14 mmol) in wet tetrahydrofuran (3 ml) under nitrogen atmosphere, then the mixture is heated at 50oC for 28 hours, cooled to room temperature and treated with an aqueous ammonium hydroxide solution for 1 hour at room temperature and 1 hour at 50oC. After cooling to room temperature the mixture was concentrated in vacuo and the residue is treated with methanol, acidified with 1N HCl/Et2O and evaporated to dryness. Purification of the residue by HPLC (HPLC) on a column of YMC Pack ODS (h), using 87% B, leads to the above-mentioned compound (54 mg, 71%) as a yellow solid, temperature decomposition 290oC (sealed ampoule);1H NMR (500 MHz, DMSO-d6): for 11.55 (br s, 1H), 9,94-9,90 (m, 1H), 9,03-8,96 (2m, 1H), 8.30 to be compared to 8.26 (m, 4H); 8,12-8,08 (m, 1H), 7,71-7,29 (series of m, 6H), 6,36 and 6,15 (2d, J = 8,9, and 9.3 Hz, 1H), 5,81 and 5.55 (2m, 2H), 4,23-3,70 (5m, 2H),

Example 39

3,9-Debtor-12-[6-amino-6-deoxy -- D-glyukopiranozil]benzofuran-[2,3-a] pyrrole[3,4-c]carbazole-5,7-dione

To stir magnetic stirrer, a solution of 3,9-debtor-12 -[- D-glyukopiranozil] benzofuro[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (50 mg, 0.09 mmol) and powdered molecular sieves 4 Angstrom (100 mg) in anhydrous pyridine (3 ml) at -30oC in argon atmosphere was added via syringe methanesulfonyl chloride (10 μl, 0.12 mmol). The reaction mixture is stirred at -30oC for 1 hour, then at -10oC for 0.5 hour, after which add an additional portion methanesulfonyl chloride (10 μl, 0.12 mmol). The resulting mixture was then stirred at 0oC for 1 hour, filtered off with suction and concentrated. The residue is treated with a mixture of EtOAc/THF (350 ml) and washed with water, dried (Na2SO4) and evaporated. The obtained residue was washed with toluene to obtain a coarse yellow product, which was directly used in next reaction without further purification. Sodium azide (62 mg, 0.95 mmol) is added to a stirred solution of 3.9-debtor-12-[6-O-(methylsulphonyl)-a-D-glyukopiranozil] benzofuran-[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione (54 mg, 0.09 mmol) in anhydrous DMF (3 ml), after which the mixture narushat (Na2SO4) and concentrated in vacuo. Coarse yellow product is directly used in the next reaction without further purification. A mixture of 3,9-debtor-12-(6-azido-6-deoxy -- D-glyukopiranozil] benzofuro[2,3-a] pyrrole[3,4-c]carbazole-5,7-dione (example 40) (49 mg, 0.09 mmol) and 10% palladium on coal (50 mg) in ethanol (3 ml) and THF (1 ml) hydronaut at 1 ATM for 21 hours. The resulting mixture was filtered, washed with methanol and THF, and concentrated in vacuo. The crude product chromatographic (60% CH2Cl2:20% THF and 20% solution of 90% MeOH and 10% NH4OH) to give the above compound (20 mg, 42%) as a yellow solid: IR (KBr) 1753, 1701, 1479 cm-1;1H NMR (DMSO-d6, 400 MHz): 8,87-8,82 (m, 1H), 8,56-8,49 (m, 1H), 8,10-to 7.99 (m, 2H), to 7.67-to 7.50 (m, 2H), 6,53 (d, 0,7 H, J = 9.0 Hz), 6,14 (d, 0,3 H, J = 9.0 Hz), 5,44-and 5.30 (m, 2H), 4,28-of 2.86 (m, 7H); HPLC (HPLC): 90,4% (247 nm).

Example 45: 300 MHz1H NMR (d6-acetone) of $ 11.97 (brs, 1H), to 9.91 (s, 1H), 9,12 (dd, 1H), 8,88 (dd, 1H), 7,92 (dd, 1H), 7,69 (dd, 1H), 7,47-of 7.23 (m, 2H), of 7.48 (ddd, 1H, J = 2,5, 8,9, and 9.1 Hz), 7,41 (ddd, 1H, J = 2,5, 8,9, and 9.1 Hz), 6.73 x (s, 1H, 1'H), 4,60-3,95 (m, 6H).

Example 47: 500 MHz1H NMR (CDCl3with the drop of d6-DMSO) 10,36 (d, 1H, JH-F = 4,2 Hz), 9,98 (brs, 1H), 8,81 (dd, 1H, J = a 9.5, 2.6 Hz), 8,68 (dd, 1H, J = a 9.5, 2.6 Hz), 7,47 (dd, 1H), 7,30-7,24 (m, 1H), 7,15? 7.04 baby mortality (m, 2H), of 5.84 (d, 1H, J = 8.5 Hz), 5,02 (d, 1H, JH-F = 45,2 Hz, JH-H = 10.1 Hz), 4.72 in (dd, 1H, JH-F = 49,6 Hz, JH-H = 10.1 Hz), 4, 8,80-7,20 (m, 1H), 6,38 (d, 1H), 5,15 is-3.45 (m, 6H); ESI (negative.) mass spectrum, m/e 540 (M-H)-.

Additional examples of compounds of the formula I, which can be synthesized by modifications of previous synthetic methods presented in the following table V, where the substituents are the same as in example 29, unless otherwise noted.

Analytical data for some of the samples shown in table V, are given below.

Example 50: yellow solid, so pl. 242-248oC decomp.:1H NMR (500 MHz, DMSO-d6): 11,55 (b m, 1H), 9,75-to 9.57 (2m, 1H), 9,01-8,87 (2m, 1H), 8,23-7,98 (3m, 2H), EUR 7.57-7,34 (2m, 2H), 6,33 and 6,21 (2d, J = 8,8, and 9.4 Hz, 1H), 5,69-5,61 (2m, 1H), 5,44-5,17 (2m, 2H), 4,12-of 3.96 (t, 4H), 3,66-3,55 (2m, 2H); IR (KBr, cm-1) 3392, 2926, 1703, 1622, 1602, 1567, 1481, 1463, 1426, 1324, 1198, 1085, 915, 806, 763, 742; MS (-ESI M-H-) m/z 557.

Example 52: yellow solid, so pl. 248-250oC:1H NMR (500 MHz, DMSO-d6): 11,73, 11,65 and are 11.62 (3s, 1H), 9,81-9,68 (2m, 1H), 9,07-8,99 (2m, 1H), 8,27-of 8.00 (m, 2H), to 7.61-to 7.50 (m, H), 6,38 and 6.26 (2d, J = 8,8, and 9.3 Hz, 1H), 5,69-to 5.21 (series of m, 3H), of 5.05-4,82 (m, 2H), 4,25-3,82 (m, 2H), 3.72 points-3,61 (m, 1H); IR (KBr, cm-1) 3384, 1706, 1622, 1602, 1568, 1481, 1463, 1325, 1198, 1086, 916, 806, 763, 742; MS (-ESI M-H-) m/z 541.

Example 54: 300 MHz1H NMR (CD3OD) 8,80 (dd, 1H, J = 9,6, and 2.3 Hz), 8,72 (dd, 1H, J = 9,9, 2,8 Hz), 7,84-7,73 (m, 2H), 7,37-7,26 (m, 2H), x 6.15 (d, 1H, J = 9.5 Hz), 4,34-4,27 (m, 1H), 4,14 (t, 1H, J = 9.5 Hz), of 3.97 (t, 1H, J = 9.0 Hz), 3,74 (t, 1H, J = 9.0 Hz), of 3.45 (dd, 1H, J = 14,8, glucopyranosyl]-3-fluoro benzo[b]thienyl[2,3-a]pyrrole[3,4-c]carbazole-5,7 Dion.

Sodium azide (216 mg, 3,30 mmol) added in one portion to a stirred solution of 3-fluoro-13-[6 (methylsulphonyl)-a-D-glyukopiranozil] benzo[b]thienyl[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione (0.20 g, 0.33 mmol) in anhydrous dimethylformamide (3 ml), after which the mixture is heated at 120oC for 3 h, cooled to room temperature and concentrated in vacuo. The residue is purified on a flash chromatography on silica gel (elution with 40% of tetrahydrofuran in hexane) to give the above product (141 mg, 78% in the form of a yellow solid, the decomposition temperature of 265oC; 1H NMR (500 MHz, DMSO-d6): 11,51 (br s, 1H), 9,94-9,87 (2m, 1H), 9,03-8,95 (2m, 1H), 8,20-7,99 (3m, 2H), to 7.67-7,63 (m, 2H), 7,53-7,49 (m, 1H), 6,37 and of 6.20 (2d, J = 8,9 and 9.4 Hz, 1H), 5,54-5,14 (series of m, 3H), 4,10-3,76 (4m, 3H), 3,67-3,26 (m, 3H); IR (KBr, cm-1) 3332, 2103, 1702, 1481, 1461, 1431, 1372, 1324, 1283, 1230, 1211, 1178, 1079, 746; MS (-ESI, M-H-) m/z 546.

Example 57: yellow solid, so pl. 268-277oC (decomp.);1H NMR (500 MHz, DMSO-d6): to 11.52 (br s, 1H), 9,75-9,51 (3m, 1H), 9,00-8,88 (2m, 1H), 8.30 to-7,97 (3m, 2H), 7,66-7,22 (3m, 2H), 6,35-6,20 (2m, 1H), 5,86-to 5.56 (m, 1H), 5,42 to 5.35 (m, 2H), 4,28-to 3.89 (m, 2H), 3.72 points of 3.56 (m, 2H), 3,50-of 3.32 (m, 1H), 3,27-3,14 (m, 1H), 2,61-2,53 (4s, 3H); IR (KBr, cm-1) 3412, 2950, 1707, 1625, 1605, 1481, 1464, 1385, 1324, 1283, 1198, 1086, 916, 746, 742; LCMS (-ESI, M-H-) m/z 685.

Example 58: yellow-orange solid (mixture of diastereomers at the fo is 5-6,10 (m, 1H), 5,80-a 5.25 (m, 3H), 4,30-3,10 (m, 6H), was 2.76, 2,74, 2,58 and 2,56 (all s, 3H); neg. ESI mass spectrum, m/e 568 (M-H)-.

Example 59: 300 MHz1H NMR (CD3OD): 8,87 (dd, 1H, J = 9,6, and 2.6 Hz), 8,78 (dd, 1H, J = 9,8, and 2.6 Hz), 7,94 (dd, 1H, J = 8,9, and 4.4 Hz), 7,83 (dd, 1H, J = 9,0, 4,1 Hz), 7,38-7,27 (m, 2H), 6,14 (d, 1H, J = 9.3 Hz), 4,34-4,18 (m, 2H), 3,94 (t, 1H, J = 9,2 Hz), to 3.73 (t, 1H, J = 8,9 Hz), 3,51-up 3.22 (m, 4H); neg. ESI mass spectrum, m/e 596 (M-H)-.

Example 60: yellow solid, so pl. 228-232oC;1H NMR (500 MHz, DMSO-d6): 11,88 and 11,76 (2br m, 1H), 9,75-RS 9.69 (2m, 1H), 8,73-8,62 (2m, 1H), 8,18 and 8,09 (2d, J = 4,8, 4,7 Hz, 1H), 7,99-7,92 (2m, 1H), 7,65-7,35 (m, 3H), 6,28 and 6,07 (2d, J = 8,9, and 9.2 Hz, 1H), from 5.29-equal to 4.97 (3m, 3H), 4,10-3,85 (3m, 2H), 3,60-of 3.48 (m, 2H), 2,97-2,70 (3m, 2H), 2,58 (m, 3H), 1.56 to the 1.44 (m, 5H), of 1.34 (m, 2H); IR (KBr, cm-1) 3406, 2934, 1705, 1622, 1481, 1461, 1430, 1374, 1321, 1284, 1179, 1081, 1038, 758, 747; MS (+ESI, M+H+) m/z 590.

Example 61: yellow solid, so pl. 228-232oC;1H NMR (500 MHz, DMSO-d6): 11,88 and 11,76 (2br m, 1H), 9,75-RS 9.69 (2m, 1H), 8,73-8,62 (2m, 1H), 8,18 and 8,09 (2d, J = 4,8, 4,7 Hz, 1H), 7,99-7,92 (2m, 1H), 7,65-7,35 (m, 3H), 6,28 and 6,07 (2d, J = 8,9, and 9.2 Hz, 1H), from 5.29-equal to 4.97 (3m, 3H), 4,10-3,85 (3m, 2H), 3,60-of 3.48 (m, 2H), 2,97-2,70 (3m, 2H), 2,58 (m, 3H), 1.56 to the 1.44 (m, 5H), of 1.34 (m, 2H); IR (KBr, cm-1) 3406, 2934, 1705, 1622, 1481, 1461, 1430, 1374, 1321, 1284, 1179, 1081, 1038, 758, 747; MS (+ESI, M+H+) m/z 590.

Example 62: yellow solid, so pl. 280-282oC;1H NMR (500 MHz, DMSO-d6): 11,64 (br s, 1H), 9,83-9,68 (2m, 1H), remaining 9.08-8,97 (2m, 1H), 8,45-7,10 (series of m, 8H), 6,37 and 6.25 (2d, J = 8,8, 9.1 Hz, 1H), 5,74-5,68 (2m MS (-ESI, M-H-) m/z 632.

Example 63: yellow solid, decomposition temperature 248oC;1H NMR (500 MHz, DMSO-d6): 11,65 (br s, 1H), 9,78-9,73 (2m, 1H), 9,07-8,97 (2m, 1H), 8.30 to-7,95 (series of m, 3H), to 7.61-7,42 (2m, 3H), 7,15-7,06 (m, 2H), 6,37 and 6.25 (2d, J = 8,8, and 9.3 Hz, 1H), 5,81-5,22 (series of m, 3H), 4,32-4,12 (3m, 3H), of 3.77-3,63 (m, 3H); IR (KBr, cm-1) 3401, 2963, 1752, 1707, 1475, 1465, 1424, 1261, 1198, 1092, 1021, 801; LCMS (+ESI, M+H+) m/z 650.

Example 64: received 15,1 mg (49%), yellow solid, so pl. 254-265oC (decomp.);1H NMR (500 MHz, DMSO-d6): of 11.61 (br s, 1H), 9,76-9,66 (2m, 1H), 9,01-8,92 (2m, 1H), 8,31-of 7.96 (3m, 2H), 7,78 (br s, 1H), 7,85 was 7.45 (m, 2H), 6.30-in and to 6.19 (2d, J = 8,9, and 9.4 Hz, 1H), of 5.99 (br s, 1H), 5,50-5,16 (series of m, 3H), 4,12-3,92 (3m, 3H), 3,61-3,39 (m, 3H); IR (KBr, cm-1) 3392, 2927, 1706, 1661, 1604, 1567, 1532, 1480, 1463, 1384, 1324, 1085, 916, 826, 807, 764, 742; MS (-ESI, M-H-) m/z 649.

Example 65: yellow solid, so pl. 244-246oC;1H NMR (500 MHz, DMSO-d6): 11,63 (br s, 1H), 9,75-9,67 (2m, 1H), 9,00-8,94 (2m, 1H), 8,28-8,20 (2m, 1H), 8,11-7,97 (2m, 1H), EUR 7.57-to 7.50 (m, 2H), 6.30-in and 6,16 (2d, J = 8,8, and 9.3 Hz, 1H), 5,63-5,19 (series of m, 3H), 4,05-was 4.02 (m, 1H), 3,61-of 3.07 (m, 6H); IR (KBr, cm-1) 3412, 1762, 1703, 1602, 1482, 1456, 1464, 1425, 1315, 1259, 1199, 1082, 916, 807, 763, 742; MS (-ESI, M-H-) m/z 637.

Example 66: received 4,7 mg (55%), yellow solid, so pl. 252-254oC (decomp.);1H NMR (500 MHz, DMSO-d6): 11,60 (br s, 1H), 9,83-9,71 (2m, 1H), 9,07-9,01 (2m, 1H), 8.30 to-8,07 (3m, 2H), 7,65-7,56 (2m, 2H), to 6.43-6,30 (2m, 1H), 5,73-5,71 (m, 1H), 5,55-5,20 (2m, 2H), 4,21-4,07 (m, 4HLASS="ptx2">

Example 67: received 10.5 mg (26%), yellow solid, decomposition temperature 290oC; 1H NMR (500 MHz, DMSO-d6): 12,34 and 12,23 (2s, 1H), 11,58 (s, 1H), 9,75-9,63 (2m, 1H), 9,01-8,92 (2m, 1H), 8,23-of 8.15 (m, 1H), 8.17-a of 7.96 (m, 1H), 7,53-7,46 (m, 2H), 7,11-6,85 (series of m, 2H), 6,32, and 6,15 (2d, J = 8,9, and 9.3 Hz, 1H), 5,85-5,14 (series of m, 3H), 4,11-3,98 (m, 2H), 3,71-to 3.49 (m, 4H); IR (KBr, cm-1) 3242, 2926, 1751, 1705, 1602, 1481, 1463, 1426, 1325, 1198, 1086, 915, 763, 742; MS (-ESI, M-H-) m/z 621.

Example 71

2,3,9,10-Titrator-12-(4-deoxy-4,4-debtor -- D-glyukopiranozil] indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

To a solution of periodinane dess-Martin (0,470 g, 1.11 mmol) in 30 ml of dichloromethane is added dropwise a solution of 6-(4-tert.butylbenzyl)-2,3,9,10-titrator-12-(2,3,6-tri-O-benzyl-a-D-glyukopiranozil] -indole[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (0,540 g, 0.55 mmol) in 20 ml of dichloromethane and the mixture is stirred at room temperature under Ar for 1 hour. Add another portion of the reagent dess-Martin and continue stirring for 2 hours. The resulting mixture was diluted with dichloromethane, washed (feast upon. NaHCO3-Na2S2O3, feast upon. NaHCO3, brine), dried (Na2SO4) and evaporated. The remainder chromatographic (SiO2/hexane-ethyl acetate, 2:1) to give the ketone (0,360 g, 67% in the form of a dark yellow solid.

To portions to which the atur under AG for 18 hours. The mixture is then partitioned between dichloromethane and feast upon. NaHCO3and the organic phase is separated, washed (brine), dried (Na2SO4) and evaporated to obtain the resin. Flash chromatography (SiO2/hexane-ethyl acetate, 3:1) gives 6-(4-tert. butylbenzyl)-2,3,9,10-titrator-12-(4-deoxy-4,4-debtor - 2,3,6-tri-O-benzyl-a-D-glyukopiranozil] -indole[2,3-a] pyrrole[3,4-c]carbazole-5,7-dione (0,054 g, 54%) as a yellow solid:

1H NMR (CDCl3, 400 MHz): of 10.21 (s, 1H), 9,14 (dd, J = 10,6, and 8.4 Hz, 1H), 9,02 (dd, J = 10,7, 8,2 Hz, 1H), 7,53 (d, J = 8.7 Hz, 2H), 7,40 (d, J = 8.7 Hz, 2H), 7,34 (m, 5H), 7,20 for 7.12 (m, 6H), 6,97 (dd, J = 10,0, 6,6 Hz, 1H), 6,80 (t, J = 7,4 Hz, 1H), 6,72 (t, J = 7,6 Hz, 1H), 6,13 (d, J = 7.2 Hz, 2H), of 5.82 (d, J = 8.6 Hz, 1H), equal to 4.97 (m, 3H), 4,80 (d, J = 11,1 Hz, 1H), 4,65 and br4.61 (ab q, J = 12.0 Hz, 2H), 4,24-4,01 (m, 6H), 3,37 (d, J = a 10.6 Hz, 1H), of 1.28 (s, 9H).

Protective groups in this compound is removed in the usual way (i. aq. NaOH, THF-EtOH; conc. HCl; ii. NH4OAc, D; iii. H2Pd(OH)2-C, CHCl3-MeOH) to give the above compound (total yield 24%) as a yellow solid:

IR (KBr) 3410, 1747, 1704, 1596, 1478, 1323 cm-1;

1H NMR (DMSO-d6, 400 MHz): is 11.39 (s, 1H), 11,34 (s, 1H), 8,93 (m, 2H), 8,03 (dd, J = 11.8 in that 6.8 Hz, 1H), 7.62mm (dd, J = 10,7, 6,9 Hz, 1H), is 6.54 (d, J = 9,2 Hz, 1H), 7,34 (m, 5H), between 6.08 (m, 2H), 5,48 (d, J = 5,9 Hz, 1H), 4,43 (m, 1H), 4,22 (m, 1H), 4,06 (m, 2H), 3,66 (m, 1H).

MS (ESI) m/e 578 (M-H).

HPLC (HPLC): to 91.1%,81 (dd, 1H), of 8.06 (dd, 1H), 7,78 (dd, 1H), 7,49-7,39 (m, 2H), 6,28 (d, 1H, 1'H, J = 8,8 Hz), to 5.85 (d, 1H, 3'OH), the 5.45 (d, 1H, 2'OH), 4,25-to 3.89 (m, 3H, 2'H, 3'H, 5'H), 3,68 (t, 1H, 4'H), of 1.42 (d, 3H, 6'H); A negative. ESI mass spectrum, m/e 531 (M-H)-. IR (KBr) 2112 cm-1.

Example 79: yellow solid: 500 MHz1H NMR (d6-DMSO) 12,72 (s, 1H), 11,18 (br s, 1H), of 8.92 (dd, 1H), 8,80 (dd, 1H), 8,21 (br s, 1H), 8,07 (dd, 1H), 7,94 (dd, 1H), of 7.48-7,39 (m, 2H), 6,60 (d, 1H, J = 7.8 Hz, 1'H), 5,98 (br s, 1H, 3'OH), of 5.48 (brs, 1H, 2'OH), 4,55-4,50 (m, 1H, 5'H), 4,07-was 4.02 (m, 2H, 2'H, 3'H), 3,19 (t, 1H, 4'H), 1,43 (d, 1H, 4'H); the Negative. ESI mass spectrum, m/e 505 (M-H)-.

Example 87: yellow solid: 300 MHz1H NMR (CD3OD) 8,84 (dd, 1H), total of 8.74 (dd, 1H), to 7.77 (dd, 1H), 7,35-7,24 (m, 2H), 6,14 (d, 1H, J = 9,2 Hz), 4,55-4,50 (m, 1H, 5'H), 4,23-3,95 (m, 4H), 3,90 (t, 1H, J = 9,2 Hz), 3,74 (t, 1H, J = 9.0 Hz); the Negative. ESI mass spectrum, m/e 547 (M-H)-.

Example 88: yellow solid: 500 MHz1H NMR (CD3OD) 8,89 (dd, 1H), 8,77 (dd, 1H), 7,81 (dd, 1H), 7,63 (dd, 1H), 7,33-7,26 (m, 2H), x 6.15 (d, 1H, J = 8,9 Hz), 4,24-3,88 (m, 3H), 4,23-3,95 (m, 4H), to 3.73 (t, 1H, J = 8,9 Hz) and 3.59 (dd, 1H, J = 9,6, and 8.9 Hz), 3,54 (t, 1H, J = 9.6 Hz); the Negative. ESI mass spectrum, m/e 521 (M-H)-.

Example 89: yellow solid: IR (KBr) 3435, 3345, 1740, 1713, 1477, 1320 cm-1;1H NMR (THF-d8, 400 MHz): 11,50 (s, 1H), 10,12 (s, 1H), 10,12 (s, 1H), remaining 9.08 (dd, J = 11.8 in, 8.6 Hz, 1H), 8,99 (dd, J = 11.0 in, and 8.4 Hz, 1H), 7,71 (dd, J = 11,5, 6,6 Hz, 1H), 7,63 (dd, J = 10,3, 6,7 Hz, 1H), 6,11 (d, J = 8,9 Hz, 1H), and 5.30 (d, J = 4.5 Hz, 1H), free 5.01 (d, J = 4,1 Hz, 1H), to 4.62 (d, J = 5,1 Hz, 1H), 4,56 (d, J = 9.7 Hz, 1H), 4.00 points (s, 3H), 3,97-l[3,4-c]carbazole-5,7-dione.

Using the methodology of Mitsunobu previously described in example 22, 250 mg (0,465 mmol) of product from example 6 and 210 mg (0,464 mmol) 2-fluoro-3,4,6-tri-O-benzyl-D-glucopyranose (obtained by treating industrial available tri-O-benzyl-D-glucola (1.5 g, 3.6 mmol) diferida xenon (1.0 g, 5,91 mmol) in acetonitrile (50 ml) and water (5 ml) for 3 h at room temperature. Subsequent typical processing flash chromatography on silica gel using 5% ethyl acetate in methylene chloride gives 380 mg (23,4%) of pure 2-fluoro-3,4,6-tri-O-benzyl-D-glucopyranose. This method is a modification of the published method: see T. Hayashi, B. W. Murray, R. Wang, and C.-H. Wong Bioorganic and Medicinal Chemistry, 1997, 5, 497-500.). Subsequent cleaning flash chromatography on silica gel using 20-60% methylene chloride in hexane obtain 120 mg (28%) sufficiently pure glycosylated product: remove the protective benzyl groups using hydrogenation conditions (95% EtOH/cyclohexan/20% Pd(OH)2A /C, boiling for onset 6 to 48 hours) with subsequent removal of 4-tert.butilkoi protective groups in terms of the basic hydrolysis of (4.45 M KOH, EtOH/boiling; conc. HCl; NH4OAc/EtOH/heating for 8-48 h) lead after a clean flash-chromatography on silica gel using acetone : methylene chloride: is stogo the above compound as a yellow-orange solid: 500 MHz1H NMR (d6-DMSO): 11,68 (br s, 1H), 11,28 (br s, 1H), 8,88 (dd, 1H), 8,78 (dd, 1H), 8,10 (dd, 1H), 7,68 (dd, 1H), 7,60-the 7.43 (m, 2H), 6,77 (dd, 1H, J = 8,8, 2,5 Hz), 6,23 (br s, 1H), 5,77 (br s, 1H), 5,62 (br s, 1H), 4,32 (dt, 1H, J = 50,7, 9.0 Hz), 4,15-of 3.80 (m, 5H); Negative. ESI mass spectrum, m/e 524 (M-H)-.

Example 91

3,9-Debtor-12 -(- D-glyukopiranozil]benzofuro[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

Yellow solid.

IR (KBr) 1757, 1706, 1483 cm-1.

1H NMR (DMSO-d6, 400 MHz): of 11.45 (br s, 1H), 8,84-8,79 (m, 1H), 8,53-8,46 (m, 1H), 8,08-7,81 (m, 1H), of 7.64-to 7.50 (m, 2H), of 6.49 (d, 0,7 H, J = 8,9 Hz), 6,07 (d, 0,3 H, J = 8,9 Hz), 5,38-5,16 (m, 3H), 4.75 V-is 4.21 (m, 1H), 3,93-to 3.49 (m, 6H).

HPLC (HPLC): 97,5% (305 nm).

Example 92

3-Bromo-9-fluoro-12 -(- D-glyukopiranozil] benzofuro[2,3-a]pyrrole[3,4-c] carbazole-5,7-dione.

Yellow solid.

IR (KBr) 1775, 1708 cm-1.

1H NMR (DMSO-d6, 400 MHz): of 11.69 and 11,49 (2 brs, 1H), 8,97 (d, 0,3 H, J = 2.0 Hz), 8,91 (d, 0,7 H, J = 2.0 Hz), cent to 8.85-7,79 (m, 1H), 8,08-to 7.77 (m, 3H), to 7.59-7,49 (m, 1H), 6,47 (d, 0,7 H, J = 9.0 Hz), 6,07 (d, 0,3 H, J = 9.0 Hz), lower than the 5.37-to 5.21 (m, 3H), 4,79-4,20 (m, 1H), 3,92-of 3.54 (m, 6H).

HPLC (HPLC): 92,5% (260 nm).

Example 93

3-Cyano-9-fluoro-12 -(- D-glyukopiranozil]benzofuro[2,3-a]pyrrole[3,4-c] carbazole-5,7-dione.

3-Bromo-9-fluoro-12 -(- D-glyukopiranozil] benzofuro[2,3-a]pyrrole[3,4-c] carbazole-5,7-dione (189 mg, 0.2 mmol) is mixed with cyanide zinc (14 mg, 0.6 mmol) and t is t at 80oC in nitrogen atmosphere for 16 hours. The mixture is cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated. The obtained residue chromatographic (hexane: EtOAc, 7:3) to give 3-cyan-9-fluoro-12-(2,3,4,6-Tetra-O-benzyl - D-glyukopiranozil)benzofuro[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (160 mg, 90% in the form of a yellow solid: IR (KBr) 2235 cm-1. To a solution of 3-cyan-9-fluoro-12-(2,3,4,6-Tetra-O-benzyl-a-D-glyukopiranozil)benzofuro[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (58 mg, 0.06 mmol) in 5 ml dry CH2Cl2added dropwise boron trichloride (of 0.39 ml, 1.0 M solution in CH2Cl2) at -78oC. the resulting solution was brought to 0oC and stirred for 2 hours and then cooled to -78oC, then add methanol (5 ml). The resulting mixture was warmed to room temperature. The solvent is removed in vacuo and the resulting residue treated with EtOAc/THF and washed with 10% aqueous HCl and brine, then dried (Na2SO4and concentrate the solvent. Purification of the residue by TLC (THF:hexane, 9:1) leads to the above-mentioned compound (18 mg, 53%) as a yellow solid: IR (KBr) 3417, 2220, 1757, 1708, 1635, 1478 cm-1.1H NMR (DMSO-d6, 400 MHz): 9,05 (s, 0,3 H), 8,9

Example 94

3-Iodine-9-fluoro-12 -(- D-glyukopiranozil]benzofuro[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

3-Bromo-9-fluoro-12 -(- D-glyukopiranozil]benzofuro[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione (189 mg, 0.2 mmol) is mixed with bis(tributylamine) (0.2 ml, 0.4 mmol) and tetrakis-(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in purified from oxygen NMP (2 ml) and the yellow slurry was heated at 90oC in nitrogen atmosphere for 18 hours. The mixture is cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated. The obtained residue chromatographic (hexane: EtOAc, 4:1) to obtain 3-tributylamine-9-fluoro-12-(2,3,4,6-Tetra-O-benzyl-a-D-glyukopiranozil)benzofuran-[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (160 mg, 90%) as a yellow oil. To a solution of this yellow oil in 5 ml of CH2Cl2add I2(33 mg, 0.13 mmol) and the mixture is stirred at room temperature for 0.5 hour. The resulting mixture was treated with saturated NaHCO3, water, brine, dried and evaporated. Coarse residue (118 mg, 91%) treated with boron trichloride (of 0.71 ml, 1.0 M solution in CH2Cl2as described above, and receive the above-mentioned compound as a yellow solid: IR (KBr) 3140, 3040, 1753, 1703, 1405 cm-1;1H NMR (DMSO-d6

Example 95

6-(4-Tert.butylbenzyl)-2,3,9,10-titrator-12-(2,3,4,6-Tetra-O-benzyl - D-glyukopiranozil)benzofuro[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

To a suspension of 6-(4-tert.butylbenzyl)-2,3,9,10-tetraploidy[2,3 - a]pyrrole[3,4-c] carbazole-5,7-dione (1,131 g of 2.08 mmol) and anhydrous Na2SO4(5.0 g) in 25 ml dry THF add finely ground KOH (0,932 g of 16.6 mmol). The resulting mixture was intensively stirred at room temperature under Ar for 1.5 hour. To the resulting dark purple mixture add a solution of 2,3,4,6-Tetra-O-benzyl-a-D-glyukopiranozil chloride (1,450 g, 2,60 mmol) in 10 ml dry THF and continue stirring for 24 hours. Add additional 0,200 g (0.36 mmol) of harihara and continue stirring for another 24 hours. The mixture is then diluted with ethyl acetate and quenched with 1N HCl. The organic phase is separated, washed (brine), dried (Na2SO4) and evaporated to a yellow foam. Flash chromatography (preabsorbed on SiO2; elute with a mixture of hexane-ethyl acetate, 5:1) gives the product as a pale yellow glassy substance. It is a vitreous substance is treated with dichloromethane and the solution was diluted with methanol. The concentration of this p 0 g, 54% as a pale yellow solid: IR (KBr) 3307, 3140, 1748, 1694, 1593, 1473, 1072 cm-1;1H NMR (DMSO-d6, 400 MHz): of 10.58 (s, 1H), 9,18 (dd, J = 10,7, 8,2 Hz, 1H), 9,07 (dd, J = 10,8, 8,2 Hz, 1H), 7,53 (d,] = 8,3 Hz, 1H), 7,41 (m, 6H), 7,28 (m, 8H), 7,22 (m, 4H), 6,94 (dd, J = 10,1, 6.5 Hz, 1H), to 6.88 (t, J = 7,3 Hz, 1H), for 6.81 (t, J = 7,3 Hz, 2H), 6,16 (d, J = 7.2 Hz, 2H), of 5.75 (d, J = 8,4 Hz, 1H), to 5.03 (d, J = 10,8 Hz, 1H), 4,96 (m, 2H), 4,78 (d, J = 10,8 Hz, 1H), with 4.64 (d, J = and 12.2 Hz, 1H), 4,58 (d, J = and 12.2 Hz, 1H), 4,29 (t, J = 10.4 Hz, 1H), 4,07 (d, J = 10.1 Hz, 1H), 4,00-of 3.85 (m, 5H) and 3.15 (d, J = 9,2 Hz, 1H), 1,28 (s, 9H).

Anal. Calc. C65H55F4N3O7: C, 73,22; H, 5,20; N, 3,94. Found: C, 72,92; H, To 5.58; N, Was 4.02.

Example 96

2,3,9,10-Titrator-12 -(- D-glyukopiranozil)indole[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione.

IR (KBr) 3432, 3310, 1743, 1702, 1475, 1331 cm-1;1H NMR (DMSO-d6, 400 MHz): up 11,86 (s, 1H), 11,31 (s, 1H), 8,99 (dd, J = 11,1, 8.5 Hz, 1H), of 8.92 (dd, J = 11,2, 8,3 Hz, 1H), 8,18 (dd, J = 11,7, 6,9 Hz, 1H), 7.62mm (dd, J = 11,0, 7,0 Hz, 1H), of 6.26 (d, J = 9.0 Hz, 1H), to 6.19 (t, J = 4,2 Hz, 2H), 5,43 (d, J = 4,8 Hz, 1H), 5,17 (d, J = 5.7 Hz, 1H), 4,99 (d, J = 5.6 Hz, 1H), 4,10 (dd, J = 10,7, 4,2 Hz, 1H), 3,92 (m, 2H), 3,82 (m, 1H), only 3.57 (m, 1H), 3,41 (m, 1H). HPLC (HPLC): to 97.1% (320 nm).

Example 97

2,3,9,10-Titrator-12-(6-fluoro-6-deoxy -- D-glyukopiranozil)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

IR (KBr) 3440, 3365, 1750, 1705, 1478 cm-1;1H NMR (DMSO-d6, 400 MHz): 12,04 (s, 0.5 H), to 11.31 (s, 0.5 H), 11,27 (s, 0.5 H), is 10.68 (s, 0.5 H), 9,07 (dd, J = 11,3, 8,8 Hz, 0.5 H), of 8.95 (dd, J = 19,4, 9,2 J = 8,8 Hz, 0.5 H), 6,32 (d, J = 7.9 Hz, 2H), 5,98-to 4.73 (m, 5H), 4,22-of 3.46 (m, 4H). HPLC (HPLC): level 98.2% (320 nm).

Example 98

6-(4-Tert. butylbenzyl)-2,3,9,10-titrator-12-(2,3,4-tri-O-benzyl-a-D-galactopyranosyl)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

A solution of 6-(4-tert.butylbenzyl)-2,3,9,10-titrator-12-(2,3,4 - tri-O-benzyl-4-O-(methoxybenzyl) -- D-galactopyranosyl)indole[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (is 0.135 g, 0.12 mmol) in 10 ml of 10% TFA-CH2Cl2stirred at room temperature under Ar for 20 minutes the mixture is diluted with dichloromethane and then washed it (feast upon. NaHCO3), dried (MgSO4) and evaporated. The obtained residue chromatographic (SiO2/acetate-hexane, 1:2) to obtain the above-mentioned compounds (0,107 g, 90%) as a yellow solid:

1H NMR (DMSO-d6, 400 MHz): 12,21 (s, 1H), 9,00 (dd, J = 11,1, an 8.4 Hz, 1H), 8,90 (dd, J = 11,2, and 8.4 Hz, 1H), 8,11 (dd, J = 12,0, 6,9 Hz, 1H), to 7.61-to 7.18 (m, 15H), of 6.71 (t, J = 7,4 Hz, 1H), 6,61 (t, J = 7.7 Hz, 2H), to 6.39 (d, J = 9,2 Hz, 1H), 6,18 (d, J = 7.2 Hz, 2H), 4,89 (s, 2H), 4,87 (d, J = a 13.9 Hz, 1H), 4,71 (d, J = 12.1 Hz, 1H), 4,58 (s, 1H), 4,49 (s, 2H), 4,33 (m, 1H), 4,20 (m, 2H), 4,00-3,66 (m, 4H), to 3.58 (d, J = 11.2 Hz, 1H), 1.26 in (s, 9H).

Example 99

6-(4-Tert. butylbenzyl)-2,3,9,10-titrator-12-(2,3,4-tri-O - benzyl-4-deoxy - D-galactopyranosyl)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

To a solution of 6-(4-tert.butylbenzyl)-2,3,9,10-tetraf the sludge added DMAP (0,100 g, 0.82 mmol), and then penishealthinformation (of 0.085 g, 0.49 mmol) and the mixture heated to boiling under reflux under Ar for 19 hours. Then add an additional 0,043 g (0.25 mmol) of penishealthinformation and 0,030 g (0.25 mmol) DMAP and the mixture is heated to boiling under reflux for 19 hours. The cooled mixture is distributed between ethyl acetate and saturated NaHCO3and the organic phase is washed, dried and evaporated. The residue is subjected to flash chromatography (SiO2/acetate-hexane, 1:3) and get thionocarbonate (0,320 g, 0.29 mmol, 70%) as a solid. This product is dissolved in 10 ml of toluene, the solution is cleaned by blowing a jet of Ar for 15 min and then added AIBN (0,010 g, 0.06 mmol) and anti-hydride (0.126 g, 0.43 mmol). The resulting solution was heated to boiling under Ar under reflux for 18 hours. Then add an additional 0,043 g (0.25 mmol) of anti-and 0.010 g of AIBN and continue heating while boiling under reflux for 4 hours. The cooled mixture was evaporated and the residue is subjected to flash chromatography (SiO2/acetate-hexane, 1:2) and receive the above-mentioned compound (0,215, 78%) as a yellow solid:

1H NMR (CDCl3, 400 MHz): 10,69 (s, 1H), 9,15 (dd, J = 10,7, 8,4 G is 4,19 of 3.75 (m, 7H), 3,30 (d, J = 10.5 Hz, 1H), 2,58 (m, 1H), 2,35 (m, 1H), 1.26 in (s, 9H).

Example 100

2,3,9,10-Titrator-12-(4-deoxy-a-D-glyukopiranozil)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

IR (KBr) 3440, 1745, 1710, 1474 cm-1;1H NMR (DMSO-d6, 400 MHz): 11,89 (s, 1H), 11,31 (s, 1H), 8,99 (dd, J = 9,8, and 8.9 Hz, 1H), of 8.92 (dd, J = 10,3, 9.0 Hz, 1H), 8,14 (dd, J = 11,7, 6.5 Hz, 1H), to 7.64 (dd, J = 10,5, 6,9 Hz, 1H), 6,21 (t, J = 4.5 Hz, 1H), 6,18 (d, J = 9,2 Hz, 1H), 5,07 (d, J = 5.6 Hz, 1H), 4,96 (d, J = 5.4 Hz, 1H), 4,28 (d, J = 12.1 Hz, 1H), 3,90 of 3.75 (m, 3H), and 2.27 (m, 1H), 2,01 (m, 1H). HPLC (HPLC): 96,7% (320 nm).

Example 101

2,3,9,10-Titrator-12-(2,3,4-tri-O-benzyl-a-D-glyukopiranozil)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

The solution 2,3,9,10-titrator-12-(2,3,4-tri-O-benzyl-6-O-(4-methoxybenzyl) -- D-glyukopiranozil)indole[2,3-a] pyrrole[3,4-c]carbazole-5,7-dione (0,410 g, 0.43 mmol) in 10 ml of 10% TFA-CH2Cl2stirred at room temperature under Ar for 15 minutes the mixture is diluted with ethyl acetate (50 ml) and then washed her (1M, NaHCO3, 2 x 50 ml; H2O, 2 x 50 ml brine, 50 ml), dried (MgSO4) and evaporated. The obtained residue chromatographic (SiO2/2-26% ethyl acetate-hexane) to obtain the above-mentioned compounds (0,346 g, 97%) as a yellow solid:

IR (CH2Cl2) 3333, 1753, 1700, 1478, 1093 cm-1;1H NMR (DMSO-d6, 400 MHz): 11,76 (s, 1H), 11,33 (s, 1H), 8,99 (dd, J = 10 is, 2H), 6,55 (d, J = 8,9 Hz, 1H), 6,44 (m, 1H), 6,10 (d, J = 7,6 Hz, 1H), 4,96 (d, J = 11,1 Hz, 1H), 4.92 in (d, J = 11.0 cm Hz, 1H), 4,82 (m, 2H), 4,23 (t, J = 9.4 Hz, 1H), 4,20-4,06 (m, 3H), 3,98-3,95 (m, 2H), 3,66 (t, J = 9.0 Hz, 1H), 2,94 (d, J = a 10.6 Hz, 1H); HPLC (HPLC): 98,9% (320 nm).

Anal. Calc. C47H35F4N3O7: C 68,03; H, 4,25; N, 5,07. Found: C, 68,00; H, 4,72; N, 4,79.

Example 102

2,3,9,10-Titrator-12-((2,3,4-tri-O-benzyl-a-D-glucopyranosid)uronate)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

To a solution of 2,3,9,10-titrator-12-(2,3,4-tri-O-benzyl-a-D-glyukopiranozil)indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione (0.125 g, 0.15 mmol) in 12 ml dry DMF, add pyridine dichromate (we used the PDH) (0,282 g, 0.75 mmol) and the mixture is stirred at room temperature for 4 hours. Add additionally we used the PDH (0,282 g (0.75 mmol) and repeat it after 24 hours. Just add 1,128 g (3.0 mmol) we used the PDH and the reaction is carried out for 4 days. The resulting mixture is cooled to 5oC, treated with 10 ml saturated NaHSOS and then diluted with water (25 ml). The mixture is extracted with a mixture of ethyl acetate-THF (1:1, 4 x 25 ml) and the combined extract was washed with (2 x 25 ml feast upon. NaHSO3, 25 ml brine), dried (MgSO4) and evaporated. The obtained residue chromatographic (SiO2/0-20% MeOH-CH2Cl2with obtaining the above-mentioned compounds (-0,069 g, 55%) as a yellow t is 11,21 (s, 1H), 9,02 (dd, J = 10,8, 8,8 Hz, 1H), to 8.57 (brs, 1H), 8,00 (m, 1H), a 7.85 (m, 1H), 7,45 (d, J = 7,0 Hz, 1H), 7,33 (m, 3H), 7,19 (s, 5H), 7,00 (t, J = 7,4 Hz, 1H), 6,86 (t, J = 7.5 Hz, 2H), 6,38 (d, J = 7.2 Hz, 1H), 6,07 (d, J = 7,3 Hz, 1H), is 4.93 (d, J = 10,8 Hz, 1H), 4,77 (d, J = 11.2 Hz, 1H), 4,73 (d, J = 10,8 Hz, 1H), with 4.64 (d, J = 11.2 Hz, 1H), 4,29 (d, J = 8,8 Hz, 1H), Android 4.04 (m, 1H), 3,89 (m, 2H), 3,35 (m, 1H), 2,82 (m, 1H).

Example 103

2,3,9,10-Titrator-12-[ (- D-glucopyranoside)uronic acid] indole-[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

A mixture of 2,3,9,10-titrator-12-[(2,3,4-tri-O-benzyl-a-D-glucopyranosid)uronate]indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione (0,030 g, 0.035 mmol) and 20% palladium hydroxide on coal (0,030 g) in a mixture of methanol (5 ml) and tetrahydrofuran (5 ml) hydronaut at 1 ATM for 20 hours. Add 30 mg of 20% palladium hydroxide on the corner and continue hydrogenation for another 24 hours. The resulting mixture is filtered, the precipitate washed with THF-MeOH-H2O (10:10:1, 4x5 ml) and the filtrate evaporated to obtain a solid residue. Flash chromatography (SiO2/2-20% MeOH-THF and the mixture is then 20% MeOH-THF containing 1-4% 2O) leads to the above-mentioned compound (0,006 g, 30%) as a yellow solid:

IR (KBr) 3425, 3260, 1740, 1707, 1600, 1475, 1322 cm-1;1H NMR (DMSO-d6, 400 MHz): 13,11 (br s, 1H), 10,96 (br s, 1H), 9,02-7,51 (m, 5H), 6,21 (d, J = 8,9 Hz, 1H), 5,4-4,0 (m, 8H).

Example 104

3-carboxy-9-fluoro-12 -(- D-glyukopiranozil)Ben is uranium[2,3-a] pyrrole[3,4-c] carbazole-5,7-dione (380 mg, 0.43 mmol) in EtOH: THF (10 ml:5 ml) was added 4.0 M NaOH solution (10 ml). The mixture is gently refluxed for 24 hours. This resulting mixture is cooled to 0oC and treated with concentrated HCl (15 ml). The solution was stirred at room temperature for 24 h and then treated EyOH: THF and washed with water and brine, then dried and concentrated solvent. To this residue is added solid ammonium acetate (5.0 g) and the mixture is melted at 150oC for 1 hour, then cooled, diluted with EtOH: THF, washed with water, brine, dried (Na2SO4) and concentrate. A portion of this crude product (60 mg) hydronaut (Pd/C), as described above with obtaining the above-mentioned compound (18 mg, 50%) as a yellow solid: IR (KBr) 3420, 1756, 1710, 1561, 1395 cm-1;1H NMR (DMSO-d6and D2O currency. , 400 MHz): 9,26 (brs, 1H), 8,83-8,76 (m, 1H), they were 8.22 (brs, 1H), 7,99-of 7.96 (m, 1H), 7,83-to 7.68 (m, 1H), 7,55 was 7.45 (m, 1H), 6,51 (d, 0,6 H, J = 8,9 Hz), of 5.99 (d, 0,4 H, J = 8,9 Hz), or 4.31-of 3.43 (m, 6H); HPLC (HPLC): 94,0% (320 nm).

Example 105

3,9-Debtor-6-[(2-guanidine)-ethyl]-12,13-dihydro-13 -(- D-glyukopiranozil] -5-indole[2,3-a]pyrrole[3,4-c]carbazole-5,7-dione.

To stir magnetic stirrer, the solution of the pure product from example 10 (3,35 g, 3.25 mmol) in absolute echinotriton vessel, until half volume of ethanol evaporates add (about 3 hours). The mixture is cooled in a stream of nitrogen and add concentrated HCl (12 N; 175 ml). The mixture is stirred for 15 min and then partitioned between water (300 ml) and ethyl acetate (800 ml). The organic layer was washed with water (300 ml), saturated aqueous sodium bicarbonate (300 ml), dried (Na2SO4) and evaporated in vacuo. The obtained solid anhydride is treated with Ethylenediamine (50 ml) and heated at boiling for about 4-5 hours, dissolved in absolute ethanol (175 ml), refluxed for 6 hours and concentrated in vacuo. Clean flash-chromatography on silica gel using 2-10% methanol in methylene chloride gives 1,72 g (55%) of pure 6N-(2-amino)-ethyl derivative of the parent compound as an orange-yellow solid: 300 MHz1H NMR (CDCl3): 10,65 (br s, 2H), 9,05 (dd, 1H), to 8.94 (dd, 1H), 7,55 (dd, 1H), 7,45-7,14 (m, 18H), of 7.00 (t, 1H), 6.87 in (t, 2H), 6,14 (d, 2H), 5,95 (d, 1H), of 5.05-4,58 (m, 6H), 4,40-4,34 (m, 1H), 4,12-of 3.85 (m, 8H), 3,22 is 3.15 (m, 2H), 2,96 (d, 1H); Position. ESI mass spectrum, m/e 927 (M+H)+.

To stir magnetic stirrer, a solution of pure videolooking product (1,72 g of 1.86 mmol) in anhydrous THF (20 ml) is added N,N-diisopropylethylamine (314 ml) and N,N'-bis(benzyloxycarbonyl)-5-methylisothiazoline (800 mg, 2,23 m hour. The solution is cooled to room temperature, evaporated in vacuo, and purified flash chromatography on silica gel using 5% ethyl acetate in methylene chloride with the receipt of 1.57 g (68%) of pure di-CBz-protected guanidine-derived amine source in the form of a yellow solid: 300 MHz1H NMR (CDCl3): RS 11.80 (br s, 1H), 10,70 (br s, 1H), 9,18 (br s, 1H), remaining 9.08 (dd, 1H), of 8.92 (dd, 1H), 7,62-7,10 (m, 24H), of 6.96 (t, 1H), 6,85

(t, 2H), 6,13 (d, 2H), 5,95 (d, 1H), 5,20-4,60 (m, 10H), 4,36 (t, 1H), 4,20-of 3.85 (m, 10H), to 3.02 (d, 1H).

To a solution of videolooking product (1,58 g, 1.38 mmol) in a mixture of 3:1 methanol/ethyl acetate (120 ml) and 1N HCl (18 ml) under nitrogen atmosphere add 20% palladium hydroxide (II) coal (722 mg). The mixture is placed in a shaker (shaking) for hydrogenation (parr shaker) at a hydrogen pressure of 65 psi for 3 days and then filtered through a small layer of celite. Celite washed with methanol (3 x 50 ml) and concentrated in vacuo to obtain an orange solid. Purification on Sephadex LH-20, elution with methanol gives 754 mg (91%) of the above compound in the form of a red-orange solid: 500 MHz1H NMR (CD3OD): 8,83 (dd, 1H, J = 9,7, 2,8 Hz), 8,73 (dd, 1H, J = 8,9 and 2.5 Hz), to 7.77 (dd, 1H, J = 9,2, 4,1 Hz), 7,63 (dd, 1H, J = 8,9, and 4.4 Hz), 7,34-7,25 (m, 2H), x 6.15 (d, 1H, J = 8.5 Hz), 4,32-4,17 (m, 2H), 4,11-of 3.97 (m, 2H), 3,91-a-3.84 (m, 2H), 3,78-3,66 (m, 2H), 3,60-of 3.53 (m, 2H). FAB mass spectrum, m/e 609 (M+H)+5,7-dione (R5, R'5= F, R2-R4= OH, X1X'1X2X'2= F, Q = NH)

The solution 2,3,9,10-titrator-12-((6-deoxy-6,6-debtor -- D-glucopyranoside[2,3-a] -pyrrole[3,4-c]carbazole-5,7-dione (0,166 g, 0.20 mmol) in 5 ml of dichloromethane is added to a cold (5oC) the solution periodinane dess-Martin (0,106 g, 0.25 mmol) in 5 ml of dichloromethane. The resulting mixture was stirred at room temperature in an argon atmosphere for 2 hours. The reaction mixture was sequentially diluted with ethyl acetate (25 ml), washed (1 M NaHCO3- 30% Na2S2O3, 2x10 ml; 1 M NaHCO3, 2x10 ml; H2O, 10 ml brine, 10 ml), dried (MgSO4) and evaporated. The obtained residue chromatographic (SiO2/2-30% ethyl acetate-hexane) and get 2,3,9,10-titrator-12-((2,3,4-tri-O-benzyl-a-D-glucopyranosid)-ronaldiho)indole[2,3-a] -pyrrole[3,4-c] carbazole-5,7-dione (amount of 0.118 g, 71% in the form of a pale yellow solid: IR (CH2Cl2) 3344, 2930, 1753, 1724, 1597, 1479 cm-1; 1H NMR (CDCl3, 400 MHz): 11,08 (s, 0,3 H), is 10.68 (s, 1H), 3,85 (s, 0,3 H), 8,97 (m, 0,3 H), 8,79 (m, 0,3 H), 8,43 (m, 1H), 7,99 (br s, 0,7 H), 7,83 (m, 1H), 7,68 (m, 0,3 H), 7,53-of 6.73 (m, 14H), 6,27 (m, 1H), equal to 6.05 (d, J = 7.2 Hz, 2H), 5,80 (d, J = 9.0 Hz, 1H), 5,61 (s, 2H), 5,09 (d, J = 11,1 Hz, 1H), 4,91 (m, 3H), 4,29-of 3.85 (m, 4H), 3,74 (t, J = 8,8 Hz, 1H), 2,92 (d, J = 10.3 Hz, 1H).

To a cold (5oC) solution of aldehyde (0,053 g 0,085 live at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate (20 ml), washed (1 M NaHCO3- 30% Na2S2O3, 2x10 ml; 1 M NaHCO3, 2x10 ml; H2O, 10 ml brine, 10 ml), dried (MgSO4) and evaporated. The remainder chromatographic (SiO2/2-24% ethyl acetate-hexane) and get 2,3,9,10-titrator-12-(2,3,4-tri-O-benzyl-6-deoxy-6,6-debtor -- D-glyukopiranozil)indole[2,3-a]-pyrrole[3,4-c]carbazole-5,7-dione (0,046 g, 85%) as a pale yellow solid: IR (CH2Cl2) 3400, 1757, 1728, 1598, 1478, 1320 cm-1;1H NMR (CDCl3, 400 MHz): 9,98 (s, 1H), cent to 8.85 (s, 2H), 7,71 (m, 1H), 7,51-7,26 (m, 11H), to 7.09 (m, 1H), 7,00 (t, J = 7,4 Hz, 1H), 6,85 (t, J = 7.5 Hz, 2H), 6,24 (t, J = 53,7 Hz, 1H), 6,13 (d, J = 7.2 Hz, 2H), 5,80 (d, J = 9.0 Hz, 1H), 5,04 (d, J = 11.2 Hz, 1H), 4,89 (s, 2H), 4,84 (d, J = 11.2 Hz, 1H), 4,23 (m, 1H), 4,3 (m, 2H), 3,95 (d, J = 10.3 Hz, 1H), 3,81 (m, 1H), 3.04 from (m, 1H); MS (ESI) m/e 848 (M-H).

A mixture of tri-O-benzylpiperazine (0.035 g, 0,041 mmol) and 20% Pd(OH)2-C in a mixture of methanol (5 ml) and chloroform (2 ml) hydronaut at a pressure of 1 ATM for 16 h. The resulting mixture was filtered and the filter cake washed with a mixture of tetrahydrofuran - methanol (1:1). The filtrate is evaporated and the residue chromatographic (SiO2/2-12% MeOH-CH2Cl2and receive the above-mentioned connection is 0.019 g, 80% in the form of a yellow solid: IR (KBr) 3385, 1748, 1713, 1595, 1476, 1326 cm-1;1H NMR (THF-d8400 M IS H), 6,18 (d, J = 7.9 Hz, 1H), 5,52 (brs, 1H), 5,10 (brs, 1H), 4,71 (brs, 1H), 4,27 (m, 1H), 3,95 (m, 1H), 3,69 (m, 2H). HPLC (HPLC): 95.2 per cent (230 nm).

1. Derived introperative formula I

< / BR>
where R1and R1adenote hydrogen or a group hexose formula B

< / BR>
provided that one of R1and R1adenotes hydrogen and the other is not hydrogen;

R2and R'2independently represent hydrogen, OH;

R3and R'3independently represent hydrogen, OH;

R4and R'4independently represent hydrogen, OH, azido, NH2, halogen;

R5, R'5, R5independently represent H, OH, azido, NR9R10, halogen, C(O)Ra, SR, OSO2Rc, OR, or together form =O; provided that R2, R3, R4, R5and R'2, R'3, R'4, R'5and R5all are not simultaneously hydrogen,

R denotes hydrogen, C1-7alkyl, heterocyclic 6-membered ring containing 1 or 2 nitrogen atom as heteroatoms, with the specified C1-7the alkyl may be substituted by phenyl;

Ra denotes OH;

Rc represents C1-7alkyl;

R6denotes hydrogen, C1-7alkyl, OH, NH2and the specified C1-7the alkyl may be substituted by phenyl, which is>
and R10independently represent hydrogen or together with the nitrogen atom to which they are attached, form a cyclic 6-membered nonaromatic ring containing one or two heteroatoms selected from the group N, O;

X1X'1X2and X'2independently denote H, halogen, -CN, -C(O)Ra, provided that X'1X2and X'2are not 1,11-dichloro, and provided that when X2and X'2indicates each H, X1and X'1each independently denotes H or halogen, R1means hexose, R7and R8together represent O, and each of R2, R5and R4represents OH, R'2, R'3, R'4, R'5and R5each denotes H, Q indicates NH, and then each of R3and R6is not NH2and R3is not methoxy when R6denotes H;

W represents C;

Q represents NH, O or S;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R2, R3and R4, each of which denotes OH, and R5means other9R10.

3. Connection on p. 1, in which R1or R1awhich means NH2.

4. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R2, R3and R4, each of which denotes OH, and R5denotes halogen.

5. Connection on p. 1, in which R7and R8taken together, represent o

6. Connection on p. 1, in which X1X'1X2and X'2independently represent halogen.

7. Connection on p. 1, in which the said halogen is fluorine.

8. Connection on p. 1, in which Q denotes O, S or NH.

9. Connection on p. 1, in which R2, R3and R5each represents OH; and R4denotes NH2, halogen or N3.

10. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R5, R3and R4, each of which denotes OH.

11. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R2and R3, each of which denotes OH.

12. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R2and R3, each of which represents OH; R5denotes halogen and R4the seat is H, in addition to R2and R3, each of which denotes hydrogen or hydroxy; R4denotes hydrogen, halogen or azido; R5denotes hydroxy, azido, halogen or NR9R10.

14. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R3and R4, each of which denotes hydrogen or hydroxy; R2denotes hydrogen and R5denotes hydroxy, azido, halogen or NR9R10.

15. Connection on p. 1, in which R1or R1aall the substituents denote H, in addition to R3and R5, each of which denotes hydrogen or hydroxy; R2denotes hydrogen and R4denotes hydroxy, azido, halogen or NH2.

16. Connection on p. 1, in which R1or R1aa, all substituents denote H, in addition to R2and R4each of them represents hydrogen or hydroxy; R3denotes hydrogen and R5denotes hydroxy, azido, halogen or NR9R10.

17. Pharmaceutical composition comprising effective against tumors of the amount of the compounds of formula I according to any one of paragraphs.1-16.

18. Method of inhibiting the growth of tumors in a mammal, kotis PP.1 - 16.

 

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< / BR>
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< / BR>
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