SK7595A3 - Tetracyclic compounds process and intermediates for their preparation and their use as antitumour agents - Google Patents

Tetracyclic compounds process and intermediates for their preparation and their use as antitumour agents Download PDF

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SK7595A3
SK7595A3 SK75-95A SK7595A SK7595A3 SK 7595 A3 SK7595 A3 SK 7595A3 SK 7595 A SK7595 A SK 7595A SK 7595 A3 SK7595 A3 SK 7595A3
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alkyl
carbazole
carboxylate
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Karl W Franzmann
Jeremy N Stables
Patric V R Shannon
Nagaraja Kodanda R Rao
Laddawan Chunchatprasert
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Wellcome Found
Univ Cardiff
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The present invention relates to heterocyclic compounds of formula (I), which have been found to have anti-tumour activity. More specifically, the invention concerns Pyrrolo (3,2-bŸ ) carbazoles, 1H-Benzofuro (3,2-fŸ ) indoles and 1H-(1) Benzothieno (2,3-fŸ ) indoles, methods for their preparation, intermediates, pharmaceutical formulations containing them and their use as anti-tumour agents.

Description

Tetracyklínové zlúčeniny, spôsoby ich výroby, medziprodukty na ich výrobu a ich použitie ako protinádorových prípravkovTetracycline compounds, processes for their preparation, intermediates for their production and their use as antitumor agents

Oblasť technikyTechnical field

Tento vynález sa týka heterocyklických zlúčenín, u ktorých bolo nájdené, že majú protinádorový účinok. Vynález sa obzvlášť týka pyrolo[3,2-bJkarbazolov, lH-benzofuro[3,2-f]indolov a lH-[l]benzotieno[2,3-fJindolov, spôsobu ich výroby, farmaceutických prostriedkov s ich obsahom a ich použitia ako protinádorových prípravkov.The present invention relates to heterocyclic compounds which have been found to have antitumor activity. In particular, the invention relates to pyrrolo [3,2-b] carbazoles, 1H-benzofuro [3,2-f] indoles and 1H- [1] benzothieno [2,3-f] indoles, a process for their preparation, pharmaceutical compositions containing them and their use as antitumor preparations.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Výskum v oblasti chemoterapie rakoviny viedol k výrobe mnohých protinádorových prípravkov, ktoré majú rôzny stupeň účinnosti. Medzi štandardné klinicky používané prípravky sa zahrňuje adriamycín, actinomycín D, metotrexát, 5-fluoruracil, cis-platina, vincristín a vinblastín. Avšak tieto teraz dostupné protinádorové prípravky sú známe tým, že majú rôzne nevýhody, ako je toxicita pre zdravé bunky a rezistencia k určitým typom nádorov.Research in the field of cancer chemotherapy has led to the production of many anticancer agents having varying degrees of efficacy. Standard clinically used formulations include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cisplatin, vincristine and vinblastine. However, these currently available antitumor agents are known to have various disadvantages such as healthy cell toxicity and resistance to certain types of tumors.

Tak existuje trvalá potreba vyvinúť nové a zlepšené protinádorové prípravky.Thus, there is a continuing need to develop new and improved anticancer agents.

Khoshtariya a kol., Khim. Geterotsikl. Soedin. 2, 203-208 /1980/ popisuje syntézu určitých indolobenzofb]tiofénov.Khoshtariya et al., Khim. Geterotsikl. Soedin. 2, 203-208 (1980) discloses the synthesis of certain indolobenzophenyl] thiophenes.

Khoshtariya a kol., Khim. Geterotsikl. Soedin. 10, 1366-1370 /1984/ popisuje syntézu niektorých iných indolobenzo[b j furánov.Khoshtariya et al., Khim. Geterotsikl. Soedin. 10, 1366-1370 (1984) describes the synthesis of some other indolobenzo [b] furans.

Kakhabrishvili a kol., Khim. Geterotsikl. Soedin. 3, 355-358 /1985/ popisuje syntézu určitých derivátov indolobenzo[5,6-d]- a indolo[5,4-d]-benzo£b]furánov.Kakhabrishvili et al., Khim. Geterotsikl. Soedin. 3, 355-358 (1985) discloses the synthesis of certain indolobenzo [5,6-d] - and indolo [5,4-d] benzo [b] furans derivatives.

Európsky patentový spis č. 447 703 uvádza syntézu niektorých benzo[5,6-b]benzofurán-2-karboxylátov.European patent specification no. No. 447,703 discloses the synthesis of some benzo [5,6-b] benzofuran-2-carboxylates.

Podstata vynálezuSUMMARY OF THE INVENTION

Teraz boli nájdené nové zlúčeniny, ktoré prejavujú protinádorový účinok na bunky a majú nízku toxicitu proti normálnym bunkovým líniám.We have now found novel compounds which exhibit an antitumor effect on cells and have low toxicity against normal cell lines.

Tak prvý znak tohoto všeobecného vzorca I vynálezu poskytuje zlúčeninyThus, a first feature of this general formula (I) of the invention provides compounds

v ktoromin which

znamená skupinu vzorcarepresents a group of the formula

znamená atóm kyslíka, atóm síry, skupinu vzorca SO, SO2, CH2, CO alebo NR7,represents an oxygen atom, a sulfur atom, a group of formula SO, SO 2 , CH 2 , CO or NR 7 ,

R znamena atóm vodíka, alkylovú, aralkylovú, arylovú, alkenylovú,. acylovú, alkinylovú, sulfonylovú alebo substituovanú sulfonylovú skupinu, znamená atóm kyslíka, atóm síry, skupinu vzorca SO, S02, CH2, CO alebo NR7,R is hydrogen, alkyl, aralkyl, aryl, alkenyl,. acyl, alkynyl, sulfonyl or substituted sulfonyl group, is O, S, a group of formula SO, S0 2, CH 2, CO or NR 7,

R1 skupinu vzorca CONHNR10R11, COO(CH2)nNR10R11, znamená conh2,R 1 is of the formula CONHNR 10 R 11, COO (CH 2) n NR 10 R 11 is CONH 2,

COR8 , COOR8,COR 8 , COOR 8

CONHR10,CONHR 10 ,

CHO, ch2oh, ch2or9,CHO, ch 2 oh, ch 2 or 9

CONR10R1:l aleboCONR 10 R 1: 1 or

R8 znamená atóm vodíka, arylovú alebo aralkylovú alkylovú, arylovú, substituovanú skupinu,R 8 represents a hydrogen atom, an aryl or aralkyl alkyl, aryl, substituted group,

R9 je acylová alebo substituovaná acylová skupinaR 9 is an acyl or substituted acyl group

R10 a R11 znamenajú nezávisle na sebe atóm vodíka, alkylovú alebo arylovú skupinu, n znamená číslo 1 až 4 atómy uhlíka,R 10 and R 11 are each independently hydrogen, alkyl or aryl, n is 1 to 4 carbon atoms,

R2 znamená atóm vodíka, skupinu vzorca COOR8, alkylovú, arylovú alebo substituovanú arylovú skupinu alebo skupinu vzorca ch2ch2co2r12,R 2 is hydrogen, a group of the formula COOR 8, an alkyl, aryl or substituted aryl group, or a group of formula CH2 CH2 CO2 R12,

R znamena alkylovú alebo arylovú skupinu,R is an alkyl or aryl group,

R3 a R4 znamenajú nezávisle na sebe atóm vodíka, hydroxyskupinu, alkylovú skupinu, halogénalkylovú skupinu, alkoxyskupinu, atóm halogénu, kyanoskupinu, nitroskupinu, amínoskupinu, alkylamínoskupinu, dialkylamínoskupinu, substituovanú alkylovú skupinu, karboxyskupinu alebo skupinu vzorca co2r12,R 3 and R 4 are each independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxy or C 2 r 12 ,

KThe

R znamena atóm vodíka, alkylovú skupinu, substituovanú alkylovú alkylovú skupinu, aralkylovú skupinu, nitroskupinu, amínoskupinu, atóm halogénu, kyanoskupinu, skupinu vzorca CHO alebo COOR8,R represents a hydrogen atom, an alkyl group, a substituted alkyl alkyl group, an aralkyl group, a nitro group, an amino group, a halogen atom, a cyano group, a group of formula CHO or COOR 8 ,

R6 znamená atóm vodíka, arylovú, alkylovú, aralkylovú skupinu,R 6 represents a hydrogen atom, an aryl, alkyl, aralkyl group,

3 nitroskupinu, atóm halogénu, skupinu vzorca CHO alebo COR a3 is nitro, halogen, CHO or COR;

R13 znamená alkylovú alebo arylovú skupinu s podmienkou, že (i) keď R2, R3, R4, R5 a R6 znamenajú vždy atóm vodíka a A predstavuje skupinu vzorcaR 13 represents an alkyl or aryl group with the proviso that (i) when R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom and A represents a group of the formula

kde Y znamená skupinu vzorca NH a X znamená atóm kyslíka alebo atóm síry, potom R1 neznamená skupinu vzorca CO2H alebo CO2Et, (ii) keď R2, R3, R4, r5 a R6 znamenajú vždy atóm vodíka a A predstavuje skupinu vzorcawhere Y is NH and X is O or S, then R 1 is not CO 2 H or CO 2 Et, (ii) when R 2 , R 3 , R 4 , r 5 and R 6 are each hydrogen and A represents a group of formula

kde Y znamená skupinu vzorca NH a X znamená atóm kyslíka, Ί potom R neznamená skupinu vzorca CHO a (iii) Y nie je atóm kyslíka, pokial X predstavuje atóm kyslíka, a ich soli a ich fyziologicky funkčné deriváty.where Y is NH and X is O, then R is not CHO and (iii) Y is not O when X is O, and salts and physiologically functional derivatives thereof.

Ešte ďalší znak tohoto vynálezu sa týka zlúčenín všeobecného vzorca I uvedených vyššie, v ktoromYet another aspect of the invention relates to compounds of formula I above wherein:

A znamená skupinu vzorcaA represents a group of formula

aleboor

znamená atóm kyslíka, atóm síry, skupinu vzorca SO, S02, CH2, CO alebo NR7,is O, S, a group of formula SO, S0 2, CH 2, CO or NR 7,

R7 znamená atóm vodíka, alkylovú, aralkylovú, arylovú, alkenylovú, acylovú, alkinylovú alebo sulfonylovú skupinu,R 7 represents a hydrogen atom, an alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl or sulfonyl group,

Y znamená atóm kyslíka, atóm síry, skupinu vzorca SO, S02, CH2, CO alebo NR7,Y is O, S, a group of formula SO, S0 2, CH 2, CO or NR 7,

R1 znamená skupinu vzorca COOR8, CHO, CH2OH, CH2OR9, CONH2, CONHNR10 alebo CONR10R11,R 1 represents a group of the formula COOR 8 , CHO, CH 2 OH, CH 2 OR 9 , CONH 2, CONHNR 10 or CONR 10 R 11 ,

R8 znamená atóm vodíka, alkylovú, arylovú, substituovanú arylovú alebo aralkylovú skupinu,’R 8 represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group;

R9 je acylová alebo substituovaná acylová skupina aR 9 is an acyl or substituted acyl group and

R10 a R11 znamenajú nezávisle na sebe alkylovú alebo arylovú skupinu,R 10 and R 11 independently are alkyl or aryl,

R2 znamená atóm vodíka, skupinu vzorca COOR8, alkylovú, arylovú, substituovanú arylovú skupinu alebo skupinu vzorca ch2ch2co2r12,R 2 is hydrogen, a group of the formula COOR 8, an alkyl, aryl, substituted aryl, or a group of formula CH2 CH2 CO2 R12,

R12 znamená alkylovú alebo arylovú skupinu,R 12 represents an alkyl or aryl group,

R3 a R4 znamenajú nezávisle na sebe atóm vodíka, hydroxyskupinu, alkylovú skupinu, halogénalkylovú skupinu, alkoxyskupinu, atóm halogénu, kyanoskupinu, nitroskupinu, aminoskupinu, alkylaminoskupinu, dialkylaminoskupinu, substituovanú alkylovú skupinu, karboxyskupinu alebo skupinu vzorca co2r12,R 3 and R 4 are each independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxy or C 2 R 12 ,

R5 znamená atóm vodíka, alkylovú, substituovanú alkylovú skupinu, aralkylovú skupinu, nitroskupinu, atóm halogénu, kyanoskupinu alebo skupinu vzorca CHO,R 5 represents a hydrogen atom, an alkyl, substituted alkyl group, an aralkyl group, a nitro group, a halogen atom, a cyano group or a group of formula CHO,

R6 znamená atóm vodíka, alkylovú, aralkylovú skupinu, nitroskupinu, atóm halogénu, skupinu vzorca CHO alebo COR13 aR 6 is H, alkyl, aralkyl, nitro, halogen, CHO or a group of formula COR 13 and

R znamena alkylovú alebo arylovu skupinu, s podmienkami opísanými vyššie.R is an alkyl or aryl group, with the conditions described above.

Alkylové skupiny prítomné vo všeobecnom vzorci I môžu byť alkylové skupiny s priamym alebo rozvetveným reťazcom a môžu obsahovať od 1 do 10 atómov uhlíka, výhodne od 1 do 6 atómov uhlíka. Príklady takýchto alkylových skupín zahrňujú metyl, etyl, terc.-butyl a podobne.The alkyl groups present in formula (I) may be straight or branched chain alkyl groups and may contain from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, tert-butyl and the like.

Acylové skupiny môžu byť priame alebo rozvetvené a môžu obsahovať od 1 do 10 atómov uhlíka, výhodne od 1 do 6 atómov uhlíka. Príklady vhodných acylových skupín zahrňujú etanoylové a propanoylové skupiny.The acyl groups may be straight or branched and may contain from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of suitable acyl groups include etanoyl and propanoyl groups.

Alkoxyskupiny môžu byť priame alebó rozvetvené a môžu obsahovať od 1 do 10 atómov uhlíka, výhodne od 1 do 6 atómov uhlíka. Príklady vhodných alkoxyskupín zahrňujú metoxyskupinu, etoxyskupinu a podobne.The alkoxy groups may be straight or branched and may contain from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy and the like.

Arylové skupiny zahrňujú ako karbocyklické arylové skupiny, tak heterocyklické arylové skupiny, bežne obsahujúce maximálne 10 atómov v kruhu. Karbocyklické arylové skupiny zahrňujú napríklad fenyl a naftyl a obsahujú aspoň jeden aromatický kruh. Heterocyklické arylové skupiny zahrňujú napríklad tienylový, furylový, pyridylový, indolylový a chinolylový kruh.Aryl groups include both carbocyclic aryl groups and heterocyclic aryl groups, typically containing a maximum of 10 ring atoms. Carbocyclic aryl groups include, for example, phenyl and naphthyl and contain at least one aromatic ring. Heterocyclic aryl groups include, for example, a thienyl, furyl, pyridyl, indolyl and quinolyl ring.

Aralkylová skupina môže obsahovať od 1 do 4 atómov v alkylovej časti a arylová časť môže byť karbocyklickou alebo heterocyklickou arylovou skupinou.The aralkyl group may contain from 1 to 4 atoms in the alkyl moiety and the aryl moiety may be a carbocyclic or heterocyclic aryl group.

Substituenty, ktoré môžu byť prítomné na alkylových, arylových alebo acylových skupinách zahrňujú alkylovú skupinu, alkoxyskupinu, atóm halogénu, sulfinylovú skupinu, amínoskupinu (prípadne substituovanú 1 alebo 2 alkylovými skupinami), halogénalkylovú skupinu (napríklad trifluormetyl), sulfinylovú, sulfonylovú skupinu a kyanoskupinu.Substituents that may be present on alkyl, aryl or acyl groups include alkyl, alkoxy, halogen, sulfinyl, amino (optionally substituted with 1 or 2 alkyl groups), haloalkyl (e.g. trifluoromethyl), sulfinyl, sulfonyl, and cyano.

Substituenty, ktoré môžu byť prítomné na sulfonylovej skupine, zahrňujú alkylovú, arylovú a aralkylovú skupinu.Substituents which may be present on the sulfonyl group include alkyl, aryl and aralkyl groups.

Atóm halogénu predstavuje atóm fluóru, chlóru, brómu alebo jódu.A halogen atom represents a fluorine, chlorine, bromine or iodine atom.

V zlúčeninách všeobecného vzorca IIn compounds of formula I

X znamená výhodne atóm kyslíka, atóm síry alebo skupinu vzorca NR7,X is oxygen, S or of the formula NR 7,

R' znamena atóm vodíka, alkylovú, sulfonylovú alebo toluénsulfonylovú skupinu,R 'represents a hydrogen atom, an alkyl, sulfonyl or toluenesulfonyl group,

Y znamená výhodne skupinu vzorca NR7,Y is preferably NR 7 ,

R1 znamená výhodne skupinu vzorca COR8, COOR8, CH2OR9, CONH2,R 1 is preferably a group of formula COR 8 , COOR 8 , CH 2 OR 9 , CONH 2,

CNHNR10R1;L, CONHR10, CONR10R11 alebo COO(CH2 )nNR10Ri:L,CNHNR 10 R 1, L, CONHR 10, CONR 10 R 11, COO (CH 2) n NR 10 R and L,

R8 znamená atóm vodíka, alkylovú, arylovú, substituovanú arylovú alebo aralkylovú skupinu,R 8 represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group,

R9 je acylová alebo substituovaná acylová skupina aR 9 is an acyl or substituted acyl group and

R10 a R13· znamenajú nezávisle na sebe atóm vodíka, alkylovú alebo arylovú skupinu, n znamená 1 až 4 atómy uhlíka,R 10 and R 13 are each independently hydrogen, alkyl or aryl, n is 1 to 4 carbon atoms,

Rz znamená výhodne skupinu vzorca COOR , alkylovú skupinuR z is preferably COOR, alkyl

Ί 2 alebo skupinu vzorca CH2CH2CO2R ,Alebo 2 or a group of the formula CH 2 CH 2 CO 2 R,

R12 znamená alkylovú alebo arylovú skupinu,R 12 represents an alkyl or aryl group,

R3 a R4 znamenajú nezávisle na sebe atóm vodíka, hydroxyskupinu, alkylovú skupinu, alkoxyskupinu, atóm halogénu, kyanoskupinu, substituovanú alkylovú skupinu alebo karboxyskupinu, r5 znamená výhodne atóm vodíka alebo alkylovú skupinu aR 3 and R 4 are each independently hydrogen, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl or carboxy, preferably R 5 is hydrogen or alkyl, and

R znamená výhodne atóm vodíka, alkylovú alebo arylovú skúpit nu a ich soli alebo ide o soli a fyziologicky funkčné deriváty takto vyjadrených zlúčenín.R is preferably a hydrogen atom, an alkyl or aryl group and salts thereof, or salts and physiologically functional derivatives of the compounds so expressed.

X výhodne predstavuje atóm síry alebo skupinu vzorca NH, A znamená výhodne skupinu vzorcaX preferably represents a sulfur atom or a group of formula NH, A preferably represents a group of formula

a Y výhodne predstavuje skupinu vzorca NH.and Y is preferably NH.

R1 s výhodou predstavuje skupinu vzorca COOR8, kde R8 výhodne výhodne predstavuje predstavuje alkylovú alebo aralkylovú skupinu, R2 atóm vodíka alebo alkylovú skupinu, R3 výhodne predstavuje atóm vodíka, alkoxyskupinu alebo atóm halogénu, R4 výhodne predstavuje atóm vodíka, alkoxyskupinu alebo atóm halogénu, R5 výhodne predstavuje alkylovú skupinu a r6 výhodne predstavuje atóm vodíka, alebo ide o soli a fyziologicky funkčné deriváty takto vyjadrených zlúčenín.R 1 preferably represents a group of the formula COOR 8 , wherein R 8 preferably represents an alkyl or aralkyl group, R 2 represents a hydrogen atom or an alkyl group, R 3 preferably represents a hydrogen atom, an alkoxy group or a halogen atom, R 4 preferably represents a hydrogen atom or an alkoxy group or halogen, R 5 is preferably an alkyl group and R 6 is preferably hydrogen, or is a salt thereof and physiologically functional derivatives of the compounds expressed by the following.

Medzi obzvlášť výhodné zlúčeniny podlá tohoto vynálezu sa zahrňuje:Particularly preferred compounds of the invention include:

3-pyridyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), / ( 3-dimetylamino)fenyl/-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát, benzyl-(1,3,4-trimetylpyrolo[3,2-b]-karbazol-2-karboxylát), fenyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát),3-pyridyl- (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), [(3-dimethylamino) phenyl] -3,4-dimethylpyrrolo [3,2-b] carbazole-2 -carboxylate, benzyl (1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) .

3,4-dimetyl-2-(1-imidazolylkarbonyl)pyrolo[3,2-b]karbazol, etyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), etyl-(3,4-dimetylbenzotieno[4,5-f]indol-2-karboxylát), benzyl-(3,4-dimetylpyrrolo[3,2-b]-karbazol-2-karboxylát), benzyl-(8-ftuór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát) , etyl-( 8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), benzyl-(3,4,6-trimetylpyrolo[3,2-b]-karbazol-2-karboxylát), etyl-(3,4,6-trimetyípyrolo[3,2-b]-karbazol-2-karboxylát), kyselina 8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylová, kyselina 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylová, etyl-(8-metoxy-3,4-dimetylpyrrolo[3,2-b]-karbazol-2-karboxylát), kyselina 3,4,6-trimetylpyrrolo[3,2-b]-karbazol-2-karboxylová a benzyl-(8-metoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát) , a ich fyziologicky funkčné deriváty.3,4-dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3,2-b] carbazole, ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (3) 4-dimethylbenzothieno [4,5-f] indole-2-carboxylate), benzyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), benzyl (8-fluoro-3, 4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), benzyl (3, 4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) 4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), 8-fluoro- 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, ethyl- (8-methoxy-3,4- dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, and benzyl- (8-methoxy-3,4-dimethylpyrolo) [3,2-b] carbazole-2-carboxylate), and their physiologically functional derivatives.

Zlúčeniny všeobecného vzorca I boli testované proti dvom zvlášť, vyvinutým bunkovým líniám, ktoré sú klonmi bunkovej línie ludského fibrosarkómu HT1080. Jeden kloň, HT1080scc2 udržuje transformovaný fenotyp základnej línie, zatial čo druhý, HT1080C, je morfologicky plochý revertant nespôsobujúci nádor.The compounds of formula I were tested against two separately developed cell lines that are clones of the human fibrosarcoma HT1080 cell line. One clone, HT1080scc2, maintains the transformed baseline phenotype, while the other, HT1080C, is a non-tumor-causing morphologically flat revertant.

Tak účinky potenciálnych protinádorových zlúčenín sa môžu ohodnotiť na základe ich schopnosti pôsobiť detransformáciu v bunkách HT1080scc2.Thus, the effects of potential antitumor compounds can be evaluated based on their ability to cause detransformation in HT1080scc2 cells.

Zlúčeniny podlá tohoto vynálezu boli nájdené ako zvlášť účinné pri tomto testovacom systéme.The compounds of this invention have been found to be particularly effective in this assay system.

Okrem toho zlúčeniny podlá tohoto vynálezu boli nájdené ako účinné proti MCF7 ľudským rakovinovým bunkám prsníkov, A431 bunkám ejpidérmoidného karcinómu a A285 bunkám melanómu.In addition, the compounds of this invention have been found to be effective against MCF7 human breast cancer cells, A431 ejpidermoid carcinoma cells, and A285 melanoma cells.

Zlúčeniny tiež prejavujú nízku toxicitu proti normálnym bunkám.The compounds also exhibit low toxicity against normal cells.

Podlá ďalšieho znaku tento vynález tiež poskytuje spôsob výroby zlúčenín všeobecného vzorca I, ktorý spočíva v katalyzovanom uzavretí kruhu u zlúčeniny všeobecného vzorca IVAccording to another feature, the present invention also provides a process for the preparation of compounds of formula I which comprises catalyzed ring closure of a compound of formula IV

(IV) v prítomnosti silnej kyseliny.(IV) in the presence of a strong acid.

Tento vynález tiež poskytuje spôsob výroby zlúčenín všeobecného vzorca IV, ktorý spočíva v tom, že buď:The present invention also provides a process for the preparation of compounds of formula IV, which comprises:

a) Nechá sa reagovať zlúčenina všeobecného vzorca II so zlúčeninou všeobecného vzorca III za vzniku zlúčeniny všeobecného vzorca IV, pričom X, Y, R1, R2, R3, R4 a R5 majú význam uvedený vyššie, podlá vzťahua) reacting a compound of formula II with a compound of formula III to form a compound of formula IV, wherein X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, according to

s nasledujúcim katalyzovaným uzavretím kruhu.followed by catalyzed ring closure.

Reakcia sa výhodne uskutočňuje pri teplote miestnosti v prítomnosti silnej kyseliny, napríklad kyseliny p-toluénsulfonovej alebo montmorillonitovej hlinky K10 ako katalyzátora, za vzniku zlúčeniny podlá tohoto vynálezu.The reaction is preferably carried out at room temperature in the presence of a strong acid, for example p-toluenesulfonic acid or montmorillonite clay K10 as a catalyst, to form a compound of the invention.

b) Nechá sa reagovať zlúčeniny všeobecného vzorca V 0b) Reacting compounds of formula V 0

v ktoromin which

4·4 ·

L znamená odstiepitelnú skupinu, ktorej vhodnými príkladmi sú skupiny vzorca -OCOCH3, OEt, -N+Me3 a atóm halogénu, so zlúčeninou všeobecného vzorca III za vzniku zlúčeniny všeobecného vzorca IV, s nasledujúcim katalyzovaným uzavretím kruhu, ako je uvedené pod a).L is a cleavable group, suitable examples of which are -OCOCH 3 , OEt, -N + Me 3 and halogen, with a compound of formula III to give a compound of formula IV, followed by catalyzed ring closure as described under a) .

c) Uskutoční sa jednostupňový reakčný postup, pri ktorom sa nechá reagovať zlúčenina všeobecného vzorca II so zlúčeninou všeobecného vzorca III v prítomnosti katalyzátora, za vzniku zlúčeniny podlá tohoto vynálezu v jedinom stupni. Výhodným katalyzátorom je montmorillonitová hlinka K10.c) A one-step reaction procedure is carried out in which a compound of formula II is reacted with a compound of formula III in the presence of a catalyst to form a compound of the invention in a single step. A preferred catalyst is montmorillonite clay K10.

Zavedenie substituentu R1 do kruhového systému napríklad spočíva v tom, že saThe introduction of R 1 into the ring systems, for example, is that they are

d) karboxyluje polyheterocyklická zlúčenina za použitiad) carboxylates the polyheterocyclic compound using

i) karbonylhalogenidu alebo ii) oxidu uhličitého, podľa známych spôsobov (J. March, Advanced Organic Chemistry, 2. vyd., McGraw Hill, New York, str. 497 až 498 /1977/).i) a carbonyl halide or ii) carbon dioxide, according to known methods (J. March, Advanced Organic Chemistry, 2nd Ed., McGraw Hill, New York, pp. 497-498 (1977)).

e) Alternatívne sa dajú vyrobiť zlúčeniny všeobecného vzorca I, v ktorom R2 znamená skupinu vzorca CHO spôsobmi známymi odborníkovi v odbore, napríklad tým, že:e) Alternatively, compounds of formula I wherein R 2 is CHO may be prepared by methods known to those skilled in the art, for example by:

i) Vhodný aromatický polyheterocyklus sa môže nechať reagovať s formylačným činidlom, ako ktoré sa tvoria reakciou medzi chloridom ciničitým a zlúčeninou vzorca C12CHOCH3 alebo ekvivalentnými reakčnými činidlami.i) An appropriate aromatic polyheterocycle can be reacted with a formylating agent, such as those formed by reaction of the tin tetrachloride and the compound of formula C 1 2 3 CKD or equivalent reagent.

Napríklad sa postupuje podlá spôsobu, ktorý opísal A.For example, the procedure of A.

Reiche a kol. v Chem. Ber. 93 , 88 /1960/ alebo za použitia iných štandardných formylačných činidiel a spôsobov známych v odbore, ako napríklad sa použije Gatterman-Kochovo reakčné činidloReiche et al. in Chem. Ber. 93, 88 (1960) or using other standard formulating agents and methods known in the art, such as using the Gatterman-Koch reagent

(CO/HCl/AlCl3/CuCl), Gattermanovo reakčné (HCN/HCl/ZnCl2) alebo Vilsmeierovo reakčné(CO / HCl / AlCl 3 / CuCl), Gatterman reaction (HCN / HCl / ZnCl 2 ) or Vilsmeier reaction činidlo činidlo agent agent

(POClg/PhN-(Me)CHO alebo POCl3/Me2NCHO) (J. March, viď viššie, str. 494 až 497) .(POClg / PhN- (Me) CHO or POCl 3 / Me 2 NCHO) (J. March, supra, pp. 494-497).

(ii) Vo vhodnom aromatickom polyheterocykle, obsahujúcom vhodnú funkčnú skupinu, sa táto skupina prevedie na aldehydovú skupinu spôsobmi známymi odborníkovi v odbore. Medzi vhodné skupiny sa zahrňujú skupiny vzorca CHBr2, CH3 a COR14, kde R14 znamená primárnu alebo sekundárnu alkylovú skupinu obsahujúcu od 1 do 6 atómov uhlíka, COOH alebo derivát tejto skupiny, ako je ester, amid, chlorid kyseliny alebo kyanid.(ii) In a suitable aromatic polyheterocycle containing a suitable functional group, the latter is converted to the aldehyde group by methods known to those skilled in the art. Suitable groups include those of the formula CHBr 2 , CH 3 and COR 14 , wherein R 14 represents a primary or secondary alkyl group containing from 1 to 6 carbon atoms, COOH or a derivative thereof such as an ester, amide, acid chloride or cyanide.

f) Zlúčenina všeobecného vzorca I, v ktorom R3· znamená skupinu vzorca CONHR10, sa môže tiež vyrobiť reakciou zlúčeniny, kde R1 znamená karboxyskupinu, alebo vhodným reaktívnym derivátom kyseliny, ako uvádza J. March, cit. vyššie. Tak napríklad sa môže nechať reagovať halogenid kyseliny so zlúčeninou všeobecného vzorca NH2R v inertnom rozpúšťadle.f) A compound of formula I wherein R 3 is CONHR 10 may also be prepared by reacting a compound wherein R 1 is carboxy, or a suitable reactive acid derivative as described in J. March, op. higher. For example, the acid halide can be reacted with a compound of formula NH 2 R in an inert solvent.

g) Konverziou jednej zlúčeniny všeobecného vzorca I na inú zlúčeninu všeobecného vzorca I.g) Conversion of one compound of formula I to another compound of formula I.

Zlúčeniny podlá tohoto vynálezu, kde R1 znamená skupinu o o vzorca COOR° a R znamena napríklad aralkylovu skupinu, sa môžu previesť na volné kyseliny, kde R8 znamená atóm vodíka, redukciou v prítomnosti vodíka a palládia ako katalyzátora, alebo kde R° znamena napríklad alkylovú skupinu, hydrolýzou v prítomnosti vhodnej zásady, napríklad uhličitanu cesného.Compounds of this invention wherein R 1 is a group O of COOR ° and R is, for example, an aralkyl group, can be converted to the free acids wherein R 8 is a hydrogen atom by reduction in the presence of hydrogen and palladium as a catalyst, or an alkyl group, by hydrolysis in the presence of a suitable base, for example cesium carbonate.

Pre odborníka v odbore je potom možné uskutočniť syntézu esterových a amidových zlúčenín, ktoré spadajú do rozsahu tohoto vynálezu, konverziou získaných volných kyselín, ktorá sa uskutoční známymi spôsobmi (viď J. March, cit. vyššie, str. 363 až 365).One skilled in the art can then synthesize the ester and amide compounds within the scope of this invention by converting the free acids obtained by known methods (see J. March, cited above, pp. 363-365).

Zlúčeniny podlá tohoto vynálezu, vyrobené ako je tu opísané, sa môžu previesť na iné zlúčeniny podlá tohoto vynálezu elektrofilnou substitúciou R5 a/alebo R6, napríklad na zavedenie skupiny vzorca N02 atómu halogénu alebo skupiny vzorca COR13, kde R13 má význam uvedený vyššie.The compounds of the invention produced as described herein can be converted to other compounds of the invention by electrophilic substitution of R 5 and / or R 6 , for example to introduce a group of formula NO 2 halogen atom or a group of formula COR 13 , wherein R 13 is as defined above. above.

Vyššie uvedené spôsoby boli opísané pre zlúčeniny, kde Ä znamená skupinu vzorcaThe above methods have been described for compounds wherein Ä is a group of formula

YY

Odborníkovi v odbore je zrejmé, že tieto spôsoby sú taktiež použiteľné, pokiaľ A znamená skupinu vzorcaOne skilled in the art will appreciate that these methods are also applicable when A is a group of formula

Z iného hľadiska sa tento vynález týka nových medziproduktov všeobecného vzorca II, III, IV alebo V.In another aspect, the invention relates to novel intermediates of formula II, III, IV or V.

Zlúčeniny podľa tohoto vynálezu sú vhodné na ošetrovanie nádorov. Tieto zlúčeniny sa môžu používať na ošetrovanie rôznych foriem rakoviny cicavcov vrátane karcinónov, napríklad žalúdka, slinivky brušnej, prsníkov, delohy a tračníka, adenokarcinómu, napríklad pľúc a tračníka, sarkómov, napríklad fibrosarkómov, leukémií, napríklad lymfocytickej leukémie a lymfómov, napríklad myeloidného lymfómu.The compounds of the invention are useful in the treatment of tumors. These compounds can be used for the treatment of various forms of mammalian cancer including carcinomas such as stomach, pancreas, breast, cervix and colon, adenocarcinoma such as lung and colon, sarcomas such as fibrosarcomas, leukemias such as lymphocytic leukemia and lymphomas such as myeloid.

Vynález tak ďalej poskytuje spôsob ošetrovania nádorov u cicavcov najmä človeka, ktorý spočíva v tom, že sa podáva klinicky vhodné množstvo- zlúčeniny všeobecného vzorca I alebo jej fyziologicky prijateľné soli alebo jej fyziologicky funkčný derivát vo farmaceutický vhodnej forme raz alebo niekoľkokrát denne alebo v niektorom časovom rozvrhu, orálne, rektálne, parenterálne alebo sa aplikuje lokálne.The invention thus further provides a method of treating tumors in a mammal, particularly a human, comprising administering a clinically appropriate amount of a compound of Formula I, or a physiologically acceptable salt thereof, or a physiologically functional derivative thereof in a pharmaceutically acceptable form, once or several times a day or at any time. orally, rectally, parenterally, or administered topically.

, i i, i i

Okrem toho je poskytnutý dalš'i alebo alternatívny znak vynálezu, zlúčenina všeobecného vzorca I alebo jej fyziologicky prijateľná soľ alebo jej fyziologicky funkčný derivát na použitie v terapii, napríklad ako protinádorový prípravok.In addition, a further or alternative feature of the invention is provided, a compound of formula I, or a physiologically acceptable salt thereof, or a physiologically functional derivative thereof, for use in therapy, for example, as an antitumor agent.

Množstvo zlúčeniny všeobecného vzorca I vyžadované na dosiahnutie účinku proti vyššie uvedeným nádorom sa bude samozrejme meniť a v konečnej fáze bude závisieť na vlastnom úsudku lekára alebo veterinárneho lekára. Okolnosti, ktoré je žiaduce vziať do úvahy, zahrňujú stav určený na ošetrovanie, cestu podania a povahu prostriedkov, hmotnosť tela cicavca, plochu povrchu, vek a všeobecný stav, a obzvlášť zlúčeninu určenú na podávanie. Vhodne účinná protinádorová dávka je v rozmedzí od približne 0,01 do 100 mg/kg telesnej hmotnosti, napríklad od 0,1 do 100 mg/kg telesnej hmotnosti, výhodne do 1 do 30 mg/kg telesnej hmotnosti. Celková denná dávka sa môže podávať ako jediná dávka, väčší počet dávok, napríklad dvakrát až šesťkrát za deň, alebo intravenóznou infúziou počas zvoleného trvania. Napríklad pre cicavce s hmotnosťou 75 kg, by dávkové rozmedzie malo byť približne od 8 do 900 mg za deň a zvyčajná dávka by mala byť okolo 50 mg za deň. Pokial sa uvádza väčší počet oddelených dáviek na ošetrovanie, malo by zvyčajne ísť o 15 mg zlúčeniny všeobecného vzorca I podávané až štyrikrát denne.The amount of the compound of formula I required to produce an effect against the above tumors will, of course, vary and will ultimately depend on the judgment of the physician or veterinarian. Circumstances to be considered include the condition to be treated, the route of administration and the nature of the compositions, the weight of the mammal's body, the surface area, age and general condition, and in particular the compound to be administered. Suitably, the effective anti-tumor dose is in the range of about 0.01 to 100 mg / kg body weight, for example 0.1 to 100 mg / kg body weight, preferably 1 to 30 mg / kg body weight. The total daily dose can be administered as a single dose, a plurality of doses, for example two to six times a day, or by intravenous infusion over a selected duration. For example, for a mammal weighing 75 kg, the dosage range should be from about 8 to 900 mg per day and the usual dose should be about 50 mg per day. If a plurality of separate doses for treatment is given, it should generally be 15 mg of a compound of formula I administered up to four times a day.

Aj keď je možné podávať aktívnu zlúčeninu samotnú, je možné predkladať aktívnu zlúčeninu vo farmaceutických prostrediach. Prostriedky podlá tohoto vynálezu, určené na použitie v medicíne, zahrňujú zlúčeninu všeobecného vzorca I alebo jej sol spolu s jednou alebo väčším počtom farmaceutický prijatelných nosných látiek a prípadne inými terapeutickými zložkami. Nosná látka alebo nosné látky by mali byť farmaceutický prijatelné v tom zmysle, že by boli kompatibilné s inými zložkami prostriedku a nemali by mať zhubný vplyv na svojho príjemcu.While it is possible to administer the active compound alone, it is possible to present the active compound in pharmaceutical compositions. Compositions of the invention for use in medicine include a compound of Formula I or a salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. The carrier (s) should be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Tento vynález preto ďalej poskytuje farmaceutický prostriedok, ktorý obsahuje zlúčeninu všeobecného vzorca I alebo jej farmaceutický prijatelnú sol alebo jej fyziologicky funkčný t I , derivát spolu so svojou farmaceutický prijatelnou nosnou látkou.The invention thus further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or physiologically functional T I, compound together with its pharmaceutically acceptable carrier.

Vynález tiež poskytuje spôsob výroby farmaceutického prostriedku spočívajúci v tom, že sa uvádza do styku zlúčenina všeobecného vzorca I alebo jej farmaceutický prijatelná sol alebo jej fyziologicky funkčný derivát a jej farmaceutický prijatelná nosná látka.The invention also provides a process for the manufacture of a pharmaceutical composition comprising contacting a compound of formula I, or a pharmaceutically acceptable salt thereof, or a physiologically functional derivative thereof, and a pharmaceutically acceptable carrier therefor.

Prostriedky podlá tohoto vynálezu zahrňujú prostriedky vhodné na orálne, lokálne, rektálne alebo parenterálne (vrátane subkutánneho, intramuskulárneho a intravenózneho) podania. Výhodné prostriedky sú také prostriedky, ktoré sú vhodné na orálne alebo parenterálne podanie.Compositions of the invention include compositions suitable for oral, topical, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred compositions are those suitable for oral or parenteral administration.

Prostriedky sa zvyčajne môžu predkladať vo forme dávkovej jednotky a môžu sa pripravovať lubovolným zo spôsobov dobre známych odborníkovi v odbore farmácie. Všetky spôsoby zahrňujú stupeň, v ktorom sa uvedie do styku aktívna zlúčenina s nosnou látkou, ktorú tvorí jeden alebo väčší počet pridaných pomocných prostriedkov. Všeobecne sa prostriedky pripravujú rovnomerným a dôkladným uvedením do styku aktívnej zlúčeniny s kvapalnou nosnou látkou alebo jemne rozmelnenou tuhou nosnou látkou alebo oboma takýmito látkami a potom, pokial je to potrebé, produkt sa tvaruje do požadovaného prostriedku.The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known to those skilled in the art of pharmacy. All methods include the step of bringing into association the active compound with a carrier which constitutes one or more adjuvants added. Generally, the compositions are prepared by uniformly and intimately bringing into association the active compound with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired composition.

Prostriedky podlá tohoto vynálezu, vhodné na orálne podanie, sa môžu predkladať ako oddelené jednotky, ako sú kapsle, kašety, tablety alebo pastylky, z ktorých každá obsahuje vopred stanovené množstvo aktívnej zlúčeniny, ako prášok alebo granule alebo ako roztok alebo suspenzia vo vodnej alebo nevodnej kvapaline, ako je sirup, elixír, emulzia alebo liek so sirupom.Compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges each containing a predetermined amount of the active compound, as a powder or granules, or as a solution or suspension in aqueous or non-aqueous a liquid such as a syrup, elixir, emulsion or syrup medicament.

Tablety sa môžu pripravovať lisovaním alebo odlievaním, prípadne s jednou alebo väčším počtom pomocných zložiek. Lisované tablety sa môžu pripravovať lisovaním, vo vhodnom prístroji, aktívne zlúčeniny vo volne tečúcej forme, ako prášku alebo granulách, prípadne zmiešané s pojivom, mazadlom, inertným riedidlom, povrchovo aktívnou látkou alebo dispergačným činidlom. Odlievané tablety sa môžu zhotovovať odlievaním, vo vhodnom prístroji, zmesi práškovej aktívnej zlúčeniny s lubovoInou vhodnou nosnou látkou.Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active compounds in free-flowing form, as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered active compound with any suitable carrier.

Sirup sa môže pripravovať pridaním aktívnej zlúčeniny ku koncentrovanému vodnému roztoku cukru, napríklad sacharózy, ku ktorému sa môžu tiež pridať lubovolné pomocné látky. Taká pomocná látka alebo také pomocné látky môžu zahŕňať ochucovadlá, prípravky zamedzujúce kryštalizácii cukru alebo prípravky na zvýšenie rozpustnosti iných zložiek, ako sú viacmocné alkoholy, napríklad glycerol alebo sorbitol.A syrup may be prepared by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which any excipients may also be added. Such excipient (s) may include flavoring agents, sugar crystallization preventing agents or solubility enhancers other than polyhydric alcohols such as glycerol or sorbitol.

Prostriedky na rektálne podanie môžu byť vo forme čípkov so zvyčajnou nosnou látkou, ako je kakaové maslo.The compositions for rectal administration may be in the form of suppositories with a conventional carrier such as cocoa butter.

Prostriedky vhodné na parenterálne podanie zvyčajne zahrňujú sterilné vodné prostriedky z aktívnej zlúčeniny, ktoré môžu byť výhodne izotonické s krvou príjemcu. Takéto prostriedky zvyčajne obsahujú roztok farmaceutický a farmakologicky prijateľnej adičnej soli zlúčeniny všeobecného vzorca I s kyselinou, ktoré sú izotonické s krvou príjemcu.Compositions suitable for parenteral administration typically include sterile aqueous formulations of the active compound, which may preferably be isotonic with the blood of the recipient. Such compositions typically comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of Formula I that is isotonic with the blood of the recipient.

Medzi vhodné prostriedky sa tiež zahrňujú koncentrované roztoky alebo tuhé látky obsahujúce zlúčeninu všeobecného vzorca I, ktoré po zriedení vhodným rozpúšťadlom poskytujú roztok na parenterálne podanie, ako je uvedené vyššie.Suitable compositions also include concentrated solutions or solids containing a compound of Formula I which upon dilution with a suitable solvent provides a solution for parenteral administration as described above.

Okrem vyššie uvedených zložiek, prostriedky podľa tohoto vynálezu môžu ďalej obsahovať jeden pomocný prostriedok alebo väčší počet pomocných prostriedkov, ktoré sú zvolené z riedidiel, pufrov, ochucovadiel, pojivových prípravkov, povrchovo aktívnych látok, zahusťovadiel, lubrikačných látok, konzervačných prostriedkov (vrátane antioxidačných činidiel) a podobne.In addition to the above ingredients, the compositions of the present invention may further comprise a single excipient or a plurality of excipients selected from diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). and so on.

Ďalší znak tohoto vynálezu sa týka použitia zlúčenín všeobecného vzorca I alebo ich farmaceutický prijateľných solí alebo ich fyziologicky funkčných derivátov na výrobu liečiva na ošetrovanie nádorov.Another aspect of the invention relates to the use of the compounds of formula I or their pharmaceutically acceptable salts or physiologically functional derivatives thereof for the manufacture of a medicament for the treatment of tumors.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Vynález bude teraz ilustrovaný príkladmi, ktorými nie je nijako obmedzený.The invention will now be illustrated by the following non-limiting examples.

Všetky teploty sú uvádzané v stupňoch Celzia (°C).All temperatures are in degrees Celsius (° C).

Infračervené spektrá sú zaznamenávané na mriežkovom spektrofotometre Perkin-Elemer 257 alebo spektrofotometre Bruker FS66.Infrared spectra are recorded on a Perkin-Elemer 257 grid spectrophotometer or a Bruker FS66 spectrophotometer.

Ultrafialové spektrá sa merajú v etanole za použitia spektrofotometra Unicam SP800.Ultraviolet spectra are measured in ethanol using a Unicam SP800 spectrophotometer.

1H NMR· spektrálnej analýzy sa stanovujú na spektrofotometre Bruker WM 360-NMR pri 360 MHz alebo na spektrofotometre Bruker AC200 pri 200 MHz. Hodnoty J sú uvádzané v Hz. 1 H NMR spectral analyzes are determined on a Bruker WM 360-NMR spectrophotometer at 360 MHz or on a Bruker AC200 spectrophotometer at 200 MHz. J values are given in Hz.

Hmotnostné spektrum sa získava na zariadeniach Varian CH5D(EI), Kratos Concept (EI) alebo Kratos Ms50 (FAB).The mass spectrum is obtained on Varian CH5D (EI), Kratos Concept (EI) or Kratos Ms50 (FAB) instruments.

Príklad 1Example 1

Spôsob výroby medziproduktovProcess for preparing intermediates

Spôsob výroby pyrolovProcess for producing pyrroles

Etyl-(4-acetyl-3,5-dimetylpyrol-2-karboxylát), benzyl-(4-acetyl-3,5-dimetylpyrol-2-karboxylát) a etyl-(4-acetyl-3-etyl-5-metylpyrol-2-karboxylát) sa vyrábajú spôsobom, ktorý opísal A. W. Johnson a kol. v J. Chem. Soc., 4254 /1958/.Ethyl (4-acetyl-3,5-dimethylpyrrole-2-carboxylate), benzyl (4-acetyl-3,5-dimethylpyrrole-2-carboxylate) and ethyl (4-acetyl-3-ethyl-5-methylpyrrole) -2-carboxylate) are prepared by the method of AW Johnson et al. in J. Chem. Soc., 4254 (1958).

Spôsob N-metylácie pyrrolov, všeobecný postup iMethod of N-methylation of pyrroles, general procedure i

Zmes 20 mmol pyrolu, 50 mmol metyljodidu a 50 mmol uhličitanu draselného sa varí pod spätným chladičom v 50 ml metyletylketónu počas 8 hodín. Pokiaí chromátografia na tenkej vrstve (zmes toluénu a etylacetátu v pomere 3:1) ukazuje, že reakcia neprebehla úplne, pridajú sa ďalšie alikvóty metyljodidu s objemom 50 mmol a uhličitanu draselného zodpovedajúcemu 50 mmol a zmes sa varí pod spätným chladičom počas ďalších 6 hodín.A mixture of 20 mmol of pyrrole, 50 mmol of methyl iodide and 50 mmol of potassium carbonate is refluxed in 50 ml of methyl ethyl ketone for 8 hours. If thin layer chromatography (toluene / ethyl acetate 3: 1) showed that the reaction was not complete, further 50 mmol aliquots of methyl iodide and 50 mmol potassium carbonate were added and the mixture was refluxed for an additional 6 hours.

Po odparení pri zníženom tlaku dosucha sa odparok vyjme horúcou vodou a trikrát extrahuje vždy 50 ml etylacetátu. Spojené extrakty sa vysušia síranom horečnatým a odparia pri zníženom tlaku, čím poskytnú žltý olej alebo tuhú látku, ktoré sa nechajú kryštalizovať z vodného etanolu.After evaporation to dryness under reduced pressure, the residue is taken up in hot water and extracted three times with 50 ml of ethyl acetate each time. The combined extracts were dried (MgSO 4) and evaporated under reduced pressure to give a yellow oil or solid which was crystallized from aqueous ethanol.

Spôsob výroby etyl-(4-acetyl-l,3,5-trimetylpyrol-2-karboxylátu)Process for the preparation of ethyl (4-acetyl-1,3,5-trimethylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa z etyl-(4-acetyl-3,5-dimetylpyrol-2-karboxylátu) vo forme bielych kryštálov s hmotnosťou 2 g, ktoré majú teplotu topenia 61 až 62 ’C. Výťažok zodpovedá 41 % teórie.The title compound is obtained from ethyl (4-acetyl-3,5-dimethylpyrrole-2-carboxylate) as 2 g white crystals having a melting point of 61-62 ° C. Yield: 41%.

Analýza pre ci2H17NO3: nájdené: 64,17 % C, 7,82 % H, 6,16 % N, vypočítané: 64,55 % C, 7,68 % H, 6,27 % N.Analysis for C 17 H I 2 NO 3: Found: 64.17% C, 7.82% H 6.16% N Found: 64.55% C, 7.68% H, 6.27% N.

1H NMR SH([2H6]-DMSO): 4,25 (2H, q, CH2CH3), 3,70 (3H, s, 1-CH3), 2,43 a 2,42 (2 x 3H, 2 x s, 3-CH3 a COCH3), 2,38 (3H, s, 5-CH3) a 1,29 (3H, t, CH2CH3) ppm. m/z (%) 224(MH+, 100), 1 H NMR SH ([ 2 H 6] -DMSO): 4.25 (2H, q, CH 2 CH 3 ), 3.70 (3H, s, 1-CH 3 ), 2.43 and 2.42 (2 x 3H, 2 xs, 3-CH 3 and COCH 3 ), 2.38 (3H, s, 5-CH 3 ) and 1.29 (3H, t, CH 2 CH 3 ) ppm. m / z (%) 224 (MH < + >, 100),

208(40), 194(20), 178(40) a 133(20) FAB. vmax (KBr kotúčJ/cm-1 208 (40), 194 (20), 178 (40) and 133 (20). v max (KBr roll / cm -1 )

2984, 1691 a 1651.2984, 1691 and 1651.

Spôsob výroby benzyl-(4-acetyl-l,3,5-trimetylpyrol-2-karboxylátu)Process for the preparation of benzyl (4-acetyl-1,3,5-trimethylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa z benzyl-(4-acetyl-3,5-dimetyl-2-karboxylátu) vo forme bielych kryštálov, ktoré majú teplotu topenia 78 až 79 ”C.The title compound is obtained from benzyl (4-acetyl-3,5-dimethyl-2-carboxylate) as white crystals, m.p. 78-79 ° C.

Analýza pre Analysis for C17H19NO3: C 17 H 19 NO 3 : nájdené: found: 71,30 % C, 6,74 71.30% C, 6.74 % H, % H, 4,79 % 4.79% N, N, vypočítané: calculated: 71,56 % C, 6,71 C, 71.56; 6.71 % H, % H, 4,91 % 4.91% N. N. 1H NMR 1 H NMR 8H([2H6J-DMSO): 8H ([2 H 6 J-DMSO): 7,52 7.52 - 7,27 - 7.27 (5H, m, ArH), 5,30 (2H, (5H, m, ArH), 5.30 (2H, s, CH2Ph),s, CH 2 Ph), 3,73 (3H, s, 1- 3.73 (3H, s, 1-) ch3) ,ch 3 ), 2,42 2.42 (6H, s, 3-CH3 a COCH3) a(6H, s, 3-CH 3 and COCH 3 ) a

2,38 (3H, s, 5-CH3) ppm. m/z (%) 285(76, M+), 270(87), 194(53), 178(23), 151(36), 136(26) a 91 (100). vmax (KBr kotúčJ/cm-1 2.38 (3H, s, 5-CH3) ppm. m / z (%) 285 (76, M < + > ), 270 (87), 194 (53), 178 (23), 151 (36), 136 (26) and 91 (100). v max (KBr roll / cm -1 )

2974, 1693 a 1641.2974, 1693 and 1641.

Spôsob výroby 5-acetoxymetyl-4-acetylpyrolov, všeobecný postupProcess for preparing 5-acetoxymethyl-4-acetylpyrroles, general procedure

K miešanej suspenzii, ochladenej na teplotu 0 °C, obsahujúcej 0,02 mol 4-acetyl-5-metylpyrolu v 20 ml suchého dietyléteru sa prikvapká počas 15 minút 2,2 ml (1,25 ekvivalentu) čerstvo destilovaného sulfurylchloridu. Reakčná zmes sa mieša ďalej a chlórmetylový derivát pomaly vykryštalizuje. Filtráciou sa získa 5-chlórmetylo'vý derivát vo forme bezfarebných kryštálov. Čistota chlórmetylpyrrolu sa preskúša XH NMR spektrálnou analýzou (90 MHz) a zlúčenina sa použije priamo bez rekryštalizácie.To a stirred suspension cooled to 0 ° C containing 0.02 mol of 4-acetyl-5-methylpyrrole in 20 ml of dry diethyl ether was added dropwise over 15 minutes 2.2 ml (1.25 equivalents) of freshly distilled sulfuryl chloride. The reaction mixture is stirred further and the chloromethyl derivative slowly crystallizes. Filtration gave the 5-chloromethyl derivative as colorless crystals. The purity is checked chloromethylpyrrole; H NMR spectral analysis (90 MHz) and was used directly without recrystallisation.

0,01 mol vyššie opísaného chlórmetylpyrolu sa pridá k roztoku 3 g octanu sodného v 50 ml kyseliny octovej a zmes sa mieša počas 2 hodín a potom vyleje na 200 ml zmesi ladu a vody. Výsledná tuhá látka sa dobre premýva vodou až sa zbaví kyseliny a potom sa vysuší.0.01 mol of the chloromethylpyrrole described above is added to a solution of 3 g of sodium acetate in 50 ml of acetic acid and the mixture is stirred for 2 hours and then poured onto 200 ml of a mixture of ice and water. The resulting solid is washed well with water until it is free of acid and then dried.

Spôsob výroby etyl-(5-acetoxymetyl-4-acetyl-3-metylpyrol-2-karboxylátu)Process for the preparation of ethyl (5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise kryštalizuje z benzénu ako bezfarebné ihličky s hmotnosťou 1,87 g (70 %), ktoré majú teplotu topenia 135,5 až 138 °C. Výťažok je 70 % teórie.The title compound crystallizes from benzene as colorless needles weighing 1.87 g (70%), mp 135.5-138 ° C. Yield: 70%.

Analýza pre C13H17NO5: nájdené: 58,6 % C, 6,45 % H, 5,15 % N, vypočítané: 58,4 % C, 6,41 % H, 5,24 % N.Analysis for C 13 H 17 NO 5: Found: 58.6% C, 6.45% H 5.15% N Found: 58.4% C, 6.41% H, 5.24% N.

XH NMR 8h(CDC13): 9,57 (1H, široký s, NH), 5,40 (2H, s, X 8 h NMR (CDC1 3): 9.57 (1 H, br s, NH), 5.40 (2H, s,

CH2OAc), 4,35 (2H, q, OCH2CH3), 2,6 (3H, s, 3-CH3), 2,5 (3H, s,CH 2 OAc), 4.35 (2H, q, OCH 2 CH 3 ), 2.6 (3H, s, 3-CH 3 ), 2.5 (3H, s,

COCH3), 2,17 (3H, s, OCOCH3) a 1,4 (3H, t,OCH2CH3) ppm. m/z (%) 267(83,M+), 224(46), 207(27), 178(100) a 162(42).COCH 3 ), 2.17 (3H, s, OCOCH 3 ) and 1.4 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 267 (83, M < + > ), 224 (46), 207 (27), 178 (100) and 162 (42).

Spôsob výroby benzyl-(5-acetoxymetyl-4-acetyl-3-metyl-pyrol-2-karboxylátu)Process for the preparation of benzyl (5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise kryštalizuje z metanolu ako bezfarebné ihličky s hmotnosťou 2,34 g, ktoré majú teplotu topenia 138 až 141 C. Výťažok je 71 % teórie.The title compound crystallizes from methanol as colorless needles, 2.34 g, m.p. 138-141 C. Yield: 71%.

Analýza pre ci8H19NO5: nájdené: 65,8 % C, 5,95 % H, 4,3 % N, vypočítané: 65,64 % C, 5,81 % H, 4,25 % N.Analysis for C 19 H i8 NO 5: Found: 65.8% C, 5.95% H, 4.3% N Found: 65.64% C, 5.81% H, 4.25% N.

^H NMR Sh(CDC13): 9,44 (1H, široký singlet, NH) , 7,49 7,32 (5H, m, ArH), 5,40 (2H, S, CH2OAc), 5,35 (2H, s, CH2Ph), 2,62 (3H, S, 3-CH3), 2,49 (3H, s, CH3CO) a 2,14 (3H, s, OCOCH3) ppm. m/z (%) 329(9, M+), 286(13), 269(4), 178(19) a 91 (100).1 H NMR δ H (CDCl 3 ): 9.44 (1H, broad singlet, NH), 7.49 7.32 (5H, m, ArH), 5.40 (2H, S, CH 2 OAc), δ 35 (2H, s, CH2 Ph), 2.62 (3H, s, 3-CH3), 2.49 (3H, s, CH 3 CO) and 2.14 (3H, s, OCOCH 3) ppm. m / z (%) 329 (9, M < + > ), 286 (13), 269 (4), 178 (19) and 91 (100).

V prípade benzyl-/5-acetoxymetyl-4-acetyl-3-(2-metoxykarbonyletyl)pyrol-2-karboxylátu/ sa táto látka nevyzráža, pokial sa roztok vyleje na ladovú vodu. Preto sa roztok trikrát extrahuje vždy 100 ml chloroformu, vysuší a rozpúšťadlo sa odparí pri zníženom tlaku. Získa sa olej, ktorý kryštalizuje zo zmesi benzénu a petroléteru a poskytne bezfarebné ihličky titulnej zlúčeniny s hmotnosťou 2,69 g, ktoré majú teplotu topenia 97 až 100 °C. Výťažok zodpovedá 67 % teórie.In the case of benzyl (5-acetoxymethyl-4-acetyl-3- (2-methoxycarbonylethyl) pyrrole-2-carboxylate), this material does not precipitate when the solution is poured onto ice water. Therefore, the solution was extracted three times with 100 ml of chloroform, dried and the solvent was evaporated under reduced pressure. An oil is obtained which crystallizes from a mixture of benzene and petroleum ether to give colorless needles of the title compound weighing 2.69 g, m.p. 97-100 ° C. Yield: 67%.

Analýza pre Analysis for C21H23NO7: C 21 H 23 NO 7 : nájdené: found: 62,9 % C, 62.9% C, 5,9 5.9 % % vypočítané: calculated: 62,8 % C, 62.8% C, 5,78 5.78 % % ΤΗ NMR Τ Η NMR 6h(CDC13):6 h (CDC1 3): : 9, : 9, 15 15

7,30 (5H, m, ArH), 5,35 (4H, OCH3), 3,37 (2H, t, CH2CH2CO), COCH3), a 2,15 (3H, s, OCOCH3) 268(6) , 250(60) a 91(100).7.30 (5H, m, Ar H), 5.35 (4 H, OCH3), 3.37 (2H, t, CH2 CH2 CO), COCH3), and 2.15 (3H, s, OCOCH 3 ) 268 (6), 250 (60) and 91 (100).

H, 3,45 % N,H, 3.45% N,

H, 3,49 % N.H, 3.49% N.

(1H, široký singlet, NH), 7,50 s, CH2Ph a CH2OAc), 3,63 (3H, s(1 H, br s, NH), 7.50 s, CH 2 Ph, and CH 2 OAc), 3.63 (3H, s

2,58 (2H, t, CH2CO), 2,51 (3H, s, ppm. m/z (%) 401 (4,M+), 341(8),2.58 (2H, t, CH2 CO), 2.51 (3H, s, ppm. M / z (%) 401 (4, M +), 341 (8),

Spôsob výroby etyl-(5-acetoxymetyl-4-acetyl-l,3-dimetyl-pyrol-2-karboxylátu)Process for the preparation of ethyl (5-acetoxymethyl-4-acetyl-1,3-dimethylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise kryštalizuje zo zmesi etylacetátu a cyklohexánu, ktoré majú teplotu topenia 100 až 101 C. Výťažok zodpovedá 61 % teórie.The title compound crystallizes from a mixture of ethyl acetate and cyclohexane having a melting point of 100-101 ° C. Yield: 61%.

Analýza pre C14HigNO5:Analysis for C 14 H ig NO 5:

nájdené: 59,38 % C, 6,73 % H, 4,95 % N, vypočítané: 59,78 % C, 6,81 % H, 4,98 % N.found: C 59.38, H 6.73, N 4.95, calculated: C 59.78, H 6.81, N 4.98.

ΤΗ NMR δΗ([2H6]-DMSO): 5,30 (2H, s, CH20Ac), 4,29 (2H, q, Τ Η NMR δΗ ([2 H 6] -DMSO): 5.30 (2H, s, CH2 0Ac), 4.29 (2H, q,

CH2CH3), 3,77 (3H, s, N-CH3), 2,43 a 2,42 (2 X 3H, 2 x s, 3-CH3 a CH3CO), 2,02 (3H, s, OCOCH3) a 1,31 (3H, t, CH2CH3) ppm. m/z (%) 281(34,M+), 238(100), 222(48) a 192(52). vmax (KBr kotúčj/cm-1 1712 a 1697.CH 2 CH 3 ), 3.77 (3H, s, N-CH 3 ), 2.43 and 2.42 (2 X 3H, 2 xs, 3-CH 3 and CH 3 CO), 2.02 (3H , s, OCOCH 3 ) and 1.31 (3H, t, CH 2 CH 3 ) ppm. m / z (%) 281 (34, M < + > ), 238 (100), 222 (48) and 192 (52). v max (KBr kotúčj / cm-1 1712 and 1697th

Spôsob výroby :benzyl-(5-acetoxymetyl-4-acetyl-l,3-dimetyl-pyrol-2-karboxylátu)Method of production : benzyl (5-acetoxymethyl-4-acetyl-1,3-dimethylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise kryštalizuje zo zmesi etylacetátu a cyklohexánu.The title compound crystallizes from a mixture of ethyl acetate and cyclohexane.

ΧΗ NMR δΗ([2H6]-DMSO): 7,51 - 7,32 (5H, m, ArH), 5,34 a Χ Η NMR δΗ ([2 H 6] -DMSO): 7.51 to 7.32 (5H, m, Ar H), 5.34 and

5,32 (2 x 2H, 2 x s, CH2Ph a CH20Ac), 3,78 (3H, s, N-CH3), 2,46 a 2,45 (2 x 3H, 2 x s, 3-CH3 a CH3CO) a 2,04 (3H, s, OCOCH3) ppm. m/z (%) 343(5,M+), 284(100) a 91(95).5.32 (2 x 2H, 2 xs, CH 2 Ph and CH 2 OAc), 3.78 (3H, s, N-CH 3 ), 2.46 and 2.45 (2 x 3H, 2 xs, 3 -CH 3 and CH 3 CO) and 2.04 (3H, s, OCOCH 3 ) ppm. m / z (%) 343 (5, M < + > ), 284 (100) and 91 (95).

Spôsob výroby etyl-(5-acetoxymetyl-4-acetyl-3-etylpyrol-2-karboxylátu)Process for the preparation of ethyl (5-acetoxymethyl-4-acetyl-3-ethylpyrrole-2-carboxylate)

Zlúčenina pomenovaná v nadpise kryštaluje zo zmesi éteru a peroléteru ako svetlo žlté ihličky, ktoré majú teplotu topenia 97 až 98 °C. Výťažok zodpovedá 61 % teórie.The title compound crystallizes from a mixture of ether and perether ether as pale yellow needles having a melting point of 97-98 ° C. Yield: 61%.

Analýza pre ci4H igNO5: nájdené: 59,44 % C, 6,78 % H, 4,80 % N, vypočítané: 59,76 % C, 6,81 % H, 4,98 % N.Analysis for C i4 H ig NO 5: Found: 59.44% C, 6.78% H 4.80% N Found: 59.76% C, 6.81% H, 4.98% N. 1H NMR 8H(CDC13): 9,40 (1H, široký singlet, 1-NH), 5,38 1 H NMR δ H (CDCl 3 ): 9.40 (1H, broad singlet, 1-NH), 5.38 (2H, s, CH2OAc), 4,38 (2H, q, J = 7 Hz, CO2CH2), 3,10 (2H, q, J(2H, s, CH2 OAc), 4.38 (2H, q, J = 7 Hz, CO2 CH2), 3.10 (2H, q, J =7,5 HZ, 3-CH2), 2,54 (3H, s, C0CH3), 2,18 (3H, s, OCOCH3),= 7.5 Hz, 3-CH2), 2.54 (3H, s, C0CH 3), 2.18 (3H, s, OCOCH 3),

1,40 (3H, t, J = 7,5 HZ, CO2CH3CH3), 1,23 (3H, t, J = 7,5 Hz,1.40 (3H, t, J = 7.5 Hz, CO 2 CH 3 CH 3 ), 1.23 (3H, t, J = 7.5 Hz,

3-CH2CH3) ppm. m/z (%) 281(42,M+), 238(61), 221(89), 206(58),3-CH 2 CH 3 ) ppm. m / z (%) 281 (42, M < + > ), 238 (61), 221 (89), 206 (58),

192(92), 175(95), 160(81), 147(59), 43(100). vmax (KBr kotúčj/cm-1 3277, 1738, 1674, 1657.192 (92), 175 (95), 160 (81), 147 (59), 43 (100). v max (KBr kotúčj / cm-1 3277, 1738, 1674, 1657th

Spôsob syntézy 3-(pyrolylmetyl)indolu, 2-(pyrolylmetyl)-benzofuránu a 3-(pyrolylmetyl)benzotiofénu, všeobecný postupMethod for the synthesis of 3- (pyrrolylmethyl) indole, 2- (pyrrolylmethyl) benzofuran and 3- (pyrrolylmethyl) benzothiophene, general procedure

Roztok 1,0 mmol 5-acetoxymetyl-4-acetylpyrolu a 1,0 mmol indolu v 10 ml 1,2-dichlóretánu sa opatrne varí pod spätným chladičom a mieša s 1 g montmorillonitovej hlinky počas 1,5 až 2 hodín. Po odfiltrovaní hlinky a dobrom premytí 1,2-dichlóretánom sa spojené filtráty odparia pri zníženom tlaku a získa sa olej. Tento olej sa podrobí velmi rýchlej chromatografii na oxide kremičitom, pri eluovaní etylacetátom v petrolétere. Získa sa 3-(3'-acetyl-5'-etoxykarbonyl-41-metylpyrol-2'-ylmetyl)indol, ktorý poskytne bezfarebné kryštály zo zmesi etylacetátu a petroléteru, s hmotnosťou 0,1465 g, ktoré majú teplotu topenia 180 až 182 “C. Výťažok zodpovedá 45 % teórie.A solution of 1.0 mmol of 5-acetoxymethyl-4-acetylpyrrole and 1.0 mmol of indole in 10 mL of 1,2-dichloroethane is carefully refluxed and stirred with 1 g of montmorillonite clay for 1.5 to 2 hours. After filtering the clay and washing well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give an oil. The oil was flash chromatographed on silica eluting with ethyl acetate in petroleum ether. To give 3- (3'-acetyl-5'-ethoxycarbonyl-4 1-methylpyrrole-2-ylmethyl) indole, which gave colorless crystals from ethyl acetate and petroleum ether, weighing 0.1465 g, mp: 180 DEG 182 “C. Yield: 45%.

Analýza pre cigH20N2°3: nájdené: 70,5 % C, 6,25 % H, 8,65 % N, vypočítané: 70,4 % C, 6,21 % H, 8,64 % N.Analysis for C 20 H ig 2 N ° 3: Found: 70.5% C, 6.25% H 8.65% N Found: 70.4% C, 6.21% H, 8.64% N .

^H NMR ind-NH), 7,45@ 1 H NMR (NH4) 7.45

7-H), 7,25 (1H,7-H), 7.25 (1 H,

7,10 (1H,7.10 (1 H,

2,63 (3H, S, 4'-CH3),2.63 (3H, s, 4'-CH3).

OCH2CH3) ppm. m/z (%) 324(100,M+), 250(38), 235(30), 207(48), 139(24), vmax (CHCl-jí/cm-1 3490, 3430, 1680,OCH 2 CH 3 ) ppm. m / z (%) 324 (100, M < + > ), 250 (38), 235 (30), 207 (48), 139 (24), in max (CHCl3 / cm < -1 > ) 3490, 3430, 1680,

8h(CDC13):8 hours (CDC1 3):

(1H, d, J t, J = 7(1H, d, J ', J = 7

S, 2-H), 4,45 'S, 2-H), 4.45 '

8,78 = 78.78 = 7

Hz, (2H,Hz, (2H,

2,53 (1H, s,2.53 (1 H, s,

HZ, 4-H),HZ, 4-H)

6-H), 7,14 s, 3-CH9), (3H,6-H), 7.14 s, 3-CH 9 ), (3H,

-··+ 8,27 (1H, s, d, J = 7 HZ, = 7 Hz, 5-H), / f f \ ΪΠ f χ 2 !- ·· + 8.27 (1H, s, d, J = 7 Hz, = 7 Hz, 5-H), / f f ΪΠ f χ 2!

S, CH3CO) a 1,25 (3H, t, 309(48), 277(25), 263(54), 130(30), 117(67) a 90(16).S, CH 3 CO) and 1.25 (3H, t, 309 (48), 277 (25), 263 (54), 130 (30), 117 (67) and 90 (16)).

1650.1650th

1,0 mmol benzofuránu, pokiaľ sa použije namiesto indolu, po chromatografii poskytne 2-(3'-acetyl-5'-etoxykarbonyl-4'-metylpyrol-2 ' -ylmetyl )benzofurán s hmotnosťou 0,106 g, ktorý má teplotu topenia 124 až 127 °C. Výťažok zodpovedá 32,6 % teórie.1.0 mmol of benzofuran when used in place of indole after chromatography affords 2- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzofuran (0.106 g), m.p. 127 [deg.] C. Yield: 32.6%.

Analýza pre cigHigN04: nájdené: 70,1 % C, 6,1 % H, 4,15 % N, vypočítané: 70,14 % C, 5,89 % H, 4,31 % N.Analysis for C H ig ig 4 N0: Found: 70.1% C, 6.1% H 4.15% N Found: 70.14% C, 5.89% H, 4.31% N.

1H NMR Sh(CDC13): 9,25 (1H, s, NH), 7,50 (1H, d, J = 7,3 Hz, 4-H), 7,44 (1H, d, J = 7,3 Hz, 7-H), 7,28 - 7,18 (2H, m, 6-H a 5-H), 6,57 (1H, s, 3-H), 4,50 (2H, s, 2-CH2), 4,31 (2H, q, 1 H NMR δ H (CDCl 3 ): 9.25 (1H, s, NH), 7.50 (1H, d, J = 7.3Hz, 4-H), 7.44 (1H, d, J) = 7.3 Hz, 7-H), 7.28-7.18 (2H, m, 6-H and 5-H), 6.57 (1H, s, 3-H), 4.50 (2H , s, 2-CH 2 ), 4.31 (2H, q,

OCH2CH3), 2,62 (3H, s, 4'-CH3), 2,50 (3H, s, CH3C0) a 1,35 (3H,OCH 2 CH 3 ), 2.62 (3H, s, 4'-CH 3 ), 2.50 (3H, s, CH 3 CO) and 1.35 (3H, s,

OCH2CH3) ppm, nasýtenie singletov 3-H pri δ 6,51 zvyšuje signály vd’aka 4H pri δ 7,50 (2,7 %) a 2-CH2 pri δ 4,50 (0,8 %). m/z (%) 325(100, M+), 310(4), 279(29), 264(17), 251(59), 236(27),OCH 2 CH 3 ) ppm, saturation of 3-H singlets at δ 6.51 increases signals due to 4H at δ 7.50 (2.7%) and 2-CH 2 at δ 4.50 (0.8%) . m / z (%) 325 (100, M < + > ), 310 (4), 279 (29), 264 (17), 251 (59), 236 (27),

208(19), 193(9), 131(7) a 118(7).208 (19), 193 (9), 131 (7) and 118 (7).

Ďalej poskytne 2,3-bis-(3'-acetyl-5'-etoxykarbonyl-4'-metylpyrol-2'-ylmetyl)benzofurán s hmotnosťou 0,0238 g, ktorý má teplotu topenia 255 až 257 °C. Výťažok zodpovedá 8,94 % teórie.It further provides 2,3-bis- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzofuran of 0.0238 g, mp 255-257 ° C. Yield 8.94% of theory.

TH T H NMR 6h(CDC13)6 h NMR (CDC1 3) (1H, (1 H, d, d. J = 7,7 HZ, J = 7.7 HZ, (1H, (1 H, t, t, J = 7,7 HZ, ' J = 7.7 Hz, ' (2H, (2H, s, with, 2-CH2), 4,402-CH 2 ), 4.40 (2H, (2H, q, q, OCH2CH3), 2,OCH 2 CH 3 ) 2 2,58 2.58 (3H, s, CH3CO),(3H, s, CH 3 CO); a 1, a 1, 31 31 (3H, t, OCH (3 H, t, OCH 444( 444 ( 9) , 9), 397(6), 324( 397 (6) 162( 162 ( 28 ) . 28). (Nájdené M' (Found M ' 532, 532. 2209 2209 ϋ. ϋ.

: 10,09 (1H, s, NH), 9,95 (1H, s NH) 4-H), 7,27 (1H, d, J = 7,7 Hz, 7-H) 6-H), 7,08 (1H, t, J = 7,7 Hz, 5-H) (2H, s, 3-CH2), 4,36 (2H, q, OCH2CH3) 64 (3H, s, 4'-CH3), 2,63 (3H, s,10.09 (1H, s, NH), 9.95 (1H, s NH) 4-H), 7.27 (1H, d, J = 7.7Hz, 7-H) 6-H), 7.08 (1H, t, J = 7.7Hz, 5-H) (2H, s, 3-CH 2 ), 4.36 (2H, q, OCH 2 CH 3 ) 64 (3H, s, 4 1 -CH 3 , 2.63 (3H, s,

2,54 (3H, s, CH3CO), 1,39 (3H, t, 2CH3) ppm. m/z (%) 532(11, M+) , 100), 282(18), 278(27), 236(20), + 532,2210 pre C30H32N2°7z 2.54 (3H, s, CH 3 CO), 1.39 (3H, t, 2 CH 3 ) ppm. m / z (%) 532 (11, M < + > ), 100), 282 (18), 278 (27), 236 (20), + 532.2210 for C 30 H 32 N 2 ° 7 z

7,327.32

7,177.17

4,454.45

4,274.27

-ch3), och2ch3) 490(24), 209(28) a vypočítané M+ -ch 3 ), 2 ch 3 ) 490 (24), 209 (28) and calculated M +

Pokiaľ sa rovnakým spôsobom použije 1,0 mmol benzotiofénu ako sa použil indol, chromátografia za použitia zmesi etylacetátu a dichlórmetánu ako elučného činidla poskytne bezfarebné kryštály 3-(3'-acetyl-5'-etoxykarbonyl-4'-metylpyrol-2'-ylmetyl)benzotiofénu s hmotnosťou 0,0963 g, ktorý má teplotu topenia 125 až 128 “C. Výťažok zodpovedá 28,2 % teórie.When 1.0 mmol of benzothiophene was used in the same manner as indole, chromatography using a mixture of ethyl acetate and dichloromethane as eluent gave colorless crystals of 3- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) of benzothiophene weighing 0.0963 g and having a melting point of 125 to 128 ° C. Yield: 28.2% of theory.

Analýza pre Analysis for C-^gHjgNO3SC ^ 3S gHjgNO nájdené: found: 66,75 % C, 66.75% C, 5,8 5.8 % H, % H, 4,1 % N, 4,1% N, vypočítané: calculated: 66,84 % C, 66.84% C, 5,61 5.61 % H, % H, 4,10 % N. 4.10% N. 1H NMR 1 H NMR 6h(CDC13):6 h (CDC1 3): 8,72 8.72 (1H, (1 H, široký singlet, NH), 7,88 (1H, broad singlet, NH), 7.88 (1H,

m, 4-H), 7,63 (1H, m, 7-H), 7,37 (2H, m, 6-H a 5-H), 7,20 (1H, s, 2-H), 4,54 (2H, s, 3,-CH2), 4,23 (2H, q, OCH2CH3), 2,62 (3H, s, 4'-CH3), 2,53 (3H, s, CH3CO) a 1,28 (3H, t, OCH2CH3) ppm, nasýtenie 3-CH2 protónov pri δ 4,54 zvyšuje signály vďaka NH pri δ 8,72 (3,3 %), 4-H pri δ 7,88 (7,7 %), 2-H pri δ 7,20 (6 %), a CH3CO pri δ 2,53 (1,3 %). m/z (%) 341(100,M+), 326(9), 298(6), 295(20), 230(39), 267(46), 252(32), 224(27), 194(26) a 148(22).m, 4-H), 7.63 (1H, m, 7-H), 7.37 (2H, m, 6-H and 5-H), 7.20 (1H, s, 2-H), 4.54 (2H, s, 3, -CH 2 ), 4.23 (2H, q, OCH 2 CH 3 ), 2.62 (3H, s, 4'-CH 3 ), 2.53 (3H, s, CH 3 CO) and 1.28 (3H, t, OCH 2 CH 3 ) ppm, saturation of 3-CH 2 protons at δ 4.54 increases the signals due to NH at δ 8.72 (3.3%), 4 -H at δ 7.88 (7.7%), 2-H at δ 7.20 (6%), and CH 3 CO at δ 2.53 (1.3%). m / z (%) 341 (100, M < + > ), 326 (9), 298 (6), 295 (20), 230 (39), 267 (46), 252 (32), 224 (27), 194 (26) and 148 (22).

Ďalej poskytne 2,3-bis-(3'-acetyl-5'-etoxykarbonyl-4'metylpyrol-2'-ylmetyl)benzotiofén, ako svetlo žltú tuhú látku s hmotnosťou 0,0264 g, ktorý má teplotu topenia 206 až 209 °C. Výťažok zodpovedá 9,6 % teórie.Further, 2,3-bis- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene provides a pale yellow solid of 0.0264 g, mp 206-209 ° C. C. The yield corresponds to 9.6% of theory.

Analýza pre Analysis for C30H32N2°6 C 30 H 32 N 2 ° 6 S: WITH: nájdené: found: 65,6 % C, 65.6% C, 5,8 5.8 % H, % H, 5,1 % N, 5,1% N, vypočítané: calculated: 65,67 % C, 65.67% C, 5,88 5.88 % H, % H, 5,11 % N. 5.11% N. 1H NMR 1 H NMR ôh(CDC13):delta h (CDC1 3): 9,77 9.77 (1H, (1 H, široký singlet, NH), 9,43 (1H, broad singlet, NH), 9.43 (1H,

široký singlet, NH), 7,70 (1H, m, 4-H), 7,49 (1H, m, 7-H), 7,26 (2H, m, 6-H a 5-H), 4,55 (2H, s, CH2), 4,53 (2H, s, CH2), 4,32 (2H, q, OCH2CH3), 4,24 (2H, q, OCH2CH3), 2,61 (3H, s, 41-CH3), 2,60 (3H, S, 4'-CH3), 2,57 (3H, s, CH3CO), 2,49 (3H, S, CH3CO), 1,35 (3H, t, OCH2CH3) a 1,28 (3H, t, OCH2CH2) ppm. m/z (%) 548(5, M+), 530(11), 340(100), 294(27) a 162(10).broad singlet, NH), 7.70 (1H, m, 4-H), 7.49 (1H, m, 7-H), 7.26 (2H, m, 6-H and 5-H), 4 55 (2H, s, CH 2 ), 4.53 (2H, s, CH 2 ), 4.32 (2H, q, OCH 2 CH 3 ), 4.24 (2H, q, OCH 2 CH 3 ) , 2.61 (3H, s, CH 3 4 1), 2.60 (3H, s, 4'-CH3), 2.57 (3H, s, CH 3 CO), 2.49 (3H, S, CH 3 CO), 1.35 (3H, t, OCH 2 CH 3 ) and 1.28 (3H, t, OCH 2 CH 2 ) ppm. m / z (%) 548 (5, M < + > ), 530 (11), 340 (100), 294 (27) and 162 (10).

Príklad 2Example 2

Spôsob výroby syntézy 3-(pyrrolylmetyl)benzotiofénov a 3-(pyrolylmetyl)indolovProcess for the synthesis of 3- (pyrrolylmethyl) benzothiophenes and 3- (pyrrolylmethyl) indoles

II

a) Spôsob výroby 3-(3'-acetyl-5'-benzyloxykarbonyl-4'-metylpyrol-2'-ylmetyl)benzotiofénua) Method for producing 3- (3'-acetyl-5'-benzyloxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene

Roztok 0,33 g (1,0 mmol) 5-acetoxymetyl-4-acetylpyrolu a 0,14 g (1,05 mmol) benzotiofénu v 10 ml 1,2 dichlóretánu sa varí pod spätným chladičom a mieša s 1 g montmorillonitovej hlinky K10 počas 2,5 hodiny. Po ochladení a odfiltrovaní hlinky, ktorá sa dobre premyje 10 ml 1,2-dichlóretánu, sa spojené filtráty odparia pri zníženom tlaku a poskytnú olej. Tento olej sa podrobí velmi rýchlej chromatografii na oxide kremičitom, pri eluovaní dietyléterom a petroléterom v pomere 1:2. Získa sa zlúčenina pomenovaná v nadpise ako bezfarebná tuhá látka.A solution of 0.33 g (1.0 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 0.14 g (1.05 mmol) of benzothiophene in 10 ml of 1,2 dichloroethane is refluxed and stirred with 1 g of K10 montmorillonite clay. for 2.5 hours. After cooling and filtering the clay, which was washed well with 10 ml of 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give an oil. The oil was flash chromatographed on silica eluting with diethyl ether and petroleum ether (1: 2). The title compound is obtained as a colorless solid.

XH NMR 6H(C): 8,72 (1H, S, NH), 7,92 - 7,84 (1H, m, 4-H), 7,69 - 7,58 (1H, m, 7-H), 7,43 - 7,16 (8H, m, 2-H, 5-H, 6-H, ArH), 5,23 (2H, s, CH2Ph), 4,50 (2H, s, 3-CH2), 2,61 (3H, s, 4'-CH3) a 2,50 (3H, s, CH3CO) ppm. m/z (%) 403(M+,100). vmax (KBr kotúčj/cm-1 3290, 1690’ a 1659. X 6 H NMR (C): 8.72 (1H, s, NH), 7.92 to 7.84 (1 H, m, 4-H), 7.69 to 7.58 (1 H, m, 7- H), 7.43-7.16 (8H, m, 2-H, 5-H, 6-H, ArH), 5.23 (2H, s, CH 2 Ph), 4.50 (2H, s, 3) -CH 2), 2.61 (3H, s, 4'-CH 3) and 2.50 (3H, s, CH 3 CO) ppm. m / z (%) 403 (M < + >, 100). max (KBr kotúčj / cm-1 3290, 1690 ', and 1659th

b) Spôsob výroby 3-(3'-acetyl-5'-etoxykarbonyl-4'-metylpyrol-2'-ylmetyl)-5-kyanindolub) 3- (3'-Acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -5-cyanindole

Roztok 0,7 g (2,6 mmol) 5-acetoxymetyl-4-acetylpyrolu a 0,41 g (2,9 mmol) 5-kyanindolu v 50 ml 1,2-dichlóretánu sa varí pod spätným chladičom a mieša s 2,1 g montmorillonitovej hlinky K10 počas 6 hodín. Po ochladení a odfiltrovaní hlinky, ktorá sa a dobre premyje 1,2-dichlóretánom, sa spojené filtráty odparia pri zníženom tlaku a poskytnú oranžovú tuhú látku. Kryštalizáciou zo zmesi dichlórmetánu a etylacetátu sa získa malé množstvo analyticky čistej zlúčeniny pomenovanej v nadpise ako krémovo sfarbených kryštálov. Odparené matečné lúhy sa podrobia velmi rýchlej chromatografii na oxide kremičitom, pri eluovaní zmesou dichlórmetánu a etylacetátu v pomere 9:1. Získa sa ďalších 0,65 g vyrábanej zlúčeniny, ktorá má teplotu topenia 213 až 214 °C. Výťažok zodpovedá 71 % teórie.A solution of 0.7 g (2.6 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 0.41 g (2.9 mmol) of 5-cyanindole in 50 ml of 1,2-dichloroethane is heated to reflux and stirred with 2. 1 g of K10 montmorillonite clay for 6 hours. After cooling and filtering the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give an orange solid. Crystallization from dichloromethane / ethyl acetate gave a small amount of the analytically pure title compound as cream-colored crystals. The evaporated mother liquors were subjected to flash chromatography on silica eluting with a 9: 1 mixture of dichloromethane and ethyl acetate. An additional 0.65 g of the product is obtained having a melting point of 213-214 ° C. Yield: 71%.

Analýza pre Analysis for C20H19N3°3: C 20 H 19 N 3 ° 3 : nájdené: found: 68,60 % C, 5,46 % H, 11,99 % C, 68.60;% H, 5.46; % % N, N, 1 1 vypočítané: calculated: 68,75 % C, 5,48 % H, 12,03 H, 5.48; H, 12.03 % % N. N. ^H NMR 1 H NMR δΗ([2H6]-DMSO): 12,05 (1H, δΗ ([ 2 H 6 ] -DMSO): 12.05 (1H, S WITH , ľ-NH), , 1'-NH), - 11, - 11, 38 38 (1H, (1 H, s, with, 1-NH), 8,20 1-NH), 8.20 (1H, m, 4-H), 7,50 (1H, d (1 H, m, 4-H), 7.50 (1 H, d d, d. J = 0,7 J = 0.7 a 8, a 8, 5 5 Hz, 7 Hz, 7 -H) , -H), 7,39 (1H, dd 7.39 (1 H, dd , J = 1,7 a 8,5, 6-H), 7, , J = 1.7 and 8.5, 6-H), 7, 18 18 (1H, s, (1H, s, 2-H) 2-H) f F 4,32 4.32 (2H, (2H, s, 3-CH2), 4s, 3-CH 2 ), 4 ,27 (2H, g, CH2CH3), 2,3327 (2H, g, CH 2 CH 3 ), 2.33 (3 (3 H, s, 4'- H, s, 4'- -CH33 -CH3 3 f F 2,51 2.51 (3H, (3H, S, ch3co)S, ch 3 co) a 1,30 (3H, t, CH2CH3)and 1.30 (3H, t, CH 2 CH 3) ppm. m/z ppm. m / z (%) (%) 35 35 O(M+,O (M + , 70) , 70),

- 27 302(16), 279(18), 237(35), 208(100) a 181(20). VmaxBr kotúč)/cm-1 3309, 2218 a 1665.- 27,302 (16), 279 (18), 237 (35), 208 (100) and 181 (20). V max Br disc) / cm- 1 3309, 2218 and 1665.

c) Spôsob výroby kyseliny 3-(31-acetyl-5'-etoxykarbonyl-4'-metyl- pyrol-2'-ylmetyl)indol-5-karboxylovejc) Preparation of 3- (3-acetyl-1 5'-ethoxycarbonyl-4'-methyl- pyrrol-2-ylmethyl) indole-5-carboxylic acid

Roztok 0,74 g (2,8 mmol) 5-acetoxymetyl-4-acetylpyrolu a 0,5 g (3 mmol) kyseliny indol-5-(karboxylovej v 50 ml toluénu sa mieša pri teplote miestnosti s 1 g montmorillonitovej hlinky K10 počas 10 dní. Po ochladení a odfiltrovaní hlinky, ktorá sa a dobre premyje toluénom, sa spojené, filtráty odparia pri zníženom tlaku a poskytnú oranžovú tuhú látkuk. Kryštalizáciou zo zmesi etylacetátu a cyklohexánu sa získa zlúčenina pomenovaná v nadpise ako šedý prášok s hmotnosťou 0,15 g, ktorý má teplotu topenia 227 až 228 “C. Výťažok zodpovedá 15 % teórie.A solution of 0.74 g (2.8 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 0.5 g (3 mmol) of indole-5- (carboxylic acid in 50 ml of toluene) is stirred at room temperature with 1 g of montmorillonite clay K10 for After cooling and filtering the clay, which was washed well with toluene, the combined filtrates were evaporated under reduced pressure to give an orange solid, which was crystallized from ethyl acetate / cyclohexane to give the title compound as a gray powder of 0.15 mass. m.p. 227 DEG-228 DEG C. The yield corresponds to 15% of theory.

Analýza pre C20H20N2°5: nájdené: 64,96 % C, 5,58 % H, 7,34 % N, vypočítané: 65,21 % C, 5,47 % H, 7,60 % N.Analysis for C 20 H 20 N 2 ° 5: Found: 64.96% C, 5.58% H 7.34% N Found: 65.21% C, 5.47% H, 7.60% N .

1H NMR SH([2H6]-DMSO): 12,35 (1H, široký signál, CO2H), 1 H NMR SH ([ 2 H 6] -DMSO): 12.35 (1H, broad signal, CO 2 H),

12,04 (1H, S, l'-NH), 11,17 (1H, s, 1-NH), 8,31 (1H, d, J =1,6 Hz, 4-H), 7,70 (1H, dd, J = 1,6 a 8,7 Hz, 6-H), 7,37 (1H, d, J = 8,7 Hz, 7-H), 6,98 (1H, s, 2H), 4,36 (2H, s, 3-CH2), 4,26 (2H, q, CH2CH3), 2,51 a 2,31 (2 x 3H, 2 x s, 4'-CH3 a CH3CO) a 1,29 (3H, t, CH2CH3 ppm. m/z (%) 369(22, (M+l)+), 351(37), 323(18), 305(19), 232(19), 208(60) a 181(20), 162(100). vmax (KBr kotúč)/ cm-1 3359 a 1676.12.04 (1H, S, 1'-NH), 11.17 (1H, s, 1-NH), 8.31 (1H, d, J = 1.6Hz, 4-H), 7.70 (1H, dd, J = 1.6 and 8.7 Hz, 6-H), 7.37 (1H, d, J = 8.7 Hz, 7-H), 6.98 (1H, s, 2H ), 4.36 (2H, s, 3-CH 2 ), 4.26 (2H, q, CH 2 CH 3 ), 2.51 and 2.31 (2 x 3H, 2 xs, 4'-CH 3) and CH 3 CO) and 1.29 (3H, t, CH 2 CH 3 ppm. m / z (%) 369 (22, (M + 1) + ), 351 (37), 323 (18), 305 ( 19), 232 (19), 208 (60) and 181 (20), 162 (100) in max (KBr roll) / cm -1 1359 and 1676.

d) Spôsob výroby 3-(3'-acetyl-5'-etoxykarbonyl-4'-metylpyrol-d) Method for producing 3- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrole-

-2'-ylmetyl)-5-brómindolu ! 2'-ylmethyl) -5-bromoindole

Roztok 1,3 g (4,9 mmol) 5-acetoxymetyl-4-acetylpyrolu a 1,09 g (5,6 mmol) 5-brómindolu v 100 ml 1,2-dichlóretánu sa varí pod spätným chladičom a mieša s 3 g montmorillonitovej hlinky K10 počas 5 hodín. Po ochladení a odfiltrovaní hlinky, ktorá sa dobre premyje 1,2-dichlóretánom, sa spojené filtráty odparia pri zníženom tlaku a poskytnú žltú tuhú látku. Kryštalizáciou zo zmesi dichlórmetánu, petroléteru a acetónu sa získa zlúčenina pomenovaná v nadpise ako krémovo sfarbené kryštály s hmotnosťou 0,33 g, ktoré majú teplotu topenia 181 až 183 °C. Výťažok zodpovedá 17 % teórie.A solution of 1.3 g (4.9 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 1.09 g (5.6 mmol) of 5-bromoindole in 100 ml of 1,2-dichloroethane is heated to reflux and stirred with 3 g. montmorillonite clay K10 for 5 hours. After cooling and filtering the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give a yellow solid. Crystallization from a mixture of dichloromethane, petroleum ether and acetone gave the title compound as cream colored crystals (0.33 g), mp 181-183 ° C. Yield: 17%.

Analýza pre Analysis for C19H19BrN2°3: C 19 H 19 BrN 2 ° 3 : nájdené: found: 56,24 % C, 4,70 C 56.24, 4.70 % H, % H, 6,86 % 6.86% N, N, vypočítané: calculated: 56,59 % C, 4,75 C 56.59, 4.75 % H, % H, 6,95 % 6,95% N. N. XH NMR X H NMR SH([2H6)-DMSO):S H ([ 2 H 6 ] -DMSO): 12, 12 00 (1H, 00 (1 H, s, ľ-NH), 11,00 s, 1'-NH), 11.00 (1H, s, (1H, s, 1-NH), 7,82 1-NH), 7.82 (1H, d, J = 1,9 (1H, d, J = 1.9) HZ, HZ, 4-H), ' 4-H), 7,31 (1H, d, J = 7.31 (1 H, d, J = 8,6 Hz, 8.6 Hz,

7-H), 7,16 (1H, dd, J = 1,9 a 8,6 Hz, 6-H), 7,02 (1H, s, 2-H), 4,30 (2H, s, 3-CH2), 4,28 (2H, q, CUHU2CH3), 2,51 a 2,33 (2 x 3H, 2 x s, 4'-CH3 a CH3CO), 1,31 (3H, t, CH2CH3) ppm. m/z (%) 404 a 402(100, M+), 389 a 387(24), 357(24), 330 a 328(32), 206(36) a 178(26). vmax(KBr kotúčj/cm-1 3373 a 1672.7-H), 7.16 (1H, dd, J = 1.9 and 8.6 Hz, 6-H), 7.02 (1H, s, 2-H), 4.30 (2H, s, 3-CH 2 ), 4.28 (2H, q, CUHU 2 CH 3 ), 2.51 and 2.33 (2 x 3H, 2 xs, 4'-CH 3 and CH 3 CO), 1.31 ( 3H, t, CH 2 CH 3 ) ppm. m / z (%) 404 and 402 (100, M < + > ), 389 and 387 (24), 357 (24), 330 and 328 (32), 206 (36) and 178 (26), respectively. v max (KBr kotúčj / cm-1 3373 and the 1672nd

Príklad 3Example 3

a) Spôsob výroby etyl-(3,4-dímetylpyrolo[3,2-b]-karbazol-2-karboxylátu)a) Process for the preparation of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Roztok 0,108 g (0,33 mmol) 3-(pyrolylmetyl)indolu sa opatrne varí pod spätným chladičom v 10 ml 1,2 dichlóretánu a mieša s 1 g montmorillonitovej hlinky K10 počas 2 hodín. Chromátografia na tenkej vrstve potom ukáže, že vznikla jediná zlúčenina a že reakcia je úplná. Po ochladení a odfiltrovaní hlinky, ktorá sa a dobre premyje 1,2-dichlóretánom, sa spojené filtráty odparia pri zníženom tlaku a poskytnú žltú tuhú látku, ktorá 1 sa kryštalizuje z etylacetátu a poskytne pyrrolof3,2-bJ-karbazol ako žltú kryštalickú látku s hmotnosťou 0,076 g, ktorá má teplotu topenia 209,5 až 211 °C. Výťažok zodpovedá 75 °C teórie.A solution of 0.108 g (0.33 mmol) of 3- (pyrrolylmethyl) indole was cautiously refluxed in 10 ml of 1.2 dichloroethane and stirred with 1 g of Montmorillonite clay K10 for 2 hours. Thin layer chromatography then showed that a single compound had formed and that the reaction was complete. After cooling and filtration from the clay, which was washed well with 1,2-dichloroethane, the combined filtrates evaporated under reduced pressure to give a yellow solid which was crystallized from 1 ethyl acetate to give pyrrolor3,2-b-carbazole as a yellow crystalline solid, weight 0.076 g, mp 209.5-211 ° C. Yield 75 ° C.

Analýza pre ci9Hi8N2°2: nájdené: 74,6 % C, 6,14 % H, 9,03 % N, vypočítané: 74,5 % C, 5,92 % H, 9,14 % N.Analysis for C i9 i8 H 2 N ° 2: Found: 74.6% C, 6.14% H 9.03% N Found: 74.5% C, 5.92% H, 9.14% N .

1H NMR 1 H NMR δΗ((2H6]-DMSO): 11,22 (1H, s, 1-NH), 10,70 (1H, s, δ Η ((2 H 6] -DMSO): 11.22 (1H, s, 1-NH), 10.70 (1H, s, 5-NH), 8,06 5-NH), 8.06 (1H, d, J = 7 Hz, 9-H), 7,85 (1H, s, 10-H), 7,40 (1H, d, J = 7Hz, 9-H), 7.85 (1H, s, 10-H), 7.40 (1H, d, J = (1 H, d, J = 7 Hz, 6-H), 7,35 (1H, t, J = 7 Hz, 7-H), 7,08 (1H, 7 Hz, 6-H), 7.35 (1H, t, J = 7Hz, 7-H), 7.08 (1H, t, J = 7 HZ, t, J = 7 Hz, 8-H), 4,35 (2H, q, OCH2H3), 2,91 a 2,90 (2 x 3H, 28-H), 4.35 (2H, q, OCH 2 H 3 ), 2.91 and 2.90 (2 x 3H, 2 x s, 3-CH3 axs, 3-CH 3 and 4-CH3) a 1,35 (3H, t, OCH2CH3) ppm. Nasýtenie 10-H4-CH 3 ) and 1.35 (3H, t, OCH 2 CH 3 ) ppm. Saturation 10-H

pri δ 7,85 zvyšuje singlety vďaka 1-NH pri δ 11,22 (3 %) a 9-Hat δ 7.85 increases singlets due to 1-NH at δ 11.22 (3%) and 9-H

pri δ 8,06 at δ 8.06 (4 %). m/z (%) 306(56, M+), 260(100), 323(39),(4%). m / z (%) 306 (56, M < + > ), 260 (100), 323 (39),

205(15), 140(18) a 130(26). vmax (CHCl3)/cm 1 3480 a 1700. lambdamax(eta- nol)/nm 226, 268, 310 posun, 327 posun, 340, 390 a 410 posun.205 (15), 140 (18) and 130 (26). at max (CHCl 3 ) / cm 1 3480 and 1700. lambda max (ethanol) / nm 226, 268, 310 shift, 327 shift, 340, 390 and 410 shift.

b) Spôsob výroby etyl-(3,4-dimetyl-lH-benzofuro[3,2-f]-indol-2-karboxylátu) mg kyseliny p-toluénsulfónovej sa vnesie do roztokub) A process for the preparation of ethyl (3,4-dimethyl-1H-benzofuro [3,2-f] indole-2-carboxylate) mg of p-toluenesulfonic acid is introduced into a solution

0,100 g (0,31 mmol) 2-(pyrolylmetyl)benzofuránu v 10 ml toluénu a reakčná zmes sa varí pod spätným chladičom počas 3 hodín. Po ochladení vzniknutá látka vykryštaluje a po filtrácii sa premyje etanolom. Získa sa zlúčenina pomenovaná v nadpise, ako svetlo žlté kryštály s hmotnosťou 0,084 g, ktoré majú teplotu topenia 262 až 265°C. Výťažok zodpovedá 88,8 % teórie.0.100 g (0.31 mmol) of 2- (pyrrolylmethyl) benzofuran in 10 ml of toluene and the reaction mixture was refluxed for 3 hours. After cooling, the product crystallized out and was washed with ethanol after filtration. The title compound is obtained as pale yellow crystals weighing 0.084 g and having a melting point of 262-265 ° C. Yield 88.8% of theory.

Analýza pre CigH17NO3:Analysis for C 17 H ig NO 3:

nájdené: 74,25 % C, 5,55 % H, 4,6 % N, vypočítané: 74,25 % C, 5,56 % H, 4,56 % N.Found: C, 74.25; H, 5.55; N, 4.6%. Calculated: C, 74.25; H, 5.56; N, 4.56.

XH NMR δΗ( [2H6]-DMSO) : 11,52 (1H, s, X δΗ NMR ([2 H 6] -DMSO): 11.52 (1H, s,

7,5 Hz, 5-H), 7,62 (1H, d, J = 7,5 Hz,7.5 Hz, 5-H), 7.62 (1H, d, J = 7.5Hz,

1-NH), 8,18 (1H,1-NH), 8.18 (1 H,

8-H), 7,46 (1H, d, J = t, J =8-H), 7.46 (1 H, d, J = t, J =

7,5 Hz, 7-H), 7,38 (1H, t, J = 7,5 Hz, 6-H), 7,38 (1H, s, 10-H),7.5 Hz, 7-H), 7.38 (1H, t, J = 7.5Hz, 6-H), 7.38 (1H, s, 10-H),

4,37 (2H, q, ÓCH2CH3), 3,14 (3H, s, 4-CH3), 2,91 (3H, s, 3-CH3) a 1,39 (3H, t, OCH2H3) ppm, nasýtenie 4-CH3 pri δ 3,14 zvyšuje signály vďaka 5-H pri δ 8,18 (4,5 %) a 3-CH3 pri δ 2,91 (2,6)% m/z (%) 307(53, M+), 261(100), 233(31) a 205(9). Vmax (nujol)/cm_1 3350 a 1686. lambdamax(etanol)/nm 240, 269, 293,4.37 (2H, q, OCH 2 CH 3 ), 3.14 (3H, s, 4-CH 3 ), 2.91 (3H, s, 3-CH 3 ) and 1.39 (3H, t, OCH 2 H 3 ) ppm, saturation of 4-CH 3 at δ 3.14 increases signals due to 5-H at δ 8.18 (4.5%) and 3-CH 3 at δ 2.91 (2.6)% m / z (%) 307 (53, M < + > ), 261 (100), 233 (31) and 205 (9). Ν max (nujol) / cm -1 1350 and 1686. λ max (ethanol) / nm 240, 269, 293,

330 a 344.330 and 344.

c) Spôsob výroby etyl-(3,4-dimetyl-lH-[1]benzotieno[3,2-f]indol-2-karboxylátu) mg kyseliny p-toluénsulfónovej sa vnesie do roztoku 0,100 g (0,29 mmol) 3-(pyrolylmetyl)benzotiofénu v 10 ml toluénu a reakčná zmes sa varí pod spätným chladičom počas 3 hodín. Odparením rozpúšťadla a premytím výslednej tuhej látky etanolom sa získa zlúčenina pomenovaná v nadpise ako svetlo žltá látka s hmotnosťou 0,0758 g, ktorá má teplotu topenia 191 až 193 °C. Výťažok zodpovedá 80 % teórie.c) A process for the preparation of ethyl (3,4-dimethyl-1H- [1] benzothieno [3,2-f] indole-2-carboxylate) mg of p-toluenesulfonic acid is added to a solution of 0.100 g (0.29 mmol) 3. - (pyrrolylmethyl) benzothiophene in 10 ml of toluene and the reaction mixture is refluxed for 3 hours. Evaporation of the solvent and washing of the resulting solid with ethanol gave the title compound as a pale yellow material (0.0758 g), m.p. 191-193 ° C. The yield corresponds to 80% of theory.

Analýza pre CigH17NO2S: nájdené: 70,3 % C, 5,5 % H, 4,2 % N, vypočítané: 70,6 % C, 5,30 % H, 4,33 % N.Analysis for C 17 H ig NO 2 S: found: 70.3% C, 5.5% H, 4.2% N Found: 70.6% C, 5.30% H, 4.33% N.

1H NMR 8h([2H6]-DMSO): 11,64 (1H, s, NH), 8,25 (1H, m, 9-H), 8,12 (1H, s, 10-H), 7,95 (1H, m, 6-H), 7,48 (2H, m, 7-H a 8-H), 4,38 (2H, q, OCH2CH3), 2,87 a 2,85 (2 x 3H, 2 x s, 3-CH3) a 1,37 (3H, t, OCH2CH3) ppm. m/z (%) 323 (53, M+), 277 (100), 249(33) a 221(15), 139(7) a 111(11). vmax (nujol)/cm-1 3350 a 1686. 1 H NMR 8h ([ 2 H 6] -DMSO): 11.64 (1H, s, NH), 8.25 (1H, m, 9-H), 8.12 (1H, s, 10-H), 7.95 (1H, m, 6-H), 7.48 (2H, m, 7-H and 8-H), 4.38 (2H, q, OCH 2 CH 3 ), 2.87 and 2, 85 (2 x 3H, 2 xs, 3-CH 3 ) and 1.37 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 323 (53, M < + > ), 277 (100), 249 (33) and 221 (15), 139 (7) and 111 (11). v max (nujol) / cm -1 3350 and 1686.

lambdamax(etanol)/nm 240, 269, 293, 330 a 344. .lambda.max (EtOH) / nm 240, 269, 293, 330 and 344th

d) Spôsob výroby benzyl-(3,4-dimetyl-lH-[1]benzotieno[3,2-f ] indol-2-karboxylátu) mg kyseliny p-toluénsulfónovej sa vnesie do roztoku 0,100 g (0,25 mmol) 3-(pyrolylmetyl)benzotiofénu v 12 ml toluénu a reakčná zmes sa varí pod spätným chladičom počas 6 hodín. Odparením rozpúšťadla a premytím výslednej tuhej látky etanolom sa získa zlúčenina pomenovaná v nadpise, ako svetlo žltá tuhá látka s hmotnosťou 0,02 g, ktorá má teplotu topenia 203 až 204 C. Výťažok zodpovedá 20 % teórie.d) Preparation of benzyl (3,4-dimethyl-1H- [1] benzothieno [3,2-f] indole-2-carboxylate) mg of p-toluenesulfonic acid is added to a solution of 0.100 g (0.25 mmol) of 3 - (pyrrolylmethyl) benzothiophene in 12 ml of toluene and the reaction mixture is refluxed for 6 hours. Evaporation of the solvent and washing of the resulting solid with ethanol gave the title compound as a pale yellow solid, 0.02 g, mp 203-204 ° C. Yield 20%.

Analýza pre C24H19NO2S: nájdené: 74,7 % C, 4,9 % H, 3,6 % N, vypočítané: 74,8 % C, 5,0 % H, 3,6 % N.Analysis for C 24 H 19 NO 2 S: found: 74.7% C, 4.9% H, 3.6% N Found: 74.8% C, 5.0% H, 3.6% N.

1H NMR SH([2H6]-DMSO): 11,64 (1H, s, NH) , 8,27 1 H NMR SH ([ 2 H 6] -DMSO): 11.64 (1H, s, NH), 8.27

8,15 (1H, m, 9-H), 8,10 (1H, s, 10-H), 7,90 - 7,89 (1H, m, 6-H), 7,60 7,30 (7H, m, 7-H, 8-H, ArH), 5,40 (2H, s, CH2) a 2,87 (6H, s, 2 x CH3) ppm. m/z (%) 385 (100, M+), 277(89), 248(25), 221(15) a8.15 (1H, m, 9-H), 8.10 (1H, s, 10-H), 7.90-7.89 (1H, m, 6-H), 7.60 7.30 (1H 7H, m, 7H, 8-H, Ar H), 5.40 (2H, s, CH2) and 2.87 (6H, s, 2 x CH3) ppm. m / z (%) 385 (100, M < + > ), 277 (89), 248 (25), 221 (15), and

91(28). v„,_v (KBr kotúč)/cm-1 3331 a 1672.91 (28). the "_ v (KBr Disc) / cm-1 3331 and the 1672nd

llLClXllLClX

e) Spôsob výroby etyl-(8-kyán-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)e) Process for the preparation of ethyl (8-cyano-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zmes 0,6 g (1,7 mmol) 3-(pyrolylmetyl)indolu a 2 g montmorillonitovej hlinky K10 v toluéne sa mmieša a varí pod spätným chladičom počas 24 hodín. Po ochladení a odfiltrovaní hlinky, ktorá sa a dobre premyje toluénom, sa spojené filtráty odparia pri zníženom tlaku a poskytnú hnedú tuhú látku, ktorá sa podrobí velmi rýchlej chromátografii na oxide kremičitom, pri eluovaní zmesou cyklohexanónu a etylacetátu v pomere 3:1. Získa sa žltá tuhá látka, ktorá kryštalizáciou zo zmesi cyklohexánu a etylacetátu poskytne zlúčeninu pomenovanú v nadpise, ako žltý prášok s hmotnosťou 0,030 g, ktorý má teplotu topenia vyššiu ako 240 °C. Výťažok zodpovedá 5 % teórie.A mixture of 0.6 g (1.7 mmol) of 3- (pyrrolylmethyl) indole and 2 g of Montmorillonite clay K10 in toluene is stirred and refluxed for 24 hours. After cooling and filtering the clay, which was washed well with toluene, the combined filtrates were evaporated under reduced pressure to give a brown solid which was subjected to flash chromatography on silica eluting with cyclohexanone / ethyl acetate 3: 1. Recrystallization from cyclohexane / ethyl acetate gave the title compound as a yellow powder of 0.030 g, m.p. > 240 ° C. The yield corresponds to 5% of theory.

Analýza pre Analysis for ^20^17^3θ2’ 0,2 H20:^ 20 ^ 17 ^ 3θ2 '0.2 H 2 0: nájdené: found: 71,54 % C, 5,18 % H, 71.54% C, 5.18% H, 12,78 12.78 % N, % N, vypočítané: calculated: 71,71 % C, 5,24 % H, % C, 71.71;% H, 5.24. 12,54 12.54 % N. % N. 1H NMR 1 H NMR δΗ( t Xl-DMSG) : 11,39δ Η (t X 1 -DMSG): 11.39 (1H, (1 H, s, 1-NH), s, 1-NH), 11,29 (1H, s, 11.29 (1 H, s, 5-NH), 8,65 5-NH), 8.65 (1H, d, J = 1,7 Hz, (1H, d, J = 1.7Hz, 9-H) , 9-H), 8,01 (1H, 8.01 (1 H, s, 10-H), 7,71 s, 10-H), 7.71 (1H, dd, J = (1 H, dd, J = : 1,7 a 8,6 Hz, 7-H), : 1.7 and 8.6 Hz, 7-H), 7,50 7.50 (1H, d, J = (1 H, d, J = = 8,6 HZ, 6-H), = 8.6 Hz, 6-H), 4,36 (2H, q, 4.36 (2 H, q, CH2CH3), 2,91 a 2,89CH 2 CH 3 ), 2.91 and 2.89 ( 2 x (2 x 3H, 2 x s, 3H, 2x s, 4-CH3 a 3-CH3)4-CH 3 and 3-CH 3 ) a 1,38 (3H, and 1.38 (3H, t, CH2CH3) ppm.t, CH 2 CH 3 ) ppm. m/z ( m / z ( :%) 331(52, % 331 (52, M+), 285(100),M + ) 285 (100)

256(32), 229(12), 167(14) a 149(40). vmax (KBr kotúč)/cm 1 3414, 3550, 12212 a 1664.256 (32), 229 (12), 167 (14) and 149 (40). v max (KBr roll) / cm 1 3414, 3550, 12212 and 1664.

f) Spôsob výroby kyseliny 3,4-dimetyl-2-etoxykarbonylpyrrolo[3,2-b]-karbazol-8-karboxylovejf) Method for the preparation of 3,4-dimethyl-2-ethoxycarbonylpyrrolo [3,2-b] carbazole-8-carboxylic acid

Zmes 0,1 g (0,3 mmol) 3-(pyrolylmetyl)indolu a 0,34 g montmorillonitovej hlinky K10 v 15 ml toluénu sa mieša a varí pod spätným chladičom počas 6 hodín. Po ochladení a odfiltrovaní hlinky, ktorá sa a dobre premyje toluénom, sa spojené filtráry odparia pri zníženom tlaku a poskytnú oranžovú tuhú látku, ktorá kryštalizáciou zo zmesi metanolu a dichlórmetánu poskytne zlúčeninu pomenovanú v nadpise, ako žltý prášok s hmotnosťou 0,027 g, ktorý má teplotu topenia vyššiu ako 260 °C. Výťažok zodpovedá 28 % teórie.A mixture of 0.1 g (0.3 mmol) of 3- (pyrrolylmethyl) indole and 0.34 g of K10 montmorillonite clay in 15 ml of toluene is stirred and refluxed for 6 hours. After cooling and filtering the clay, which was washed well with toluene, the combined filters were evaporated under reduced pressure to give an orange solid, which crystallized from methanol / dichloromethane to give the title compound as a yellow powder, 0.027 g, having a temperature of mp > 260 ° C. Yield: 28%.

Analýza pre C2qH18N2O4. 0,05 H2O:Analysis for C q H 2 O 2 18 N 4th 0.05 H 2 O:

nájdené: found: 68,12 % C, 5,19 % H, 68.12% C, 5.19% H, 7,91 % N, 7.91% N, vypočítané: calculated: 68,39 % C, 5,19 % H, 68.39% C, 5.19% H, 7,98 % N. 7.98% N. 1H NMR 1 H NMR δΗ([2H6]-DMS°): 12δ Η ([ 2 H 6 ] -DMS °): 12 ,42 (1H, široký signál, COOH), , 42 (1H, broad signal, COOH), 11,30 (1H, 11.30 (1 H, s, 1-NH), 11,09 (1H, s, 1-NH), 11.09 (1 H, s, 5-NH), 8,68 (1H, s, 10-H), s, 5-NH), 8.68 (1 H, s, 10-H), 8,07 - 7,93 8.07 - 7.93 (2H, m, 7-H a 9-H), (2H, m, 7H and 9H), 7,45 (1H, d, J = 9 Hz, 6-H), 4, 7.45 (1H, d, J = 9Hz, 6-H);

(2H, q, CH2CH3), 2,94 a 2,90 (2 x 3H, 2 x s, 4-CH3 a 3-CH3) a 1,39 (3H, t, CH2CH3) ppm. m/z (%) 350(100, M+), 304(100),(2H, q, CH 2 CH 3 ), 2.94 and 2.90 (2 x 3H, 2 xs, 4-CH 3 and 3-CH 3 ) and 1.39 (3H, t, CH 2 CH 3 ) ppm. m / z (%) 350 (100, M < + > ), 304 (100),

278(40), 232(35) a 181(38). vmax (KBr kotúč)/cm-1 3459, 1697 a 1674.278 (40), 232 (35) and 181 (38). v max (KBr roll) / cm -1 3459, 1697 and 1674.

g) Spôsob výroby etyl-(8-bróm-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)g) Process for the preparation of ethyl (8-bromo-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zmes 0,3 g (0,74 mmol) 3-(pyrolylmetylindolu a 1 g montmorillonitovej hlinky K10 v toluéne sa mieša a varí pod spätným chladičom počas 6 hodín. Po ochladení a odfiltrovaní hlinky, ktorá sa dobre premyje toluénom, sa spojené filtráty odparia pri zníženom tlaku a poskytnú hnedú tuhú látku, ktorá sa podrobí velmi rýchlej chromatografii na oxide kremičitom, pri eluovaní zmesou dichlórmetánu a petroléteru v pomere 7:3. Získa sa žltá tuhá látka, ktorá kryštalizuje zo zmesi cyklohexánu a etylacetátu 'poskytne zlúčeninu pomenovanú v nadpise, ako žltý prášok s hmotnosťou 0,070 g, ktorý má teplotu topenia 204 a 205 °C (rozklad). Výťažok zodpovedá 24 % teórie.A mixture of 0.3 g (0.74 mmol) of 3- (pyrrolylmethylindole) and 1 g of Montmorillonite clay K10 in toluene was stirred and refluxed for 6 hours. After cooling and filtering the clay, which was well washed with toluene, the combined filtrates were evaporated under reduced pressure to give a brown solid which was subjected to flash chromatography on silica eluting with a 7: 3 mixture of dichloromethane and petroleum ether to give a yellow solid which crystallized from a mixture of cyclohexane and ethyl acetate to give the title compound. Yield: 24% of theory.

Analýza pre C19H17BrN2O2:Analysis for C 19 H 17 BrN 2 O 2 :

nájdené: 59,17 % C, 4,43 % H, 7,30 % N, vypočítané: 59,23 % C, 4,45 % H, 7,27 % N.found: C 59.17, H 4.43, N 7.30, calculated: C 59.23, H 4.45, N 7.27.

ΧΗ NMR δΗ([2H6]-DMSO): 11,26 (1Η, s, 1-NH), 10,79 (1H, s, 5-NH), 8,30 (1H, d, J = 2,2 Hz, 9-H), 7,92 (1H, s, 10-H), 7,47 (1H, dd, J = 2,2 a 8,8 Hz, 7-H), 7,35 (1H, d, J = 8,8 Hz, 6-H) , 4,36 (2H, q, CH2CH3), 2,89 a 2,88 (2 x 3H, 2 x s, 4-CH3 a 3-CH3) a 1,38 (3H, t, CH2CH3) ppm. m/z (%) 386 a 384(100, M+), 340 a 338(70), 232(60) a 181(50). vmax (KBr kotúč)/cm-1 3350, 1705 a 1663 . Χ Η NMR δΗ ([2 H 6] -DMSO): 11.26 (1Η, s, 1-NH), 10.79 (1H, s, 5-NH), 8.30 (1H, d, J = 2 2 Hz, 9-H), 7.92 (1H, s, 10-H), 7.47 (1H, dd, J = 2.2 and 8.8 Hz, 7-H), 7.35 (1H, 1 H, d, J = 8.8 Hz, 6-H), 4.36 (2H, q, CH 2 CH 3), 2.89 and 2.88 (2 x 3H, 2 x s, 4-CH 3 and 3-CH 3 ) and 1.38 (3H, t, CH 2 CH 3 ) ppm. m / z (%) 386 and 384 (100, M < + > ), 340 and 338 (70), 232 (60) and 181 (50), respectively. v max (KBr roll) / cm -1 3350, 1705 and 1663.

Príklad 4..Example 4 ..

Spôsob výroby pyrrolokarbazolov v jednej reakčnej nádobe, všeobecný postupProcess for preparing pyrrolocarbazoles in one reaction vessel, general procedure

Roztok 1,0 mmol indolu a 1,0 mmol 5-acetoxymetyl-4-axetylpyrolu v 10 ml 1,2-dichlóretánu sa opatrne vari pod spätným chladičom a mieša s 1 g montmorillonitovej hlinky K10 počas 3 až 4 hodín. Farba hlinky prejde na svelo hnedú a podlá chromátografie na tenkej vrstve je reakcia úplná. Po odfiltrovaní hlinky a dobrom premytí 1,2-dichlóretánom sa spojené filtráty odparia a poskytnú pyrolo[3,2-b]karbazoly, ktoré sa získajú ako žlté kryštály, po kryštalizácii zo zmesi dichlórmetánu a etylacetátu.A solution of 1.0 mmol of indole and 1.0 mmol of 5-acetoxymethyl-4-axylpyrrole in 10 mL of 1,2-dichloroethane was gently refluxed and stirred with 1 g of montmorillonite clay K10 for 3-4 hours. The clay color turns to light brown and the reaction is complete by thin layer chromatography. After filtering the clay and washing well with 1,2-dichloroethane, the combined filtrates are evaporated to give pyrrolo [3,2-b] carbazoles, which are obtained as yellow crystals, after crystallization from a mixture of dichloromethane and ethyl acetate.

a) Spôsob výroby etyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)a) Process for the preparation of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,199 g zlúčeniny pomenovanej v nadpise sa získa reakciou indolu a 5-acetoxymetyl-4-acetylpyrolu, vo výťažku zodpovedajúcem 65 % teórie. Táto zlúčenina je identická vo všetkých smeroch s pyrolo[3,2-b]-karbazolom z príkladu 1.0.199 g of the title compound is obtained by reaction of indole and 5-acetoxymethyl-4-acetylpyrrole in a yield corresponding to 65% of theory. This compound is identical in all directions to the pyrrolo [3,2-b] carbazole of Example 1.

b) Spôsob výroby benzyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2karboxylátu)b) Method for producing benzyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,179 g zlúčeniny pomenovanej v nadpise sa získa reakciou indolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 229 až 232 “C. Výťažok zodpovedá 48,8 % teórie.0.179 g of the title compound is obtained by reacting indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 229-232 ° C. Yield 48.8% of theory.

Analýza pre Analysis for C24H20N2°2: C 24 H 20 N 2 ° 2 : nájdené: found: 78,2 % C, 5,65 78.2% C, 5.65 % % H, 7,8 H, 7.8 % N, % N, vypočítané: calculated: 78,23 % C, 5,47 78.23% C, 5.47 % % H, 7,60 H, 7.60 % N. % N. ΧΗ NMR Χ Η NMR SH([2H6J-DMS°):S H ([ 2 H 6 J-DMS °)]: 11 11 ,29 (1H, 29 (1H, s, with, 1-NH), 10,65 (1H, s, 1-NH), 10.65 (1 H, s, 5-NH), 8,08 5-NH), 8.08 (1H, d, H = 8 (1 H, d, H = 8 Hz , Hz, 9-H), 7 9-H), 7 ,89 89 (1H, s, 10-H), 7,56 - (1H, s, 10-H), 7.56-

7,34 (7Η, m, ArH, 6-H a 7-H), 7,08 (1H, t, J = 7 Hz, 8-H), 5,42 (2H, s, CH2Ph) a 2,92 (6H, s, 3-CH3 a 4-CH3) ppm. m/z (%) 368(74, M+), 354(10), 260(100), 246(13), 231(20) a 91(31).7.34 (7Η, m, Ar H, 6-H and 7-H), 7.08 (1H, t, J = 7 Hz, 8-H), 5.42 (2H, s, CH 2 Ph), and 2.92 (6H, s, 3-CH3 and 4-CH3) ppm. m / z (%) 368 (74, M < + > ), 354 (10), 260 (100), 246 (13), 231 (20), and 91 (31).

0,166 g pyrolo[3,2-b]karbazolu sa tiež získa reakciou indolu a 4-acetyl-5-(etoxymetyl)pyrolu. Výtažok zodpovedá 45 % teórie.0.166 g of pyrrolo [3,2-b] carbazole is also obtained by reaction of indole and 4-acetyl-5- (ethoxymethyl) pyrrole. Yield: 45%.

c) Spôsob výroby etyl-(8-metoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)c) Process for the preparation of ethyl (8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciouThe title compound is obtained by reaction

5-metoxyindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčeninu má teplotu topenia 119 až 122 ’C.5-methoxyindole; and 5-acetoxymethyl-4-acetylpyrrole. The compound has a melting point of 119-122 ° C.

Analýza pre Analysis for C20H20N2°3: C 20 H 20 N 2 ° 3 : nájdené: found: 71,6 % C, 6,0 71.6% C, 6.0 % H, 8 % H, 8 ,05 % N, .05% N, vypočítané: calculated: 71,4 % C, 5,99 71.4% C, 5.99 % H, 8 % H, 8 ,33 % N. , 33% N. XH NMR X H NMR 6H([2H6]-DMSO)6 H ( 2 H 6 -DMSO) : 11,20 : 11,20 (1H, s, (1H, s, 1-NH), 1-NH), 10, 10. 38 (1H, s, 38 (1 H, s, 5-NH), 7,85 5-NH), 7.85 (1H, s, 10-H) (1 H, s, 10-H) , 7,62 , 7.62 (1H, d, J (LH, d, J) = 2,5 = 2.5 Hz , Hz, 9-H), 7,31 9-H), 7.31 (1H, d, J = (1 H, d, J = 9 Hz, 6-H), 7, 9 Hz, 6-H), 01 (1H, 01 (1 H, dd, J = 9 dd, J = 9 a 2,5 and 2.5 Hz , Hz, 7-H), 4,38 7-H), 4.38

(2H, q, OCH2CH3), 3,88 (3H, s, OCH3), 2,89 a 2,87 (2 x 3H, 2 x s, 3-CH3 a 4-CH3) a 1,39 (3H, t, OCH2CH3) ppm. m/z (%) 386 (60, M+), 290(100), 275(5), 262(4), 247(23), 219(8) a 145(9).(2H, q, OCH 2 CH 3 ), 3.88 (3H, s, OCH 3 ), 2.89 and 2.87 (2 x 3H, 2 xs, 3-CH 3 and 4-CH 3 ) and 1 39 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 386 (60, M < + > ), 290 (100), 275 (5), 262 (4), 247 (23), 219 (8), and 145 (9).

d) Spôsob výroby benzyl-(8-metoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)d) Method for the preparation of benzyl (8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,139 g zlúčeniny pomenovanej v nadpise sa získa reakciou 5-metoxyindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 212 až 215 °C. výťažok zodpovedá 35 % teórie.0.139 g of the title compound is obtained by reaction of 5-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 212-215 ° C. yield corresponds to 35% of theory.

Analýza pre nájdené:Analysis for found:

6,95 % N, vypočítané: 75,4 % C, 5,57 % H, 7,03 % N.N, 6.95. Found: C, 75.4; H, 5.57; N, 7.03.

XH NMR δΗ([2H6]-DMSO): 11,29 (1H, s, 1-NH), 10,38 (1H, s, 5-NH), 7,88 (1H, s, 10-H), 7,65 (1H, d, J = 2,5 Hz, 9-H), 7,58 7,36 (5H, m, ArH), 7,32 (1H, d, J = 9 Hz, 6-H), 7,02 (1H, dd, J = 9 a 2,5 Hz, 7-H), 5,43 (2H, s, CH^Ph), 3,88 (3H, s, OCH3), 2,92 (3H, S, 4-CH3) a 2,89 (3H, S, 3~CH3)ppm. m/z (%) 398(73, M+), 290(100), 262(10), 247(15), 219(7) a 91(17). X δΗ NMR ([2 H 6] -DMSO): 11.29 (1H, s, 1-NH), 10.38 (1H, s, 5-NH), 7.88 (1H, s, 10-H 7.65 (1H, d, J = 2.5Hz, 9-H), 7.58 7.36 (5H, m, ArH), 7.32 (1H, d, J = 9Hz, 6) -H), 7.02 (1H, dd, J = 9 and 2.5 Hz, 7-H), 5.43 (2H, s, CH 2 Ph), 3.88 (3H, s, OCH 3 ) , 2.92 (3H, s, 4-CH3) and 2.89 (3H, s, 3-CH3) ppm. m / z (%) 398 (73, M < + > ), 290 (100), 262 (10), 247 (15), 219 (7) and 91 (17).

e) Spôsob výroby etyl-(8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)e) Process for the preparation of ethyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,131 g zlúčeniny pomenovanej v nadpise sa získa reakciou 5-fluorindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 231 až 234 C. Výťažok zodpovedá 40,5 % teórie.0.131 g of the title compound is obtained by reaction of 5-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound had a melting point of 231-234 C. The yield was 40.5% of theory.

Analýza pre cigHi7FN2°2: nájdené: 70,5 % C, 5,3 % H, 8,4 % N, vypočítané: 70,4 % C, 5,28 % H, 8,64 % N.Analysis for C H ig i7 FN 2 ° 2: Found: 70.5% C, 5.3% H, 8.4% N Found: 70.4% C, 5.28% H, 8.64% N .

XH NMR δΗ([2H6]-DMSO): 11,27 (1H, s, 1-NH), 10,64 (1H, s, X δΗ NMR ([2 H 6] -DMSO): 11.27 (1H, s, 1-NH), 10.64 (1H, s,

5-NH), 7,93 (1H, dd, J = 9 a 2,5 Hz, 9-H), 7,88 (1H, s, 10-H), 7,36 (1H, dd, J = 9 a 6 Hz, 6-H), 7,19 (1H, dt, J = 9 a 2,5 Hz, 7-H), 4,36 (2H, q, OCH2CH3), 2,88 (6H, s, 3-CH3 a 4-CH3) a 1,37 (3H, t, OCH2CH3) ppm. m/z (%) 324 (50, M+), 278(100),5-NH), 7.93 (1 H, dd, J = 9 and 2.5 Hz, 9-H), 7.88 (1 H, s, 10-H), 7.36 (1 H, dd, J = 9 and 6 Hz, 6-H), 7.19 (1H, dt, J = 9 and 2.5 Hz, 7-H), 4.36 (2H, q, OCH 2 CH 3 ), 2.88 ( 6H, s, 3-CH 3 and 4-CH 3 ) and 1.37 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 324 (50, M < + > ), 278 (100),

250(31), 220(10), 139(8), 125(7) a 111(8).250 (31), 220 (10), 139 (8), 125 (7), and 111 (8).

f) Spôsob výroby benzyl-(8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)f) Method for the preparation of benzyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,155 g zlúčeniny pomenovanej v nadpise sa získa z 5-fluorindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 217 až 219 “C. Výťažok zodpovedá 40 % teórie.0.155 g of the title compound is obtained from 5-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 217-219 ° C. Yield: 40%.

Analýza pre C24HigFN2O2:Analysis for C 24 H ig FN 2 O 2:

nájdené: 74,6 % C, 4,95 % H, 7,3 % N, vypočítané: 74,6 % C, 4,96 % H, 7,25 % N.Found:% C, 74.6;% H, 4.95;% N, 7.3. Calculated:% C, 74.6;% H, 4.96;

1H NMR SH([2H6]-DMSO): 11,36 (1H, s, 1-NH), 10,86 (1H, s, 5-NH), 7,94 (1H, dd, J = 9 a 2,5 Hz, 9-H), 7,88 (1H, s, 10-H), 7,56 - 7,38 (5H, m, ArH), 7,39 (1H, dd, J = 9 a 4 Hz, 6-H),7,21 (1H, dt, J = 9 a 2,5 Hz, 7-H), 5,42 (2H, s, CH2Ph), 2,91 a2.90 (2 x 3H, 2 x s, 3-CH3 a 4-CHg) ppm. m/z (%) 386(68,M 1 H NMR SH ([ 2 H 6] -DMSO): 11.36 (1H, s, 1-NH), 10.86 (1H, s, 5-NH), 7.94 (1H, dd, J = 9) and 2.5 Hz, 9-H), 7.88 (1H, s, 10-H), 7.56-7.38 (5H, m, ArH), 7.39 (1H, dd, J = 9) and 4 Hz, 6-H), 7.21 (1H, dt, J = 9 and 2.5 Hz, 7-H), 5.42 (2H, s, CH2 Ph), 2.91 a2.90 (2 x 3H, 2 xs, 3-CH 3 and 4-CH 3) ppm. m / z (%) 386 (68, M < + >)

278(100), 249(22) a 91(43).278 (100), 249 (22) and 91 (43).

g) Spôsob výroby etyl-(3,4,6-trimetylpyrolo[3,2-b]-karbazol-2karboxylátu)g) Process for the preparation of ethyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,206 g zlúčeniny pomenovanej v nadpise sa získa reakciou 7-metylindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 230 ’C (rozklad). Výťažok zodpovedá 64,4 % teórie.0.206 g of the title compound is obtained by reaction of 7-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 230 ° C (decomposition). Yield: 64.4%.

Analýza pre C20H20N2°2: nájdené: 74,9 % C, 6,25 % H, 8,65 %N, vypočítané: 75,0 % C, 6,29 % H, 8,74 %N.Analysis for C 20 H 20 N 2 ° 2: Found: 74.9% C, 6.25% H 8.65% N Found: 75.0% C, 6.29% H, 8.74% N .

XH NMR δΗ([2H6]-DMSO): 11,20 (1H, s, 1-NH), 10,11 (1H, s, 5-NH), 7,89 (1H, d, J = 7,5 Hz, 9-H), 7,84 (1H, s, 10-H),7,18 (1H, d, J = 7,5, 7-H), 7,01 (1H, t, J = 7,5 Hz, 8-H), 4,37(2H, q, OCH2CH3), 2,98 (3H, s, 4-CH3), 2,91 (3H, s, 3-CH3), 2,58 (3H, s, 6-CH3) a 1,34 (3H, t, OCH2CH3) ppm. m/z (%) 320(54, M+) , 274(100), 246(30), 230(5), 137(9), 123(7) a 109(6). X δΗ NMR ([2 H 6] -DMSO): 11.20 (1H, s, 1-NH), 10.11 (1H, s, 5-NH), 7.89 (1H, d, J = 7 5 Hz, 9-H), 7.84 (1H, s, 10-H), 7.18 (1H, d, J = 7.5, 7-H), 7.01 (1H, t, J = 7.5 Hz, 8-H), 4.37 (2H, q, OCH 2 CH 3 ), 2.98 (3H, s, 4-CH 3 ), 2.91 (3H, s, 3-CH 3 ), 2.58 (3H, s, 6-CH 3 ) and 1.34 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 320 (54, M < + > ), 274 (100), 246 (30), 230 (5), 137 (9), 123 (7), and 109 (6).

h) Spôsob výroby benzyl-(3,4,6-trimetylpyrolo[3,2-b]-karbazol2-karboxylátu)h) Method for the preparation of benzyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,167 g zlúčeniny pomenovanej v nadpise sa získa reakciou 7-metylindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 222 Výťažok zodpovedá 43,7 % teórie.0.167 g of the title compound is obtained by reaction of 7-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound had a melting point of 222, yielding 43.7% of theory.

C (rozklad).C (decomposition).

Analýza pre Analysis for C25H22N2°2: C 25 H 22 N 2 ° 2 : nájdené: found: 78,5 % C, 5,9 % 78.5% C, 5.9% H, H, 7,25 % 7.25% N, N, vypočítané: calculated: 78,5 % C, 5,80 % 78.5% C, 5.80% H, H, 7,33 % 7.33% N. N. 1H NMR 1 H NMR SH([2H6]-DMSO):S H ([ 2 H 6 ] -DMSO): 11 11 ,27 (1H, .27 (1H, , s, , with, 1-NH), 1-NH), 10,11 (1H, s, 10.11 (1 H, s, 5-NH), 7,89 5-NH), 7.89 (1H, d, J = 7 Hz (1H, d, J = 7Hz) '· t '· T 9-H), 7, 9-H), ,85 85 (1H, s, (1H, s, 10-H), 7,56 - 10-H), 7.56- 7,35 (5H, m, 7.35 (5 H, m, ArH), 7,18 (1H, ArH), 7.18 (1H, d, d. J = 7 J = 7 Hz, Hz, 7-H), 7 7-H), 7 ,08 (1H, t, J, 0.08 (1H, t, J, 8-H), 5,43 8-H), 5.43 (2H, s, CH2Ph),(2H, s, CH2 Ph); 2, 2 99 (3H, 99 (3H, s, with, 4-CH3), 4-CH3); 2,93 (3H, s, 2.93 (3H, s,

3-CHj) a 2,59 (3H, s, 6-CH-j) ppm. m/z (%) 382(71, M+) , 274(100), 246(19 ) a 91(22).3-CH3) and 2.59 (3H, s, 6-CH3) ppm. m / z (%) 382 (71, M < + > ), 274 (100), 246 (19) and 91 (22).

i) Spôsob výroby benzyl-/3-(2-metoxykarbonyletyl)-4-metylpyrolo[3,2-b]-karbazol-2-karboxylátu/i) Process for the preparation of benzyl [3- (2-methoxycarbonylethyl) -4-methylpyrrolo [3,2-b] carbazole-2-carboxylate]

0,230 g zlúčeniny pomenovanej v nadpise sa získa z indolu a 5-acetoxymetyl-4-acetylpyrrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 211 až. 213 ’C. Výťažok zodpovedá 52,3 % teórie.0.230 g of the title compound was obtained from indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 211 to 210 ° C. 213 ’C. Yield: 52.3%.

Analýza pre Analysis for C27H24N2°4: C 27 H 24 N 2 ° 4 : nájdené: found: 73,7 % C, 5,6 % H, 73.7% C, 5.6% H, 6,2 % N, 6.2% N, vypočítané: calculated: 73,6 % C, 5,49 % H, 73.6% C, 5.49% H, 6,36 % N. 6.36% N. XH NMR X H NMR δΗ([2H6]-DMSO): 11δ Η ([ 2 H 6 ] -DMSO): 11 ,51 (1H, s, 51 (1H, s) 1-NH), 1-NH), 10,71 (1H, s, 10.71 (1 H, s, 5-NH), 8,75 5-NH), 8.75 (1H, d, J = 7,5 Hz, (1H, d, J = 7.5Hz, 9-H), 7,92 9-H), 7.92 (1H, S, (1 H, S, 10-H), 7,57 - 10-H), 7.57- 7,44 (7H, m, ArH, 6-H a 7-H), 7.44 (7H, m, ArH, 6-H and 7-H), 7,18 (1H, 7.18 (1 H, t, J = t, J = 7,5 Hz, 8-H), 7.5 Hz, 8-H), 5,43 (2H, S 5.43 (2H, s) , CH2Ph), 3,63 (3H,CH 2 Ph) 3.63 (3H, s, och3), :s, and 3 ): 3,59 (2H, 3.59 (2H, , obzvlášť zle , especially bad viditeľné, visible, t, CH2CH2CO), 2,88t, CH 2 CH 2 CO 2 , 2.88 (3H, S, 4· (3H, S, 5 · -CH3) a-CH 3 ) a 2,65 (2H, t, 2.65 (2 H, t, CH2CO) ppm.CH 2 CO) ppm. m/z (%) 440(100, M+ m / z (%) 440 (100, M < + >) ) , 332(20), ), 332 (20), 290(47) 290 (47) a 91(57). and 91 (57).

j) Spôsob výroby etyl-(3,4,5-trimetylpyrolo[3,2-b]-karbazol-2karboxylátu)j) Process for the preparation of ethyl (3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,140 g zlúčeniny pomenovanej v nadpise sa získa reakciou (v rozsahu 2,65 mmol) N-metylindolu a 5-acetoxymetyl-4380.140 g of the title compound is obtained by reaction (in the range of 2.65 mmol) of N-methylindole and 5-acetoxymethyl-438

-acetylpyrrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 208 °C (rozklad). Výťažok zodpovedá 16 % teórie.-acetylpyrrolu. The title compound has a melting point of 208 ° C (dec.). Yield 16%.

Analýza pre Analysis for C20H20N2°2: C 20 H 20 N 2 ° 2 : nájdené: found: 75,12 % C, 6,40 75.12% C, 6.40 % H, 8,69 % % H, 8.69% N, N, vypočítané: calculated: 74,98 % C, 6,29 74.98% C, 6.29 % H, 8,74 % % H, 8.74% N. N. 1H NMR 1 H NMR δΗ([1 2H6]-DMSO) :δ Η ([ 1 2 H 6 ] -DMSO): 11,28 (1H, 11.28 (1 H, S, 1-NH), 8,08 (1H, d, J S, 1-NH), 8.08 (1H, d, J)

= 7,9 Hz, = 7.9 Hz, 9-H), 7,88 9-H), 7.88 (1H, (1 H, s, 10-H), s, 10-H), 7,44 (2H, m, 7.44 (2 H, m, 6-H, 6-H, 7-H), 7,07 7-H), 7.07 7,  7 17 (1H 17 (1H in, 8-H) , in, 8-H), 4,36 4.36 (2H, q, (2 H, q, CH2CH3), 4,01CH 2 CH 3 ), 4.01 (3H, (3H, S, 5-CH3),S, 5-CH3); 3,13 3.13 (3H, (3H, s, 4-CH3),s, 4-CH3); 2,90 2.90 (3H, s, (3H, s, 3-CH3) a 1,38 3-CH3) and 1.38 (3H, (3H, t, ch2ch3)t, ch 2 ch 3 ) ppm. ppm. m/z ( m / z ( %) 320(72, 320) (72, M+) ,M + ), 274(100) 274 (100) , 245(16), 149(28) 245 (16) a 137(12). and 137 (12). v max in max (KBr (KBr kotúč)/cm“ Disc) / cm " 1 3329 1 3329 a 1670. and 1670.

k) Spôsob výroby benzyl-(3,4,5-trimetylpyrolo[ 3,2-b]-karbazol2-karboxylátu)k) Method for the preparation of benzyl (3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,220 g zlúčeniny pomenovanej v nadpise sa získa reakciou N-metylindolu a 5-acetoxymetyl-4-acetylpyrolu v toluéne pri teplote 55 ’C, katalyzované kyselinou toluén-4-sulfónovou.0.220 g of the title compound is obtained by reacting N-methylindole and 5-acetoxymethyl-4-acetylpyrrole in toluene at 55 ° C, catalyzed by toluene-4-sulfonic acid.

Vyrobená zlúčenina má teplotu topenia 228 až 229 ’C. Výťažok zodpovedá 57 % teórie.The compound produced has a melting point of 228-229 ° C. Yield: 57%.

Analýza pre Analysis for C25H22N2°2 ‘ °' C 25 H 22 N 2 ° 2 '°' 33 H20:33 H 2 0 nájdené: found: 77,17 % C, 5,73 77.17% C, 5.73 % H, 7,09 % H, 7.09 % N, % N, vypočítané: calculated: 77,31 % C, 5,88 77.31% C, 5.88 % H, 7,21 % H, 7.21 % N. % N. XH NMR X H NMR 6H([2H6]-DMSO):6 H ([2 H 6] -DMSO): 11,28 (lHj 11.28 (1H, 1H); - s, - with, 1-NH), 8,03 1-NH), 8.03 (1H, d, J (LH, d, J) = 7,5 Hz, = 7.5 Hz, 9-H), 7,88 (1H, 9-H), 7.88 (1 H, S, 10-H), S, 10-H), 7,56 7.56 - 7,34 (7H, - 7.34 (7H, m, ArH, m, ArH,

6-H, 7-H), 7,15 - 7,07 (1H, m, 8-H),.5,40 (2H, s, CH^Ph), 4,02 (3H, s, 5-CH3), 3,14 (3H, s, 4-CH3) a 2,91 (3H, s, 3-CH3) ppm. m/z (%) 382(72, M+), 291(4), 274(100) a 91 (34). Vmax (KBr kotúč)/cm_1 3337 a 1674.6-H, 7-H), 7.15-7.07 (1H, m, 8-H), 5.40 (2H, s, CH 2 Ph), 4.02 (3H, s, 5-) CH 3 ), 3.14 (3H, s, 4-CH 3 ) and 2.91 (3H, s, 3-CH 3 ) ppm. m / z (%) 382 (72, M < + > ), 291 (4), 274 (100) and 91 (34). V max (KBr disc) / cm -1 1337 and 1674.

1) Spôsob výroby etyl-(1,3,4-trimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)1) Process for the preparation of ethyl (1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,060 g zlúčeniny pomenovanej v nadpise sa získa reakciou (v rozsahu 2,5 mmol) indolu a 5-acetoxymetyl-4-acetylpyrolu.0.060 g of the title compound was obtained by reaction (in the range of 2.5 mmol) of indole and 5-acetoxymethyl-4-acetylpyrrole.

Zlúčenina pomenovaná v nadpise má teplotu topenia 188 až 189 °C.The title compound has a melting point of 188-189 ° C.

Výťažok zodpovedá 7 % teórie.Yield: 7%.

Analýza pre Analysis for C20H20N2°2: C 20 H 20 N 2 ° 2 : nájdené: found: 74,86 % C, 6,32 % H, 8,65 H, 6.32; H, 8.65 % N, % N, vypočítané: calculated: 75,98 % C, 6,29 % H, 8,74 H, 6.29; H, 8.74 % N. % N. 1H NMR 1 H NMR δΗ([2H6]-DMSO): 10,66 (1H, δΗ ([ 2 H 6 ] -DMSO): 10.66 (1H, ’ S, ' WITH, 5-NH), 8,14 5-NH), 8.14 (1H, (1 H, d, J d, J = 7,7 Hz, = 7.7 Hz, 9-H), 8,03 (1H, s, 10-H), 9-H), 8.03 (1 H, s, 10-H), 7,45 7.45 - 7,31 (2H, - 7.31 (2H, , m, , m, 6-H, 6-H, 7-H), 7,06 7-H), 7.06 - 7,15 (1H, m, 8-H), 4,38 7.15 (1H, m, 8-H), 4.38 (2H, (2H, q, CH2CH3),q, CH 2 CH 3 ), 3,98 3.98 (3H, (3H, s, 1-CH3),s, 1-CH3); 2,91 (3H, s, 4-CH3), 2,832.91 (3H, s, 4-CH3), 2.83 (3H, (3H, s, 3-CH3) as, 3-CH3) and 1,38 1.38 (3H, (3H, t, ch2ch3)t, ch 2 ch 3 ) ppm. m/z (%) 320(M+,100),ppm. m / z (%) 320 (M < + >, 100) 306 (: 306 (: 10), 292(30), 10) 292 (30) , 2471 , 2471 (8) a (8) a 231(10). Vm 231 (10). In m _v (KBr kotúč)/cm“1 3385 a d X v (KBr roll) / cm -1 1385 ad X 1657 1657 • •

m) Spôsob výroby benzyl-(1,3,4-trimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)m) Method for the preparation of benzyl (1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,240 g zlúčeniny pomenovanej v nadpise sa získa reakciou ( v rozsahu 2,7 mmol) indolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 186 až 187 °C. Výťažok zodpovedá 28 % teórie.0.240 g of the title compound is obtained by reaction (2.7 mmol) of indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 186-187 ° C. Yield: 28%.

Analýza pre C25H22N2°2: nájdené: 78,63 % C, 5,83 % H, 7,32 % N, vypočítané: 78,51 % C, 5,80 % H, 7,32 % N.Analysis for C 25 H 22 N 2 ° 2: Found: 78.63% C, 5.83% H 7.32% N Found: 78.51% C, 5.80% H, 7.32% N .

1H NMR δΗ([2H6]-DMSO): 10,66 (1H, s, 5-NH), 8,14 (1H, d, J = 7,4 Hz, 9-H), 8,02 (1H, s, 10-H), 7,56 - 7,31 (7H, m, ArH, 6-H, 7-H), 7,06 - 7,15 (1H, m, 8-H), 5,41 (2H, s, CH2Ph), 3,98 (3H, s, 1-CH3), 2,90 (3H, s, 4-CH3) a 2,83 (3H, s, 3-CH3) ppm. m/z (%) 382(M+,100), 338(10), 291(44), 247(18) a 231(10). Vmax (KBr kotúč)/cm-1 3343 a 1697. 1 H NMR δΗ ([ 2 H 6] -DMSO): 10.66 (1H, s, 5-NH), 8.14 (1H, d, J = 7.4 Hz, 9-H), 8.02 ( 1H, s, 10-H), 7.56-7.31 (7H, m, ArH, 6-H, 7-H), 7.06-7.15 (1H, m, 8-H), 5 , 41 (2H, s, CH2 Ph), 3.98 (3H, s, 1-CH3), 2.90 (3H, s, 4-CH3) and 2.83 (3H, s, 3- CH3) ppm. m / z (%) 382 (M < + >, 100), 338 (10), 291 (44), 247 (18) and 231 (10). V max (KBr roll) / cm -1 3343 and 1697.

n) Spôsob výroby etyl-(1,3,4,5-tetrametylpyrolo[3,2-b]-karbazol-2-karboxylátu)n) Process for the preparation of ethyl (1,3,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,220 g zlúčeniny pomenovanej v nadpise sa získa reakciou ( v rozsahu 2,2 mmol) N-metylindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 165,5 až 167 “C (rozklad). Výťažok zodpovedá 30 % teórie.0.220 g of the title compound is obtained by reaction (in the range of 2.2 mmol) of N-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 165.5-167 ° C (dec.). The yield corresponds to 30% of theory.

Analýza pre c2iH22N2°2: Analysis for c 21 H 22 N 2 ° 2 : nájdené: 75,50 % C, 6,65 found: C, 75.50, 6.65 % H, % H, 8,30 % N, N, 8.30% vypočítané: 75,47 % C, 6,63 calculated: 75.47% C, 6.63 % H, % H, 8,38 % N. 8.38% N. 1H NMR δΗ([2H6]-DMSO): 1 H NMR δΗ ([ 2 H 6] -DMSO): 8,15 8.15 (1H, d, J (LH, d, J) = 7,5 Hz, 9-H), = 7.5 Hz, 9-H), 8,07 8.07 (1H, s, 10-H), 7,50-7,38 (1H, s, 10-H), 7.50-7.38 (2H, (2H, m, 6-H, 7- m, 6-H, 7- -H), 7,09 - 7,19 -H), 7.09-7.19 (1H, (1 H, m, 8-H), 4,38 (2H, q, CH2CH3 m, 8-H), 4.38 (2H, q, CH 2 CH 3 ), 4, ), 4, ,03 (3H, s, , 02 (3H, s, 5-CH3), 3,96 (3H5-CH 3 ), 3.96 (3H , s, , with,

1-CH3), 3,14 (3H, s, 4-CH3), 2,84 (3H, s, 3-CH3) a 1,39 (3H, t, CH2CH3) ppm. m/z (%) 334(100,M+), 306(18) a 245(6). vmax (KBr kotúč)/cm“1 1690 a 1528.1-CH 3 ), 3.14 (3H, s, 4-CH 3 ), 2.84 (3H, s, 3-CH 3 ) and 1.39 (3H, t, CH 2 CH 3 ) ppm. m / z (%) 334 (100, M < + > ), 306 (18) and 245 (6). v max (KBr roll) / cm -1 1190 and 1528.

o) Spôsob výroby benzyl-(1,3,4,5-tetrametylpyrolo[ 3,2-b]-karbazol-2-karboxylátu)o) Method for preparing benzyl (1,3,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,070 g zlúčeniny pomenovanej v nadpise sa získa reakciou (v rozsahu 1,4 mmol) N-metylindo.lu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 196 až 198 ’C. Výťažok zodpovedá 13 % teórie.0.070 g of the title compound is obtained by reaction (in the range of 1.4 mmol) of N-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 196-198 ° C. Yield: 13%.

Anál anal ýza SIS OF pre C26H24N2°2: for C 26 H 24 N 2 ° 2 : ná jd ná jd ené INTENDED : 78,45 % C, 6,16 % H, % H, 6.16;% C, 78.45; 6,94 % N 6.94% N f F vypo calculated čít. cit. ané: 78,76 % C, 6,10 % H, %: 78.76% C, 6.10% H, 7,07 % N N, 7.07 • • NMR δΗ([2H6]-DMSO): 8,15 Δ Η NMR ([2 H 6] -DMSO): 8.15 (1H, d, (1 H, d, J = 7,8 HZ, 9-H), J = 7.8 Hz, 9-H), 8,07 8.07 (1H, (1 H, s, with, 10-H), 7,59 - 7,29 (7H, 10-H), 7.59-7.29 (7H, m, ArH, m, ArH, 6-H, 7-H), 7,10 - 6-H, 7-H), 7,20 7.20 (1H, (1 H, m, m. 8-H), 5,42 (2H, S, CH2 8-H), 5.42 (2H, S, CH2 ) Ph), 4,03 Ph), 4.03 (3H, s, 5-CH3),(3H, s, 5-CH3); 3,97 3.97 (3H, (3H, s, with, 1-CH3), 3,13 (3H, s, 4- 1-CH3), 3.13 (3H, s, 4 CH3) a 2,CH 3 ) and 2, 83 (3H, s, 3-CH3)83 (3H, s, 3-CH3) ppm. ppm. m/z m / z (% (% ) 396(100, M+), 305(38),) 396 (100, M + ), 305 (38) 245(16) 245 (16) a 235(10). vmax and 235 (10). in max (KBr (KBr

kotúč)/cm 1 1696 a 1529.roll) / cm 1 1696 and 1529.

p) Spôsob výroby benzyl-/3,4-dimetyl-5-(4-toluénsulfonyl)pyrolo[3,2-b]-karbazol-2-karboxylátu/p) Process for the preparation of benzyl (3,4-dimethyl-5- (4-toluenesulfonyl) pyrrolo [3,2-b] carbazole-2-carboxylate)

0,012 g zlúčeniny pomenovanej v nadpise sa získa reakciou (v rozsahu 0,6 mmol) N-(4-toluénsulfonyl)indolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 270 'C. Výťažok zodpovedá 4 % teórie.0.012 g of the title compound is obtained by reacting (in the range of 0.6 mmol), N- (4-toluenesulfonyl) indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 270 ° C. Yield: 4%.

Analýza pre C31H26N2°4S: nájdené: 70,83 % C, 5,01 % H, 5,23 % N, vypočítané: 71,24 % C, 5,01 % H, 5,36 % N.Analysis for C 31 H 26 N 2 ° 4 S: Found: 70.83% C, 5.01% H 5.23% N Found: 71.24% C, 5.01% H, 5.36% N.

1H NMR δΗ([2H6]-DMSO): 11,58 (1H, s, N-H), 8,28 - 8,08 (3H, m, 6-H, 9-H, 10-H), 7,66 - 7,21 (11H, m, ArH, TsH, 7-H, 8-H), 5, 40 (2H, S, CH2Ph), 3,04 (3H, S, 4-CH3), 2,88 (3H, S, 3~CH3) a 2,20 (3H, s, Ts-CH3) ppm. m/z (%) 523(30, (M++l)), 446(20), 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.58 (1H, s, NH), 8.28-8.08 (3H, m, 6-H, 9-H, 10-H), 7 , 66 to 7.21 (11 H, m, Ar H, TSH, 7-H, 8-H), 5, 40 (2H, s, CH2 Ph), 3.04 (3H, s, 4-CH3) , 2.88 (3H, S, 3-CH 3 ) and 2.20 (3H, s, Ts-CH 3 ) ppm. m / z (%) 523 (30, (M + +1)), 446 (20),

367(30), 348(56), 33(100), 295(30) a 274(90). vmax (KBr kotúč)/cm-1 3358 a 1666.367 (30), 348 (56), 33 (100), 295 (30) and 274 (90). v max (KBr roll) / cm -1 3358 and 1666.

q) Spôsob výroby etyl-(7-acetoxy-3,4-dimetyl-6-metoxy-pyrolo[3,2-b]-karbazol-2-karboxylátu)q) Process for the preparation of ethyl (7-acetoxy-3,4-dimethyl-6-methoxy-pyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou 6-acetoxy-7-metoxyindolu a 5-acetoxymetyl-4-acetylpyrolu. Táto zlúčenina má teplotu topenia 241 až 244 °C. Výťažok zodpovedá 7 % teórie.The title compound is obtained by reacting 6-acetoxy-7-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. This compound has a melting point of 241-244 ° C. Yield: 7%.

1H NMR δΗ([2H6]-DMSO): 8,59 (1H, široký singlet, NH) , 7,78 d, J = 8 ch2ch3), 1 H NMR δΗ ([ 2 H 6] -DMSO): 8.59 (1H, broad singlet, NH), 7.78 d, J = 8 ch 2 ch 3 ),

4-CH3 a ppm. m/z4-CH 3 and ppm. m / z

263(21) a 87(73). vmax (metan°l)/nm (nájdené: M+, 394, (1H, široký singlet, NH), 7,76 (1H, s, 10-H), 7,74 (1H, Hz, 9-H), 6,88 (1H, d, J = 8 Hz, 8-H), 4,44 (2H, q, 4,04 (3H, s, 6-OCH3), 2,96 a 2,92 (2 x 3H, 3 x s, 3-CH3), 2,42 (3H, s, 7-CH3COO) a 1,46 (3H, t, CH2CH3) (%) 394(100, M+), 352(47), 348(33), 306(87) vmax (nujol)/cm-1 3413, 3341, 1739263 (21) and 87 (73). max (methane ° l) / nm (Found: M +, 394, (1 H, br s, NH), 7.76 (1H, s, 10-H), 7.74 (1 H, Hz, H-9 ), 6.88 (1H, d, J = 8Hz, 8-H), 4.44 (2H, q, 4.04 (3H, s, 6-OCH3 ) ), 2.96 and 2.92 ( 2 x 3H, 3 xs, 3-CH 3 ), 2.42 (3H, s, 7-CH 3 COO) and 1.46 (3H, t, CH 2 CH 3 ) (%) 394 (100, M + ), 352 (47), 348 (33), 306 (87) at max (nujol) / cm -1 3413, 3341, 1739

405, 386, 339, 325, 305, 269, 240405, 386, 339, 325, 305, 269, 240

1529, pre C22H22N2°5 vypočítané 394,1529).1529, calcd. For C 22 H 22 N 2 O 5 394.1529).

r a 1675.r and 1675.

a 2 26,a 2 26,

r) Spôsob výroby etyl-(9-metoxy-3,4,5-trimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)(r) Production method of ethyl (9-methoxy-3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou 4-metoxy-1-metylindolu a 5-acetoxymetyl-4-acetylpyrrolu. Táto zlúčenina má teplotu topenia 263 až 266 “C.The title compound is obtained by reaction of 4-methoxy-1-methylindole and 5-acetoxymethyl-4-acetylpyrrole. This compound has a melting point of 263-266 ° C.

Analýza pre C2iH22N2°3: nájdené: 71,84 % C, 6,34 % H, 7,91 % N, vypočítané: 71,98 % C, 6,33 % H, 7,99 % N.Analysis for C 22 H 2 R 2 N ° 3: Found: 71.84% C, 6.34% H 7.91% N Found: 71.98% C, 6.33% H, 7.99% N .

XH NMR δΗ([2H6]-DMSO): 8,60 (1H, široký singlet, NH), 8,15 (1H, s, 10-H), 7,40 (1H, t, J = 8 Hz, 7-H), 6,95 (1H, d, J = 8 X δΗ NMR ([2 H 6] -DMSO): 8.60 (1H, br s, NH), 8.15 (1 H, s, 10-H), 7.40 (1H, t, J = 8 Hz 7-H), 6.95 (1H, d, J = 8)

Hz, 6-H), 6,66 (1H, d, J = 8 Hz, 8-H), 4,43 (2H, q, OCH2CH3),Hz, 6-H), 6.66 (1H, d, J = 8Hz, 8-H), 4.43 (2H, q, OCH 2 CH 3 ),

4,10 a 4,04 (2 x 3H, 2 x s, N-CH3 a OCH3), 3,19 (3H, S, 4-CH3),4.10 and 4.04 (2 x 3H, 2 xs, N-CH 3 and OCH 3 ), 3.19 (3H, S, 4-CH 3 ),

2,98 (3H, s, -3-CH3) a 1,46 (3H, t, OCH2CH3) ppm. m/z (%) 350(74,2.98 (3H, s, -3-CH 3 ) and 1.46 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 350 (74

M+), 304(100), 276(17), 223(10) a 152(19).M + ), 304 (100), 276 (17), 223 (10), and 152 (19).

s) Spôsob výroby benzyl-(8-chlór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)s) Method for the preparation of benzyl (8-chloro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,069 g zlúčeniny pomenovanej v nadpise sa získa reakciou 5-chlórindolu a 5-acetoxymetyl-4-acetylpyrolu. Zlúčenina pomenovaná v nadpise má teplotu topenia 215 až 220 °C (rozklad). Výťažok zodpovedá 17 % teórie.0.069 g of the title compound is obtained by reaction of 5-chloroindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 215-220 ° C (dec.). Yield: 17%.

Analýza pre C24H19C1N2°2: nájdené: 71,42 % C, 4,96 % H, 7,11 % N, vypočítané: 71,55 / C, 4,75 % H, 6,95 % N.Analysis for C 24 H 19 C1N 2 ° 2: Found: 71.42% C, 4.96% H 7.11% N Found: 71.55 / C, 4.75% H, 6.95% N .

XH NMR SH([2H6]-DMS0): 11,39 (1H, s, 1-NH), 10,84 (1H, s, 5-NH), 8,17 (1H, s, 9H), 7,93 (1H, s, 10-H), 7,54 (1H, J = 7 Hz, X H NMR? H ([2 H 6] -DMS0): 11.39 (1H, s, 1-NH), 10.84 (1H, s, 5-NH), 8.17 (1H, s, 9 H); 7.93 (1H, s, 10-H), 7.54 (1H, J = 7Hz,

7-H), 7,48 - 7,34 (6H, m, ArH a 6-H), 5,42 (2H, s, CH2Ph) a 2,88 (6H, s, 3-CH3 a 4-CH3) ppm. m/z (%) 402(30, M+), 358(5),7-H), 7.48 to 7.34 (6H, m, Ar-H and 6 H), 5.42 (2H, s, CH 2 Ph), and 2.88 (6H, s, 3-CH 3 and 4-CH3) ppm. m / z (%) 402 (30, M < + > ), 358 (5),

294(65), 267(25) a 91(100).294 (65), 267 (25) and 91 (100).

II

Matečné lúhy z kryštalizácie sa podrobia veľmi rýchlej chromatografii na oxide kremičitom. Eluovaním zmesí etylacetátu a petroéteru sa pritom získa ďalšia zlúčenina pomenovaná v nadpise, ktorá sa kryštalizuje z etylacetátu. Získa sa 0,030 g vyrábanej zlúčeniny, čo zodpovedá výťažoku 7 % teórie, a ďalejThe mother liquors from the crystallization were subjected to flash chromatography on silica. Elution with mixtures of ethyl acetate and petroether yields another title compound, which is crystallized from ethyl acetate. 0.030 g of compound is obtained, which corresponds to a yield of 7% of theory, and further

3-(3'-acetyl-5'-benzyloxykarbonyl-4'-metylpyrol-2'-ylmetyl)-5-chlórindol vo forme krémovo sfarbených kryštálov s hmotnosťou3- (3'-Acetyl-5'-benzyloxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -5-chloroindole as cream colored crystals of a mass

0,152 g, zodpovedá 0.152 g, corresponding ktorý má teplotu 36 % teórie. which has a temperature 36% of theory. topenia mp 141 až 143 C. 141 to 143 C. Výťažok yield Analýza pre C24H21C1N2O3:Analysis for C 24 H 21 ClN 2 O 3 : nájdené: found: 68,20 % C, 5,18 % 68.20% C, 5.18% H, H, 6,60 % 6.60% N, N, vypočítané: 68,49 % C, 5,03 % calculated: 68.49% C, 5.03% H, H, 6,65 % 6.65% N. N. 1H NMR δΗ([2H6]-DMSO): 8 1 H NMR δΗ ([ 2 H 6] -DMSO): δ ,72 72 (1H, (1 H, s, ľ-NH), 8,26 s, 1'-NH), 8.26 (1H, s, (1H, s, 1-NH), 7, 1-NH), 7, 38 (1H, d, J = 2 Hz 38 (1 H, d, J = 2 Hz) f F 4-H) , 4-H), 7,35 (6H, m, ArH 7.35 (6H, m, Ar H) a 6-H), and 6-H), 7,18 (1H, 7.18 (1 H, dd, J = 8 a 2 Hz, 2 dd, J = 8 and 2 Hz, 2 -H) H) , 7,09 , 7.09 (1H, d, J = 2 Hz, 2-H), (1 H, d, J = 2 Hz, 2-H), 5,23 (2H, 5.23 (2H, s, CH2Ph), 4,39 (2H,s, CH2 Ph), 4.39 (2H, s, with, 3-CH2 3-CH2 ), 2,64 (3H, s, 4 ), 2.64 (3H, s, 4) '-CH3) a-CH 3 ) a 2,52 (3H, 2.52 (3H, s, CH3CO) ppm. m/zs, CH 3 CO) ppm. m / z (%) (%) 420(20, M+), 405(10),420 (20, M + ), 405 (10) 311(20) , 311 (21), 151(15) a 151 (15) a 91(100) . 91 (100). t) Spôsob t) Method výroby etyl-(3,4-dimetyl-8-hydroxypyrolo[3,2- production of ethyl- (3,4-dimethyl-8-hydroxypyrolo [3,2- b]-kar- b] -kar-

bazol-2-karboxylátu)Bazoli-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou 5-hydroxyindolu s 5-acetoxymetyl-4-acetylpyrrolom a kryštaluje sa z metanolu. Zlúčenina má teplotu topenia 250 °C (rozklad).The title compound is obtained by reacting 5-hydroxyindole with 5-acetoxymethyl-4-acetylpyrrole and crystallizing from methanol. Mp 250 ° C (dec.).

1H NMR δΗ([2H6]-DMSO): 11,11 (1H, s, 1-NH), 10,21 (1H, s, 5-NH), 8,83 (1H, S, OH), 7,73 (1H, s, 10-H), 7,37 (1H, d, J = 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.11 (1H, s, 1-NH), 10.21 (1H, s, 5-NH), 8.83 (1H, S, OH), 7.73 (1H, s, 10-H); 7.37 (1H, d, J =

2,5 Hz, 9-H), 7,21 (1H, d, J = 8 Hz, 6-H), 6,87 (1H, dd, J = 8 a 2,5, 9-H), 7,21 (2H, q, OCH2CH3), 2,87 (3H, s, 4-CH3), 2,84 (3H, s, 3-CH3) a 1,38 (3H, t, OCH2CH3) ppm. m/z (%) 322(69, M+), 276(100), 248(24), 220(3) a 138(15), (nájdené: M+, 322,1322, pre C19H18N2°3 vypočítané 322,1317).2.5 Hz, 9-H), 7.21 (1H, d, J = 8Hz, 6-H), 6.87 (1H, dd, J = 8 and 2.5, 9-H), 7 21 (2H, q, OCH 2 CH 3 ), 2.87 (3H, s, 4-CH 3 ), 2.84 (3H, s, 3-CH 3 ) and 1.38 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 322 (69, M +), 276 (100), 248 (24), 220 (3) and 138 (15), (Found: M +, 322.1322, for C 19 H 18 N 2 ° 3 (calculated 322.1317).

Z reakčnej zmesi sa tiež izoluje 3-(3'-acetyl-5'-etoxykarbonyl-4 ' -metylpyrol-2 ' -ylmetyl ) -5-hydroxyindol . Táto zlúčenina má teplotu topenia 99 až 102 °C.3- (3'-Acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -5-hydroxyindole is also isolated from the reaction mixture. This compound has a melting point of 99-102 ° C.

Analýza pre Analysis for C19H20 C 19 H 20 N2°4: N 2 ° 4 : nájdené: found: 66,89 66,89 % C, 6,17 % C, 6.17 % H, % H, 8,03 % N, 8.03% N, vypočítané: calculated: 67,04 67.04 % C, 5,92 % C, 5.92 % H, % H, 8,23 % N. 8.23% N.

1H NMR δΗ([2H6]-DMSO): 8,84 (1H, s, ľ-NH), 8,14 (1H, s, 1 H NMR δΗ ([ 2 H 6] -DMSO): 8.84 (1H, s, 1'-NH), 8.14 (1H, s,

1- NH), 7,201-NH), 7.20

2- H), 6,812 H, 6.81

Hz, 6-H),Hz, 6-H),

4,21 (2H,4.21 (2H,

3'-COCH3)3'-COCH 3 )

325(44), 2325 (44), 2

147(20) a 1147 (20) and 1

Hz, 7-H),Hz, 7-H),

Hz, 4-H), singlet, 2,58 (3H,Hz, 4-H), singlet, 2.58 (3H,

7,10 (1H, d,7.10 (1 H, d,

6,79 (1H, dd,6.79 (1 H, dd,

5-OH), 4,31 s, 4'-CH3),5-OH), 4.31 s, 4'-CH3).

u) Spôsob výroby benzyl-(3,4-dimetyl-7-fluórmetylpyrrolo[3,2-b]-karbazol-2-karboxylátu) a benzyl-(3,4-dimetyl-8-fluór-pyrrolo[3,2-b]-karbazol-2-karboxylátu)u) Process for the preparation of benzyl (3,4-dimethyl-7-fluoromethylpyrrolo [3,2-b] carbazole-2-carboxylate) and benzyl (3,4-dimethyl-8-fluoro-pyrrolo [3,2- b] carbazole-2-carboxylate)

Zlúčeniny pomenované v nadpise sa získajú ako zmes izomérov, reakciou 6-fluórindolu s 5-acetoxymetyl-4-acetylpyrolom. Chromátografické delenie poskytne 0,139 g [3,2-b]-izoméru, ktorý má teplotu topenia 205 °C (rozklad) vo výťažku zodpovedajúcom 36 % teórie.The title compounds are obtained as a mixture of isomers by reaction of 6-fluoroindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gives 0.139 g of the [3,2-b] isomer having a melting point of 205 ° C (decomposition) in a yield corresponding to 36% of theory.

1H NMR δΗ([2H6]-DMSO): 11,32 (1H, s, 1-NH), 10,85 (1H, s, 5-NH), 8,08 (1H, dd, J = 9 a 6 Hz, 9-H), 7,86 (1H, s, 10-H), 7,57 = 7,35 (5H, m, ArH), 7,12 (1H, dd, J = 10 a 2 Hz, 6-H), 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.32 (1H, s, 1-NH), 10.85 (1H, s, 5-NH), 8.08 (1H, dd, J = 9) and 6 Hz, 9-H), 7.86 (1H, s, 10-H), 7.57 = 7.35 (5H, m, ArH), 7.12 (1H, dd, J = 10 and 2) Hz, 6-H),

6,90 (1H, dt, J = 9 a 2 Hz, 8-H), 5,43 (2H, s, CH2Ph), 2,91 (3H, s, 3-CH3) a 290 (3H, s, 4-CH3) ppm. m/z (%) 386(55, M+), 342(5), 295(4), 278(100), 249(45), 236(20), 222(25) a 91(95), (nájdené:6.90 (1H, dt, J = 9 and 2 Hz, 8-H), 5.43 (2H, s, CH2 Ph), 2.91 (3H, s, 3-CH3) and 290 (3 H , s, 4-CH3) ppm. m / z (%) 386 (55, M < + > ), 342 (5), 295 (4), 278 (100), 249 (45), 236 (20), 222 (25) and 91 (95); found:

MH+, 387,1509, pre C24H20FN2°2 vypočítané 387,1509).MH +, 387.1509, for C 24 H 20 FN 2 Calc'd 387.1509 ° 2).

Delením sa získa [2,3-b]izomér, ktorý má teplotu topenia 190 až 193 °C.Separation gave the [2,3-b] isomer having a melting point of 190-193 ° C.

XH NMR δΗ([2H6]-DMSO): 8,54 (1H, široký singlet, 1-NH), X δΗ NMR ([2 H 6] -DMSO): 8.54 (1H, br s, NH-1),

8,10 (1H, dd, J = 9a 6 Hz, 5-H), 7,87 (1H, široký singlet, 9-NH), 7,51 - 7,34 (5H, m, ArH), 7,34 (1H, s, 10-H), 7,22 (1H, dd, prekryté 10-H, 8-H), 6,93 (1H, dt, J = 2 a 9 Hz, 6-H), 5,41 (2H, s, CH2Ph), 3,20 (3H, s, 4-CH3) a 3,00 (3H, s, 3-CH3) ppm. m/z (%) 386(100, M+), 295(12), 278(96), 250(27), 236(7), 222(8) a 91(59), (nájdené: M+, 386, 1433, pre C24H19FN2°2 vypočítané8.10 (1H, dd, J = 9 and 6 Hz, 5-H), 7.87 (1H, broad singlet, 9-NH), 7.51-7.34 (5H, m, ArH), 7, 34 (1H, s, 10-H), 7.22 (1H, dd, overlapped by 10-H, 8-H), 6.93 (1H, dt, J = 2 and 9 Hz, 6-H), 5 , 41 (2H, s, CH2 Ph), 3.20 (3H, s, 4-CH3) and 3.00 (3H, s, 3 CH3) ppm. m / z (%) 386 (100, M < + > ), 295 (12), 278 (96), 250 (27), 236 (7), 222 (8) and 91 (59), (found: M < + > 386, 1433, calcd. For C 24 H 19 FN 2 ° 2

386,1431) .386.1431).

v) Spôsob výroby etyl-(3,4-dimetyl-7-fluórmetylpyrolo[3,2-b]-karbazol-2-karboxylátu) a etyl-(3,4-dimetyl-8-fluórpyrrolo[2,3-b]-karbazol-2-karboxylátu)v) A process for the preparation of ethyl (3,4-dimethyl-7-fluoromethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (3,4-dimethyl-8-fluoropyrrolo [2,3-b] carbazole-2-carboxylate)

Zlúčeniny pomenované v nadpise sa získajú ako zmes izomérov reakciou 6-fluórindolu s 5-acetoxymetyl-4-acetylpyrolom. Chromatografické oddelenie poskytne [3,2-b]izomér, ktorý sa kryštalizuje z dichlórmetánu. Získaná zlúčenina má teplotu topenia 231 až 234 °C.The title compounds are obtained as a mixture of isomers by reaction of 6-fluoroindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatography gave the [3,2-b] isomer which was crystallized from dichloromethane. Mp 231-234 ° C.

Analýza pre cigHi7FN2O2: nájdené: 70,45 % C, 5,53 % H, 8,66 %N, vypočítané: 70,36 % C, 5,28 % H, 8,64 %N.Analysis for C H ig i7 FN 2 O 2: Found: 70.45% C, 5.53% H 8.66% N Found: 70.36% C, 5.28% H, 8.64% N .

1H NMR δΗ([2H6J-DMSO): 11,27 (1H, široký singlet, 1-NH), 1 H NMR δΗ ([ 2 H 6 J-DMSO): 11.27 (1H, broad singlet, 1-NH),

10,82 (1H, široký singlet, 5-NH), 8,90 (1H, dd, J = 9 a 6Hz,10.82 (1H, broad singlet, 5-NH), 8.90 (1H, dd, J = 9 and 6Hz,

9-H), 7,85 (1H, s, 10-H), 7,12 (1H, dd, J = 10 a 2 Hz,6-H),9-H), 7.85 (1H, s, 10-H), 7.12 (1H, dd, J = 10 and 2 Hz, 6-H),

6,89 (1H, dt, J = 2 a 9 Hz, 8-H), 4,37 (2H, g, OCH2CH3), 2,89 (6H, s, 4-CH3), 1,39 (3H, t, OCH2CH3) ppm. m/z (%) 324(60, M+) , 278(100), 250(34), 222(10) a 139(7), (nájdené: M+, 324,1267, pre C19H17FN2°2 vypočítané 324,1274).6.89 (1H, dt, J = 2 and 9 Hz, 8-H), 4.37 (2H, g, OCH 2 CH 3 ), 2.89 (6H, s, 4-CH 3 ), 1, 39 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 324 (60, M +), 278 (100), 250 (34), 222 (10), and 139 (7), (Found: M +, 324.1267, C 19 to 17 H FN 2 ° 2 (calc. 324.1274).

Delením sa d’alej získa [ 2,3-b] izomér, ktorý má teplotu topenia 262 až 265 °C.Separation further yields the [2,3-b] isomer having a melting point of 262-265 ° C.

NMR δΗ( [2H6]-DMS0) : 11,14 (1H, široký singlet, 1-NH),NMR δ Η ([ 2 H 6 ] -DMSO): 11.14 (1H, broad singlet, 1-NH),

11,06 (1H, široký singlet, 9-NH), 8,12 (1H, dd, J = 6 a 9 Hz, 5-H), 7,19 (1H, s, 10-H), 7,15 (1H, dd, J = 10 a 2 Hz, 8-H), 6,92 (1H, dt, J = 2 a 9 Hz, 6-H), 4,36 (2H, q, 0CH2CH3), 3,13 (3H, s, 4-CH3), 2,93 (3H, s, 3-CH3) a 1,39 (3H, t, OCH2CH3) ppm. m/z (%) 324(72, M+), 278(100), 250(39), 222(9), 139(6) a 125(7), (nájdené: M+, 324,1280, pre CigH17FN2O2 vypočítané 324,1274).11.06 (1H, broad singlet, 9-NH), 8.12 (1H, dd, J = 6 and 9 Hz, 5-H), 7.19 (1H, s, 10-H), 7.15 (1H, dd, J = 10 and 2 Hz, 8-H), 6.92 (1H, dt, J = 2 and 9 Hz, 6-H), 4.36 (2H, q, OCH 2 CH 3 ) , 3.13 (3H, s, 4-CH3), 2.93 (3H, s, 3-CH3) and 1.39 (3H, t, OCH 2 CH 3) ppm. m / z (%) 324 (72, M < + > ), 278 (100), 250 (39), 222 (9), 139 (6) and 125 (7), (found: M + , 324.1280, for C ig H 17 FN 2 O 2 Calc'd 324.1274).

w) Spôsob výroby etyl-(3,4-dimetyl-9-hydroxymetylpyrolo[3,2-b]-karbazol-2-karboxylátu) a etyl-(3,4-dimetyl-5-hydroxypyrolo[2,3-b]-karbazol-2-karboxylátu)w) Method for the preparation of ethyl (3,4-dimethyl-9-hydroxymethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (3,4-dimethyl-5-hydroxypyrolo [2,3-b] carbazole-2-carboxylate)

Zlúčeniny pomenované v nadpise sa získajú ako zmes izomérov reakcií 4-hydroxyindolu s 5-acetoxymetyl-4-acetylpyrolom. Chromatografické delenie poskytne [3,2-b]izomér, ktorý sa kryštalizuje zo zmesi etylacetátu a petroléteru, a ktorý má teplotu topenia 260 až 262 °C (rozklad).The title compounds are obtained as a mixture of isomers by reacting 4-hydroxyindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gives the [3,2-b] isomer, which is crystallized from ethyl acetate / petroleum ether, m.p. 260 DEG-262 DEG C. (decomposition).

NMR SH((2H6]-DMSO): 11,13 (1H, s, 1-NH), 10,56 (1H, s, 5-NH) , 10,00 (1H, s, OH), 8,02 (1H, s, 10-H), 7,12 (1H, t, J =NMR δ H (( 2 H 6 ) -DMSO): 11.13 (1H, s, 1-NH), 10.56 (1H, s, 5-NH), 10.00 (1H, s, OH), 8.02 (1 H, s, 10-H), 7.12 (1 H, t, J =

7,5 Hz, 7-H), 6,83 (1H, d, J = 7,5 Hz, 6-H), 6,48 (1H, d, J =7.5 Hz, 7-H), 6.83 (1H, d, J = 7.5Hz, 6-H), 6.48 (1H, d, J

7,5 Hz, 8-H), 4,39 (2H, q, OCH2CH3), 2,87 (3H, s, 4-CH3), 2,85 (3H, s, 3-CH3) a 1,38 (3H, t, OCH2CH3) ppm. m/z (%) 322(61, M+), 276(100), 248(20), 219(5) a 138(11), (nájdené: M+, 322,1305, pre C19H18N2°3 vypočítané 322,1317).7.5 Hz, 8-H), 4.39 (2H, q, OCH 2 CH 3 ), 2.87 (3H, s, 4-CH 3 ), 2.85 (3H, s, 3-CH 3) ) and 1.38 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 322 (61, M +), 276 (100), 248 (20), 219 (5) and 138 (11), (Found: M +, 322.1305, for C 19 H 18 N 2 ° 3 (calculated 322.1317).

Delenie ďalej poskytne [2,3-b]izomér, ktorý sa nechá kryštálováť z etylacetátu, a ktorý má teplotu topenia 251 až 254 ° C (rozklad).Separation further affords the [2,3-b] isomer which is crystallized from ethyl acetate and has a melting point of 251-254 ° C (dec.).

1H NMR δΗ([2H6)-DMSO): 10,95 (1H, s, 1-NH), 10,85 (1H, s, 9-H), 9,89 (1H, s, OH), 7,08 (1H, t, J = 7,5 Hz, 7-H), 7,07 (1H, s, 10-H), 6,77 (1H, d, J = 7,5 Hz, 8-H), 6,52 (1H, d, J = 7,5 1 H NMR δ (( 2 H 6) -DMSO): 10.95 (1H, s, 1-NH), 10.85 (1H, s, 9-H), 9.89 (1H, s, OH), 7.08 (1H, t, J = 7.5Hz, 7-H), 7.07 (1H, s, 10-H), 6.77 (1H, d, J = 7.5Hz, 8-) H, 6.52 (1H, d, J = 7.5)

Hz, 7-H), 4,32 (2H, q, OCH2CH3), 3,44 (3H, s, 4-CH3), 2,92 (3H, s, 3-CH3) a 1,37 (3H, t, OCH2CH3) ppm. m/z (%) 322(65, M+), 276(100), 248(88), 219(15), 205(10), 191(10), 178(5), 165(5),Hz, 7-H), 4.32 (2H, q, OCH 2 CH 3 ), 3.44 (3H, s, 4-CH 3 ), 2.92 (3H, s, 3-CH 3 ) and 1 37 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 322 (65, M < + > ), 276 (100), 248 (88), 219 (15), 205 (10), 191 (10), 178 (5), 165 (5),

138(10) a 115(10), (nájdené: M+, 322,1317, pre CigHlgN2O3 vypočítané 322,1317).138 (10), and 115 (10), (Found: M +, 322.1317, C to H ig g of N 2 O 3 Calc'd 322.1317).

x) Spôsob výroby etyl-(6,9-dimetoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu) a etyl-(5,8-dimetoxy-3,4-dimetylpyrolo[2,3-b]-karbazol-2-karboxylátu)x) A process for the preparation of ethyl (6,9-dimethoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (5,8-dimethoxy-3,4-dimethylpyrrolo [2, 3-b] carbazole-2-carboxylate)

Zlúčeniny pomenované v nadpise sa získajú ako zmes izomérov reakciou 4,7-dimetoxyindolu s 5-acetoxymetyl-4-acetylpyrolom. Chromatografické delenie poskytne [3,2-b]izomér, ktorý má teplotu topenia 256 až 258 °C. Výťažok zodpovedá 13,7 % teórie.The title compounds are obtained as a mixture of isomers by reaction of 4,7-dimethoxyindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gives the [3,2-b] isomer having a melting point of 256-258 ° C. Yield 13.7% of theory.

Analýza pre c2iH22N2°4: nájdené: 68,98 % C, 6,23 % H, 7,89 % N, vypočítané: 68,84 % C, 6,05 % H, 7,65 % N.Analysis for C 22 H 2 R 2 N ° 4: Found: 68.98% C, 6.23% H 7.89% N Found: 68.84% C, 6.05% H, 7.65% N .

ΧΗ NMR δΗ([2H6]-DMSO): 8,58 (1Η, s, široký singlet, NH), 8,08 (1H, s, 10-H), 7,84 (1H, široký singlet, NH), 6,82 (1H, d, J = 8 Hz, 7-H), 6,50 (1H, d, J = 8 Hz, 8-H), 4,43 (2H, q, Χ Η NMR δΗ ([2 H 6] -DMSO): 8.58 (1Η, s, br s, NH), 8.08 (1H, s, 10-H), 7.84 (1H, br s, NH 6.82 (1H, d, J = 8Hz, 7-H), 6.50 (1H, d, J = 8Hz, 8-H), 4.43 (2H, q,

OCH2CH3), 4,05 (3H, s, 9-OCH3), 3,98 (3H, s, 6-OCH3), 2,96 (3H, s, 4-CH3), 2,92 (3H, s, 3-CH3) a 1,44 (3H, t, OCH2CH3) ppm. m/z (%) 366(73, M+), 326(100), 305(11), 290(11), 277(23), 262(15),OCH 2 CH 3 ), 4.05 (3H, s, 9-OCH 3 ), 3.98 (3H, s, 6-OCH 3 ), 2.96 (3H, s, 4-CH 3 ), 2, 92 (3H, s, 3-CH 3 ) and 1.44 (3H, t, OCH 2 CH 3 ) ppm. m / z (%) 366 (73, M < + > ), 326 (100), 305 (11), 290 (11), 277 (23), 262 (15),

183(10), 160(17), 152(19) a 131(7). vmax (nujol)/cm-1 3474, 3323 a 1674. lambdamax (metanol)/nm 415, 387, 344, 330(posun),183 (10), 160 (17), 152 (19), and 131 (7). v max (nujol) / cm -1 3474, 3323 and 1674. lambda max (methanol) / nm 415, 387, 344, 330 (shift),

305(posun), 266, 246 a 220.305 (offset), 266, 246, and 220.

Delením sa ďalej získa [2,3-b]izomér, ktorý má teplotu topenia 193 až 195 “C. Výťažok zodpovedá 9,3 % teórie..Separation further affords the [2,3-b] isomer having a melting point of 193-195 ° C. Yield: 9.3%.

Analýza pre C21H22N2°4: nájdené: 69,03 % C, 6,29 % H, 7,42 % N, vypočítané: 68,84 % C, 6,05 % H, 7,65 % N.Analysis for C 21 H 22 N 4 ° 2: Found: 69.03% C, 6.29% H 7.42% N Found: 68.84% C, 6.05% H, 7.65% N .

1H NMR δΗ( [ 2H6 ]-DMSO) : 8,44 (1H, s, široký singlet, NH)', 8,10 (1H, široký singlet, NH), 7,06 (1H, s, 10-H), 6,82 (1H, d, J = 8 Hz, 7-H), 6,56 (1H, d, J =8 Hz, 6-H), 4,40 (2H, q, OCH2CH3), 3,98 (3H, s, OCH3), 3,97 (3H, s, OCH3), 3,42 (3H, s, 4-CH3), 3,00 (3H, s, 3-CH3) a 1,43 (3H, t, OCH2CH3) ppm. m/z (%) 1 H NMR δΗ ([ 2 H 6] -DMSO): 8.44 (1H, s, broad singlet, NH) ', 8.10 (1H, broad singlet, NH), 7.06 (1H, s, 10- H), 6.82 (1H, d, J = 8Hz, 7-H), 6.56 (1H, d, J = 8Hz, 6-H), 4.40 (2H, q, OCH 2 CH) 3 ), 3.98 (3H, s, OCH 3 ), 3.97 (3H, s, OCH 3 ), 3.42 (3H, s, 4-CH 3 ), 3.00 (3H, s, 3 -CH 3 ) and 1.43 (3H, t, OCH 2 CH 3 ) ppm. m / z (%)

366(100, M+), 320(82), 292(20), 277(24), 262(10), 183(14),366 (100, M + ), 320 (82), 292 (20), 277 (24), 262 (10), 183 (14).

160(28), 131(3). vmax (nujol)/cm“1 3457, 3345 a 1660. lambdamax (metanol)/nm 381, 365, 293, 247 a 219.160 (28), 131 (3). in max (nujol) / cm -1 1357, 3345 and 1660. lambda max (methanol) / nm 381, 365, 293, 247 and 219.

y) Spôsob výroby etyl-(7-metoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu) a etyl-(7-metoxy-3,4-dimmetylpyrolo[2,3-b]-karbazol-2-karboxylátu)y) A process for the preparation of ethyl (7-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (7-methoxy-3,4-dimethylpyrrolo [2,3-b] carbazole-2-carboxylate)

II

Zlúčeniny pomenované v nadpise sa získajú ako zmes izomérov, reakciou 6-metoxyindolu s 5-acetoxymetyl-4-acetylpyrrolom. Veľmi rýchla chromátografia na oxide kremičitom, pri eluovaní zmesou etylacetátu a cyklohexánu v pomere 1:1, poskytne [3,2-b]izomér, ktorý sa nechá kryštalovať zo zmesi etylacetátu a cyklohexánu, a ktorý má teplotu topenia 239 až 241 ’C (rozklad).The title compounds are obtained as a mixture of isomers by reaction of 6-methoxyindole with 5-acetoxymethyl-4-acetylpyrrole. Flash chromatography on silica, eluting with ethyl acetate / cyclohexane (1: 1) affords the [3,2-b] isomer, which is crystallized from ethyl acetate / cyclohexane and has a melting point of 239-241 ° C ( dec).

XH NMR δΗ([2H6]-DMSO): 11,09 (1Η, S, 1-NH), 10,49 (1H, s, 5-NH), 7,91 (1H, d, J = 8,7 Hz, 9-H), 7,73 (1H, s, 10-H), 6,88 (1H, d, J = 2,3 Hz, 6-H), 6,68 (1H, dd, J = 8,7 a 2,3 Hz, 8-H) , X δΗ NMR ([2 H 6] -DMSO): 11.09 (1Η, S, 1-NH), 10.49 (1H, s, 5-NH), 7.91 (1H, d, J = 8 7 Hz, 9-H), 7.73 (1H, s, 10-H), 6.88 (1H, d, J = 2.3Hz, 6-H), 6.68 (1H, dd, J = 8.7 and 2.3 Hz, 8-H),

4,35 (2H, q, OCH2CH3), 3,84 (3H, S, 7-OCH3), 2,87 (3H, S,4.35 (2H, q, OCH 2 CH 3 ), 3.84 (3H, S, 7-OCH 3 ), 2.87 (3H, S,

3- CH3), 2,86 (3H, s, 4-CH3) a 1,37 (3H, t, OCH2CH3) ppm. m/z (%)3-CH 3 ), 2.86 (3H, s, 4-CH 3 ) and 1.37 (3H, t, OCH 2 CH 3 ) ppm. m / z (%)

336(84, M+), 290(100), 262(32), 247(16) a 219(16). vmax (KBr kotúč)/cm_1 3342, 1674 a 1628.336 (84, M < + > ), 290 (100), 262 (32), 247 (16) and 219 (16). v max (KBr disc) / cm -1 1342 , 1674 and 1628.

Delením sa ďalej získa [2,3-b]izomér, ktorý sa nechá kryštalizovať z etylacetátu a cyklohexánu, a ktorý má teplotu topenia 260 ’C (rozklad).Separation further affords the [2,3-b] isomer which is crystallized from ethyl acetate and cyclohexane and has a melting point of 260 ° C (decomposition).

XH NMR δΗ([2H6]-DMSO): 10,98 (1H, s, 1-NH), 10,74 (1H, s, 9-NH), 8,00 (1H, d, J = 8,7 Hz, 5-H), 7,13 (1H, s, 10-H), 6,87 (1H, d, J = 2,7 Hz, 8-H), 6,70 (1H, dd, J = 8,7 a 2,7 Hz, 6-H), X δΗ NMR ([2 H 6] -DMSO): 10.98 (1H, s, 1-NH), 10.74 (1H, s, 9-NH), 8.00 (1 H, d, J = 8 7 Hz, 5-H), 7.13 (1H, s, 10-H), 6.87 (1H, d, J = 2.7Hz, 8-H), 6.70 (1H, dd, J = 8.7 and 2.7 Hz, 6-H),

4,34 (2H, q, OCH2CH3), 3,83 (3H, s, 7-OCH3), 3,10 (3H, s,4.34 (2H, q, OCH 2 CH 3 ), 3.83 (3H, s, 7-OCH 3 ), 3.10 (3H, s,

4- CH3), 2,91 (3H, s, 3-CH3) a 1,37 (3H, t, OCH2CH3) ppm. m/z (%)4-CH 3 ), 2.91 (3H, s, 3-CH 3 ) and 1.37 (3H, t, OCH 2 CH 3 ) ppm. m / z (%)

336(56, M+), 290(70), 262(26), 145(16), 129(14). vmax (KBr kotúč)/cm-1 3379, 3339 a 1663.336 (56, M < + > ), 290 (70), 262 (26), 145 (16), 129 (14). v max (KBr roll) / cm -1 3379, 3339 and 1663.

z) Spôsob výroby etyl-(3-etyl-4-metylpyrolo[3,2-b]-karbazol-2-karboxylátu)z) Process for the preparation of ethyl (3-ethyl-4-methylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,956 g zlúčeniny pomenovanej v nadpise sa získa reakciou (v rozsahu 11 mmol) indolu s etyl-(5-acetoxymetyl-4-acetyl-3-etylpyrol-2-karboxylátom), po rekryštalizácii z toluénu. Zlúčenina pomenovaná v nadpise má teplotu topenia 248 až 249 °C (rozklad). Výťažok zodpovedá 27 % teórie.0.956 g of the title compound is obtained by reacting (11 mmol) indole with ethyl (5-acetoxymethyl-4-acetyl-3-ethylpyrrole-2-carboxylate) after recrystallization from toluene. The title compound has a melting point of 248-249 ° C (dec.). Yield: 27%.

Analýza pre Analysis for C20H20N2°2: C 20 H 20 N 2 ° 2 : nájdené: found: 74,93 % C, 6,35 74.93% C, 6.35 % % H, H, 8, 8 60 % 60% N, N, vypočítané: calculated: 74,98 % C, 6,29 74.98% C, 6.29 % % H, H, 8, 8 74 % 74% N. N. XH NMR X H NMR δΗ([2h6]-dmso)δ Η ([ 2 h 6 ] -dmso) J J 11, 11 27 27 (1H, (1 H, s, N-H), 10,63 (1H, s s, N-H), 10.63 (1 H, s 5-NH), 8,09 5-NH), 8.09 (1H, d, J = 8 (1 H, d, J = 8) HZ HZ , 9 , 9 -H) H) , 7, , 7, 93 (1H, s, 10-H), 7,31 93 (1 H, s, 10-H), 7.31

7,47 (2H, m, 6-H, 7-H), 7,09 (1H, ddd, J = 8, 5,5 a 2 Hz, 8-H),7.47 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J = 8.5, 5.5 and 2 Hz, 8-H),

4,40 (2H, q, J =7 Hz, CO2CH2), 3,37 (2H, q, J = 7 Hz, 3-CH2),4.40 (2H, q, J = 7 Hz, CO2 CH2), 3.37 (2H, q, J = 7 Hz, 3-CH2).

2,91 (3H, s, 4-CH3), 1,41 (3H, t, J = 7 Hz, CO2CH2CH3), 1,30 (3Η, t, J = 7,5 Hz, 3-CH2CH3) ppm.m/z (%) 320(100, M+), 274(96). v__,v (KBr kotúč)/cm-1 3344, 3327, 1680, 1664, 1238.2.91 (3H, s, 4-CH 3 ), 1.41 (3H, t, J = 7Hz, CO 2 CH 2 CH 3 ), 1.30 (3Η, t, J = 7.5Hz, 3-CH 2 CH 3 ) ppm.m / z (%) 320 (100, M + ), 274 (96). v ν, v (KBr disc) / cm -1 3344, 3327, 1680, 1664, 1238.

lllcLXlllcLX

Príklad 5Example 5

Spôsob výroby kyseliny pyrolof3,2-b]-karbazol-2-karboxylovej , všeobecný postupProcess for preparing pyrrolo [3,2-b] carbazole-2-carboxylic acid, general procedure

K roztoku benzyl(pyrolo[3,2-b]-karbazol-2-karboxylátu) v 10 ml suchého tetrahydrofuránu sa pridá 50 mg 10% paládia na uhlí. Reakčná zmes sa hydrogenuje pri teplote miestnosti pri tlaku 100 kPa. Potom, čo ustane absorbcia vodíka, katalyzátor sa odfiltruje cez rozsievkovú zeminu (Celíte) a dobre premyje tetrahydrofuránom. Spojené filtráty sa odparia pri zníženom tlaku. Kryštalizácia výslednej tuhej látky z acetónu, metyletylketónu alebo vodného metanolu poskytne kyselinu pyrolo[3,2-b]-karbazol-2-karboxylovú ako žlté kryštály.To a solution of benzyl (pyrrolo [3,2-b] carbazole-2-carboxylate) in 10 mL of dry tetrahydrofuran was added 50 mg of 10% palladium on carbon. The reaction mixture is hydrogenated at room temperature at 100 kPa. After hydrogen uptake ceased, the catalyst was filtered off through diatomaceous earth (Celite) and washed well with tetrahydrofuran. The combined filtrates were evaporated under reduced pressure. Crystallization of the resulting solid from acetone, methyl ethyl ketone or aqueous methanol affords pyrrolo [3,2-b] carbazole-2-carboxylic acid as yellow crystals.

a) Spôsob výroby kyseliny 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxyloveja) Method for the preparation of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Získa sa 0,234 g zlúčeniny pomenovanej v nadpise, ktorá má teplotu topenia 237 °C (rozklad). Výťažok zodpovedá 84,3 % teórie.0.234 g of the title compound of melting point 237 DEG C. (decomposition) is obtained. Yield 84.3% of theory.

-’-H NMR δΗ( [2H6 J-DMSO): 12,74 (1H, široký singlet, CO2H) ,-'- H NMR δ Η ([2 H 6 J-DMSO): 12.74 (1H, br s, CO 2 H);

11,13 (1H, s, 1-NH), 10,60 (1H, s, 5-NH), 8,05 (1H, d, J = 7,511.13 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.05 (1H, d, J = 7.5

Hz, 9-H), 7,87 (1H, s, 10-H), 7,42 (1H, d, J = 7,5 Hz, 6-H),Hz, 9-H), 7.87 (1H, s, 10-H), 7.42 (1H, d, J = 7.5Hz, 6-H),

7,36 (1H, t, J = 7,5 Hz, 7-H), 7,08 (1H, t, J = 7,5 Hz, 8-H),7.36 (1H, t, J = 7.5Hz, 7-H), 7.08 (1H, t, J = 7.5Hz, 8-H),

2,92 a 2,91 (2 x 3H, 2 x s, 3-CH3 a 4-CH3) ppm. m/z (%) 278(30, M+), 260(39), 234(100), 218(19), 204(8), 167(8), 149(16),2.92 and 2.91 (2 x 3H, 2 xs, 3-CH 3 and 4-CH 3 ) ppm. m / z (%) 278 (30, M < + > ), 260 (39), 234 (100), 218 (19), 204 (8), 167 (8), 149 (16),

130(10) a 117(25), (nájdené: M+, 278,1060, pre C17H14N2O2 vypočítané 278,1055).130 (10) and 117 (25), (found: M + , 278.1060, calcd for C 17 H 14 N 2 O 2 278.1055).

b) Spôsob výroby kyseliny 8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovejb) Process for the preparation of 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Získa sa 0,0845 g zlúčeniny pomenovanej v nadpise, ktorá má teplotu topenia 236 až 239 ’C. Výťažok zodpovedá 85,6 % teórie.This gives 0.0845 g of the title compound, m.p. 236-239 ° C. Yield 85.6% of theory.

1H NMR δΗ([2H6]-DMS0): 12,80 (1H, široký singlet, CO2H), 1 H NMR δΗ ([ 2 H 6] -DMSO): 12.80 (1H, broad singlet, CO 2 H),

11,19 (1H, s, 1-NH), 10,60 (1H, s, 5-NH), 7,91 (1H, dd, J = 9 a11.19 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 7.91 (1H, dd, J = 9 and

2,5 Hz, 9-H), 7,86 (1H, s, 10-H), 7,37 (1H, dd, J = 9 a 4 Hz, 6-H), 7,20 (1H, dt, J = 9 a 2,5 Hz, 7-H), 2,89 (6H, S, 2 X CH3) ppm. m/z (%) 296(51,M+), 278(71), 252(100), 250(37), 236(19),2.5 Hz, 9-H), 7.86 (1H, s, 10-H), 7.37 (1H, dd, J = 9 and 4 Hz, 6-H), 7.20 (1H, dt , J = 9 and 2.5 Hz, 7-H), 2.89 (6H, s, 2 × CH 3) ppm. m / z (%) 296 (51, M < + > ), 278 (71), 252 (100), 250 (37), 236 (19),

222(13), 139(22), 125(36) a 111(28), (nájdené: M+, 296,0960, pre C17H13FN2O2 vypočítané 296,0961).222 (13), 139 (22), 125 (36) and 111 (28), (found: M + , 296.0960, calcd for C17H13FN2O2: 296.0961).

c) Spôsob výroby kyseliny 3,4,6-trimetylpyrolo[3,2-b]-karbazol-2-karboxylovejc) Method for the preparation of 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Získa sa 0,065 g zlúčeniny pomenovanej v nadpise, ktorá má teplotu topenia 230 ’C (rozklad). Výťažok zodpovedá 85 % teórie.This gives 0.065 g of the title compound having a melting point of 230 ° C (decomposition). Yield: 85%.

Analýza pre ci8H16N2°2: nájdené: 74,2 % C, 5,55 % H, 9,4 % N, vypočítané: 74,0 % C, 5,52 % H, 9,58 % N.Analysis for C 16 H i8 2 N ° 2: Found: 74.2% C, 5.55% H, 9.4% N Found: 74.0% C, 5.52% H, 9.58% N .

XH NMR δΗ((2H6]-DMSO): 12,80 (1H, široký singlet, CO2H), X δΗ NMR ((2 H6] -DMSO) 12.80 (1H, br s, CO 2 H);

11,01 (1H, s, 1-NH), 10,08 (1H, s, 5-NH), 7,90 (1H, d, J = 7,5 Hz, 9-H), 7,82 (1H, s, 10-H), 7,16 (1H, d, J = 7,5 Hz, 7-H), 7,01 (1H, t, J = 7,5 Hz, 8-H), 2,97 (3H, s, 4-CH3), 2,92 (3H, s, 3-CH3) a 2,58 (3H, s, 6-CH3) ppm. m/z (%) 292(72, M+), 274(100), 246(50), 230(11), 137(25), 122(24) a 109(30).11.01 (1H, s, 1-NH), 10.08 (1H, s, 5-NH), 7.90 (1H, d, J = 7.5Hz, 9-H), 7.82 (1H 1H, s, 10-H), 7.16 (1H, d, J = 7.5Hz, 7-H), 7.01 (1H, t, J = 7.5Hz, 8-H), 2 , 97 (3H, s, 4-CH3), 2.92 (3H, s, 3-CH3) and 2.58 (3H, s, 6-CH3) ppm. m / z (%) 292 (72, M < + > ), 274 (100), 246 (50), 230 (11), 137 (25), 122 (24) and 109 (30).

d) Spôsob výroby kyseliny 3-(2-metoxykarbonyletyl)-4-metylpyrolo[3,2-b]-karbazol-2-karboxylovejd) Process for the preparation of 3- (2-methoxycarbonylethyl) -4-methylpyrrolo [3,2-b] carbazole-2-carboxylic acid

II

Získa sa 0,0673 g zlúčeniny pomenovanej v nadpise, ktorá máThis gives 0.0673 g of the title compound which it has

teplotu teórie. temperature theory. topenia mp 255 ’C 255 ’C (rozklad). (Decomposition). Výťažok zodpovedá 84,6 Yield 84.6 Analýza pre nájdené: vypočítané: Analysis for found: calculated: c20h 68,4 68,6 c 20 h 68.4 68.6 18N2°4: % C, 5,3 % C, 5,1818 N 2 O 4 : % C, 5.3% C, 5.18 % H, 7,75 % % H, 8,00 % % H, 7.75% % H, 8.00% N, N. N, N.

1H NMR δΗ([2H6]-DMSO): 12,88 (1Η, široký singlet, CO2H), 11,34 (1H, s, 1-NH), 10,65 (1H, s, 5-NH), 8,06 (1H, d, J = 7,5 Hz, 9-H), 7,88 (1H, s, 10-H), 7,42 (1H, d, J = 7,5 Hz, 6-H), 1 H NMR δΗ ([ 2 H 6] -DMSO): 12.88 (1Η, broad singlet, CO 2 H), 11.34 (1H, s, 1-NH), 10.65 (1H, s, 5- NH), 8.06 (1H, d, J = 7.5Hz, 9-H), 7.88 (1H, s, 10-H), 7.42 (1H, d, J = 7.5Hz) , 6-H),

7,36 (1H, t, J = 7,5 Hz, 7-H), 7,07 (1H, t, J = 7,5 Hz, 8-H), 3,66 (3H, s, 0CH3), 3,63 (2H, čiastočne nezreteľné t, CH2CH2CO), 2,89 (3H, s, 4-CH3), 2,66 (2H, t, CH2CO) ppm. m/z (%) 350(100, M+), 332(17), 306(30), 290(63), 272(22), 259(32) a 233(47).7.36 (1H, t, J = 7.5Hz, 7-H), 7.07 (1H, t, J = 7.5Hz, 8-H), 3.66 (3H, s, OCH3 ) ), 3.63 (2H, partially obscured t, CH2 CH2 CO), 2.89 (3H, s, 4-CH3), 2.66 (2H, t, CH2 CO) ppm. m / z (%) 350 (100, M < + > ), 332 (17), 306 (30), 290 (63), 272 (22), 259 (32) and 233 (47).

e) Spôsob výroby kyseliny 1,3,4-trimetylpyrolo[3,2-b]-karbazol-2-karboxyloveje) Process for the preparation of 1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Získa sa 0,060 g zlúčeniny pomenovanej v nadpise, teplota topenia 215 až 216 °C (rozklad). Výťažok zodpovedá 44 % teórie.This gives 0.060 g of the title compound, m.p. 215 DEG-216 DEG C. (decomposition). Yield: 44%.

Analýza pre cigH16N2O2: nájdené: 73,69 % C, 5,51 % H, 9,41 % N, vypočítané: 73,95 % C, 5,52 % H, 9,58 % N.Analysis for C IgH 16 N 2 O 2: Found: 73.69% C, 5.51% H 9.41% N Found: 73.95% C, 5.52% H, 9.58% N.

•^H NMR δΗ( [ 2H6 3-DMSO) : 12,94 (1H, široký singlet, COOH),^ • H-NMR δ Η ([2 H 6 3-DMSO): 12.94 (1H, br s, COOH).

10,63 (1H, s, 5-NH), 8,13 (1H, d, J = 7,9 Hz, 9-H), 8,00 (1H, s, 10-H), 7,45 - 7,30 (2H, m, 6-H, 7-H), 7,14 - 7,04 (1H, m, 8-H),10.63 (1H, s, 5-NH), 8.13 (1H, d, J = 7.9Hz, 9-H), 8.00 (1H, s, 10-H), 7.45- 7.30 (2H, m, 6-H, 7-H), 7.14-7.04 (1H, m, 8-H),

3,99 (3H, s, 1-CH3), 2,91 (3H, s, 4-CH3) a 2,85 (3H, s, 3-CH3) ppm. m/z (%) 292(95, M+), 275(10), 247(40), 232(30), 180(100) a3.99 (3H, s, 1-CH3), 2.91 (3H, s, 4-CH3) and 2.85 (3H, s, 3 CH3) ppm. m / z (%) 292 (95, M < + > ), 275 (10), 247 (40), 232 (30), 180 (100);

135(100). vmax(KBr kotúč)/cm-1 3375, 2930 a 1709.135 (100). v max (KBr roll) / cm -1 3375, 2930 and 1709.

f) Spôsob výroby kyseliny 3,4,5-trimetylpyrolo[3,2-b]-karbazol-2-karboxylovejf) Process for the preparation of 3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Získa sa 0,015 g zlúčeniny pomenovanej v nadpise, teplota topenia 239 až 240 °C (rozklad). Výťažok zodpovedá 18 % teórie.The solid was dried in vacuo giving 0.015 g of the title compound, m.p. 239-240 ° C (dec.). Yield: 18%.

Analýza pre Analysis for C18H16N2°2: C 18 H 16 N 2 ° 2 : nájdené: found: 74,11 % C, 5,38 74.11% C, 5.38 % H, 9,39 % H, 9.39 % N, % N, vypočítané: calculated: 73,95 % C, 5,52 73.95% C, 5.52 % H, 9,58 % H, 9.58 % N. % N. 1H NMR 1 H NMR δΗ([2h 6]-DMS°)·δ Η ([ 2h 6 ] -D MS °) · 11,15 (1H, 11.15 (1 H, . S, . WITH, 1-NH), 8,04 1-NH), 8.04 (1H, d, J (LH, d, J) = 7,5 Hz, = 7.5 Hz, 9-H), 7,88 (1H, 9-H), 7.88 (1 H, s, 10-H), s, 10-H), 7,48 7.48 - 7,41 (2H, - 7.41 (2H, m, 6—H, m, 6 — H,

7-Η), 7,17 - 7,06 (1Η, m, 8-H), 4,03 (3H, s, 5-CH3), 3,16 (3H, s, 4-CH3) a 2,93 (3H, s, 3-CH3) ppm. m/z (%) 292(90, M+),7-Η), 7.17-7.06 (1Η, m, 8-H), 4.03 (3H, s, 5-CH 3 ), 3.16 (3H, s, 4-CH 3 ) and 2.93 (3H, s, 3 CH3) ppm. m / z (%) 292 (90, M < + > ),

274(75), 232(70), 197(35), 181(60), 149(30) a 130(100). Vmax (KBr kotúč)/cm”3 3454, 2926 a 1670.274 (75), 232 (70), 197 (35), 181 (60), 149 (30), and 130 (100). V max (KBr roll) / cm 3 3454, 2926 and 1670.

g) Spôsob výroby kyseliny 1,3,4,5-tetrametylpyrolo[3,2-b]-karbazol-2-karboxylovejg) Process for the preparation of 1,3,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Získa sa 0,030 g zlúčeniny pomenovanej v nadpise, teplota topenia 215 až 217 “C (rozklad). Výťažok zodpovedá 32 % teórie.This gives 0.030 g of the title compound, m.p. 215 DEG-217 DEG C. (decomposition). Yield: 32%.

Analýza pre ci9Hi8N2°2: nájdené: 74,44 % C, 6,00 % H, 9,14 % N, vypočítané: 74,49 % C, 5,92 % H, 9,14 % N.Analysis for C i9 i8 H 2 N ° 2: Found: 74.44% C, 6.00% H 9.14% N Found: 74.49% C, 5.92% H, 9.14% N .

•J-H NMR δΗ( [ 2H6]-DMSO) : 12,98 (1H, široký singlet, COOH) ,• H NMR δ Η ([2 H 6] -DMSO): 12.98 (1H, br s, COOH).

8,14 (1H, d, J = 7,6 Hz, 9-H), 8,04 (1H, s, 10-H), 7,48 = 7,38 (2H, m, 6-H, 7-H), 7,18 - 7,08 (1H, m, 8-H), 4,01 (3H, s,8.14 (1H, d, J = 7.6Hz, 9-H), 8.04 (1H, s, 10-H), 7.48 = 7.38 (2H, m, 6-H, 7H); -H), 7.18-7.08 (1H, m, 8-H), 4.01 (3H, s,

5-CH3), 3,97 (3H, s, 1-CH3), 3,12 (3H, s, 4-CH3) a 2,84 (3H, s, 5-CH3), 3.97 (3H, s, 1-CH3), 3.12 (3H, s, 4-CH3) and 2.84 (3H, s,

3-CH3) ppm. m/z (%) 306(100, M+), 279(25), 232(38), 197(34), 3-CH3) ppm. m / z (%) 306 (100, M < + > ), 279 (25), 232 (38), 197 (34),

181(80) a 149(25). vffiax (KBr kotúč)/cm_1 1935 a 1659.181 (80) and 149 (25). in ffiax (KBr Disc) / cm _1 and 1935 1659th

h) Spôsob výroby kyseliny 3,4-dimetylpyrolo[3,2-b]-karbazol-2karboxylovejh) A process for the preparation of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

500 mg (1,6 mmol) etylesteru v 15 ml vody a 35 ml metanolu sa varí pod spätným chladičom a potom pridá dostatok metanolu, aby sa dosiahlo rozpustenie tuhej fázy. K reakčnej zmesi sa pridá 5,32 g (16 mmol) uhličitanu cezného a zmes sa varí pod spätným chladičom pod dusíkovou atmosférou počas 18 hodín. Po ochladení sa rozpúšťadlo odparí pri zníženom tlaku a získa sa približne 20 ml roztoku, ktorý sa uvedie na hodnotu pH 3 prídavkom 0,1-molárnej kyseliny chlorovodíkovej, čím sa vyzráža zlúčenina pomenovaná v nadpise. Filtráciou, premytím vodou a vysušením pri zníženom tlaku sa získa 437 mg analyticky čistej vyrábanej zlúčeniny, ktorá je spektroskopicky identická so zlúčeninou získanou v príklade 5a. Výťažok zodpovedá 96 % teórie.500 mg (1.6 mmol) of ethyl ester in 15 ml of water and 35 ml of methanol are refluxed and then enough methanol is added to dissolve the solid. To the reaction mixture, 5.32 g (16 mmol) of cesium carbonate was added and the mixture was refluxed under nitrogen for 18 hours. After cooling, the solvent was evaporated under reduced pressure to give approximately 20 ml of a solution which was brought to pH 3 by addition of 0.1 molar hydrochloric acid to precipitate the title compound. Filtration, washing with water and drying under reduced pressure gave 437 mg of analytically pure compound produced, which was spectroscopically identical to the compound obtained in Example 5a. Yield 96%.

Príklad 6Example 6

Spôsob výroby esterov kyseliny pyrolo[3,2-b]-karbazol-2-karboxylovej, všeobecný postupProcess for preparing pyrrolo [3,2-b] carbazole-2-carboxylic acid esters, general procedure

1,0 mmol kyseliny pyrolo[3,2-b]-karbazol-2-karboxylovej a 1,1 mmol N,N'-karbonyldiimidazolu sa rozpusti v čerstvo destilovanom tetrahydrofuráne pod dusíkovou atmosférou. Výsledná suspenzia sa mieša pri teplote miestnosti počas aspoň 1 hodiny a ukončenie konverzie kyseliny na imidazolidový medziprodukt sa overí chromatografiou na tenkej vrstve. V jedinej dávke sa pridá alkohol alebo fenol v množstve 1,5 až 2,0 mol, to znamená v prebytku, a výsledná zmes sa varí pod spätným chladičom až chromatografia na tenkej vrstve ukáže úplné spotrebovanie imidazolového medziproduktu. Zlúčenina pomenovaná v nadpise sa získa stĺpcovou chromatografiou na oxide kremičitom a potom rekryštalizáciou.1.0 mmol of pyrrolo [3,2-b] carbazole-2-carboxylic acid and 1.1 mmol of N, N'-carbonyldiimidazole are dissolved in freshly distilled tetrahydrofuran under a nitrogen atmosphere. The resulting suspension was stirred at room temperature for at least 1 hour and the completion of the conversion of the acid to the imidazolide intermediate was verified by thin layer chromatography. Alcohol or phenol is added in a single portion in an amount of 1.5 to 2.0 moles, i.e. in excess, and the resulting mixture is refluxed until thin layer chromatography shows complete consumption of the imidazole intermediate. The title compound was obtained by column chromatography on silica and then recrystallized.

a) Spôsob výroby fenyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)a) Method for the preparation of phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s fenolom. Chromatografia (eluovanie zmesou 10 % acetónu a 90 % petrolétereru) s nasledujúcou rekryštalizáciou zo zmesi acetónu a petroléteru poskytne oranžovú kryštalickú látku s hmotnosťou 0,230 g, ktorá má teplotu topenia vyššiu ako 230 ’C (rozklad). Výťažok zodpovedá 65 % teórie.The title compound is obtained by reacting the imidazolide intermediate with phenol. Chromatography (eluting with 10% acetone and 90% petroleum ether) followed by recrystallization from acetone / petroleum ether gave an orange crystalline solid of 0.230 g, mp> 230 ° C (dec.). Yield: 65%.

Analýza pre C23H18N2O2: nájdené: 78,17 % C, 5,09 % H, 7,77 % N, vypočítané: 77,95 % C, 5,12 % H, 7,90 % N.Analysis for C2 3 H 18 N 2 O 2: Found: 78.17% C, 5.09% H 7.77% N Found: 77.95% C, 5.12% H, 7.90% N .

1H NMR SH([1 2H6]-DMSO): 11,55 (1H, s, 1-NH), 10,64 (1H, s, 5-NH), 8,10 (1H, d, J = 7,5 Hz, 9-H), 7,94 (1H, s, 10-H), 7,30 7,58 (7H, m, PhH, 6-H, 7-H), 7,09 (1H, ddd, J = 7,5, 5,5, 2 Hz, 8-H) a 2,97 a 2,95 (2 x 3H, 2 x s, 3-CH3 a 4-CH3) ppm. m/z (%) 1 H NMR SH ([ 1 H 2 ] -DMSO): 11.55 (1H, s, 1-NH), 10.64 (1H, s, 5-NH), 8.10 (1H, d, J = 7.5 Hz, 9-H), 7.94 (1H, s, 10-H), 7.30 7.58 (7H, m, PhH, 6-H, 7-H), 7.09 (1H , ddd, J = 7.5, 5.5, 2 Hz, 8-H) and 2.97 and 2.95 (2 x 3H, 2 xs, 3-CH 3 and 4-CH 3 ) ppm. m / z (%)

355(40, M+). vmax (KBr kotúč)/cm-1 3396, 1701 a 1180.355 (40, M < + > ). v max (KBr roll) / cm -1 3396, 1701 and 1180.

b) Spôsob výroby (2-dimetylamíno)etyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)b) Method for producing (2-dimethylamino) ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s (2-dimetylamino)etanolom. Chromátografia (eluovanie zmesou 10 % metanolu a 90 % dichlórmetánu) poskytne žltú tuhú látku s hmotnosťou 0,350 g. Výťažok zodpovedá 99 % teórie. Rekryštalizáciou časti produktu z dichlórmetánu sa získa žltá kryštalická látka, ktorá má teplotu topenia 174;0 až 175,7 °C (rozklad).The title compound is obtained by reacting the imidazolide intermediate with (2-dimethylamino) ethanol. Chromatography (eluting with 10% methanol and 90% dichloromethane) gave a yellow solid of 0.350 g. Yield: 99%. Recrystallization of a portion of the product from dichloromethane gave a yellow crystalline solid having a melting point of 174.0 ° C to 175.7 ° C (dec.).

Analýza pre C21H23N3°2 * 0,15 CH2C12: nájdené: 70,46 % C, 6,48 % H, 11,76 % N, vypočítané: 70,29 % C, 6,45 % H, 11,55 % N.Analysis for C 21 H 23 N 3 ° 2 * 2 0.15 CH 2 C1: Found: 70.46% C, 6.48% H, 11.76% N Found: 70.29% C, 6.45 % H, 11.55% N.

1H NMR δΗ([2H6]-DMSO): 11,18 (1H, s, 1-NH) 10,60 (1H, s, 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.18 (1H, s, 1-NH) 10.60 (1H, s,

5-NH), 8,07 (1H, d, J = 8 Hz, 9-H), 7,89 (1H, s, 10-H), 7,30 7,43 (2H, m, 6-H, 7-H), 7,09 (1H, ddd, J = 8,6, 2,5 Hz, 8-H),5-NH), 8.07 (1H, d, J = 8Hz, 9-H), 7.89 (1H, s, 10-H), 7.30 7.43 (2H, m, 6-H) 7-H), 7.09 (1 H, ddd, J = 8.6, 2.5 Hz, 8-H),

4,41 (2H, t, J = 6 HZ, OCH2), 2,91 (6H, s, 3-CH3 a 4-CH3), 2,69 (2H, t, J = 6,0 Hz, NCH2) a 2,27 (6H, s, N(CH3)2) ppm. m/z (%) 350(46, M+l)+), 261(68) a 133(100 ) . vmax (KBr kotúč)/cm-1 3377, 1661 a 1238.4.41 (2H, t, J = 6 Hz, OCH2), 2.91 (6H, s, 3-CH3 and 4-CH3), 2.69 (2H, t, J = 6.0 Hz , NCH 2 ) and 2.27 (6H, s, N (CH 3 ) 2 ) ppm. m / z (%) 350 (46, M + 1) < + > ), 261 (68) and 133 (100). v max (KBr roll) / cm -1 3377, 1661 and 1238.

c) Spôsob výroby (3-dirnetylamino)fenyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)c) Method for producing (3-dimethylamino) phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s (3-dimetylamino)fenolom. Chromátografia (eluovanie zmesou 10 % etylacetátu a 90 % toluénu) s nasledujúcou rekryštalizáciou z etýlacetátu poskytne žltú kryštalickú látku s hmotnosťou 0,272 g, ktorá má teplotu topenia 240 až 242 “C (rozklad). Výťažok zodpovedá 72 % teórie.The title compound is obtained by reacting the imidazolide intermediate with (3-dimethylamino) phenol. Chromatography (eluting with 10% ethyl acetate and 90% toluene) followed by recrystallization from ethyl acetate gave a yellow crystalline solid, 0.272 g, m.p. 240-242 ° C (dec.). Yield: 72%.

Analýza pre C25H23N3°2: nájdené: 75,37 % C, 5,71 % H, 10,36 % N, vypočítané: 75,55 % C, 5,83 % H, 10,57 % N.Analysis for C 25 H 23 N 3 ° 2: Found: 75.37% C, 5.71% H, 10.36% N Found: 75.55% C, 5.83% H, 10.57% N .

1H NMR δΗ([2H6)-DMSO): 11,49 (1Η, s, 1-NH), 10,64 (1H, s, 5-NH), 8,08 (1H, d, J = 8 Hz, 9-H), 7,91 (1H, s, 10-H), 7,34 7,48 (2H, m, 6-H, 7-H), 7,27 (1H, t, J = 8 Hz, 5'-H), 7,10 (1H, ddd, J = 8, 6, 2 Hz, 8-H), 6,56 - 6,70 (3H, m, 2'-H, 4'-H, 6'-H), 2,96 (3H, s) a 2,94 (9H, s, 3-CH3, 4-CH3, N(CH3)2) ppm. m/z (%) 398(38, (M+l)+), 261(25), 232(21) a 217(100). vmax (KBr kotúč)/cm-1 3350, 1674 a 1610 a 1232. 1 H NMR δ (( 2 H 6) -DMSO): 11.49 (1Η, s, 1-NH), 10.64 (1H, s, 5-NH), 8.08 (1H, d, J = 8) Hz, 9-H), 7.91 (1 H, s, 10-H), 7.34 7.48 (2 H, m, 6-H, 7-H), 7.27 (1 H, t, J = 8 Hz, 5'-H), 7.10 (1H, ddd, J = 8.6, 2 Hz, 8-H), 6.56-6.70 (3H, m, 2'-H, 4 ' -H, 6'-H), 2.96 (3H, s) and 2.94 (9H, s, 3-CH 3 , 4-CH 3 , N (CH 3 ) 2 ) ppm. m / z (%) 398 (38, (M + 1) < + > ), 261 (25), 232 (21) and 217 (100). v max (KBr roll) / cm -1 3350, 1674 and 1610 and 1232.

d) Spôsob výroby 3-pyridyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)d) Method for the preparation of 3-pyridyl- (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s 3-hydroxypyridínom. Chromatografia (eluovanie zmesou 50 % etylacetátu a 50 % petroléteru) s nasledujúcou rekryštalizáciou z acetónu poskytne žltú kryštalickú látku s hmotnosťou 0,230 g, ktorá má teplotu topenia vyššiu ako 270 C (rozklad). Výťažok zodpovedá 65 % teórie.The title compound is obtained by reacting the imidazolide intermediate with 3-hydroxypyridine. Chromatography (eluting with 50% ethyl acetate and 50% petroleum ether) followed by recrystallization from acetone gave a yellow crystalline solid (0.230 g), mp > 270 C (dec.). Yield: 65%.

Analýza pre C22H17N3°2 . 0,2 H2O:Analysis for C 22 H 17 N 3 ° 2. 0.2 H 2 O:

nájdené: 73,88 % C, 4,76 % H, 11,50 % N, vypočítané: 73,61 % C, 4,89 % H, 11,71 % N.Found: C, 73.88; H, 4.76; N, 11.50. Calculated: C, 73.61; H, 4.89; N, 11.71.

1H NMR 1 H NMR

5-NH), 8,635-NH3, 8.63

6'-H), 8,10 δΗ([2H6]-DMS0): 11,59 (1H, s, 1-NH), 10,65 (1H, s, (1H, d, J = 2, 2'-H), 8,55 (1H, dd, J = 4, 1 Hz, (1H, d, J =8 Hz, 9-H), 7,90 (1H, s, 10-H), 7,86 (1H, ddd, J = 8, 3, 1 Hz, 5'-H), 7,58 (1H, dd, J = 8, 5 Hz, 4' H), 7,32 - 7,45 (2H, m, 6-H, 7-H), 7,09 (1H, ddd, J = 8, 6, 26'-H), 8.10 δ ( ( 2 H 6 ) -DMSO): 11.59 (1H, s, 1-NH), 10.65 (1H, s, (1H, d, J = 2) 2'-H), 8.55 (1H, dd, J = 4.1Hz, (1H, d, J = 8Hz, 9-H), 7.90 (1H, s, 10-H), 7.86 (1H, ddd, J = 8,1,1 Hz, 5'-H), 7,58 (1H, dd, J = 8,5 Hz, 4'H), 7,32-7,45 (2H, m, 6-H, 7-H), 7.09 (1 H, ddd, J = 8.6, 2)

Hz, 8-H) a 2,97 a 2,94 (2 x 3H, 2 X S, 3-CH3 a 4-CH3) ppm. m/z (%) 356(15, (M+l)+). vmax (KBr kotúč)/cm_1 3377, 1715 a 1173.Hz, 8-H) and 2.97 and 2.94 (2 x 3H, 2 x s, 3-CH3 and 4-CH3) ppm. m / z (%) 356 (15, (M + 1) < + > ). v max (KBr disc) / cm -1 1377 , 1715 and 1173.

e) Spôsob výroby 4-karbamoylfenyl-(3,4-dimetylpyrolo[3,2-bJ-karbazol-2-karboxylátu)e) Process for preparing 4-carbamoylphenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s 3-hydroxybenzamidom. Rekryštalizáciou z etanolu sa získa žltý prášok a znečistený zvyšok. Tento zvyšok sa ďalej čistí stĺpcovou chromatografiou na oxide kremičitom, pri eluovani zmesou 5 % metanolu a 95 % dichlórmetánu a potom 10 % metanolu a 90 % dichlórmetánu, a potom rekryštalizáciou z etanolu. Získa sa 0,262 g pripravovanej zlúčeniny, ktorá má teplotu topenia vyššiu ako 250 °C (rozklad). Výťažok zodpovedá 66 % teórie.The title compound is obtained by reacting the imidazolide intermediate with 3-hydroxybenzamide. Recrystallization from ethanol gave a yellow powder and a impure residue. This residue was further purified by column chromatography on silica, eluting with a mixture of 5% methanol and 95% dichloromethane and then 10% methanol and 90% dichloromethane, followed by recrystallization from ethanol. 0.262 g of compound is obtained having a melting point of greater than 250 DEG C. (decomposition). Yield: 66%.

Analýza pre C24H19N3°3 ‘ 0,2 H20: nájdené: 71,72 % C, 4,81 % H, 10,26 % N, vypočítané: 71,88 % C, 4,88 % H, 10,48 % N.Analysis for C 24 H 19 N 3 ° 3 '0.2 H 2 0: Found: 71.72% C, 4.81% H, 10.26% N Found: 71.88% C, 4.88% H, 10.48% N.

XH NMR δΗ( [2H6]-DMSO) : 11,56 (1H, s, 1-NH) , 10,63 (1H, s, 5-NH), 7,90 - 8,12 (5H, m, 9-H, 10-H, 3'-H, 5’-H, amidový N-H), 7,33 - 7,49 (5H, m, 6-H, 7-H, 2'-H, 6'-H, amidový N-H), 7,09 (1H, ddd, J = 8,5, 6, 1,5 Hz, 8-H) a 2,95 a 2,93 (2 x 3H, 2 x s, 3-CH3 a 4-CH3) ppm. m/z (%) 398(10) (M+l)+), 297(100). vmax (KBr kotúč/cm-1 3423, 1717 a 1695 a 1171. X δΗ NMR ([2 H 6] -DMSO): 11.56 (1H, s, 1-NH), 10.63 (1H, s, 5-NH), 7.90 to 8.12 (5H, m 9-H, 10-H, 3'-H, 5'-H, amide NH), 7.33-7.49 (5H, m, 6-H, 7-H, 2'-H, 6 ' -H, amide NH), 7.09 (1H, ddd, J = 8.5, 6, 1.5 Hz, 8-H) and 2.95 and 2.93 (2 x 3H, 2 xs, 3- CH 3 and 4-CH 3 ) ppm. m / z (%) 398 (10) (M + 1) < + > ), 297 (100). v max (KBr disc / cm -1 3423, 1717 and 1695 and 1171).

f) Spôsob výroby (pyridyl-4-metyl)-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)f) Method for producing (pyridyl-4-methyl) - (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu so 4-pyridylkarbinolom. Chromátografia (eluovanie zmesou etylacetátu a petroléteru, gradient 60%, 80%, 100% etylacetátu, potom zmesou metanolu a etylacetátu, gradient 10%, 20%) s nasledujúcou rekryštalizáciou z tetrahydrofuránu poskytne oranžovú kryštalickú látku s hmotnosťou 0,168 g, ktorá má teplotu topenia vyššiu ako 240 °C (rozklad). Výťažok zodpovedá 46 % teórie.The title compound is obtained by reacting the imidazolide intermediate with 4-pyridylcarbinol. Chromatography (eluting with a mixture of ethyl acetate and petroleum ether, gradient of 60%, 80%, 100% ethyl acetate, then a mixture of methanol and ethyl acetate, gradient of 10%, 20%) followed by recrystallization from tetrahydrofuran gave an orange crystalline solid weighing 0.168 g. > 240 ° C (decomposition). Yield: 46%.

Analýza pre C23H19N3°2 · 0/7 H20: nájdené: 72,16 % C, 5,12 % H, 10,73 % N, vypočítané: 72,31 % C, 5,38 % H, 11,00 % N.Analysis for C 23 H 19 N 3 ° 2 · 0/7 H 2 0: Found: 72.16% C, 5.12% H, 10.73% N Found: 72.31% C, 5.38% H, 11.00% N

1H NMR δΗ([2H6]-DMSO): 11,31 (1H, s, 1-NH), 10,62 (1H, s, 5-NH), 8,62 (2H, dd, J = 4,5, 0,5 Hz, 2'-H, 6'-H), 8,08 (1H, d, 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.31 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.62 (2H, dd, J = 4) 0.5 Hz, 2'-H, 6'-H), 8.08 (1H, d,

J = 7,5 Hz, 9-H), 7,89 (1H, s, 10-H), 7,53 (2H, d, J = 5,5 Hz,J = 7.5Hz, 9-H), 7.89 (1H, s, 10-H), 7.53 (2H, d, J = 5.5Hz,

3'-H, 5'-H), 7,32 - 7,43 (2H, m, 6-H, 7-H), 7,07 (1H, ddd, J = 8, 5, 1 HZ, 8-H), 5,45 (2H, s, ArCH2) a 2,94 a 2,92 (2 X 3H, 2 X 3-CH3 a 4-CH3) ppm. m/z (%) 369(27, (M+l)+), 327(70) a 295(100). vmax (KBr kotúč)/cm 1 3400, 1709 a 1232.3'-H, 5'-H), 7.32-7.43 (2H, m, 6-H, 7-H), 7.07 (1H, ddd, J = 8.5, 1 HZ, 8) -H), 5.45 (2H, s, ArCH 2 ) and 2.94 and 2.92 (2 X 3 H, 2 X 3 -CH 3 and 4-CH 3 ) ppm. m / z (%) 369 (27, (M + 1) < + > ), 327 (70) and 295 (100). v max (KBr roll) / cm 1 3400, 1709 and 1232.

g) Spôsob výroby (1,3-dibezyloxy-2-propyl)-(3,4-dimetylpyrolo- [3,2-b]-karbazol-2-karboxylátu)g) Method for producing (1,3-dibezyloxy-2-propyl) - (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa ( v rozsahu 1,5 mmol) reakciou imidazolidového medziproduktu s 1,3-dibenzyloxy-2-propanolom. Chromátografia (eluovanie zmesou 20 % etylacetátu a 80 % toluénu a potom zmesou 40 % etylacetátu a 60 % toluénu) s nasledujúcou rekryštalizáciou zo zmesi etylacetátu, éteru a petroléteru poskytne žlté kryštály s hmotnosťou 0,776 g, ktoréThe title compound is obtained (within 1.5 mmol) by reaction of the imidazolide intermediate with 1,3-dibenzyloxy-2-propanol. Chromatography (eluting with 20% ethyl acetate and 80% toluene followed by 40% ethyl acetate and 60% toluene) followed by recrystallization from ethyl acetate / ether / petroleum ether gave 0.776 g of yellow crystals, which

majú teplotu topenia zodpovedá 97 % teórie. have a melting point of 97% of theory. 124,8 124.8 až 126 to 126 °C ° C (rozklad). (Decomposition). Výťažok yield Analýza pre C34H32N2°4Analysis for C 34 H 32 N 2 O 4 z from nájdené: 76,35 % C, found: C, 76.35; 6,07 6.07 % H, % H, 5,12 % 5,12% N, N, vypočítané: 76,67 % C, calculated: 76.67% C, 6,06 6.06 % H, % H, 5,26 % 5.26% N. N. 1H NMR 8h([2H6]- 1H NMR 8H ([2 H 6] - DMSO): DMSO): 11, 11 18 (1H, 18 (1 H, s, with, 1-NH), 1-NH), 10,60 10.60 (1H, s, (1H, s, 5-NH), 8,06 (1H, d, J 5-NH), 8.06 (1 H, d, J) = 7,5 = 7.5 Hz, Hz, 9-H), 7 9-H), 7 ,88 88 (1H, s, (1H, s, 10-H) 10-H) , 7,22 - , 7.22 - 7,42 (12H, m 2 x PhH5,7.42 (12H, m 2 x PhH 5 , 6-H, 6-H, 7-H) 7-H) , .7,07 , .7.07 (1H, (1 H, ddd, J ddd, J = 8, = 8, 6,5, 1,5 6.5, 1.5

Hz, 8-H), 5,44 (1H, kvintet, J = 5 Hz, l'-H), 4,60 a 4,53 (2 x 2H, 2 x dd, J = 12 Hz, 2 x PhCH2O), 3,77 (4H, d, J = 5,5 OCH(CH2)2) a 2,91 a 2,89 (2 x 3H, 2 x s, 3-CH3 a 4-CH3) ppm. m/z (%) 532(50, M+), 260(65) a 91(100). vmax (KBr kotúč)/cm_1 3358, 1681 a 1234.Hz, 8-H), 5.44 (1H, quintet, J = 5 Hz, 1'-H), 4.60 and 4.53 (2 x 2H, 2 x dd, J = 12 Hz, 2 x PhCH) 2 O), 3.77 (4H, d, J = 5.5 OCH (CH 2 ) 2 ) and 2.91 and 2.89 (2 x 3H, 2 xs, 3-CH 3 and 4-CH 3 ) ppm. m / z (%) 532 (50, M < + > ), 260 (65) and 91 (100). v max (KBr disc) / cm -1 1358 , 1681 and 1234.

h) Spôsob výroby 4-metylsulfinylfenyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)h) Method for preparing 4-methylsulfinylphenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu so 4-metylsulfinylfenolom. Chromátografia (eluovanie zmesou etylacetátu a petroléteru, gradient 90%, 95%, 100% etylacetátu, potom zmesou 10% metanolu v etylacetáte) s nasledujúcou rekryštalizáciou z tetrahydrofuránu poskytne žltý prášok s hmotnosťou 0,261 g, ktorý má teplotu topenia vyššiu ako 230 ‘C (rozklad). Výťažok zodpovedá 63 % teórie.The title compound is obtained by reacting the imidazolide intermediate with 4-methylsulfinylphenol. Chromatography (eluting with a mixture of ethyl acetate and petroleum ether, gradient 90%, 95%, 100% ethyl acetate, then 10% methanol in ethyl acetate) followed by recrystallization from tetrahydrofuran gave a yellow powder, 0.261 g, m.p. > 230 ° C ( dec). Yield: 63%.

Analýza analysis pre for C24H20N2°3S * 0/3 H20: C 24 H 20 N 2 ° 3 N * 0/3 H 2 0: nájdené found 68,40 % C, 4,81 % H, 6,44 % N, % C, 68.40;% H, 4.81;% N, 6.44. vypočítané: calculated: 68,32 % C, 4,92 % H, 6,64 % N. H, 4.92; N, 6.64. NMR NMR SH([2H6]-DMSO): 11,59 (1H, s, 1-NH)S H ([ 2 H 6 ] -DMSO): 11.59 (1H, s, 1-NH) , 10,68 (1H, s, 10.68 (1 H, s, 5-NH), 5-NH), 8,10 8.10 (1H, d, J =8 HZ, 9-H), 7,93 (1H, (1H, d, J = 8 Hz, 9-H), 7.93 (1H, s, 10-H), 7,82 s, 10-H), 7.82 (2H, d, (2H, d, J = J = 9,5 Hz, 3'-H, 5'-H), 7,59 (2H, d, J 9.5 Hz, 3'-H, 5'-H), 7.59 (2H, d, J) = 9,5 Hz, 2'-H, = 9.5 Hz, 2'-H, 6'-H), 6'-H), 7,33 7.33 - 7,45 (2H, m, 6-H, 7-H), 7,09 (1H, 7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J = 8, 6, ddd, J = 8.6, 2,5 Hz, 2.5 Hz, 8-H) 8-H) , 2,99 a 2,95 (2 x 3H, 2 X s, 3-CH3 2.99 and 2.95 (2 * 3H, 2 * s, 3-CH3 ) a 4-CH3) a 2,82and 4-CH 3 ) and 2.82 (3H, s, (3H, s, CH3SO) ppm·. m/z (%) 417 (2, (M+l) + ), 261(CH 3 SO) ppm ·. m / z (%) 417 (2 (M + 1) + ), 261 ( 100) a 233(75). 100) and 233 (75).

vmax (KBr k°túč)/cm-1 3427, 3288, 1717 a 1200. v max (KBr k kt) / cm -1 3427, 3288, 1717 and 1200.

i) Spôsob výroby metyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu)i) Method for the preparation of methyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s metanolom. Chromátografia (eluovanie zmesou 30% etylacetátu v petrolétere) s nasledujúcou rekryštalizáciou z etylacetátu poskytne žltý prášok s hmotnosťou 0,188 g, ktorý má teplotu topenia 211 až 213 °C (rozklad). Výťažok zodpovedá 64 % teórie.The title compound is obtained by reacting the imidazolide intermediate with methanol. Chromatography (eluting with 30% ethyl acetate in petroleum ether) followed by recrystallization from ethyl acetate gave a yellow powder (0.188 g), mp 211-213 ° C (dec.). Yield: 64%.

Analýza pre C18H16N2O2:Analysis for C 18 H 16 N 2 O 2 :

nájdené: 74,06 % C, 5,49 % H, 9,42 % N, vypočítané: 73,95 % C, 5,52 % H, 9,52 % N.Found: C, 74.06; H, 5.49; N, 9.42. Calculated: C, 73.95; H, 5.52; N, 9.52.

1H NMR δΗ([2H6]-DMSO): 11,25 (1H, s, 1-NH), 10,62 (1H, s, 5-NH), 8,08 (1H, d, J = 8 Hz, 9-H), 7,89 (1H, s, 10-H), 7,33 7,58 (2H, m, 6-H, 7-H), 7,09 (1H, ddd, J = 8, 6, 1 Hz, 8-H), 3,92 (3H, s, OCH3), 2,92 a 2,91 (2 x 3H, 2 k s, 3-CH3 a 4-CH3) ppm. m/z (%) 292(68, M+), 260(100), 232(39). vmax (KBr) kotúč/cm-1 3342, 1684 a 1236. 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.25 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.08 (1H, d, J = 8) Hz, 9-H), 7.89 (1 H, s, 10-H), 7.33 7.58 (2 H, m, 6-H, 7-H), 7.09 (1 H, ddd, J = 8,6,1 Hz, 8-H), 3,92 (3H, s, OCH 3 ), 2,92 and 2,91 (2 x 3H, 2 pcs, 3-CH 3 and 4-CH 3 ) ppm . m / z (%) 292 (68, M < + > ), 260 (100), 232 (39). v max (KBr) disc / cm -1 3342, 1684 and 1236.

j) Spôsob výroby (2-metylsulfonyl)etyl-(3,4-dimetylpyrolo[3,2-j) Method for producing (2-methylsulfonyl) ethyl- (3,4-dimethylpyrrolo [3,2-

-b]-karbazol-2-karboxylátu)b] carbazole-2-carboxylate)

Zlúčenina pomenovaná v nadpise sa získa reakciou imidazolidového medziproduktu s (2-metylsulfonyl)etanolom. Chromatografia (eluovanie zmesou etylacetátu a petroléteru, gradient 30 až 100%) s nasledujúcou rekryštalizáciou z acetónu poskytne jemné žlté kryštály s hmotnosťou 0,222 g, ktoré majú teplotu topenia 255 až 257 C (rozklad). Výťažok zodpovedá 58 % teórie.The title compound is obtained by reacting the imidazolide intermediate with (2-methylsulfonyl) ethanol. Chromatography (eluting with a mixture of ethyl acetate and petroleum ether, gradient 30 to 100%) followed by recrystallization from acetone gave fine yellow crystals weighing 0.222 g, m.p. 255-257 ° C (dec.). The yield corresponds to 58% of theory.

Analýza pre C20H20N2°4S: nájdené: 62,33 % C, 5,25 % H, 7,08 % N, vypočítané: 62,48 % C, 5,24 % H, 7,29 % N.Analysis for C 20 H 20 N 2 ° 4 S: Found: 62.33% C, 5.25% H 7.08% N Found: 62.48% C, 5.24% H, 7.29% N.

1H NMR δΗ([2H6]-DMS0): 11,19 (1H, s, 1-NH), 10,60 (1H, s, 5-NH), 8,09 (1H, d, J = 7,5 Hz, 9-H), 7,89 (1H, S, 10-H), 7,32 7,45 (2H, m, 6-H, 7-H), 7,09 (1H, ddd, J = 7,5, 5,5, 3 Hz, 8-H) , 4,69 (2H, t, J = 5,5 Hz, OCH2), 3,69 (2H, t, J = 5,5 Hz, SO2CH2), 3,12 (3H, s, SO2CH2), 2,93 (6H, s, 3-CH3 a 4-CH3) ppm. m/z (%) 384(17, M+), 260(13), 59(100). vmax (KBr kotúč)/cm_1 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.19 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.09 (1H, d, J = 7) 5 Hz, 9-H), 7.89 (1H, s, 10-H), 7.32 7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J = 7.5, 5.5, 3 Hz, 8-H), 4.69 (2H, t, J = 5.5 Hz, OCH 2 ), 3.69 (2H, t, J = 5.5) Hz, SO 2 CH 2 ), 3.12 (3H, s, SO 2 CH 2 ), 2.93 (6H, s, 3-CH 3 and 4-CH 3 ) ppm. m / z (%) 384 (17, M < + > ), 260 (13), 59 (100). v max (KBr Disc) / cm _1

3387, 1661, 1234.3387, 1661, 1234.

k) Spôsob výroby terc.-butyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátú)k) Process for the preparation of tert-butyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0,86 mmol kyseliny pyrolo[3,2-b]-karbazol-2-karboxylovej a 0,91 mmol (1,05 ekvivalentu) trifenylfosfínu sa rozpustí v čerstvo destilovanom tetrahydrofuráne pod dusíkovou atmosférou. Injekčnou striekačkou sa zavedie 2,12 mmol (2,5 ekvivalentu) terc.-butanolu a počas 10 minút sa nakoniec prikvapne 0,95 mmol (1,1 ekvivalentu) dietylazodikarboxylátu. Výsledná suspenzia sa mieša pri teplote miestnosti počas 2 hodín a po tejto dobe chromatografia na tenkej vrstve ukáže na úplné spotrebovanie východzej kyseliny. Zlúčenina pomenovaná v nadpise sa získa zo surovej reakčnej zmesi v niekoľkých stupňoch a to stĺpcovou chromatografiou na oxide kremičitom, pri eluovaní zmesou 20 % éteru a 80 % petroléteru a potom zmesou 50 % éteru a 50 % petroléteru, stĺpcovou chromatografiu na oxyde kremičitom, pri eluovaní zmesi 25 % éteru a 75 % petroléteru a potom 40 % éteru % petroléteru a nakoniec rekryštalizáciou z dichlórmetánu. Získa sa žltý prášok s hmotnosťou 0,030 g, ktorý má teplotu topenia 187 až 189 °C (rozklad). Výťažok zodpovedá 10 % teórie.0.86 mmol of pyrrolo [3,2-b] carbazole-2-carboxylic acid and 0.91 mmol (1.05 equivalent) of triphenylphosphine are dissolved in freshly distilled tetrahydrofuran under nitrogen. Tert-butanol (2.12 mmol, 2.5 equivalents) was introduced via syringe and 0.95 mmol (1.1 equivalents) of diethyl azodicarboxylate was finally added dropwise over 10 minutes. The resulting suspension was stirred at room temperature for 2 hours, after which time thin layer chromatography indicated complete consumption of the starting acid. The title compound was obtained from the crude reaction mixture in several steps by column chromatography on silica eluting with 20% ether and 80% petroleum ether followed by a mixture of 50% ether and 50% petroleum ether, column chromatography on silica, eluting with silica. of a mixture of 25% ether and 75% petroleum ether and then 40% ether% petroleum ether and finally recrystallization from dichloromethane. A yellow powder of 0.030 g is obtained having a melting point of 187-189 ° C (decomposition). The yield corresponds to 10% of theory.

Analýza pre C2iH22N2°2 ' °/15 ch2C’í2: nájdené: 73,24 % C, 6,53 % H, 7,93 % N, vypočítané: 73,18 % C, 6,47 % H, 8,07 % N.Analysis for C 22 H 2 R 2 N ° 2 '° / 15 CH 2 C' 2 s: Found: 73.24% C, 6.53% H 7.93% N Found: 73.18% C, 6 H, 47.07; N, 8.07.

1H NMR δΗ([2H6]-DMSO): 10,95 (1H, s, 1-NH), 10,57 (1H, s, 5-NH), 8,05 (1H, d, J = 8 Hz, 9-H), 7,88 (1H, s, 10-H), 7,29 7,43 (2H, m, 6-H, 7-H), 7,05 (1H, ddd, J = 8, 6, 1 Hz, 8-H), 1 H NMR δΗ ([ 2 H 6] -DMSO): 10.95 (1H, s, 1-NH), 10.57 (1H, s, 5-NH), 8.05 (1H, d, J = 8) Hz, 9-H), 7.88 (1 H, s, 10-H), 7.29 7.43 (2 H, m, 6-H, 7-H), 7.05 (1 H, ddd, J = 8.6 (1 Hz, 8-H),

2,89 a 2,87 (2 x 3H, 2 x s, 3-CH3 a 4-CH3) a 1,59 (9H, s,2.89 and 2.87 (2 x 3H, 2 xs, 3-CH 3 and 4-CH 3 ) and 1.59 (9H, s,

C(CH3)3) ppm. m/z (%) 355(62, (M+l)+), 278(90), 233(38),C (CH 3 ) 3 ppm. m / z (%) 355 (62, (M + 1) < + > ), 278 (90), 233 (38),

126(32), 91(78) a 57(100). vmax (KBr kotúč)/cm-1 3337, 1664,126 (32), 91 (78) and 57 (100). v max (KBr roll) / cm -1 3337, 1664,

1240.1240th

Príklad 7Example 7

Spôsob výroby amidov kyseliny pyrolof3,2-b]-karbazol-2-karboxylovejA process for the preparation of pyrrolo [3,2-b] carbazole-2-carboxylic acid amides

a) Spôsob výroby 3,4-dimetyl-2-(1-imidazolkarbonyl)pyrolo[3,2-b]-karbazolua) Method for the preparation of 3,4-dimethyl-2- (1-imidazolecarbonyl) pyrrolo [3,2-b] carbazole

0,280 g (1,0 mmol) kyseliny 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovej a 0,164 g (1,0 mmol) N,N'-karbonyldiimidazolu sa rozpustí v 5 ml čerstvo destilovaného tetrahydrofuránu pod dusíkovou atmosférou. Výsledná suspenzia sa mieša pri teplote miestnosti počas 2 hodín a chromátografiou na tenkej vrstve sa overí úplné prebehnutie konverzie kyseliny na imidazolid. Tetrahydrofurán sa odparí a odparok sa rekryštalizuje z etylacetátu. Získa sa zlúčenina pomenovaná v nadpise ako žltá tuhá látka s hmotnosťou 0,125 g, ktorá má teplotu topenia 252 ’C (rozklad). Výťažok zodpovedá 38 % teórie.0.280 g (1.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and 0.164 g (1.0 mmol) of N, N'-carbonyldiimidazole are dissolved in 5 ml of freshly distilled tetrahydrofuran under a nitrogen atmosphere. The resulting suspension was stirred at room temperature for 2 hours, and complete conversion of the acid to imidazolide was verified by thin layer chromatography. The tetrahydrofuran was evaporated and the residue was recrystallized from ethyl acetate. The title compound is obtained as a yellow solid, 0.125 g, m.p. 252 DEG C. (decomposition). Yield: 38%.

Analýza pre C20H16N4O:Analysis for C 20 H 16 N 4 O:

nájdené: 73,17 % C, 4,87 % H, 16,80 % N, vypočítané: 73,15 % C, 4,91 % H, 17,06 % N.Found: C, 73.17; H, 4.87; N, 16.80. Calculated: C, 73.15; H, 4.91; N, 17.06.

1H NMR δΗ([2H6]-DMSO): 11,53 (1Η, s, 1-NH), 10,20 (1H, s, 5-NH), 8,30 (1H, s, 2'-H), 8,12 (1H, d, J = 8 Hz, 9-H), 7,94 (1H, s, 10-H), 7,79 (1H, s, 5'-H), 7,33 - 7,47 (2H, m, 6-H, 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.53 (1Η, s, 1-NH), 10.20 (1H, s, 5-NH), 8.30 (1H, s, 2'- H), 8.12 (1H, d, J = 8Hz, 9-H), 7.94 (1H, s, 10-H), 7.79 (1H, s, 5'-H), 33-7.47 (2H, m, 6-H,

7-H), 7,19 (1H, s, 3'-H), 7,09 (1H, ddd, J = 8, 6, 2 Hz, 8-H), 2,95 (3H, s, 3-CH3), 2,73 (3H, s, 4-CH3) ppm. m/z (%) 261(40). vmax (KBr kotúč)/cm_1 3427, 1699 a 1242.7-H), 7.19 (1H, s, 3'-H), 7.09 (1H, ddd, J = 8.6, 2Hz, 8-H), 2.95 (3H, s, 3 -CH 3 ), 2.73 (3H, s, 4-CH 3 ) ppm. m / z (%) 261 (40). v max (KBr Disc) / cm _1 3427, 1699 and 1242nd

b) Spôsob výroby etyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxamidu)b) Process for the preparation of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxamide)

0,278 g (1,0 mmol) kyseliny 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovej sa rozpustí v 10 ml dimetoxyetánu a získa sa žltý roztok. K tomuto roztoku sa pridá 0,260 g (2,0 mmol) diizopropyletylamínu, 0,245 g (3,0 mmol) hydrochloridu elylamínu a 0,482 g (1,5 mmol) tetrafluórborátovej soli O-benzotriazolyl-Ν,Ν,Ν',N'-tetrametylurónia (TBTU) a získa sa biela suspenzia v žltom roztoku. Reakčná zmes sa mieša pri teplote miestnosti počas 24 hodín a po tejto dobe chromatografia na tenkej vrstve ukáže, že nezostala zachovaná žiadna kyselina. Rozpúšťadlo sa odparí pri zníženom tlaku á získa sa žltohnedá tuhá látka. Tá sa podrobí stĺpcovej chromatografii na oxide kremičitom, pri eluovaní najskôr dichlórmetánom a potom zmesou 10 % etylacetátu a 90 % dichlórmetánu. Získa sa etylamidová zlúčenina ako žltá tuhá látka s hmotnosťou 0,240 g. Výťažok zodpovedá 79 % teórie. Na odstránenie stôp nečistoty sa časť látky rekryštalizuje zo zmesi dichlóretánu a petroléteru. Získa sa analyticky čistá zlúčenina, ako žltý prášok, ktorý má teplotu topenia 235 C (rozklad).0.278 g (1.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid is dissolved in 10 ml of dimethoxyethane to give a yellow solution. To this solution are added 0.260 g (2.0 mmol) of diisopropylethylamine, 0.245 g (3.0 mmol) of elylamine hydrochloride and 0.482 g (1.5 mmol) of tetrafluoroborate salt of O-benzotriazolyl-Ν, Ν, Ν ', N'- tetramethyluronium (TBTU) to give a white suspension in a yellow solution. The reaction mixture was stirred at room temperature for 24 hours, after which time thin layer chromatography showed no acid was left. The solvent was evaporated under reduced pressure to give a tan solid. This was subjected to column chromatography on silica, eluting first with dichloromethane and then with a mixture of 10% ethyl acetate and 90% dichloromethane. The ethyl amide compound is obtained as a yellow solid weighing 0.240 g. Yield: 79%. To remove traces of impurity, some of the material was recrystallized from a mixture of dichloroethane and petroleum ether. An analytically pure compound is obtained as a yellow powder having a melting point of 235 DEG C. (decomposition).

Analýza pre i Analysis for and C19H19 C 19 H 19 n3o . 0,1n 3 o. 0.1 C2H4C12: C 2 H 4 C1 2 : nájdené: found: 73,21 73.21 % C, 6,10 % C, 6.10 % H, 13,33 % H, 13.33 % N, % N, vypočítané: calculated: 73,15 73.15 % C, 6,20 % C, 6.20 % H, 13,32 % H, 13.32 % N. % N.

1H NMR δΗ([2Η6]- 1 H NMR δΗ ([ 2 Η6] - -DMSO) DMSO) 10,72 (1H 10.72 (1H , S, 1-NH), 10,57 (S, 1-NH), 10.57 (1H, s, (1H, s, 5-NH), 8,09 (1H, d, 5-NH), 8.09 (1 H, d, J = J = 8 8 Hz, 9H), Hz, 9H), 7,93 (1H, t, J 7.93 (1 H, t, J) = 5 HZ, = 5 HZ, ammidový N-H), 7,83 N-H), 7.83 (1H, (1 H, s, with, 10-H), 10-H), 7,27 - 7,41 (2H, 7.27 - 7.41 (2H, m, 6-H, m, 6-H 7-H), 7,06 (1H, d, J 7-H), 7.06 (1 H, d, J) = 8 = 8 HZ HZ , 8-H), , 8-H), 3,35 (2H, q, J = 3.35 (2 H, q, J = 7,5 Hz, 7.5 Hz, GH2CH3), 2,89 a 2,71GH 2 CH 3 ), 2.89 and 2.71 (2 x (2 x 3H 3H , 2 x s, , 2 x s, 3-CH3 a 4-CH3), 13-CH 3 and 4-CH 3 ), 1 ,18 (3H, 18 (3H,

t, J =7,5, CH2CH3) ppm. rn/z (%) 305(65, M+), 260(100). Vmax (KBr kotúč)/cm_1 3314, 1603 a 1545.t, J = 7.5, CH 2 CH 3 ) ppm. m / z (%) 305 (65, M < + > ), 260 (100). V max (KBr disc) / cm _1 3314, 1603 and 1545th

c) Spôsob výroby 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxamiduc) A process for the preparation of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxamide

0,556 g (2,0 mmol) kyseliny 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovej sa rozpustí v 20 ml dimetoxyetánu na žltý roztok. K tomuto roztoku sa pridá K 0,520 g (4,0 mmol) diizopropyletylamínu, 0,321 g (6,0 mmol) amoniumhydrochloridu ,a 0,963 g (3,0 mmol) tetrafluórborátovej soli O-benzotriazolyl-Ν,Ν,Ν',N'-tetrametylurónia (TBTU) a získa sa biela suspenzia v žltom roztoku. Reakčná zmes sa mieša pri teplote miestnosti počas 24 hodín a po tejto dobe chromátografia na tenkej vrstve ukáže, že nezostala zachovaná žiadna kyselina. Rozpúšťadlo sa odparí pri zníženom tlaku a získa sa žltohnedá tuhá látka. Tá sa podrobí stĺpcovej chromátografii na oxide kremičitom, pri gradientovom eluovaní etylacetátom a dichlórmetánom (gradient od 10 do 30 %). Získa sa amidová zlúčenina, ako žltá tuhá látka s hmotnosťou 0,350 g. Výťažok zodpovedá 63 % teórie. Na odstránenie stôp nečistoty sa časť látky rekryštalizuje zo zmesi etylacetátu a petroléteru a potom sa čistí preparatívne vysoko účinnou kvapalinovou chromátografiou (kolóna dĺžky 25 cm s vnútorným priemerom 2,12 cm, naplnená náplňou Cg Zorbax, pri gradientovom eluovaní 5 % acetonitrilu a 95 % vody až 95 % acetonitrilom vo vode, s detekciou pri vlnovej dĺžke 340 nm). Získa sa žltý prášok, ktorý má teplotu topenia 240 “C (rozklad).0.556 g (2.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid is dissolved in 20 ml of dimethoxyethane to a yellow solution. To this solution is added to 0.520 g (4.0 mmol) of diisopropylethylamine, 0.321 g (6.0 mmol) of ammonium hydrochloride, and 0.963 g (3.0 mmol) of tetrafluoroborate salt of O-benzotriazolyl-Ν, Ν, Ν ', N' -tetramethyluronium (TBTU) to give a white suspension in a yellow solution. The reaction mixture was stirred at room temperature for 24 hours, after which time thin layer chromatography showed that no acid was left. The solvent was evaporated under reduced pressure to give a tan solid. This was subjected to column chromatography on silica, eluting with a gradient of ethyl acetate and dichloromethane (gradient from 10 to 30%). The amide compound is obtained as a yellow solid weighing 0.350 g. Yield: 63%. To remove traces of the impurity, a portion of the substance is recrystallized from ethyl acetate / petroleum ether and then purified by preparative high performance liquid chromatography (25 cm long column with 2.12 cm internal diameter, packed with Cg Zorbax), eluting with 5% acetonitrile and 95% water up to 95% acetonitrile in water, with detection at 340 nm). A yellow powder is obtained having a melting point of 240 DEG C. (decomposition).

XH NMR δΗ([2H6]-DMSO): 10,82 (1H, S, 1-NH), 10,54 (1H, s, 5-NH), 8,08 (1H, d, J = 7,5 Hz, 9-H), 7,84 (1H, s, 10-H), 7,29 7,43 (4H, m, 6-H, 7-H, NH2), 7,07 (1H, ddd, J = 8, 5,5, 2 Hz, X δΗ NMR ([2 H 6] -DMSO): 10.82 (1H, s, 1-NH), 10.54 (1H, s, 5-NH), 8.08 (1H, d, J = 7 5 Hz, 9-H), 7.84 (1H, s, 10-H), 7.29 7.43 (4H, m, 6-H, 7-H, NH 2 ), 7.07 (1H , ddd, J = 8, 5.5, 2Hz,

8-H), 2,89 a 2,85 (2 x 3H, 2 X S, 3-CH3 a 4-CH3) ppm. m/Z (%) 277(62, M+), 260(100), 232(44). vmax (KBr kotúč)/cm-1 3317,8-H), 2.89 and 2.85 (2 x 3H, 2 X, 3-CH 3 and 4-CH 3 ) ppm. m / z (%) 277 (62, M < + > ), 260 (100), 232 (44). v max (KBr roll) / cm -1 3317,

1628, 1595, (nájdené: M+, 277,1205 pre ci7Hi5N3° vypočítané1628, 1595, (found: M + , 277.1205 for c 17 H 15 N 3 ° calculated

277,1215).277.1215).

d) Spôsob výroby fenyl 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxamidud) Process for the preparation of phenyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxamide

0,278 g (1,0 mmol) kyseliny 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovej sa rozpustí v 10 ml dimetoxyetánu a získa sa žltý roztok. K tomuto roztoku sa pridá 0,130 g (1,0 mmol) diizopropyletylamínu, 0,190 g (2,0 mmol anilínu a 0,482 g (1,5 mmol) tetrafluórborátovej soli 0-benzo- triazolyl-Ν,Ν,Ν', N'-tetrametylurónia (TBTU) a získa sa biela suspenzia v žltom roztoku. Reakčná zmes sa mieša pri teplote miestnosti počas 42 hodín a po tejto dobe chromátografia na tenkej vrstve ukáže, že nezostala zachovaná žiadna kyselina. Rozpúšťadlo sa odparí pri zníženom tlaku a získa sa žltá tuhá látka, ktorá sa rozpustí v etylacetáte a výsledný roztok sa premyje vodou. Organická vrstva sa vysuší síranom horečnatým, odparí a podrobí stĺpcovej chromatografii na oxide kremičitom, pri graduentovom eluovaní etylacetátom a petroléterom (gradient od 5 do 100 %), s nasledujúcou rekryštalizáciou z acetónu. Získa sa fenylamidová zlúčenina, ako žltý prášok s hmotnosťou 0,10 g, ktorý má teplotu topenia 260 ’C (rozklad). Výťažok zodpovedá 30 % teórie.0.278 g (1.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid is dissolved in 10 ml of dimethoxyethane to give a yellow solution. To this solution is added 0.130 g (1.0 mmol) of diisopropylethylamine, 0.190 g (2.0 mmol of aniline and 0.482 g (1.5 mmol) of tetrafluoroborate salt of O-benzotriazolyl-Ν, Ν, Ν ', N'-). tetramethyluronium (TBTU) to give a white suspension in a yellow solution The reaction mixture was stirred at room temperature for 42 hours, after which time thin layer chromatography showed no acid was left, the solvent was evaporated under reduced pressure to give a yellow solid The organic layer was dried over magnesium sulfate, evaporated, and subjected to column chromatography on silica eluting with ethyl acetate and petroleum ether (gradient from 5 to 100%) followed by recrystallization from acetone. The title compound was obtained as a yellow powder (0.10 g), m.p. 260 DEG C. (decomposition), yielding 30% of theory.

Analýza pre C23HigN3O:Analysis for C 23 H ig N 3 O:

nájdené: 77,79 % C, 5,26 % H, 11,64 % N, vypočítané: 78,16 % C, 5,42 % H, 11,89 % N.found: C 77.79, H 5.26, N 11.64. Calculated: C 78.16, H 5.42, N. 11.89.

1H NMR δΗ([2H6]-DMSO): 11,10 (1H, s, 1-NH), 10,59 (1H, s, 5-NH), 9,96 (1H, s, amidový N-H), 8,10 (1H, d, J = 7,5 Hz, 9-H), 7,89 (1H, s, 10-H), 7,79 (2H, d, J = 9 Hz, 2'-H, 6'-H), 7,29 7,45 (4H, m, 6-H, 7-H, 3'-H, 5'-H), 7,00 - 7,14 (2H, m, 8-H, 4'-H), 2,93 a 2,88 (2 x 3H, 2 x s, 3-CH3) ppm. m/z (%) 353(46, M+), 260(100). vmax (KBr kotúč)/cm-1 3310, 1614, 1595 a 1317. 1 H NMR δΗ ([ 2 H 6] -DMSO): 11.10 (1H, s, 1-NH), 10.59 (1H, s, 5-NH), 9.96 (1H, s, amide NH) 8.10 (1H, d, J = 7.5Hz, 9-H), 7.89 (1H, s, 10-H), 7.79 (2H, d, J = 9Hz, 2'- H, 6'-H), 7.29 7.45 (4H, m, 6-H, 7-H, 3'-H, 5'-H), 7.00-7.14 (2H, m, 8-H, 4'-H), 2.93 and 2.88 (2 x 3H, 2 xs, 3-CH 3 ) ppm. m / z (%) 353 (46, M < + > ), 260 (100). v max (KBr roll) / cm -1 3310, 1614, 1595 and 1317.

e) Spôsob výroby 3,4-dimetyl-2-(hydrazínokarbonyl)pyrolo[3/2-b]-karbazolue) Method for preparing 3,4-dimethyl-2- (hydrazinocarbonyl) pyrrolo [3/2-b] carbazole

500 mg etyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylátu) a 5 ml 95% hydrazínu sa mieša a zahrieva na teplotu 120 °C počas 6 hodín v Readiho trubici. Zmes sa nechá stáť cez noc, ochladí ladom a filtruje. Výsledná žltá tuhá látka sa starostlivo premyje vodou a vysuší. Získa sa 350 mg zlúčeniny pomenovanej v nadpise. Teplota topenia tejto zlúčeniny nie je ostrá, ale dochádza k rozkladu pri 285 ’C. Výťažok zodpovedá 73 % teórie.500 mg of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and 5 ml of 95% hydrazine are stirred and heated to 120 ° C for 6 hours in a Readi tube. The mixture was allowed to stand overnight, ice-cooled and filtered. The resulting yellow solid was washed thoroughly with water and dried. This gives 350 mg of the title compound. The melting point of this compound is not sharp, but decomposes at 285 ° C. Yield: 73%.

Analýza pre ^17^16^4θ * θ,Χ ^2θ nájdené: 69,19 % C, 5,57 % H, 19,38 % N, vypočítané: 69,42 % C, 5,55 % H, 19,05 % N.Analysis for C 17 ^ 16 ^ * 4θ θ, 2θ Χ ^ Found: 69.19% C, 5.57% H, 19.38% N Found: 69.42% C, 5.55% H, 19, 05% N.

1H NMR SH([2H6]-DMSO): 10,80 (1H, s, vymenitelné, NH), 1 H NMR SH ([ 2 H 6] -DMSO): 10.80 (1H, s, exchangeable, NH),

10,55 (1H, s, vymeniteľné, NH), 9,20 (1H, s, vymeniteľné, NH),10.55 (1H, s, exchangeable, NH), 9.20 (1H, s, exchangeable, NH),

8,06 (1H, d, J = 7,5 Hz, 9-H), 7,81 (1H, s, 10-H), 7,42 - 7,28 (2H, m, 6-H a 7-H), 7,12 - 7,01 (1H, m, 8-H), 4,5 (2H, široký singlet, vymeniteľné, NH2) a 2,4 a 2,3 (2 x s, 4-CH3 a 3-CH3) ppm. m/z 293 [(M+l)+, FAB].8.06 (1H, d, J = 7.5Hz, 9-H), 7.81 (1H, s, 10-H), 7.42-7.28 (2H, m, 6-H and 7) -H), 7.12-7.01 (1H, m, 8-H), 4.5 (2H, broad singlet, exchangeable, NH 2 ) and 2.4 and 2.3 (2 xs, 4-CH) 3 and 3-CH3) ppm. m / z 293 [(M + 1) < + >, FAB].

Príklad 8Example 8

Spôsob výroby 2-acetyl-3,4-dimetylpyrolo[3,2-b]-karbazoluProcess for preparing 2-acetyl-3,4-dimethylpyrrolo [3,2-b] carbazole

Stupeň 1Stage 1

2,4-Diacetyl-3,5-dimetylpyrol sa vyrobí z acetylacetónu a kyseliny hydroxylamín-O-sulfónovej podľa spôsobu, ktorý opísal Y. Tamura, S. Kato a M. Ikeda (Chem. & Ind., 767 /1971/).2,4-Diacetyl-3,5-dimethylpyrrole is prepared from acetylacetone and hydroxylamine-O-sulfonic acid according to the method described by Y. Tamura, S. Kato and M. Ikeda (Chem. & Ind., 767 (1971)) .

Stupeň 2Stage 2

Spôsob výroby 2-acetoxymetyl-3,5-diacetyl-4-metylpyroluProcess for the preparation of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole

K miešanej zmesi 1,0 g 2,4-diacetyl-3,5-dimetylpyrolu, 35 ml dichlórmetánu a 7,73 g uhličitanu draselného pri teplote 0 až 5 “C sa pridá roztok 0,79 g sulfurylchloridu v 15 ml dichlórmetánu. Teplota zmesi sa udržuje na 0,5 ’C počas pridávania vonkajším chladením a potom sa zmes mieša pri tejto teplote až sa dokáže, že prebehla kvantitatívne (podľa chromatografie na tenkej vrstve, počas približne 2 hodín). Zmes sa potom filtruje a odparením sa získa surový 2-chlórmetyl-3,5-diacetyl-4-metyl65 pyrrol. Táto látka sa rozpustí v 10 ml kyseliny octovej, pridá sa 1,83 g octanu sodného a potom ďalších 10 ml kyseliny octovej. Zmes sa mieša cez noc pri teplote miestnosti, odparí pri zníženom tlaku a odparok sa mieša s ľadovou vodou počas 2 hodín. Tuhá látka sa zachytí filtráciou a filtrát sa dvakrát extrahuje etylacetátom. Extrakty sa vysušia síranom horečnatým, odparia a odparok sa spojí s tuhou látkou uvedenou vyššie. Tak sa získa surová látka. Chromatografiou na oxide kremičitom, pri eluovaní zmesou etylacetátu a hexánu v pomere 1:1, sa získa 0,075 g čistej zlúčeniny ako belavej tuhej látky, ktorá má teplotu topenia 112,5 až 114,5 °C.To a stirred mixture of 1.0 g 2,4-diacetyl-3,5-dimethylpyrrole, 35 ml dichloromethane and 7.73 g potassium carbonate at 0-5 ° C was added a solution of 0.79 g sulfuryl chloride in 15 ml dichloromethane. The temperature of the mixture is maintained at 0.5 ° C during the addition by external cooling, and then the mixture is stirred at this temperature until it is shown to have been quantitative (by thin layer chromatography, for approximately 2 hours). The mixture was then filtered and evaporated to give crude 2-chloromethyl-3,5-diacetyl-4-methyl-65-pyrrole. This material was dissolved in 10 mL of acetic acid, 1.83 g of sodium acetate was added, followed by an additional 10 mL of acetic acid. The mixture was stirred at room temperature overnight, evaporated under reduced pressure and the residue was stirred with ice water for 2 hours. The solid was collected by filtration and the filtrate was extracted twice with ethyl acetate. The extracts were dried (MgSO4), evaporated and the residue combined with the solid above. This gives the crude material. Silica chromatography, eluting with 1: 1 ethyl acetate: hexane gave 0.075 g of pure compound as an off-white solid, mp 112.5-114.5 ° C.

m/z 238 (M++l, FAB). 1H NMR 5H(CDC13): 2,16 (3H, s, OCOCH3), 2,50 (3H, s, CH3), 2,53 (3H, s, CH3), 2,62 (3H, s, CH3), 5,38 (2H, s, OCH2) ppm.m / z 238 (M @ + +1, FAB). 1 H NMR δ H (CDCl 3 ): 2.16 (3H, s, OCOCH 3 ), 2.50 (3H, s, CH 3 ), 2.53 (3H, s, CH 3 ), 2.62 ( 3H, s, CH 3 ), 5.38 (2H, s, OCH 2 ) ppm.

Stupeň 3Stage 3

K roztoku 0,200 g 2-acetoxymetyl-3,5-diacetyl-4-metylpyrolu a 0,098 g indolu v 90 ml dichlóretánu sa pridá 0,30 g montmorilloňitovej hlinky K 10. Zmes sa mieša a varí pod spätným chladičom počas 80 hodín. Po ochladení sa hlinka odfiltruje a filtrát sa odparí na objem približne 20 ml pri zníženom tlaku. Surová látka sa odfiltruje a potom chromatografuje na oxide kremičitom. Eluovaním zmesou chloroformu a metanolu v pomere 60:1 sa získa 0,08 g zlúčeniny pomenovanej v nadpise ako žltej tuhej látky, ktorá má teplotu topenia 258 až 260 °C.To a solution of 0.200 g of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole and 0.098 g of indole in 90 ml of dichloroethane is added 0.30 g of Montmorillonite clay K10. The mixture is stirred and refluxed for 80 hours. After cooling, the clay was filtered off and the filtrate was evaporated to a volume of approximately 20 ml under reduced pressure. The crude material was filtered off and then chromatographed on silica. Elution with 60: 1 chloroform-methanol gave 0.08 g of the title compound as a yellow solid, mp 258-260 ° C.

m/z (EI) 276 (M+). 1H NMR δΗ([2Hg]-DMSO): 2,58 (3H, s,m / z (EI) 276 (M < + > ). 1 H NMR δΗ ([ 2 Hg] -DMSO): 2.58 (3H, s,

COCH3), 2,88 (3H, s, CH3), 2,92 (3H, s, CH3), 7,05 (1H, m, 8-H), 7,38 (2H, m, 6-H, 7-H), 7,85 (1H, s, 10-H), 8,08 (1H, J = 8 Hz,COCH 3 ), 2.88 (3H, s, CH 3 ), 2.92 (3H, s, CH 3 ), 7.05 (1H, m, 8-H), 7.38 (2H, m, 6 -H, 7-H), 7.85 (1H, s, 10-H), 8.08 (1H, J = 8Hz,

9-H), 10,6 (1H, S, NH), 11,17 (1H, s, NH) ppm.9-H), 10.6 (1H, s, NH), 11.17 (1H, s, NH) ppm.

Analýza pre ci8Hi6N2° ' 0,14 EtOAc: nájdené: 77,0 % C, 5,74 % H, 9,76 % N, vypočítané: 77,2 % C, 5,98 % H, 9,70 % N.Analysis for C H i6 i8 N ° 2 '0.14 EtOAc: Found: 77.0% C, 5.74% H, 9.76% N. Found: 77.2% C, 5.98% H, 9 , 70% N.

Príklad 9Example 9

Spôsob výroby etyl-(1,5-dihydroindeno[ 2,1-f]indol-2-karboxylátu)Process for the preparation of ethyl 1,5-dihydroindeno [2,1-f] indole-2-carboxylate

Stupeň 1Stage 1

Spôsob výroby etyl-(2-azido-3-fluoren-2-ylakrylátu)Process for the preparation of ethyl (2-azido-3-fluoren-2-ylacrylate)

1,7 ekvivalentu sodíka sa vnesie pri miešaní do absolútneho etanolu pod dusíkovou atmosférou pri teplote miestnosti. Keď dôjde k úplnému rozpusteniu sodíka, reakčná zmes sa ochladí na -10 °C a k roztoku sa prikvapká 1 ekvivalent fluóren-2-karboxyldehydu a 3 ekvivalenty etyl-azidoacetátu, ktoré sú spolu rozpustené v minimálnom množstve tetrahydrofuránu. Zmes sa mieša pri teplote -10 C počas 20 hodín a potom sa reakcia rýchle preruší pridaním vody a dichlórmetánu. Spojené organické extrakty sa vysušia síranom horečnatým a odparia pri zníženom tlaku. Velmi rýchla chromatografia poskytne požadovanú zlúčeninu. Výťažok zodpovedá 37 % teórie.1.7 equivalents of sodium are introduced with stirring into absolute ethanol under a nitrogen atmosphere at room temperature. When sodium is completely dissolved, the reaction mixture is cooled to -10 ° C and 1 equivalent of fluorene-2-carboxyldehyde and 3 equivalents of ethyl azidoacetate are added dropwise and dissolved in a minimum amount of tetrahydrofuran. The mixture was stirred at -10 ° C for 20 hours and then quenched by the addition of water and dichloromethane. The combined organic extracts were dried (MgSO 4) and evaporated under reduced pressure. Flash chromatography gave the title compound. The yield corresponds to 37% of theory.

vmax (CHCl3)/cm_1 2120 a 1765. max (CHCl 3) / cm _1 2120 and 1765th

Stupeň 2Stage 2

Etyl-(2-azido-3-fluorén-2-ylakrylát) suspendovaný v suchom toluéne sa varí pod spätným chladičom počas 1 hodiny a výsledný • roztok sa potom odparí dosucha pri zníženom tlaku. Výsledná zmes etyl-(1,5-dihydroindino[2,1-f]indol-2-karboxylátu) a etyl-(1,10- * -dihydroindino[l,2-g]indol-2-karboxylátu sa kryštalizuje z etanolu. Tak sa odstráni väčšia časť [1,2-g]izoméru a získa saEthyl (2-azido-3-fluoren-2-ylacrylate) suspended in dry toluene was refluxed for 1 hour and the resulting solution was then evaporated to dryness under reduced pressure. The resulting mixture of ethyl (1,5-dihydroindino [2,1-f] indole-2-carboxylate) and ethyl (1,10- * dihydroindino [1,2-g] indole-2-carboxylate) is crystallized from ethanol This removes most of the [1,2-g] isomer and recovered

I zlúčenina pomenovaná v nadpise, ktorá obsahuje približne' 30 % [1,2-g]izoméru v matečných lúhoch, ktoré sa odparia dosucha.I title compound which contains approximately 30% of the [1,2-g] isomer in mother liquors which evaporated to dryness.

XH NMR Sh(CDC13): 9,11 (1H, široký singlet, 1-NH), 7,82 7,76 (3H, m), 7,56 - 7,52 (1H, m), 7,37 (H, dd, J = 1 a 7 Hz), 7,34 - 7,28 (1H, m), 7,25 (1H, dd, J = 1 a 2 Hz), 4,45 (2H, q, OCH2CH3), 3,97 (2H, s, CH2) a 1,46 (3H, t, OCH2CH3) ppm. X H NMR H (CDC1 3): 9.11 (1H, br s, 1-NH), 7.82 7.76 (3H, m), 7.56 to 7.52 (1 H, m), 7 37 (H, dd, J = 1 and 7 Hz), 7.34-7.28 (1H, m), 7.25 (1H, dd, J = 1 and 2 Hz), 4.45 (2H, q, OCH 2 CH 3 ), 3.97 (2H, s, CH 2 ) and 1.46 (3H, t, OCH 2 CH 3 ) ppm.

- 67 Príklad 1067 Example 10

Účinok zlúčenín podlá tohoto vynálezu na detransformačný test (test stabilizácie) za použitia bunkových línií HT1080scc2 a HT10801C.Effect of Compounds of the Invention on Detection Transformation (Stabilization Assay) Using HT1080scc2 and HT10801C Cell Lines.

Bunkové línie a podmienky kultivácieCell lines and culture conditions

Transformovaná a revertantná sublínia HT1080, rovnako ako HT1080scc2 a HT10801C sa získajú z Inštitúte of Cancer Research, Chester Beatty Laboratories, Fulham Road, Londýn. Tieto línie sa udržujú zvyčajným spôsobom v Eagleovom prostredí modifikovanom podlá Dulbecco (DMEM), doplnenom 10 % fetálnym telacím sérom (FCS) a 1% roztokom penicilínu alebo streptomycínu s obsahom 10 000 jednotiek na ml. Všetky reakčné činidlá sú získané od firmy Gibco Ltd.The transformed and reverting sub-lines HT1080 as well as HT1080scc2 and HT10801C are obtained from the Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London. These lines are maintained as usual in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 1% penicillin or streptomycin solution containing 10,000 units per ml. All reagents are obtained from Gibco Ltd.

Bunky sa inkubujú v nádobách z plastickej hmoty akosti pre tkaninové kultúry pri teplote 37 °C, vo vzduchu obsahujúcom 5 % oxidu uhličitého.The cells are incubated in tissue culture plastic flasks at 37 ° C, in air containing 5% carbon dioxide.

Test aktivity zlúčenínCompound activity assay

Test proliferácie buniek alebo cytotoxicity pre bunky sa uskutočňuje na mikrotitračnej platni s 96 jamkami akosti pre tkaninové kultúry (Costar). Bunky v logaritmickom raste sa pridajú do platní pri koncentrácii 1x103 buniek na jamku v deň 0 a v deň 1 sa potom pridajú sériovo zriedené zlúčeniny. Platne sa potom inkubujú pri teplote 37 ’C vo vzduchu s obsahom 5 % oxidu uhličitého počas ďalších 4 dní.The cell proliferation or cell cytotoxicity assay is performed in a 96-well tissue culture microtiter plate (Costar). Cells in logarithmic growth are added to the plates at a concentration of 1x10 3 cells per well on day 0 and on day 1 serially diluted compounds are then added. Plates are then incubated at 37 ° C in air containing 5% carbon dioxide for an additional 4 days.

Pre stanovenie kvantity rastu buniek sa použije spôsob farbenia biomasy metylénovou modrou. Hodnoty dosiahnuté pri teste sa odpočítajú na vyhodnocovacom zariadení Multiscan plate pri vlnovej dĺžke 620 nm. Morfológia buniek sa preskúma mikroskopicky pri fázovom kontraste bezprostredne pred fixáciou a odfarbením metylénovou modrou a po mikroskopickom stanovení vo zvyčajnom svetle. Hodnoty IC50 pre aktívne zlúčeniny sa získajú za použitia počítačového programu GS1 a tiež sa graficky vynesú smernice dávka - odozva.A method for staining biomass with methylene blue is used to determine the amount of cell growth. The values obtained in the test are read on a Multiscan plate at 620 nm. Cell morphology is examined microscopically at phase contrast immediately prior to fixation and staining with methylene blue and after microscopic determination in normal light. IC 50 values for the active compounds are obtained using the GS1 computer program and also plot the dose-response slopes graphically.

Zlúčeniny sa testujú na aktivitu pri teste tvorby kolónií, pričom použité spôsoby sú identické so spôsobmi opísanými skôr, s tým rozdielom, že sa sériovo riedená zlúčenina pridá k agaru kašovitého charakteru, keď test sa pripraví na začatie a doplňuje sa pri rovnakej koncentrácii v deň 7. Výsledky testu sa odpočítajú v deň 14.The compounds are tested for activity in the colony formation assay, the methods used being identical to those described above, except that the serially diluted compound is added to the slurry agar when the assay is ready to start and replenished at the same concentration on day 7. The test results are subtracted on day 14.

VýsledkyThe results

Komparaívny rast a morfológia HT1080scc2 a HT10801 cComparative growth and morphology of HT1080scc2 and HT10801 c

Rýchlosť rastu s ohladom na počet buniek je podobná pri obidvoch líniách do dňa 4, ale potom bunky HT1080scc2 sa trvalo delia na bohato nasýtené hustoty približne dvakrát až trikrát vyššej ako u HT10801C do dňa 5.The growth rate with respect to cell number is similar for both lines up to day 4, but then HT1080scc2 cells are persistently divided into richly saturated densities approximately two to three times higher than for HT10801C by day 5.

Fenotypové rozdiely medzi oboma líniami sú jasne zrejmé. HT10801C bunky sa prejavia v mnohom plochejšej morfológii ako transformované bunky a iba niekoľko mitotických buniek sa ukazuje v splývavých plochách kultúry. Bunky HT1080scc2 však pokračujú v delení s radom mitotických buniek viditeľných po súbehu.The phenotypic differences between the two lines are clearly evident. HT10801C cells display much flatter morphology than transformed cells, and only a few mitotic cells show up in confluent areas of culture. However, HT1080scc2 cells continue to divide with a number of mitotic cells visible after overlap.

Pri raste za podmienok nezávislých na zachytení v mäkkom agare HT1080scc2 produkuje niekolko velkých kolónií, zatiaľ čo bunky HT10801C nie sú úspešné pri produkcii akýchkoľvek kolónií s priemerom väčším ako 0,1 mm.When growing under conditions independent of capture in soft agar, HT1080scc2 produces several large colonies, while HT10801C cells fail to produce any colonies larger than 0.1 mm in diameter.

Účinky vybraných zlúčenínEffects of selected compounds

Rad zlúčenín podľa tohoto vynálezu sa hodnotil na účinok proti bunkovým líniám.A number of compounds of the invention were evaluated for activity against cell lines.

Zlúčeniny podľa tohoto vynálezu prejavovali nízku toxicitu s hodnotami IC50 v rozmedzí do 50 do 100 μιηοΐ.The compounds of the invention exhibited low toxicity with IC 50 values ranging from 50 to 100 μιηοΐ.

Ďalej sú uvedené výsledky detransformačného testu zlúčenín podľa tohoto vynálezu na bunky.The results of a cell-based detransformation assay of the compounds of the invention are shown below.

b b Zlúčenina compound Detransformácia (μιηοΐ) Detransformation (μιηοΐ) Príklad 3 Example 3 0,04 0.04 * * Príklad 4 (a) Example 4 (a) 0,04 0.04 « « Príklad 4 (b) Example 4 (b) 0,04 0.04 Príklad 4 (f) Example 4 (f) 0,8 0.8 ŕ à Príklad 4 (e) Example 4 (e) 0,8 0.8 Príklad 4 (h) Example 4 (h) 25 25 Príklad 4 (g) Example 4 (g) 25 25

Zlúčeniny sú účinné pri dosiahnutí detransformácie pri úrovniach významne nižších, ako zodpovedá ich úrovniam toxicity.The compounds are effective at achieving detransformation at levels significantly lower than their levels of toxicity.

Rovnaké zlúčeniny sa tiež testovali testami, pri ktorých sa použili rakovinové bunky ľudského prsníka MCF7, bunky epidermoidného karcinónu A431 a bunky melanómu A285. Vo všetkých prípadoch boli zlúčeniny účinné v rozmedzí od 1 do 5 μπιοί.The same compounds were also tested in human breast cancer cells MCF7, A431 epidermoid carcinoma cells and A285 melanoma cells. In all cases, the compounds were active in the range of 1 to 5 μπιοί.

Claims (10)

1. Zlúčenina všeobecného vzorca I (I) v ktorom znamená skupinu vzorca aleboA compound of formula I (I) wherein is a group of formula or X znamená atóm kyslíka, atóm síry, skupinu vzorca SO, SO2, CH2, CO alebo NR7,X is O, S, SO, SO 2 , CH 2 , CO or NR 7 7 i , L7 i, L R znamena atóm vodíka, alkylovú, aralkylovú, arylovú, alkenylovú, acylovú, alkinylovú, sulfonylovú alebo substituovanú sulfonylovú skupinu, znamená atóm kyslíka, atóm síry, skupinu vzorca SO, SO2, CH2, CO alebo NR7,R is hydrogen, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulfonyl or substituted sulfonyl, is oxygen, sulfur, SO, SO 2 , CH 2 , CO or NR 7 , - 71 znamená skupinu vzorca conh2, CONHNR10R11, COO(CH2)nNR10R11,- 71 represents a group of the formula conh 2 , CONHNR 10 R 11 , COO (CH 2 ) n NR 10 R 11 , COR8, COOR8, CHO, CH2OH, CH2OR9,COR 8 , COOR 8 , CHO, CH 2 OH, CH 2 OR 9 , CONHR10, CONR10Ri:L aleboCONHR 10 , CONR 10 R 1: L or R8 znamená atóm vodíka, alkylovú, arylovú, substituovanú arylovú alebo aralkylovú skupinu,R 8 represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group, R9 je acylová alebo substituovaná acylová skupinaR 9 is an acyl or substituted acyl group R10 a R11 znamenajú nezávisle na sebe atóm vodíka, alkylovú alebo arylovú skupinu, n znamená číslo 1 až 4 atómy uhlíka,R 10 and R 11 are each independently hydrogen, alkyl or aryl, n is 1 to 4 carbon atoms, R2 znamená atóm vodíka,.skupinu vzorca COOR8, alkylovú, arylovú alebo substituovanú arylovú skupinu alebo skupinu vzorca ch2ch2co2r12,R 2 is H hydroxyalkyl, hydroxybenzyl the formula COOR 8, an alkyl, aryl or substituted aryl group, or a group of formula CH2 CH2 CO2 R12, R12 znamená alkylovú alebo arylovú skupinu,R 12 represents an alkyl or aryl group, R3 a R4 znamenajú nézávisle na sebe atóm vodíka, hydroxyskupinu, alkylovú skupinu, halogénalkylovú skupinu, alkoxyskupinu, atóm halogénu, kyanoskupinu, nitroskupinu, amínoskupinu, alkylamínoskupinu, dialkylamínoskupinu, substituovanú alkylovú skupinu, karboxyskupinu alebo skupinu vzorca co2r12,R 3 and R 4 independently of one another are hydrogen, hydroxyl, alkyl, haloalkyl, alkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxy or a group of CO 2 R 12, R5 znamená atóm vodíka, alkylovú skupinu, substituovanú alkylovú alkylovú skupinu, aralkylovú skupinu, nitroskupinu, amínoskupinu, atóm halogénu, kyanoskupinu, skupinu vzorca CHO alebo' COOR8,R 5 represents a hydrogen atom, an alkyl group, a substituted alkyl alkyl group, an aralkyl group, a nitro group, an amino group, a halogen atom, a cyano group, CHO or COOR 8 , R6 znamená atóm vodíka, arylovú, alkylovú, aralkylovú skupinu, nitroskupinu, atóm halogénu, skupinu vzorca CHO alebo COR13 aR 6 is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or a group of formula COR 13 and R13 znamená alkylovú alebo arylovú skupinu s podmienkou, že (i) keď R2, R3, R4, R5 a R6 znamenajú vždy atóm vodíka a A predstavuje skupinu vzorca kde Y ' znamená skupinu vzorca NH a X znamená atóm kyslíka * 1 alebo atóm síry, potom R neznamená skupinu vzorca CO2H alebo CO2Et, (ii) keď R2, R3, R4, R5 a R6 znamenajú vždy atóm vodíka a A predstavuje skupinu vzorca kde Y znamená skupinu vzorca NH a X znamená atóm kyslíka, Ί # potom R neznamená skupinu vzorca CHO a (iii) Y nie je atóm kyslíka, pokiaľ X predstavuje atóm kyslíka, a ich soli a ich fyziologicky funkčné deriváty.R 13 represents an alkyl or aryl group with the proviso that (i) when R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom and A represents a group of formula wherein Y 'represents a group of formula NH and X represents an oxygen atom * 1 or a sulfur atom, then R is not a group of formula CO 2 H or CO 2 Et, (ii) when R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom and A represents a group of the formula of formula NH and X is oxygen, Ί # then R is not CHO and (iii) Y is not oxygen when X is oxygen, and salts and physiologically functional derivatives thereof. 2. Zlúčenina podľa nároku 1, kde 1 ' 7A compound according to claim 1, wherein 1 '7 X znamena atóm kyslíka, atóm síry alebo skupinu vzorca NR ,X is O, S or NR; R7 znamená atóm vodíka, alkylovú, sulfonylovú alebo toluénsulfonylovú skupinu,R 7 represents a hydrogen atom, an alkyl, sulfonyl or toluenesulfonyl group, Y znamená skupinu vzorca NR7,Y is NR 7 , R1 znamená skupinu vzorca COR8, COOR8, CH2OR9, CONH2, CNHNR10R11, CONHR10, CONR10R1:L alebo COO(CH2 )nNR10Ri:L R 1 is COR 8 , COOR 8 , CH 2 OR 9 , CONH 2, CNHNR 10 R 11 , CONHR 10 , CONR 10 R 1: L or COO (CH 2 ) n NR 10 R 11 : L R8 znamená atóm vodíka, alkylovú, arylovú, substituovanú arylovú alebo aralkylovú skupinu,R 8 represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group, R9 znamená acylovú alebo substituovanú acylovú skupina,R 9 represents an acyl or substituted acyl group, R10 a R11 znamenajú nezávisle na sebe atóm vodíka, alkylovú * alebo arylovú skupinu, n znamená 1 až 4 atómy uhlíkaR 10 and R 11 are each independently hydrogen, alkyl * or aryl, n is 1 to 4 carbon atoms Rz znamená skupinu vzorca COOR°, alkylovú skupinu alebo skupinu vzorca CH2CH2CO2R12,R 2 represents a group of formula COOR °, an alkyl group or a group of formula CH 2 CH 2 CO 2 R 12 , R12 znamená alkylovú alebo arylovú skupinu,R 12 represents an alkyl or aryl group, R3 a R4 znamenajú nezávisle na sebe atóm vodíka, hydroxyskupinu, alkylovú skupinu, alkoxyskupinu, atóm halogénu, kyanoskupinu, substituovanú alkylovú skupinu alebo karboxyskupinu ,R 3 and R 4 independently of one another hydrogen, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl, or carboxy, R5 znamená atóm vodíka alebo alkylovú skupinu aR 5 represents a hydrogen atom or an alkyl group and R znamená atóm vodíka, alkylovú alebo arylovú skupinu , a ich soli • spolu s ich solamia ich fyziologicky funkčnými dervátmi.R represents a hydrogen atom, an alkyl or aryl group, and salts thereof together with their salts to physiologically functional dervates. II 3. Zlúčenina podlá nároku 1 alebo 2, kdeA compound according to claim 1 or 2, wherein X predstavuje atóm síry alebo skupinu vzorca NH,X is sulfur or NH, Y predstavuje skupinu vzorca NH,Y is NH, - 74 A znamená skupinu vzorca- 74 A represents a group of the formula Ί Q QΊ Q Q R predstavuje skupinu vzorca COOR , kde R znamená alkylovú alebo aralkylovú skupinu,R represents a group of the formula COOR, wherein R represents an alkyl or aralkyl group, R2 predstavuje atóm vodíka alebo alkylovú skupinu,R 2 is H or alkyl, R3 predstavuje atóm vodíka, alkoxyskupinu alebo atóm halogénu,R 3 is H, alkoxy or halogen, R4 predstavuje atóm vodíka, alkoxyskupinu alebo atóm halogénu,R 4 represents a hydrogen atom, an alkoxy group or a halogen atom, R5 predstavuje alkylovú skupinu,R 5 represents an alkyl group, R6 predstavuje atóm vodíka, alebo jej soli a jej fyziologicky funkčné deriváty. R 6 represents a hydrogen atom, or a salt thereof, and physiologically functional derivatives thereof. 4. Zlúčenina zvolená zo súboru zahrňujúceho4. A compound selected from the group consisting of 3-pyridyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), f /(3-dimetylamino)fenyl/-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát, • benzyl-(1,3,4-trimetylpyrolo[3,2-b]-karbazol-2-karboxylát), fenyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), 3,4-dimetyl-2-(1-imidazolylkarbonyl)pyrolo[3,2-b]karbazol, etyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), etyl-(3,4-dimetylbenzotieno[4,5-f]indol-2-karboxylát), benzyl-(3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), benzyl-(8-ftuór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), etyl-(8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), benzyl-(3,4,6-trimetylpyrolo[3,2-b]-karbazol-2-karboxylát) , etyl-(3,4,6-trimetylpyrolo[3,2-b]-karbazol-2-karboxylát), kyselinu 8-fluór-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovú, kyselinu 3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylovú, etyl-( 8-metoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát), kyselinu 3,4,6-trimetylpyrolo[3,2-b]-karbazol-2-karboxylovú a benzyl-(8-metoxy-3,4-dimetylpyrolo[3,2-b]-karbazol-2-karboxylát) a ich soli a ich fyziologicky funkčné deriváty.3-pyridyl (3,4-dimethyl-pyrrolo [3,2-b] carbazole-2-carboxylate), F / (3-dimethylamino) phenyl / -3,4-dimethyl-pyrrolo [3,2-b] -karbazol- 2-carboxylate, • benzyl (1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2- carboxylate), 3,4-dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3,2-b] carbazole, ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl - (3,4-dimethylbenzothieno [4,5-f] indole-2-carboxylate), benzyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), benzyl (8-fluoro) -3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), benzyl- (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), acid 8 -fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, ethyl- (8-methoxy-3) (4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and benz yl (8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and their salts and their physiologically functional derivatives. 5. Farmaceutický prostriedok, vy značujúci satým, že obsahuje zlúčeninu všeobecného vzorca I podlá nároku 1 spolu s jej farmaceutický prijateľnou nosnou látkou.A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 together with a pharmaceutically acceptable carrier therefor. 6. Zlúčenina všeobecného vzorca I podľa nárokov 1 až 4 na použitie v medicíne.A compound of formula I according to claims 1 to 4 for use in medicine. 7. Použitie zlúčeniny všeobecného vzorca I alebo jej farmaceutický prijateľnej soli alebo jej fyziologicky funkčného derivátu na výrobu liečiva pre ošetrovanie nádorov.Use of a compound of formula I or a pharmaceutically acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumors. 8. Spôsob ošetrovania nádorov u živočíchov, vyznačuj úc i sa tým, že sa im podáva účinné množstvo zlúčeniny všeobecného vzorca I alebo jej soli alebo jej fyziologicky funkčného derivátu.8. A method of treating tumors in an animal comprising administering an effective amount of a compound of formula I or a salt thereof, or a physiologically functional derivative thereof. 9. Spôsob výroby zlúčenín všeobecného vzorca I podľa nároku 1, vyznačujúci sa tým, že saA process for the preparation of compounds of the formula I according to claim 1, characterized in that it is: a) katalytický uzavrie kruh v zlúčenine všeobecného vzorca IVa) catalytic ring closure in a compound of formula IV - 76 (IV) v ktorom- 76 (IV) in which X, Y, R1, R2, R3, R4 a R5 majú význam uvedený vyššie, v prítomnosti silnej kyseliny, aleboX, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, in the presence of a strong acid, or b) konverguje jedna zlúčenina všeobecného vzorca I na inú zlúčeninu všeobecného vzorca Ib) converging one compound of formula I to another compound of formula I 10. Nové medziprodukty všeobecného vzorca II, III, IV alebo V.10. New intermediates of formula II, III, IV or V.
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GB9401921D0 (en) * 1994-02-01 1994-03-30 Wellcome Found Heterocyclic compounds
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US7419992B2 (en) 2001-02-14 2008-09-02 Wisconsin Alumni Research Foundation Use of aryl hydrocarbon receptor ligand as a therapeutic intervention in angiogenesis-implicated disorders
CA2437579C (en) * 2001-02-14 2012-05-01 Hector F. Deluca Preparations and use of an ah receptor ligand, 2-(1'h-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester
GB0302094D0 (en) 2003-01-29 2003-02-26 Pharmagene Lab Ltd EP4 receptor antagonists
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WO2010019271A1 (en) 2008-08-15 2010-02-18 Georgetown University Fluorescent regulators of rassf1a expression and human cancer cell proliferation
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KR20160066490A (en) 2014-12-02 2016-06-10 주식회사 씨앤드씨신약연구소 Heterocyclic derivatives and use thereof
US11053255B2 (en) 2015-06-22 2021-07-06 Georgetown University Synthesis of mahanine and related compounds
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YU50293A (en) 1997-01-08
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