BG99359A - Tetracyclic compounds, method and intermediate compounds for their preparation and their application as antitumour compositions - Google Patents

Abstract

The invention relates to heterocyclic compounds having antitumor activity, in particular pyrrolo [3,2-b] carbazoles, 1H-benzofuro [3,2-f] indoles and 1H- [1] benzothieno [ indoles of the formula, to methods and intermediates for their preparation, to pharmaceutical compositions containing them and to their use as antitumor agents.

Description

TETRACYCLIC COMPOUNDS, METHOD AND INTERMEDIATE COMPOUNDS FOR THEIR PREPARATION AND APPLICATION AS ANTI-TUMOR AGENTS

The present invention relates to

With heterocyclic compounds found to have antitumor activity. More particularly, the invention relates to pyrrolo [3,2-b] carbazoles, 1H-benzofuro [3,2-b] indoles, and 1H- [1] benzothieno [2,3-b] indoles, to methods for their preparation, to pharmaceutical compositions containing them and until used as antitumor agents.

Research into cancer chemotherapy has led to the production of a number of antitumor compounds that have varying degrees of efficacy. Standard clinical compounds used include adriamycin, actinomycin D, methotrexate, 5 fluorouracil, cis-platinum, vincristine, and vinblastine. However, these currently available anti-tumor substances are known to have a number of disadvantages, such as toxicity to healthy cells and resistance to certain tumor types.

Therefore, there is an ongoing need to develop new and improved antitumor agents.

Khoshtariya et al, Khim. Heterocycle. Soedin. (1980), (2)

203-8, published the synthesis of some indolobenzo [b] thiophenes.

Khoshtariya et al, Khim. Heterocycle. Soedin. (1984), (10) 1366-70, published the synthesis of some indolobenzo [b] furan.

Kakhabrishvili et al, Khim. Heterocycle. Soedin. (1985), (3) 355-8, published the synthesis of some indole derivatives [5,6-d] and (5,4-d] benzo [b] furan.

The patent specification EP 447, 703 discloses the synthesis of certain benzo (5,6-b) benzofuran-2-carboxylates.

New compounds are now being disclosed that show C activity for tumor cells and lower toxicity to healthy cell lines.

A

Thus, on the one hand, the present invention provides a compound of general formula (I) ί

and salts and physiologically active derivatives thereof, wherein A is

R ¹

R ²

R ¹

ALL

R ²

R ²

R ¹ '

SO, SO ₂ , CH ₂ , aryl, alkenyl,

R ¹

CO or NR ⁷ wherein R ⁷ is H, acyl, alkynyl, sulfonyl or r 2.

X is O, S, alkyl, aralkyl, substituted sulfonyl;

Ye O, S, Sp, SO ₂ , CH ₂ , CO or NR ⁷ ; /

R1 e COR ^8, COOR ^8, CHO, CH2OH, CH2OR ^9, CONH2, CONHNR10RH, CONHR10, CONRIORH , COO (CH _{2) n} NR10RH, wherein R ⁸ is H, alkyl, aryl, substituted aryl or aralkyl, R ⁹ is acyl or substituted acyl, R ¹⁰ and R ¹¹ are independently hydrogen, alkyl or aryl and n is from 1 to 4 carbon atoms;

R ² is hydrogen, COOR ⁸ , alkyl, aryl, substituted aryl or CH ₂ CH ₂ CO ₂ R 12, where R 12 is alkyl or aryl;

R ³ and R ⁴ are independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxyl or CO ₂ R 12;

R ⁵ is hydrogen, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano, CHO, COOR ⁸ ;

R ⁶ is hydrogen, alkyl, aralkyl, nitro, halogen, CHO, COR ¹³ , where R ¹³ is alkyl or aryl, provided that | and:

(i) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is

where Y is NH and X is O or S, then R ¹ is not CO2 or CO ₂ Et; and (ii) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is

where Y is NH and X is O or S, then R ¹ is not CHO; and (iii) Y is not O when X is O.

One embodiment wherein A is a further aspect of the invention is a compound of the above formula (I),

R ¹

OR

R ²

R ¹

CO or NR ⁷ wherein R ⁷ is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl or sulfonyl;

Y is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ ;

R1 is COOR ⁸ , CHO, CH2OH, CH2OR ⁹ , CONH2, CONHR10, CONR ¹⁰ R ⁿ , where R ⁸ is H, alkyl, aryl, substituted aryl or aralkyl, R ⁹ is acyl or substituted acyl, R ¹⁰ and R ¹¹ are independently of one another alkyl or aryl;

R ² is hydrogen, COOR ⁸ , alkyl, aryl, substituted aryl or CH ₂ CH ₂ CO ₂ R ¹² , where R ¹² is alkyl or aryl;

X is O, S,

R ¹ *

SO, so ₂ , dream ₂ ,

R ³ and R ⁴ are independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxyl or CO2R ¹² ;

R ⁵ is hydrogen, alkyl, substituted alkyl, aralkyl, nitro, halo, cyano, CHO;

R ⁶ is hydrogen, alkyl, aralkyl, nitro, halo, CHO, COR ¹³ , where R ¹³ is alkyl or aryl, under the conditions described above.

The alkyl groups u present in the general formula (I) may be straight or branched and may contain from 1 to 10 carbon atoms, suitably containing from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like.

The acyl groups may be straight and branched and may contain from 1 to 10 carbon atoms, and suitably contain from 1 to 6 carbon atoms. Examples of such acyl groups include ethanoyl and propanoyl groups.

with alkoxy groups may be straight and branched and may contain from 1 to 10 carbon atoms, suitably containing from 1 to 6 carbon atoms. Examples of such alkoxy groups include methoxy, ethoxy and the like.

The aryl groups also include carbocyclic aryl moieties 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, thienylene, furylene, pyridylene, indole and quinoline rings.

ΐ

6.

I

An aralkyl group may contain from 1 to 4 atoms 8 its alkyl moiety and the aryl moiety may be a carbocyclic or heterocyclic aryl group.

Substituents that may be present in the alkyd, aryl or acyl groups include alkyl, alkoxy, halo, sulfinyl, amino (optionally substituted by one or two alkyl groups), haloalkyl (e.g. trifluoromethyl), sulfinyl, sulfonyl and cyano.

Substituents which may be present in the sulfonide group include alkyl, aryl and aralkyl.

Halogen is fluorine, chlorine, bromine or iodine.

In the compounds of formula (I)

X is preferably O, S or NR ⁷ , wherein R ⁷ is H, alkyl, sulfonyl or toluenesulfonyl;

Y is preferably NR ⁷ ;

R1 is preferably CO ^ ⁸ , COOR ⁸ , CH2OR ⁹ , CONH2, CNHNR10RH, CONHR10, CONR10RH, COO (CH ₂ ) _and NR10RH, where R ⁸ is H, alkyl, aryl, substituted aryl or aralkyl, R ⁹ is acyl or substituted acyl, and R ¹⁰ and R ¹¹ are independently hydrogen, alkyl or aryl and n is from 1 to 4 carbon atoms;

R ² is preferably COOR ⁸ , alkyl or CH ₂ CH ₂ CO ₂ R ¹² , where R ¹² is alkyl or aryl;

R ³ and R ⁴ are independently hydrogen, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl or carboxyl;

R ⁵ is preferably hydrogen or alkyl;

R ⁶ is preferably H, alkyl or aryl, as well as their salts and physiologically active derivatives.

X is preferably S or NH and A is preferably

R ¹

[where Y is preferably ΝΉ.

R ¹ is preferably COOR ⁸ , where R ⁸ is preferably alkyl or aralkyl.

R ² is preferably hydrogen or alkyl.

R ³ is preferably hydrogen, alkoxy or halogen.

R ⁴ is preferably hydrogen, alkoxy or halogen.

R ⁵ is preferably alkyl and

R ⁶ is preferably H as well as their salts and physiologically active derivatives.

Particularly preferred compounds of the present invention include: 3-Pyridyl-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate; [(3-Dimethylamino) phenyl] -3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate;

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-b] indole-2-carboxylate;

Benzyl, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate;

Benzyl, 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate;

Ethyl, 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate;

Benzyl, 3,4,6-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-2carboxylate;

3,4,6-Trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and Benzyl, 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate and their physiologically functional derivatives.

Compounds of formula (I) have been tested for two specially developed cell lines that are clones of the human fibrosarcoma cell line, HT1080. One clone, HT1080scc2, retains the transformed phenotype of the parental line, while the other, HT10801c, is morphologically flat, non-tumorigenic, revertant.

Thus, the potency of potential antitumor compounds can be evaluated on the basis of; their ability to effect reverse transformation in HT1080scc2 cells.

In these test systems, the compounds of the present invention were found to be particularly effective. ,

In addition, the compounds of the present invention have been found to be effective against MCF7 breast cancer cells, A431 epidermoid carcinoma cells and A285 melanoma cells.

The compounds also show low toxicity to normal cells.

On the other hand, the present invention provides a process for the preparation of compounds of formula (I), which method consists in catalytic ring closure of the compound of formula (IV) in the presence of a strong acid.

(IV)

ύ ......

The present invention also provides a process for the preparation of compounds of formula (IV), which method consists in one of the following: |

a) Interaction of a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV), wherein X, Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined :

and subsequent catalytic closure of the ring.

In order to obtain the compound of the invention, it is preferable to carry out the reaction at room temperature in the presence of a strong acid, for example p-toluenesulfonic acid, or to use montmorillonite clay K10 as a catalyst;

B) Interaction of the compound of formula (V) with a compound of formula (III) to obtain a compound of formula (IV) and subsequent, as in (a), catalytic ring closure.

(V)

where L is a leaving group. Examples of leaving groups include -OCOCCH3, OET, -N + Mez and halo;

(c) Performing the reaction in one step by reacting Q with a compound of formula (II) with a compound of formula (III) in the presence of a catalyst to give a single compound of the invention. A preferred catalyst is montmorillonite clay K10;

Insertion of substituent R ¹ into the ring system, for example:

I (d) Carboxylation of the polyheterocyclic compound using (i) carbonyl halide (j) carbon dioxide

C according to known methods (J. March, Advanced Organic Chemistry, 2nd ed, McGraw Hill, New York, 1977, p 497-498).

(f) Alternatively, the compound of formula (I) wherein R2 is CHO can be prepared by methods known in the art, for example:

(i) A suitable aromatic polyheterocycle may be reacted with a formylating compound, for example obtained by reaction between SnCX1. and CI2CHOCH3 or similar reagents.

For example, according to the method of A Reiche et al., Chem. Ber. 93, 88 (1960), or no art-known methods using other standard formylating compounds, for example by applying the reaction of the Gatterman-Koch (CO \ HC1 \ A1S1 ₃ \ SiS1), the reaction of Gatterman (HCN \ HCl \ ZnC12) and the Vilsmeier reaction (POCL3 \ PhN- (Me) CHO or! POa ₃ \ Me ₂ NCHO) (J. March, Vide Supra, p 494-497); or (ii) from a suitable aromatic polyheterocycle having the corresponding functional groups, which groups are converted to aldehydes by methods known in the art. Suitable functional groups include CH ₂ Br 2, CH ₃ , COR ¹⁴ , where R ¹⁴ is a purity or secondary C 1-8 alkyl group, COOH or a derivative thereof, such as an ester, amide, acid chloride or CN; or (f) A compound of formula (I) wherein R1 is CONHR ¹⁰ may also be prepared by reacting a compound wherein R1 is COOH or a suitable reactive acid derivative thereof as set forth in J. March, Vide Supra. For example, an acid halide may be subjected to / reacted with compound NHR10 in an inert solvent medium.

(g) Conversion of a compound of formula (I) to another compound of formula (I).

Compounds of the invention in which R ¹ is COOR ⁸ and R ⁸ is, for example aralkyl, can be converted to the free acids, in which R ⁸ is H, by reduction in the presence of H ₂ and palladium catalyst; or if R ⁸ is, for example, alkyl, by hydrolysis in the presence of a suitable base, for example cesium carbonate.

By converting the free acids obtained by known methods, one skilled in the art can further synthesize ester and amide compounds, r

according to the object of the invention (See J. March, Vide Supra, p 363-365).

Compounds of the invention prepared as described

I here way may baat converted into other compounds of the invention by electrophilic substitution at position R5 and / or R ⁶ to input, for example, NO2, halogen, COR ^13, where R ¹³ is as given here definition.

The above processes are described for compounds wherein

It is clear to the expert that they are equally applicable when A is:

OR

On the other hand, the present invention relates to novel intermediates of formulas (II), (III), (IV) or (V).

The compounds of the present invention are useful for the treatment of tumors. They can be used to treat various forms of mammalian cancer, including sarcomas, such as the stomach, pancreas, breast, uterus, and colon; in adenocarcinomas, such as the lung and colon, sarcomas, such as fibrosarcoma; in leukemias, for example lymphocytic leukemia, and in lymphomas, such as myeloid lymphoma.

The invention further provides a method of treating tumors in animals, including mammals, and in particular in humans, comprising administering a clinically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or physiologically effective derivative thereof , in a pharmaceutically acceptable form, once or several times daily, or with other appropriate prescription, orally, rectally, parenterally or by topical application.

Further, in a further or alternative aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or physiologically effective derivative thereof for use in therapy, for example as an antitumor compound.

The amount of the compound of formula (I) required to effect the tumors described above varies, of course, and is essentially a matter for the practitioner of a human or veterinary practitioner. Factors to be considered include the type of disease being treated, the route of administration and the type of composition, the weight of the mammal, the surface area, the age and general condition, and the particular compound to be administered. Suitable effective antitumor dosages range from about 0.01 to about 100 mg / kg body weight, for example from 0.1 to about 100 mg / kg body weight and preferably 1-30 mg / kg body weight. The total daily dose can be given as a single dose or as multiple doses, for example two to six times a day, or by an intravenous infusion of a fixed duration. For example, in a mammal weighing 75 kg, the dosage would be about 900 mg per day, with a typical dose of 50 mg per day. If the use of small multiple doses is indicated, the treatment f F will usually be 15 mg of a compound of formula (I) taken up to 4 times a day.

Although it may be possible to administer the active compound on its own, it is preferable for it to be present in a pharmaceutical composition. The compositions of the invention for therapeutic use contain a compound of formula (I) or a salt thereof together with one or more pharmaceutically acceptable carriers and other therapeutic ingredients of choice. The carrier (s) should be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not detrimental to the recipient thereof.

Also provided is a method of preparing pharmaceutical compositions comprising admixing a compound of formula (I) or a pharmaceutically acceptable salt or physiologically effective derivative thereof with a pharmaceutically acceptable carrier.

The compositions of the present invention include those which are suitable for oral, superficial, rectal and parenteral (including subcutaneous, intramuscular and intravenous) administration.

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into contact with a carrier that contains one or more additives. Generally, the compositions are prepared by uniformly mixing the active compound with a liquid or finely divided solid carrier or with both carriers and then, if necessary, forming the resulting mixture in the desired form of the composition.

ij съ The compositions suitable for oral administration according to I ^{1 of the} present invention may be in the form of individual unit forms, for example capsules, wafers, pastels, each containing a predetermined amount of the active compound; in the form of powder or granules; or in the form of solutions and suspensions in aqueous or non-aqueous liquids, for example syrup or elixir, emulsion or liquid.

The tablets may be formulated by compaction or compression into molds, optionally with one or more additional ingredients. The compacted tablets may be prepared by compacting a suitable machine of the active compound in an undetermined form, for example powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be obtained by compressing a suitable machine into a mixture of the powdered active compound with any suitable carrier.

The syrup can be prepared by adding the active compound to a concentrated aqueous sugar solution, for example sucrose, to which additional ingredients may also be added. These additional ingredients include flavors, a substance that slows the crystallization of sugar or increases the solubility of other ingredients, such as polyvalent alcohol, such as glycerol or sorbitol.

Formulations for rectal administration may be in the form of suppositories prepared with conventional f carriers, for example cocoa butter.

Suitable for parenteral administration

include a sterile aqueous solution of the active compound, which is preferably isotonic, and the blood of the recipient. Suitably such solutions comprise a solution of a pharmaceutically or pharmacologically acceptable acid addition salt of a compound of formula (I) which is isotonic with the blood of the recipient.

Applicable compositions also contain concentrated solutions or solids containing the compound of formula (I) which, when diluted with a suitable solvent, give as above _; solution for parenteral administration.

In addition to the ingredients mentioned above, the compositions of

the present invention may also include one or more additional ingredients selected from diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.

In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a physiologically functional derivative for the manufacture of medicaments for the treatment of tumors.

The invention will be illustrated by the following non-limiting examples:

All temperatures are given in degrees Celsius (° C).

Infrared spectra were recorded on a Perkin-Elmer 257 diffraction spectrophotometer or a Bruker FS 66 I I spectrophotometer.

Ultraviolet spectra were recorded in an ethanol medium on a Unicam SP 800 spectrophotometer.

1H NMR spectra were obtained on a Bruker WM 360 NMR spectrometer at 360 MHz or on a Bruker WM 200 spectrophotometer at 200 MHz. The value of J is given in MHz.

The mass spectra were obtained on Varian CH5D (EI) or Kratos Ms50 (FAB) apparatus.

Example 1

Getting pyrrole ^^ Getting pyrrole

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 were prepared by the method of A. W. Johnson et al, J. Chem. Soc., 4254 (1958).

N-methylation of pyrrole - General method

A mixture of pyrrole (20 mmol), methyl iodide (50 mmol) and potassium carbonate (50 mmol) was refluxed for 8 hours in methyl ethyl ketone (50 ml). If thin layer chromatography (toluene / ethyl acetate 3: 1) indicated that the reaction was not complete, equal amounts of methyl iodide (50 mmol) and potassium carbonate (50 mmol) were added and the mixture was heated for a further 6 hours at reflux. After evaporation to dryness in vacuo, the residue was dissolved in warm water and extracted with ethyl acetate (3 x 50 ml). Combined, the extracts were dried over magnesium sulfate and evaporated in vacuo to give a yellow oily or solid which was crystallized from an aqueous solution of ethanol.

Ethyl 4-acetyl-1 _g 3 _g 5-trimethylpyrrole-2-carboxylate obtained from ethyl 4-acetyl-3,5-dimethylpyrrole-2-carboxylate as white crystals (2 g; 41%), melting point 61- 62 ° C; (Found: C, 64.17; H, 7.82; N 6.16. C ₁₂ H ₇ NO ₃ requires: C, 64.55; H, 7.68; N 6.27%) 8h ([2H 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 x s, 3-CH 3 and COCH 3), 2.38 (3H, s, 5-CH 3) and 1.29 (3H, t, CH ₂ CH ₃ ); m / z (%) 224 (MH +, 100), 208 (40), 194 (20), 178 (40) and 133 (20) (FAB); v _max (KBr tablet) / cm ^_1 2984,1691 and 1651.

Benzyl 4 = acetyl-1,3,5-trimethylpyrrole-2-carboxylate obtained from benzyl 4-acetyl-3,5-dimethylpyrrole-2-carboxylate in the form of white crystals, mp 78-79 ° C; (Found: C, 71.30; H, 6.74; N, 4.79. C17H19NO3 requires C, 71.56; H, 6.71; 4.91%) bp ([2H _6] -DMSO) 7.52-7.27 ($ H, m Ar H)

5.30 (2H, s, CH ₂ Ph), 3.73 (3H, s, 1-CH ₃ ), 2.42 (6H, s, 3-CH 3 and COCH 3) and 2.38 (3H, s 5-CH 3); m / z (%) 285 (76, M +), 270 (87), 194 (53), 178 (23), 151 (36), 136 (26) and 91 (100); v _max (KBr tablet) / cm ^-1 2974,1693,1641.

Preparation of 5-Acetoxymethyl-4-acetylpyrroles - General method

To a cooled (0 ° C) and stirred suspension of 4acetyl-5-methylpyrrole (0.02 mol) in dry diethyl ether (20 cm ³ ) was added dropwise over 15 minutes freshly distilled sulfuryl chloride (2.2 cm ³ , 1.25 eq.). . The reaction mixture was stirred further, slowly starting to crystallize the chloromethyl methyl. Filtration gave the 5-chloromethyl derivative in the form of colorless crystals. The purity of chloromethylpyrrole was verified by 1 H NMR spectroscopy (90 MHz). The compound was used directly without further recrystallization.

t ____________!

f The resulting chloromethylpyrrole (0.01 mol) was added to a solution of sodium acetate (3 g) in acetic acid (50 cm ³ ). The mixture was stirred for 2 hours and poured into water-ice (200 cm ³ ). Before drying, the resulting solid phase is thoroughly washed with water until complete acid is removed. Ethyl 5-acetoxyl. Ethyl-4-acetyl-32L. Ethylpyrrole-2carboxylate recrystallized from benzene as colorless needles (1.87 g, 70%), mp 135.5-138 ° C (Found: C, 58.6; H, 6.45; N, 5.15. Ci ₃ Hi ₇ NO ₅ requires C, 58.4; H, 6.41; N 5.24%) 5h (CDCl ₃ ) 9.57 (1H, br s, NH), 5.40 (2H, s, CH ₂ OAc ), 4.35 (2 H, q, OCH ₂ CH ₃ ), 2.6 (3H, s, 3-CH ₃ ) 2.5 (3 H, s, COCH ₃ ), 2.17 (3H, s, OCOCH ₃ ) in 1.4 (3H) , t, OCH ₂ CH ₃ ); m / z (%) 267 (83, MH +), 224 (46), 207 (27), / 178 (100) in 162 (42). /

Benzyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2carboxylate recrystallized from methanol as colorless needles (2.34 g, 71%), mp 138-141 ° C (Found: C, 65.8; H, 5.95; N , 4.3. C ₁₈ H ₉ NO ₅ requires C, 65.64; H, 5.81; N 4.25%) 8h (CDCl ₃ ) 9.44 (1H, br s, NH), 7.49-7.32 (5 H, m, ArH), 5.40 (2 H, s, CH ₂ OAc), 5.35 (2 H, s, CH ₂ Ph), 2.62 (3H, s, 3-CH ₃ ) 2.49 (3 H, s, CH ₃ CO) in 2.14 (3H. s, OCOCH ₃ ); m / z (%) 329 (9, M +), 286 (13), 269 (4), 178 (19) in 91 (100).

In the case of benzyl 5-acetoxymethyl-4-acetyl-3- (2-methoxycarbonylethyl) -pyrrole-2-carboxylate, when the solution is poured into an ice-water mixture, no precipitation occurs. Extraction with chloroform (3 x 100 cm ³ ), drying and removal of the solvent under reduced pressure gave an oily residue which was crystallized from benzene-light gasoline to give colorless needles (2.69 g,

I i

67%), melting point 97 -10 ° C (Found: C, 62.9; H, 5.9; N, 3.45. Requires,, .8, 78, requires C, 62.8; H, 5.78; N 3.49%) bn (CDd ₃ ) 9.15 (1H, br s, NH), 7.50-7.30 (5 N, t, ArH), 5.35 (4 H, s, CH ₂ Ph and CH ₂ OAc), 3.63 (3H, s, OCH ₃ ) 3.37 (2 H, t, CH ₂ CH ₂ CO) 2.58 (2 H, t, CH ₂ CO), 2.51 (3 H, s, COCH 3) and 2.15 (3H, s, OCOCH 3); m / z (%) 401 (4, M +), 341 (8), 268 (6), 250 (60) and 91 (100). Ethyl 5-acetoxymethyl-4-ethyl-1,3-azethylpyrrole-2carboxylate recrystallized from ethyl acetate / cyclohexane (61%), mp 100-101 ° C (Found: C, 59.38; H, 6.73; N, 4.95. Ci 4 H _W NO ₅ requires C, 59.78; H, 6.81; N 4.98%) bn ([ ² H ₆ ] DMSO) 5.30 (2 H, s, CH 2 OAc), 4.29 (2 H, q, CH 2 CH 3), 3.77 (3H, s, N -CH ₃ ) 2.43 and 2.42 (2 x 3H, 2 x s 3 -CH 3 and CH 3 CO) and 2.02 (3H, s, OCOCH 3) and 1.31 (3H, t, CH ₂ CH ₃ ); m / z (%) 281 (34, M +), 238 (100), 222 (48), 192 (52); in _ml (KBr tablet) / cm-11712 and 1697.

Benzyl 5-acetoxymethyl-4-acetyl-1,3-dimethylpyrrole-2carboxylate recrystallized from ethyl acetate / cyclohexane bz (pH ^ J-DMSO) 7.51-7.32 (5H, m ArH), 5.34 and 5.32 (2 x 2H, 2 x s , CH ₂ Ph and CH ₂ OAc), 3.78 (3H, s, N-CH 3), 2.46 and 2.45 (2 x 3H, 2 x s, 3-CH 3 and CH ₃ CO) and 2.04 (3H, s, OCOCH 3) ; m / z (%) 343 (5, M +), 284 (100) and 91 (95). Ethyl 5-aethoxymethyl-4-acetyl-3-ethylpyrrole-2carboxylate recrystallized from ether / gasoline as beige needles (61%), mp 97-98 ° C (Found: C, 59.44; H, 6.78; N. 4.80. Ci ₄ H ₁₉ NO ₅ requires C, 59.76; H, 6.81; N 4.98%) bn (CDCl 3) 9.40 (1H, br s, 1-NH), 5.38 (2H, s, CH ₂ OAc), 4.38 ( 2 H, q, J 7, CO ₂ CH ₂ ), 3.10 (2H, q, J 7.5, 3-CH ₂ ) 2.54 (3H, s, COCH 3), 2.18 (3H, s, OCOCH 3), 1.40 (3H, t, J 7.5, COCH 2 CH 3), 1.23 (3H, t, J 7.5, 3-CH 2 CH 3); m / z (%) 281 (42, M +), 238 (61), 221 (89), 206 (58), 192 (92), 175 (95), 160 (81), 147 (59), 43 ( 100); (KBr tabletUspg ¹ 3277.1738.1674, 1657.

Synthesis of 3- (Pyrrolylmethyl) indole, 2 (Pyrrolylmethyl) benzofuran and 3- (Pyrrolylmethyl) benzothiophene General Method

A solution of 5-acetoxymethyl-4-acetylpyrrole (1.0 mmol) and indole (1.0 mmol) in 1,2-dichloroethane (10 cm ³ ) was heated at gentle reflux and stirred with montmorillonite clay (1 g). 1.5-2 hours. After separation from the clay by filtration and a good wash with 1,2 dichloroethane, the combined filtrates are evaporated under reduced pressure to give an oily residue. This residue was flash chromatographed on silica gel eluting with ethyl acetate in light gasoline to give 3- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) indole, which crystallized from ethyl acetate light gasoline as colorless crystals (0.1465 g, 45%). Mp 180-182 ° C (Found: C, 70.5; H, 6.25; N, 8.65. C19H20N2O3 requires C, 70.4; H, 6.21; N 8.64%)? H (CDC1 ₃₎ 8.78 (1H, s, pyr- NH), 8.27 (1H, s, ind-NH), 7.45 (1H, d, J 7, 4-H), 7.42 (1H, d, J 7, 7-H), 7.25 (1H, t, J 7 , 6-H), 7.14 (1H, t, J 7, 5-H), 7.10 (1H, s, 2-H), 4.45 (2H, s, 3-CH ₂ ), 4.22 (2H, q, OCH2CH3 ), 2.63 (3H, s, 4'-CH ₃ ), 2.53 (3H, s, CH ₃ CO), 1.25 (3H, t, OCH ₂ CH ₃ ); m / z (%) 324 (100, M +), 309 (48), 277 (25), 263 (54), 250 (38), 235 (30), 207 (48), 139 (24), 130 ( 30), 117 (67) in 90 (16); v _max (CHCl 3) / cm-1 3490, 3430, 1680 and 1650.

When benzofuran (1.0 mmol) was used instead of indole, chromatography gave 2- (3'-acetyl-5'22 epoxycarbonyl-4'-methylpyrrol-2'-ylmesyl) benzofuran (0.106 g, 32.6%), m.p. 124-127 ° C (Found: C, 70.1; H, 6.1; N, 4.15. C 10 H 14 NOD requires C, 70.14; H, 5.89; N, 4.31%); bn (CDd ₃ ) 9.25 (1H, s, NH), 7.50 (1H, d, J 7, 4-H), 7.44 (1H, d, J 73).

7-H), 7.28-7.18 (2H, m, 6-H and 5-H), 6.57 (1H, s, 3-H), 4.50 (2H, s, 2CH ₂ ), 4.31 (2H, q, OCH ₂ CH ₃ ), 2.62 (3H, s, 4'-CH ₃ ), 2.50 (3H, s, CH ₃ CO), 1.35 (3H, t, OCH ₂ CH ₃ ); saturation of the 3-H singlet at δ 651, amplification of the signals due to 4H at δ 750 (2.7%) and 2-CH ₂ at δ 450 (0.8%); m / z (%) 325 (100, M +), 310 (4), 279 (29), 264 (17), 251 (59), 236 (27), 208 (19), 193 (9), 131 (7) and 118 (7); and 2, 3-bis (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzofuran (0.0238 g, 8.94%), mp 255-257 ° C; _beta (CDd ₃ ) 10.09 (1H, s, NH), 9.95 (1H, s, NH), 7.32 (1H, d, J 7.4-H),

7.27 (1H, d, J 7.7, 7-H), 7.17 (1H, t, J 7.7, 6-H), 7.08 (1H, t, J 7.7, 5H), 4.45 (2H, a, 2-CH ₂ ), 4.40 (2H, s, 3-CH ₂ ), 4.36 (2H, q, OCH ₂ CH ₃ ),

4.27 (2H, q, OCH ₂ CH ₃ ), 2.64 (3H, s, 4'-CH ₃ ), 2.63 (3H, s, 4'-CH ₃ ), 258 (3H, s, CH ₃ CO), 254 (3H, s, CH ₃ CO), 1.39 (3H, t, OCH ₂ CH ₃ ) and 131 (3H, t, OCH ₂ CH ₃ ); m / z (%) 532 (11, M +), 490 (24), 444 (9), 397 (6), 324 (100), 282 (18), 278 (27), 236 (20), 209 (28) and 162 (28) (Found: M ⁺ , 532.2210. C ₃ (jH ₃₂ N ₂ O7, requires M, 532.2209).

When benzothiophene (1mmol) was used in the same manner as indole, chromatography using ethyl acetate in dichloromethane as eluent gave colorless crystals of 3- (3'-acetyl-5'-ethoxycarbonyl-4'methylpyrrol-2'- ilmethyl) benzothiophene (0.0963 g, 28.2%), mp 125-128 ° C; (Found: C, 66.75; H, 5.8; N, 4.1. C ₁₉ H _w NO ₃ S requires C, 66.84; H, 5.61; N, 4.10%); bn (CDd ₃ ) 8.72 (1H, br, s, NH), 7.88 (1H, m, 4-H), 7.63 (1H, m, 7-H), 737 (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, i

I

OCH2CH3); saturation of the 3-CH 2 protons at 8 4.54, amplification of the signals due to NH at δ 8.72 (3.3%), 4-H at δ 7.88 (7.7%) and 2-H at δ 7.20 (6%) and CH ₃ CO at δ 2.53 (jl.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); and 2, 3-bis (3'-acetyl-5'ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene in the form of pale yellow solid (0.0264 g, 9.6%), mp 206-209 ° C; (Found: C, 66.6; H, 5.8; N,

5.1. C ₃ oH 32 N ₂ O ₆ S requires C, 65.67; H, 5.88; N, 5.11%); 8H (CDCl3) 9.77 (1H, br, s, NH), 9.43 (1H, br, s, NH), 7.70 (1H, t, 4-H), 7.49 (1H, t, 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, OCH2CH3), 4.24 (2H, q, OCH2C3) , 2.61 (H, s, 4'-CH _3), 2.60 (H, s, 4'-CH), 2.57 (H, s, CH3 CO), 2.49 (H, s, CH3 CO), 1.35 (H, t, OCH ₂ CH 3) and 1.28 (3H H, t, OCH ₂ CH ₃ ); m / z (%) 548 (5, M +), 530 (11), 340 (100), 294 (27) and 162 (10).

Example 2 j I

Synthesis of 3- (Pyrrolylmethyl) benzothiophenes and 3 (Pyro / schmethyl) icdoles

a) N - (N - Acetyl-N-benzyloxycarbonyl-methyl-pyrrol-ylmethyl) benzothiophene

A solution of 5-acetoxymethyl-4-acetylpyrrole (0.33 g; 1.0 mmol) and benzothiophene (0.14 g; 1.05 mmol) in dichloroethane (10 cm ³ ) was refluxed and stirred with montmorillonite clay K 10 (1 g) in for 2.5 hours. After cooling and separation by filtration from the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to leave a yellow oily residue. Flash chromatography on silica gel eluting with diethyl ether / light gasoline (1: 2) gave the title compound as a colorless solid

A. 24.

substance, 8H (CDd ₃ ) 8.72 (1H, s, NH), 7.92-754 (1H, m, 4-H),

7.69-758 (1H, m, 7-H), 7.43-7.16 (8H, m, 2H, 5-H, 6-H, ArH), 5.23 (2H, s, CH ₂ Ph), 450 (2H, s , 3-CH ₂ ), 2.61 (3H; s, 4'-CH ₃ ) in 2.50 (3H, s, CH ₃ CO); m / z (%) 403 (M +, 100); v _max (KBr tablet1k) / cm2

3290,1690 u1659.

b) 3- (3'-Acetyl-N-ethoxycarbonyl-4'-methyltrol-2-ylmethyl)

-5-cyanoindole

A solution of 5-acetoxymethyl-4-acetylpyrrole (0.7 g; 2.6 mmol) and 5-cyanoindole (0.41 g; 2.9 mmol) in 1,2-dichloroethane (50 cm ³ ) was refluxed and stirred with montmorillonite clay K 10 (1 g) for 6 hours. After cooling and separation by filtration from the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to leave an orange solid. Recrystallization from dichloromethane / ethyl acetate afforded a small amount of analytically pure title compound as cream crystals. Evaporated mother liquors were flash chromatographed on silica gel eluting with dichloromethane / ethyl acetate (9: 1) to give the following compound (0.65 g, 71%); mp 213-214 ° C; (Found: C, 68.60; H, 5.46; N, 11.99. C20H19N3O3 requires C, 68.75; H, 5.48; N, 12.03%); bz (PH ₆ ] -DMSO) 12.05 (1H, s, Γ-ΝΉ), 11.38 (1H, s, 1-NH), 8.20 (1H, m, 4-H), 7.50 (1H, dd, J 0.7 and 8.5, 7-H), 7.39 (1H, dd, J 1.7 and 8.5, 6-H), 7.18 (1H, s, 2H), 4.32 (2H, s, 3-CH ₂ ), 4.27 (2H, q, CH2CH3), 2.33 (H, s, 4'-CH _3), 2.51 (H, s, CH ₃ CO) and 1.30 (H, t, CH ₂ CH _3); m / z (%) 350 (M +, 70) 302 (16), 279 (18), 237 (35), 208 (100) and 181 (20); v _max (KBr tablet) / cm ^_ 1 3309, 2218 and 1665.

c) 3- (3'-Acetyl-5 ^, -ethoxycarbonyl-4'-methyl-1-methyl-2 ^, -ylmethyl) -

2.8 mmol) and indole-5-carboxylic acid (0.5 g; 3 mmol) 8 toluene (50 cm ³ ) were stirred at room temperature with montmorillonite clay K 10 (1 g) for 10 days. After cooling and separation by filtration from the clay, which was washed well with toluene, the combined filtrates were evaporated under reduced pressure to leave an orange solid. Recrystallization from ethyl acetate / cyclohexane gave the title compound as a gray powder (0.15 g, 15%); melting point

Mp 227-228 ° C; (Found: C, 64.96; H, 5.58; N, 7.34. C20H20N2O3 requires C, 65.21; H, 5.47; N, 7.60%); bz (PH ₆ ] -DMSO) 12.35 (1H, br, CO ₂ H), 12.04 (1H, s, Γ-ΝΗ), 11.17 (1H, s, 1-NH), 8.31 (1H, d, J 1.6, / 4-H), 7.70 (1H, dd, J 1.6 and 8.7, 6-H), / 7.37 (1H, d, J 8.7, 7-H), 6.98 (1H, s, 2-H), 4.36 ( 2H, s, 3-CH ₂ ), 4.26 (2H, q, CH2CH3), 2.51 and 2.31 (2 x 3H, 2 x s, 4'-CH ₃ and CH ₃ CO) and 1.29 (3H, t, CH ₂ CH ₃ ); m / z (%) C 369 (22 (M + 1) +), 351 (37), 323 (18), 305 (19), 232 (19), 208 (60) and 181 (20), 162 ( 100); (KBr tablet) / cm-1 3359 and 1676.

d) 3- (3'-Acetyl-57-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -

5-bromoindole

A solution of 5-acetoxymethyl-4-acetylpyrrole (1.3 g;

4.9 mmol) and 5-bromoindole (1.09 g; 5.6 mmol) in 1,2-dichloroethane (100 cm ³ ) were stirred at room temperature with montmorillonite clay K 10 (1 g) for 10 days. After cooling and separation by filtration from the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to leave a yellow solid. On recrystallization from dichloromethane (light gasoline) _; 26 i

acetone afforded the title compound as cream crystals (0.33 g, 17%); mp 181183 ° C; (Found: C, 56.24; H, 4.70; N, 6.86. C 16 H 26 Br 2 O 3 requires C, 56.59; H, 4.75; N, 6.95%); bd (PH ₆ ] -DMSO) 12.00 (1H, s, 1'-NH), 11.00 (1H, s, 1-NH), 7.82 (1H, d, J 1.9, 4-H), 7.31 (1H, d , J 8.6,7-H), 7.16 (1H, dd, J 1.9 in 8.6 6-H), 7.02 (1H, s, 2-H), 4.30 (2H, s, 3-CH ₂ ), 4.28 (2H , q, CH2CH3), 2.51 in 2.33 (2 x 3H, 2 xs, 4'-CH _{3 in} CH3CO) in 1.31 (3H, t, CH2CH3); m / z (%) 404 in 402 (100 M +), 389 in 387 (24), 357 (24), 330 in 328 (32), 206 (36) in 178 (26); v _raax (KBr tablet) / cm ^-1 3373 u 1672.

Example 3

a) Ethyl. 3,4-dimethylgtrolo [3.2-b] carbazole-2-carboxylate

A solution of 3- (pyrrolylmethyl) indole (1.108 g; 0.33 mmol) in 1,2-dichloroethane (100 cm ³ ) was stirred at low boiling with montmorillonite clay K 10 (1 g) for 2 hours. Subsequent thin layer chromatography showed that a single compound was formed / formed and that the reaction was complete. After separation by filtration from the clay, which was washed well with 1,2-dichloromethane, the combined filtrates were evaporated under reduced pressure to leave a yellow solid which, upon recrystallization from ethyl acetate, gave pyrrolo [3,2-b] -carbazole in the form of yellow crystals (0.076 g, 75%); mp 209.5-211 ° C; (Found: C, 74.6; H, 6.14; N, 9.03. C19H18N2O2 requires C, 74.5; H, 5.92; N, 9.14%); bd (pH ₆ ] -DMSO) 11.22 (1H, s, 1-NH), 10.70 (1H, s, 5-NH), 8.06 (1H, d, J 7.9-H), 7.85 (1H, s. 10-H), 7.40 (1H, d, J 7, 6H), 7.35 (1H, t, J 7, 7-H), 7.08 (1H, t, J 7, 8-H), 4.35 (2H , q, OCH2CH3), 2.91 and 2.90 (2 x 3H, 2 x s, 3-CH3 and 4-CH ₃ and 1.35 (3H, t, OCH2CH3); Saturation at 10-H at δ 7.85 amplification of singlets due by 1-ΝΗ at δ 11.22 (3%) and 9-H at δ

8.06 (4%); m / z (%) 306 (56, M +), 260 (100), 323 (39), 205 (15), 140 (18) in 130 (26); (CHCl3) / spn1 3480 and 1700; Xmax (EtOH) / nm 226, 268,310 c displacement, 340,390 u 410 c displacement. !

b) Ethyl 3 _t 4-guMemuA-1H-6eH ^ ypo [3 _t 2 -f] uHgoA-2carboxylate

To a solution of 2- (pyrrolylmethyl) benzofuran (0.100 g 0.31 mmol) in toluene (10 cm ³ ) was added toluene-p-sulfonic acid (50 mg) and the reaction was refluxed for 3 hours. On crystallisation the crystalline phase crystallized out and, after filtration and washing with ethanol, the title compound was obtained as pale yellow crystals (0.084 g, 88.8%), mp 262-265 ° C; (Found: C, 74.25; H, 5.55; N, 4.6. C19H17NO3 requires C, 74.25; H, 5.56; N, 4.56%); (pH ₆ ] -DMSO) 11.52 (1H, s, 1-NH),

8.18 (1H, d, J7.5, 5-NH), 7.62 (1H, d, J7.5, 8-H), 7.46 (1H, t, J7.5, 7H), 7.38 (1H, s, 10 -H), 437 (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 CH ₃ ); Saturation of 4-CH ₃ at δ 3.14 amplification of the 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), 333 (31), 205 (9); (HyuoAj / cnr ¹ 3350 and 1686; Xm (EtOH) / nm 240,269,293,330 and 344.

c) Ethyl 3 '4-dimethyl-1H-benzothieno [3 _g 2-f] indole-2carboxylate

To a solution of 3- (pyrrolylmethyl) benzothiophene (0.100 g 0.29 mmol) in toluene (10 cm ³ ) was added toluene-p-sulfonic acid (45 mg) and the reaction was heated to reflux for 3 hours. Evaporation and washing of the resulting solid with ethanol gave the title compound as a pale yellow solid (0.0758 g, 80%), mp 191-193 ° C; (Received:

...... 4 ^

C, 70.3; 5.5, 5.5; N, 4.2. C ₁₉ H ₁₇ NO ₂ S requires C, 70.6; H, 5.30; N, 4.33%); Sfc (pHgJ-DMSO) 11.64 (1H, s, NH), 8.25 (1H, τη, 9-H), 8.12 (1H, s, 10-H), 7.95 (1H, m, 6-H), 7.48 ( 2H, m, 7-H (in 8-H), 4.38 (2H, q, OCH2CH3), 2.87 in 2.85 (2 x 3H, 2 xs, 3-CH3) in 137 (3H, t, OCH2CH3); m / z (%) 323 (53, M +), 277 (100), 249 (33), 221 (15), 139 (7) in 111 (11); v _max (nuyol) / cm ^-1 3350 u 1686; Xmax (EtOH) / nm 240.269, 293, 330 in 344.

d) Benzyl 3 _t 4 ~ dimethyl-1H-benzothieno [3,2-}] indole-2carboxylate

To a solution of 3- (pyrrolylmethyl) benzothiophene (0.100 g 0.25 mmol) in toluene (12 cm ³ ) was added toluene-p-sulfonic acid (40 mg) and the reaction was heated to reflux for 6 hours. Evaporation and washing of the resulting solid with ethanol gave the title compound as a pale yellow solid (0.02 g, 20%), mp 203-204 ° C; (Found: C, 74.7; H, 4.9; N, 3.6. C24H19NO2S requires C, 74.8; H, 5.0; N, 3.6%); δ h ^([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 in ArH), 5.40 (2H, s, CH ₂ ), 2.87 (6H, s, 2 x CH 3); m / z (%) 385 (100, M +), 277 (89), 248 (25), 221 (15) in 91 (28); v _max (KBr tablet) / cm-1 3331 in 1672.

e)

Ethyl 8-cyano-3, 4-dimethylpyrrolo [3 _s 2-b] k

carboxylate

A mixture of 3- (pyrrolylmethyl) indole (0.6 g, 1.7 mmol) and montmorillonite clay K10 (2 g) in toluene was stirred and refluxed for 24 hours. After cooling and separation by filtration from the clay, which is washed well with toluene, the combined filtrates are evaporated under reduced pressure to leave a brown solid residue,

which was subjected to flash chromatography on silica gel eluting with cyclohexane / ethyl acetate (3: 1) to give f * as a yellow solid. Recrystallization from cyclohexane / ethyl acetate afforded the title compound as a yellow powder (0.030 g, 5%), mp> 240 ° C; (Found: C, 71.54; H, 5.18; N, 12.78. C20H17N3O2.O.2H2O requires C, 71.71; H, 5.24; N, 12.54%); δκ (pHgJ-DMSO) 11.39 (1H, s, 1-NH), 11.29 (1H, s, 5-NH), 8.65 (1H, d, J 1.7, 9-H), 8.01 (1H, s, 10- H), 7.71 (1H, dd, J 1.7 in 8.6, 7-H), 7.50 (1H, d, J 8.6,6-H), 4.36 (2H, s, CH ₂ CH ₃ ), 2.91 in 2.89 (2 x 3H, 2 xs, 4CH ₃ and 3-CH 3) and 1.38 (3H, t, CH 2 CH 3); m / z (%) 331 (52, M +), 285 (100), 256 (32), 229 (12), 167 (14) in 149 (40); v _max (KBr tablet) / cm1 3414,3550,2212 in 1664.

f) 3 _g 4-Dimethyl-2 ~ ethoxycarbonylpyrrolo [3.2-b] carbazole-8- carboxylic acid

I A mixture of 3- (pyrrolylmethyl) indole (0.1 g, 0.3 mmol) and montmorillonite clay K10 (0.34 g) in toluene (15 cm ³ ) was stirred and refluxed for 6 hours. After cooling and separation by filtration from the clay, which was washed well with toluene, the combined filtrates were evaporated under reduced pressure to leave an orange solid. Recrystallization from methanol / dichloromethane gave the title compound as a yellow powder (0.027 g, 28%), mp> 260 ° C; (Found: C, 68.12; H, 5.19; N, 7.91. C2oH ₁₈ N ₂ 0 ₄ .0.05H20 requires C, 68.39; H, 5.19; N, 7.98%) ; 8d (PH ₆ ] -DMSO) 12.42 (1H, br, COOH), 11.30 (1H, s, 1-NH), 11.09 (1H, s, 5-NH), 8.68 (1H, s, 10H), 8.07- 7.93 (2H, m, 7-H and 9-H), 7.45 (1H, d, J 9, 6-H), 4.38 (2H, q, CH2CH3), 2.94 and 2.90 (2 x 3H, 2 x s, 4-CH ₃ and 3-CH ₃ ) and 1.39 (3H, t,

CH ₂ CH ₃ ); m / z (%) 350 (100, M +), 304 (100, 278 (40), 232 (35) in 181 (38); v _m "(KBr tablet) / cm ^_ 1 3459,1697 in 1674.

g) Ethyl 8-bromo-3 _g 4-dimethylpyrrolo [3 _g 2-b] k

carboxylate

Cmsc of 3- (pyrrolylmethyl) indole (0.3 g, 0.74 mmol) and montmorillonite clay K10 (1 g) in toluene were stirred and refluxed for 6 hours. After cooling and separation by filtration from the well washed with toluene, the combined filtrates were evaporated under reduced pressure to leave a brown solid residue which was subjected to flash chromatography on silica gel eluting with dichloromethane / light gasoline (7: 3). to give a yellow solid. Recrystallization from cyclohexane / ethyl acetate afforded the title compound as a yellow powder (0.070 g, 24%), mp> 204-205 ° C (decomposed); (Found: C, 59.17; H, 4.43; N,

7.30 C ₁₉ Hi ₇ BrN ₂ O ₂ , requires C, 59.23; H, 4.45; N, 7.27%); (pH _b ] DMSO) 11.26 (1H, s, 1-NH), 10.79 (1H, s, 5-NH), 8.30 (1H, d, J 2.2).

9-H), 7.92 (1H, s, 10-H), 7.47 (1H, dd, J 2.2 and 8.8 7-H), 7.35 (1H, d, J

8.8,6-H), 4.36 (2H, q, CH ₂ CH ₃ ), 2.89 and 2.88 (2 x 3H, 2 x s, 4-CH ₃ and 3CH ₃ ) and 1.38 (3H, t, CH ₂ CH 3) ; m / z (%) 386 and 384 (100, M +), 340 and 338 (70), 232 (60) and 181 (50); v _max (KBr tablet) / cm-1 3350, 1705 and 1663.

Example 4

Synthesis of Pyrrolocarbazoles in Only One Grade

A solution of indole (1.0 mmol) and 5-acetoxymethyl-4-acetylpyrrole (1.0 mmol) in 1,2-dichloroethane (10 cm ³ ) was stirred at low boiling water with montmorillonite clay K 10 (1 g) for 3-4 hours. The color of the clay changes to a pale brown and the completion of the reaction was determined by thin layer chromatography. After separation by filtration of the clay, which is well washed with 1,2-dichloroethane, the combined filtrates are evaporated. Recrystallization from dichloromethane or ethyl acetate afforded pyrrolo [3,2-Scarbazoles as yellow crystals.

a) Ethyl 3,4-dimetilgshrolo [3 ₁ 2-b] carbazole-2-carboxylate (0.199 g, 65%) was obtained from the reaction of indole and 5atsetoksimetil-4-acetylpyrrole. He is identical in every one

ratio with the pyrrolo [3,2-b] carbazole of Example 1.

B) Benzyl 3,4-dimethylpyrrolo [3 _! 2-b] carbazole-2-carboxylate (0.179 g, 48.8%) was obtained by the reaction of indole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 229-232 ° C (Found: C, 78.2; H, 5.65; N, 7.8. C24H20N2O2, requires C, 78.23; H, 5.47; N, 7.60%); bd (PH ₆ ] -DMSO) 11.29 (1H, s,

1-NH), 10.65 (1H, s, 5-NH), 8.08 (1H, d, J 8, 9-H), 7.89 (1H, s, 10-H) - 7.56-7.34 (7H, t, ArH , 6-H and 7-H), 7.08 (1H, t, J 7, 8-H), 5.42 (2H, s, CH ₂ Ph), 2.92 (6H, s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 368 (74, M +), 354 (10), 260 (100), 264 (13), 231 (20) and 91 (31).

Pyrrolo [3,2-Scarbazole (0.166 g, 45%) was also obtained by the reaction of indole and 4-acetyl-5- (ethoxymethyl) pyrrole.

^c )

Ethyl 8-methoxy-3, 4-dimethylpyrrolo [3,2-b] k

ZOL-2-.

carboxylate is obtained by the reaction of 5-methoxyindole and 5 acetoxymethyl-4-acetylpyrrole. It has a melting point of 119-122 ° C (Found: C, 71.6; H, 6.0; N, 8.05. C20H20N2O3 requires C, 71.4; H, 5.99; N, 8.33%); bd (PH ₆ ] -DMSO) 11.20 (1H, s,

1-NH), 10.38 (1H, s, 5-NH), 7.85 (1H, s, 10-H), 7.62 (1H, d, J 2.5, 9H), 7.31 (1H, d, J 9, 6- H), 7.01 (1H, dd, J 9 and 2.5, 7-H), 4.38 (2H, q,

OCH 2 CH 3), 3.88 (3H, s, OCH 3), 2.87 (2 x 3H, 2 x s, 3-CH 3 and 4-CH ₃ ) and 1.39 (3H, t, OCH ₂ CH 3); m / z (%) 336 (60, M +), 290 (100), 275 (5), 262 (4), 247 (23), 219 (8) and 145 (9). '

d) Benzyl 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate (0.139 g, 35%) was reacted with the reaction of 5methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 212-215 ° C (Submitted: C, 75.4; H, 5.55; N, 6.95. C25H22N2O3 requires C, 75.4; H, 5.57; N, 7.03%); 5H ([2H 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 2.5, 9-H), 7.58 -7.36 (5H, m, AgH), 7.32 (1H, d, J 9, 6H), 7.02 (1H, dd, J 9 and 2.5, 7-H), 5.43 (2H, s, CT), 3.88 (3H , s, OCH3), 2.92 (3H, s, 4-CH3) and 2.89 (3H, s, 3-CH3); m / z (%) 398 (73, M +), 290 (100), 262 (10), 247 (15), 219 (7) and 91 (17).

e) Ethyl 8-fluoro-3, 4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate / (0.131 g, 40.5%) was obtained by the reaction of 5-

fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 231-234 ° C (Found: C, 70.5; H, 5.3; N,

8.4. C ₁₉ Hi ₇ FN ₂ O ₂ requires C, 70.4; H, 5.28; N, 8.64%); 5h (pH ₆ ) -

DMSO) 11.27 (1H, s, 1-ΝΉ), 10.64 (1H, s, 5-NH), 7.93 (1H, dd, J 9 and

2.5, 9-H), 7.88 (1H, s, 10-H), 7.36 (1H, dd, J 9 and 6, 6-H), 7.19 (1H, dt, J 9 and 2.5, 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 ); m / z (%) 324 (50, M +), 278 (100), 250 (31), 220 (10), 139 (8), 125 (7) and 111 (8).

f) Benzyl 8-fluoro- _3f 4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate (0.155 g, 40%) was obtained by reacting 5fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 217-219 ° C (Found: C, 74.6; H, 4.95; N,

73. C24H _u FN2O ₂ requires C, 74.6; Η, 4.96; N, 7.25%; H ^([2 H _6] DMSO) 11.36 (1H, s, 1-NH), 10.86 (1H, s, 5-NH), 7.94 (1H, dd, J 9 u 25,9-H), 7.89 (IH , s, 10-H), 7.56-7.38 (5H, m, ArH), 739 (1H, dd, J 9 in 4,6-H), 7.21 (1H, dt, J 9 in 2.5, 7-H) , 5.42 (2H, s, CH ₂ Ph), 2.91 in 2.90 (2 x 3H, 2 xs, 3-CH _{3 in} 4-CH ₃ ); m / z (%) 386 (68, M +), 278 (100), 249 (22) in 91 (43).

g) Ethyl 3,4, 6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate (0.206 g, 64.4%) was obtained by the reaction of 7methylindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 230 ° C (decomposition). (Found: C, 74.9; H, 6.25; N, 8.65. C ₂ OH 2 O ₂ requires C, 75.0; H, 6.29; N, 8.74%); bn (PH ₆ ] -DMSO) 11.20 (1H, s, 1-NH), 10.11 (1H, s, 5-NH), 7.89 (1H, d, J 75, 9-H), 7.84 (1H, s. 10-H), 7.18 (1H, d, J 75, 7-H), 7.01 (1H, t, J 75.8-H), 4.37 (2H, q, OCH2CH3), 2.98 (3H, s, 4- CH ₃ ), 2.91 (3H, s, 3CH 3), 258 (3H, s, 6-CH 3) and 134 (3H, t, OCH ₂ CH ₃ ); m / z (%) 320 (54, M +), 274 (100), 246 (30), 230 (5), 137 (9), 123 (7) and 109 (6).

h) Benzyl 3,4,6-trimethylpyrrolo [3.2-b] carbazole-2-carboxylate

(0.167 g, 43.7%) was obtained by reacting 7 methylindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 222 ° C (decomposition). (Found; C, 785; H, 5.9; N, 7.25. C ^ H ^ O 2 requires C, 785; H, 5.80; N, 7.33%); bn (HPLC-DMSO) 11.27 (1H, s, 1-NH), 10.11 (1H, s, 5-NH), 7.89 (1H, d, J 7.9-H), 7.85 (1H, s, 10- H), 756-7.35 (5H, m, ArH), 7.18 (1H, d, J 7, 7-H), 7.08 (1H, t, J, 8-H), 5.43 (2H, s, CH ₂ Ph. ), 2.99 (3H, s, 4-CH _3),

2.93 (3H, s, S-CH3) u 259 (3H, s, 6-CH _3); m / z (%) 382 (71, M +), 274 (100), 246 (19) in 91 (22).

i) Benzyl 3- (2-l {ethoxycarbonylethyl) -4-methylpyrrolo [3.2-b] carbazole-2-carboxylate (0.230 g, 52.3%) was obtained by the reaction of indole and 5acetoxymethyl-4-acetylpyrrole. It has a melting point! 211-213 ° C (Found: C, 73.7; H, 5.6; N, 6.2. C27H24N2O4 requires C, 73.6; H, 5.49; N, 6.36%); bn (pH ₆ ] -DMSO) 11.51 (1H, s,

1-NH), 10.71 (1H, s, 5-ΝΉ), 8.75 (1H, d, J 7.5, 9-H), 7.92 (1H, s, 10H), 7.57-7.44 (7H, t, ArH, 6 -H and 7-H), 7.18 (1H, t, J 7.5, 8-H), 5.43 (2H, s, CH2PH), 3.63 (3H, s, OCH3), 3.59 (2H, partially shaded, t, CH ₂ CH ₂ CO), 2.88 (3H, s, 4-CH 3) and 2.65 (2H, t, CH ₂ CO); m / z (%) 440 (100, M +), 332 (20), 290 (47) and 91 (57).

j) Ethyl 3 _r 4 _t 5-trimethylpyrrolo [3'2-b] carbazole-2carboxylate (0.140 g, 16%) was obtained by reacting (2.65 calculated) between N-methylindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 208 ° C (decomposition). (Found: C, 75.12; H, 6.40; N, 8.69. C20H20N2O2 requires C, 74.98; H, 6.29; N, 8.74%); / 5h (PH ₆ ] -DMSO) 11.28 (1H, s, ί-ΝΗ) ; 8.08 (1H, d, J 7.9, 9H), 7.88 (1H, s, 10-H), 7.44 (2H, m, 6-H, 7-H), 7.07-7.17 (1H, m, 8H), 4.36 (2H, q, CH2CH3), 4.01 (3H, s, 5-CH _3), 3.13 (3H, s, 4-CH _3), 2.90 (3H, s, H-CH 3) u 1.38 (3H, t, CH ₂ CH ₃ ); m / z (%) 320 (72, M +), 274 (100), 245 (16), 149 (28) in 137 (12); (KBr tablet) / cm-1 3329 u1670.

k) Benzyl 3 _t 4,5-trimethylpyrrolo [S] b] carbazole-2carboxylate (0.220 g, 57%) was obtained by reaction between N-methylindole and 5-acetoxymethyl-4-acetylpyrrole in toluene at 55 ° C catalyzed by toluene-4 -sulfonic acid. It has a melting point of 228-229 ° C. (Found: C, 77.17; H, 5.73; N, 7.09. C25H22N2O2.O.33H2O requires C, 77.31; H, 5.88; N, 7.21%); bd (pH ₆ ] -DMSO) 11.28 (1H, s, 1-NH), 8.03 (1H, d, J 7.5, 9-H), 7.88 (1H, s, 10-H), 7.56-7.34 (7H, m, ArH, 6-H, 7-H), 7.15-7.07 (1H, m, 835)

Η), 5.40 (2Η, s, CH ₂ Ph), 4.02 (3H, s, 5-CH ₃ ), 3.14 (3H, s, 4-CH ₃ ) in

2.91 (3H, s, 3-CH ₃ ); m / z (%) 382 (72, M +), 291 (4), 274 (100) in 91 (34); Vmax (KBr tablet) / cm ^-1 3337 in 1674.

1) Ethyl 1,3 _r 4-trimethylpyrrolo [3 _t 2-b] carbazole-2-carboxylate

(0.060 g, 7%) was obtained by reacting (2.5 mmol calculated) between indole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 188-189 ° C. (Found: C, 74.86; H, 6.32; N, 8.65. C ₂ oH ₂ oN ₂ 02 requires C, 75.98; H, 6.29; N, 8.74%) ;

5H (PH ₆ ] -DMSO) 10.66 (1H, s, 5-NH), 8.14 (1H, d, J 7.7, 9-H), 8.03 (1H, s, 10-H), 7.45-7.31 (2H. m, 6-H, 7-H), 7.06-7.15 (1H, t, 8-H), 4.38 (2H, q, CH ₂ CH ₃ ), 3.98 (3H, s, 1-CH ₃ ), 2.91 ( 3H, s, 4-CH ₃ ), 2.83 (3H, s, 3-CH ₃ ) and 1.38 (3H, t, CH ₂ CH 3); m / z (%) 320 (M +, 100), 306 (10), 292 (30), 247 (8) and 231 (10); v _max (KBr tablet) / cm-1 3385 and 1657.

t) l _f 3 _f 4-mpu3iemuAnupo4o [3 _f 2-b] kap6a3Q4-2-

carboxylate (0.240 g, 28%) was obtained by reaction (2.7 mmol calculated) between indole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 186-187 ° C. (Found: C, 78.63; H, 5.83; N, 7.32. C25H22N2O2. Requires C, 78.51; H, 5.80; N, 7.32%); 8H (pH ₆ ] DMSO) 10.66 (1H, s, 5-NH), 8.14 (1H, d, J 7.4, 9-H), 8.02 (1H, s, 10H), 7.56-7.31 (7H, m, AgH , 6-H, 7-H), 7.06-7.15 (1H, m, 8-H), 5.41 (2H, s, CH ₂ Ph), 3.98 (3H, s, 1-CH ₃ ), 2.90 (3H, 3H). s, 4-CH ₃ ) and 2.83 (3H, s, 3-CH ₃ ); m / z (%) 382 (M +, 100), 338 (10), 291 (44), 247 (18) and 231 (10); v _max (KBr tablet) / cm ^-1 3443 and 1697.

n) Ethyl 1,3,4, 5 _f -tetrametilpirolo [3,2-b] carbazole-2-carboxylate (0.220 g, 30%) was obtained from the reaction (2.2 calculated) between Nmetilindol and 5-acetoxymethyl-4-acetylpyrrole. It has a ³⁶ ί mp 165.5-167 ° C (decomposition). (Found: C, 75.50; H, 6.65; Ν, 8.30. C12 H14 N4 requires C, 75.47; H, 6.63; N, 8.38%); bn (pHgJ-DMSO) 8.15 (1H, d, J 7.5, 9-H), 8.07 (1H, s, 10H), 7.50-7.38 (2H, m, 6-H, 7-H), 7.09-7.19 ( 1H, m, 8-H), 4.38 (2H, q, CH2CH3), 4.03 (3H, s, 5-CH3), 3.96 (3H, s, I-CH3), 3.14 (3H, s, 4CH3), 2.84 (3H, s, 3-CH 3) and 1.39 (3H, t, CH ₂ CH 3); m / z (%) 334 (100, M +), 306 (18) and 245 (6); y _t "(KBg tabletUspg ¹ 1690 and 1528.

o) Benzyl 1,3,4,5-tepts> amethylpyrrolo [3,2-b] carbazole-2carboxylate (0.070 g, 13%) was obtained by reaction (1.4 mmol calculated) between N-methylindole and 5-acetoxymethyl-4 -acceptspyrrole. It has a melting point of 196-198 ° C. (Found: C, 78.45; H, 6.16; N, 6.94. S2bN ^ ₂ O ₂ requires C, 78.76; H, 6.10; N, 7.07%) ; H ^([2 H _6] DMSO) 8.15 (1H, d, J 7.8,9-H), 8.07 (1H, s, 10-H), 7:59 to 7:29 (7H, m, Ar H, 6-H, 7 H), 7.10-7.20 (1H, m, 8-H), 5.42 (2H, s, CH ₂ Ph), 4.03 / (3H, s, 5-CH 3), 3.97 (3H, s, I-CH 3). 3.13 (3H, s, 4-CH ₃ ) and 2.83 (3H, s, 3-CH 3); m / z (%) 396 (100, M +), 305 (38), 245 (16) and 235 (10);

(KBr tablet) / cmg ¹ 1696 and 1529.

p) Benzyl 3,4-dimethyl-5- (4-toluenesulfonyl) pyrrolo [3,2-b] carbazole-2-carboxylate (0.012 g, 4%) was obtained by reaction (0.6 mmol calculated) between N- (4- toluenesulfonyl) indole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 270 ° C. (Found: C, 70.83; H, 5.01; N, 5.23. C 1 H 2 Cl 2 S requires C, 71.24; H, 5.01; N, 5.36%);

(pHg] -DMSO) 11.58 (1H, s, NH), 8.28-8.08 (3H, m, 6-H, 9-H, 10H), 7.66-7.21 (11H, m, AgH, TsH, 7-H. 8-H), 5.40 (2H, s, CH ₂ Ph), 3.04 (3H, s, 4-CH 3) and 2.88 (3H, s, 3-CH 3) and 2.20 (3H, s, Ts-CH ₃ ); m / z (%) 523 (30, M (+ 1)), 446 (20), 367 (30), 348 (56), 33 (100), 295 (30) and 274 (90); v _max (KBr tablet) / cm ^-1 3558 and 1666.

4m

q) Ethyl 7-acetoxy-3 _{ 4-dimethyl-6-methoxypyrrolo [3 _! 2-b] carbazole-2-carboxylate (7%) was obtained by reaction between 6-acetoxy-7-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. It has a temperature of

mp 241-244 ° C. bn (CDCl3) 8.59 (1H, s, br, NH), 7.78 (1H, s, br, NH), 7.76 (1H, s, 10-H), 7.74 (1H, d, J 8.9-H) , 6.88 (1H, d, J 8, 8-H), 4.44 (2H, q, CH ₂ CH ₃ ), 4.04 (3H, s, 6-OCH 3) 2.96 in 2.92 (2 x 3H, 2 xs, 4- CH3 and 3-CH3), 2.42 (3H, s, 7-CH3COO) in 1.46 (3H, t, CH ₂ CH ₃ ); m / z (%) 394 (100, M +), 352 (47), 348 (33), 306 (87), 263 (21) in 87 (73); v _max (nuyol) / cm ^-1 3413,3341,1739 u 1675; in _max (MeOH) / nm 405, 386,

339, 325, 305, 269, 240 at 226. (Found: M + 1, 394, 1529.

C ₂₂ H ₂₂ N ₂ O5 requires 394.1529.)

r) Ethyl 9-m, ethoxy-3.4 _{g of} 5-trimethylpyrrolo [3 _! 2-b] carbazole-

2-Carboxylate was obtained by reaction between 4-methoxy-1-methylindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 263-266 ° C. (Found: C, 71.84; H, 6.34; N, 7.91. C ₂₁ H ₂₂ N ₂ O ₃ requires C, 71.98; H, 6.33; N, 7.99%); 5H (CDCl 3) 8.60 (1H, s, br, NH), 8.15 (1H, s, 10-H), 7.40 (1H, t, J 8, 7-H), 6.95 (1H, d, J 8.6) -H), 6.66 (1H, d, J 8.8-H), 4.43 (2H, q, CH ₂ CH ₃ ), 4.10 and 4.04 (2 x 3H, 2 x s, N-CH 3 and OST), 3.19 (3H, s, 4-CH ₃ ), 2.98 (3H, s, 3-CH 3) and 1.46 (3H, t, OCH ₂ CH 3); m / z (%) 350 (74, M +), 304 (100), 276 (17), 223 (10) and 152 (19).

s) Benzyl 8-chloro-3, 4-dimethylpyrrolo [3.2-b] carbazole-2carboxylate (0.069 g, 17%) was obtained by reacting 5-chloroindole and 5-acetoxymethyl-4-acetylpyrrole. It has a melting point of 215-220 ° C (decomposed) (Found: C, 71.42; H, 4.96; N, 7.11. C 1 H H 2 Cl 2 O 2 requires C, 71.55; H, 4.75; N, 6.95%); 5H (pH ₆ ] DMSO) 11.39 (1H, s, 1-NH), 10.84 (1H, s, 5-NH), 8.17 (1H, s, 9-H), j38

7.93 (1H, s, 10-H), 7.54 (1H, d, J 7, 7-H), 7.48-7.34 (6H, m, ArH in 6H), 5.42 (2H, s, CH ₂ Ph), 2.88 (6H, s, 3-CH _{3 in} 4-CH ₃ ); m / z (%) 402 (30, M +), 358 (5), 294 (65), 267 (25) in 91 (100). The crystallization liquids are subjected to flash chromatography on silica gel. Elution with ethyl acetate / light gasoline gave the title compound which was recrystallized from ethyl acetate (0.030 g, 7%) and 3- (3 ^, -acetyl-5 ^, -benzyloxycarbonyl4 ^, -methylpyrrol-2 ^T -methyl) -5-chloroindole in the form of beige colored crystals (0.152 g, 36%), mp 141-143 ° C (Found: C, 68.20; H, 5.18; N, 6.60. C24H21CIN2O2 requires C, 68.49; H, 5.03; N, 6.65 %); 5H (CDCl 3) 8.72 (1H, s, Γ-ΝΗ), 8.26 (1H, s, 1-NH), 7.38 (1H, d, J 2,4-H), 7.35 (6H, m, ArH and 6- H), 7.18 (1H, dd, J 8 and 2, 2-H), 7.09 (1H, d, J 2, 2-H), 5.23 (2H, s, CH ₂ Ph), 4.39 (2H, s, 3-CH 3), 2.64 (3H, s, 4'-CH ₃ ) and 2.52 (3H, s, CH ₃ CO); m / z (%) 420 (20, M +), 405 (10), 311 (20, 151 (15) and 91 (100). I

t) Epilab.2 N -di-ethyl-in-hydroxypyrrolo [3,2-b / carbazole-2carboxylate was obtained by reaction between 5-hydroxyindole and 5acetoxymethyl-4-acetylpyrrole. It has a melting point of 250 ° C (decomposition). 8Hz (pHgJ-DMSO) 11.11 (1H, s, b, 1NH), 10.21 (1H, s, 5-NH), 8.83 (1H, s, OH), 7.73 (1H, s, 10-H), 7.37 ( 1H, d, J 2.5, 9-H), 7.21 (1H, d, J 8, 6-H), 6.87 (1H, dd, J 8 in 2.5, 9H), 7.21 (2H, q, OCH2CH3), 2.87 (3H, s, 4-CH ₃ ) in 2.84 (2H, s, 3CH ₃ ) in 1.38 (3H, t, OCH 2 CH ₃ ); m / z (%) 322 (69, M +), 276 (100), 248 (24) 220 (3) in 138 (15); (Found: M +, 322. 1322 C ₁₉ Hi ₈ N ₂ O 3 requires M, 322.1317). The reaction mixture was isolated also hd ^{(3'-atsetid-5-ethoxycarbonyl-4'-mstiApirol-2 T} -ilmstil) -5hidroksiindol, which has a melting point 99-102 ° C (Found: C, 66.89; H, 6.17; N, 8.03 C19H20N2O4 requires C, 67.04;

H, 5.9¾ Ν, 8.23%); 8H (CDd ₃ ) 8.84 (1Η, s, Γ-ΝΗ), 8.14 (1H, s, 1NH), 7.20 (1H, d, J 8, 7-H), 7.10 (1H, d, J 2.5, 2- H), 6.81, d, J 1.5, 4H), 6.79 (1H, dd, J 1.5 ΰ 8.6-H), 5.60 (1H, s, br, 5-OH), 4.31 (2H, s, CH ₂ ), 4.21 (2H, q, OCH ₂ CH ₃ ), 2.58 (3H, s, 4'-CH ₃ ), 2.48 (3H, s, 3'COCH ₃ ) at 1.27 (3H, t, OCH ₂ CH ₃ ) ; m / z (%) 340 (100, M +)> 325 (44), 293 (21), 279 (35), 266 (35), 251 (31) 223 (25), 196 (5), 147 (20 ) at 133 (36).

u) Benzyl 3,4-dimethyl-7-fluoropyrrolo [3,2-b] carbazole-2carboxylate and Benzyl 3,4-dimethyl-8-fluoropyrrolo [23-b / carbazole-2-carboxylate were prepared as a mixture of isomers by reaction of 6fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gave the [3,2-b] isomer (0.139 g, 36%), mp 205 ° C (decomposed) 5h (pHjJ-DMSO) 11.32 (1H, s, 1-NH), 10.85 ( 1H, s, 5-NH), 8.08 (1H, dd, J 9 and 6,9-H), 7.86 (1H, s, 10-H), 7.57-7.35 (5H, m, AgH), 7.12 (1H , dd, J 10 and 2, 6H), 6.90 (1H, dt, J 9 and 2, 8-H), 5.43 (2H, s, CH ₂ Ph), 2.91 (3H, s, 3CH ₃ ) and 2.90 ( 3H, s, 4-CH ₃ ); m / z (%) 386 (55, M +), 342 (5), 295 (4), 278 (100), 249 (45), 236 (20), 222 (25) and 91 (95); (Found: MH +, 387. 1509. C ₂₄ H ₂₀ FN ₂ O ₂ requires 387.1509); and [2 _D 3-b] isomer, mp 190-193 ° C; 5h (CDCl ₃ ) 8.54 (1H, s br, 1-NH), 8.10 (1H, dd, J 9 and 6, 5-H), 7.87 (1H, s, br, 9-NH), 7.51-7.34 ( 5H, m, Ar), 7.34 (1H, s, 10-H), 7.22 (1H, dd, shaded by 10-H, 8-H), 6.93 (1H, dt, J 2 and 9, δ-Η) , 5.41 (2H, s, CH ₂ Ph). 3.20 (3H, s, 4-CH ₃ ), and 3.00 (3H, s, 3-CH ₃ ); m / z (%) 386 (100, M +), 295 (12) 278 (96), 250 (27), 236 (7), 222 (8) and 91 (59). (Found: M +, 386.1433. C ₂₄ H ₁ 9FN ₂ O ₂ requires 386.1431.)

ν) Ethyl 3,4-dimethyl-7-fluoropyrrolo [3,2-b] carbazole-2carboxylate and Ethyl 3,4-dimethyl-8-fluoropyrrolo [23-b] carbazole-2-carboxylate were taught as a mixture of isomers at The interaction of 6fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gave the [3,2-b] isomer recrystallized from dichloromethane, mp 231-234 ° C (Found: C, 70.45; H, 5.53; N, 8.66. C ₁₉ H ₁₇ FN ₂ O ₂ requires C, 70.36; H, 5.28; N, 8.634%); 5H (HPLC-DMSO) 11.27 (1H, s, br, 1-NH), 10.82 (1H, s, br, 5-NH), 8.90 (1H, dd, J 9 in 6, 9-H), 7.85 ( 1H, s, 10-H), 7.12 (1H, dd, J 10 in 2,6-H), 6.89 (1H, dt, J 2 in 9, 8-H),

4.37 (2H, q, OCH2CH3) , 2.89 (6H, s, 4-CH ₃₎ u 1.39 (3H, t, © OCH ₂ CH _3); m / z (%) 324 (60, M +), 278 (100 ), 250 (34), 222 (10), u

139 (7); (Found: M +, 324.1267. Ci ₉ H ₁₇ FN ₂ O ₂ requires 324.1274); and the [2,3-b] isomer. mp 262-265 ° C; bz (pHv] DMSO) 11.14 (1H, s, br, 1-NH), 11.06 (1H, s, br, 9-NH), 8.12 (1H, dd, J6 and 9.5-H), 7.19 ( 1H, s, 10-H), 7.15 (1H, dd, J 10 in 2, 8-H), 6.92 (1H, dt, J 2 in 9, 6-H), 4.36 (2H, q, OCH ₂ CH _3), 3.13 (3H, s, 4-CH _3),

2.93 (3H, s, 3-CH ₃ ) in 1.39 (3H, t, OCH ₂ CH ₃ ); m / z (%) 324 (72, M +), 278 (100), 250 (39), 222 (9), 139 (6) in 125 (7). (Found: M +, 324. 1280. Ci ₉ H ₁₇ FN ₂ O ₂ requires 324.1274.)

w) Ethyl 3,4-dimethyl-9-hydroxy pyrrolo [3,2-b] carbazole-2 © carboxylate and Ethyl 3,4-dimethyl-5-hydroxypyrrolo [2.3-b] carbazole-2-carboxylate were prepared as a mixture of isomers by reaction between 4-hydroxyindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gave the [3,2-b] isomer. which is recrystallized from ethyl acetate / light gasoline, mp 260-262 ° C (decomposition); bn (pHeJ-DMSO) 11.13 (1H, s, 1NH), 10.56 (1H, s, 5-NH), 10.00 (1H, s, OH), 8.02 (1H, s, 10-H), 7.12 (1H. t, J 7.5 7-H), 6.83 (1H, d, J 7.5, 6-H), 6.48 (1H, d, J 7.5, 8-H), 4.39 (2H, q, OCH ₂ CH ₃ ), 2.87 (3H, s, 4-CH ₃ ), 2.85 (3H, s, 3-CH ₃ )

1.38 (3H, t, OCH ₂ CH ₃ ); m / z (%) 322 (61, M +), 276 (100), 248 (20),

219 (5), at 138 (11); (Found: M +, 322.1305. CwHigNjCb requires 322.1317); and the [2.3-b] isomer which is recrystallized from ethyl acetate, mp 251-254 ° C (decomposed); bz (PH ₆ ] -DMSO) 10.95 (1H, s, 1-NH), 10.85 (1H, s, 9-H), 9.89 (1H, s, OH), 7.08 (1H, t, J 7.5, 7- H), 7.07 (1H, s, 10-H), 6.77 (1H, d J 7.5, 8H), 6.52 (1H, d, J 7.5, 7-H), 4.32 (2H, q, OCH ₂ CH ₃ ) , 3.44 (3H, s, 4CH ₃ ), 2.92 (3H, s, 3-CH ₃ ) in 1.37 (3H, t, OCH ₂ CH ₃ ); m / z (%) 322 (65, M +), 276 (100), 248 (88), 219 (15), 205 (10), 191 (10), 178 (5), 165 (5), 138 ( 10) in 115 (10). (Found: M < + >, 322. 1317. CiHiHiNgOi requires 322.1317.)

x) Ethyl 6 _{g of} 9-dimethoxy-3,4-dimethylpyrrolo [3,2-b] carbazole2-carboxylate and Ethyl 5,8-guemeno-3,4-dimethylpyrrolo [2,3-b] carboxazole-2-carboxylate were obtained as a mixture of isomers by reaction between 4,7-dimethoxyindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gave the [3,2-b] isomer (13.7%), mp 256-258 ° C; (Found: C, 68.98; H, 6.23; N, 7.89. C ₂₁ H ₂₂ N ₂ O ₄ requires C, 68.84; H, 6.05; N, 7.65%); δ h (CDQ ₃ ) 8.58 (1H, s, br, 1-NH), 8.08 (1H, s, 10-H), 7.84 (1H, s, br, NH), 6.82 (1H, d, J 8). 7-H), 6.50 (1H, d, J 8, 8-H), 4.43 (2H, q, 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 ), at 1.44 (3H, t, OCH ₂ CH ₃ ); m / z (%) 366 (73, M +), 326 (100), 305 (11), 290 (11), 277 (23), 262 (15), 183 (10), 160 (17), 152 ( 19) at 131 (7); v _mal (nuyol) / cm-1 3474, 3323 and 1674;

(MeOH) / nm 415, 387, 344, 330 (c offset), 305 (c offset), 266, 246 u 220; and [? 3-b] isomer (9.3%), mp 193-195 ° C; (Found: C, 69.03; H, 6.29; N, 7.42. C ₂ H ₂₂ N ₂ O ₄ requires C, 68.84; H, 6.05; N, 7.65%); (CDQ ₃ ) 8.44 (1H, s, br, NH), 8.10 (1H, s, br, NH), 7.06 (1H, s, 10-H), 6.82 (1H, d, J 8, 7-H) ,

6.56 (1H, d, J 8.6-H), 4.40 (2H, q, OCH ₂ CH ₃ ), 3.98 (3H, s, 9-OCH ₃ ),

3.97 (3H, s, 6-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 ); m / z (%) 366 (100, M +), 320 (82), 292 (20), 277 (24), 262 (10), 183 (14), 160 (28), and 131 (3); (nuyol) / cm-1 3457, 3345 and 1660; (MeOH) / pt 381, 365 '293,247 and 219.

y) Ethyl 7-methoxy-3-dimethylpyrrolo [3 _: 2-b] carbazole-2-carboxylate and Ethyl 7-methoxy-3,4-dimethylpyrrolo [2'3-b] carbazole-2-carboxylate were obtained as a mixture of isomers at the interaction between 6-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. Flash chromatography on silica gel eluting with ethyl acetate / cyclohexane (1: 1) gave the [3.2-b] isomer. which is recrystallized from ethyl acetate / cyclohexane, mp 239-241 ° C (decomposed); H ^([2 H _6] -DMSO) 11.09 (1H, s, 1-NH), 10.49 (1H, s, 5-NH), 7.91 (1H, d, J 8.7, 9-H), 7.73 (1H, s, 10H), 6.88 (1H, d, J 2.3, 6-H), 6.68 (1H, dd, J 8.7 and 2.3, 8-H), 4.35 (2H, q, OCH ₂ CH ₃ ), 3.84 (3H , s, 7-OCH ₃ ), 2.07 (3H, s, 3-CH ₃ ), 2.86 (3H, s, 4-CH ₃ ) and 1.37 (3H, t, OCH ₂ CH 3); m / z (%) 336 (84, M +), 290 (100), 262 (32), 247 (16) and 219 (16); v _max (KBr tablet) / cm-1 3342, 1674 and 1628; and [2,3-b] isomer which is recrystallized from ethyl acetate / cyclohexane, mp 260 ° C (decomposed); bn ([2H ₆ ] -DMSO) 10.98 (1H, s, 1-NH), 10.74 (1H, s, 9-NH), 8.00 (1H, d, J 8.7, 5-H), 7.13 (1H, s , 10-H), 6.87 (1H, d, J 2.7, 8-H), 6.70 (1H, dd, J 8.7 and 2.7, 6-H), 4.34 (2H, q, OCH ₂ CH ₃ ), 3.83 ( 3H, s, 7-OCH ₃ ), 3.10 (3H, s, 4-CH ₃ ), 2.91 (3H, s, 3-CH ₃ ) and 1.37 (3H, t, OCH ₂ CH ₃ ); m / z (%) 336 (56, M +), 290 (70), 262 (26), 145 (16) and 129 (14); v _max (KBr tablet) / cm ^-1 3379, 3339 and 1663.

ζ) Ethyl 3-ethyl-4-methylpyrrolo [3 _g 2-b] carbazole-2-carboxylate (0.956 g, 27%) was obtained by the reaction (11 mmol calculated) between indole and ethyl 5-acetoxymethyl-4-acetyl- 3ethylpyrrole-2-carboxylate. After recrystallization from toluene, it has a melting point of 248-249 ° C (decomposed) (Found: C, 74.93; H, 6.35; N, 8.60. C20H20N2O2 requires C, 74.98;

H, $ .29; N, 8.74%); bd (pH ₆ ] -DMSO) 11.27) (1H, s, 1-NH), 10.63 (1H, s, 5-NH), 8.09 (1H, d, J 8, 9-H), 7.93 (1H, s , 10-H), 7.47-7.31 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J 8, 5.5, 2, 8-H), 4.40 (2H, q, J 7, CO ₂ CH ₃ ), 3.37 (2H, q, J, 3-CH ₂ ), 2.91 (3H, s, 4-CH ₃ ), 1.41 (3H, t, J 7, CO ₂ CH ₂ CH ₃ ) at 1.30 (3H, t, J 7.5, 3-CH ₂ CH ₃ ); m / z (%) 320 (M +, 100), 274 (96); v _max (KBr tablet) / cm-1 3344, 3327, 1680, 1664,1238.

Example 5

Pyrrolo [3,2-b] carbazole-2-carboxylic acids. General method of production

To a solution of benzylpyrrolo [3,2-b] carbazole-2carboxylate in dry tetrahydrofuran (THF) (10 cm ³ ) was added a catalyst of 10% Pd on C (50 mg). The reaction mixture is hydrogenated at room temperature and under one atmosphere. After the H 2 was no longer removed, the catalyst was removed by filtration through celite and washed thoroughly with tetrahydrofuran. The combined filtrates were evaporated under reduced pressure. Recrystallization of the resulting dry residue from acetone, methyl ethyl ketone or aqueous methanol afforded pyrrolo [3,2-b] carbazole-2carboxylic acids as yellow crystals.

a) 3,4-Dimethylpyrrolo [3.2-b] carbazole-2-carboxylic acid (0.234 g, 84.3%); mp 237 ° C (dec), bp ^([2 H _6] -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 7.5, 9-H), 7.87 (1H, s, 10-H), 7.42 (1H, d, J 7.5, 6-H), 7.36 (1H, t , J 7.5, 7-H), 7.08 (1H, t, J 7.5, 8-H), 2.92 and

2.91 (2 x 3H, 2 x s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 278 (30, M +), 260 (39), *

234 (100), 218 (19), 204 (8), 167 (8), 149 (16), 130 (10) in 117 (25).

(Found: M +, 278.1060. C47H14N2O2 requires Μ, 278.1055.)

B) 8-Fluoro-3,4-dimethylpyrrolo [3.2-b] carbazole-2-carboxylic acid (0.0845 g, 85.6%); mp 236-239 ° C. db (pHv] DMSO) 12.80 (1H, br, s, CO ₂ H), 11.19 (1H, s, 1-NH), 10.60 (1H, s, 5NH), 7.91 (1H, dd, J 9 and 2.5, 9-H), 7.86 (1H, s, 10-H), 7.37 (1H, dd, J 9 and 4,6-H), 7.20 (1H, dt, J 9 and 2.5, 7-H) and 2.89 and 2.91 (6H, s, 2 x 3CH3); m / z (%) 296 (51, M +), 278 (71), 252 (100), 250 (37), 236 (19), 222 (13), 139 (22), 125 (36) and 111 (28) (Found: M +, 296.0960. C47H13FN2O2 requires M, 296.0961.)

c) 3,4,6-Trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.065 g, 85%); mp 230 ° C (decomposition). (Found: C, 74.2; H, 5.55; N, 9.4. C18H16N2O2 requires C, 74.0; H, 5.52; N, 9.58%); bd (PH ₆ ] -DMSO) 12.80 (1H, br, s, CO ₂ H), 11.01 (1H, s, 1-NH), 10.08 (1H, s, 5-NH), /.90 (1H, d , J 7.5, 9-H), 7.82 (1H, s, 10-H), 7.16 (1H, d, J 7.5, 7-H), 7.01 (1H, t, J 7.5, 8-H), 2.97 ( 3H, s, 4-CH3), 2.92 (3H, s, 3-CH3) and 2.58 (3H, s, 6-CH3); m / z (%) 292 (72, M +), 274 (100), 246 (50), 230 (11), 137 (25), 122 (24) and 109 (30).

d) 3- (2-Methoxycarbonylethyl) -4-methylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.0673 g, 84.6%); mp 255 ° C (decomposition). (Found: C, 68.4; H, 5.3; N, 7.75. C20H18N2O4 requires C, 68.6; H, 5.18; N, 8.00%); 5H (PH ₆ ] -DMSO) 12.88 (1H, br, s, CO ₂ H), 11.34 (1H, s, 1-NH), 10.65 (1H, s, 5-NH), 8.06 (1H, d, J 7.5, 9-H), 7.88 (1H, s, 10-H), 7.42 (1H, d, J 7.5, 6-H), 7.36 (1H, d, J 7.5.7-H), 7.07 (1H, t, J 7.5, 8-H), 3.66 (3, H, s, OCH ₃ ), 3.66 (2, H, partially shaded t CH2CH2CO), 2.89 (3H, s, 4-CH3), 2.66 (2H, t , CH ₂ CO); m / z (%) 350 (100, M +), 332 (17), 306 (30), 290 (63), 272 (22), 259 (32) and 233 (47).

f) 1,3,4, -Trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.060 g, 44%); mp 215-216 ° C (decomposition). (Found: C, 73.69; H, 5.51; N, 9.41. C18H16N2O2 requires C, 73.95; H, 5.52; N, 9.58%); 5H (pH ₆ ] -DMSO) 12.94 (1H, br, s, COOH), 10.63 (1H, s, 5-NH), 8.13 (1H, d, J 7.9, 9-H), 8.00 (1H, s. 10-H), 7.45-7.30 (1H, m, 6-H, 7-H), 7.14-7.04 (1H, m, 8-H), 3.99 (3H, s, I-CH 3), 2.91 (3H, 3H). s, 4-CH3) and 2.85 (3H, s, 3-CH3); m / z (%) 292 (95, M +), 275 (10), 247 (40), 232 (30), 180 (100) and 135 (100); v _max (KBr tablet) / cm ^_ 1 3375, 2930 and 1709.

3,4,5-Trimethylpyrrolo [3.2-b] carbazole-2-carboxylic acid (0.015 g, 18%); mp 239-240 ° C (decomposition). (Found: C, 74.11; H, 5.38; N, 9.39. C18H16N2O2 requires C, 73.95; J, 5.52; N, 9.58%); 5H (pH ₆ ] -DMSO) 11:15 (1H, s, 1-NH), 8.04 (1H, d, J 7.5, 9-H), 7.88 (1H, s, 10-H), 7.48-7.41 ( 2H, m, 6-H, 7-H), 7.177.06 (1H, m, 8-H), 4.03 (3H, s, 5-CH ₃ ), 3.16 (3H, s, 4-CH ₃ ) and 2.93 (3H, S, 3-CH 3); m / z (%) 292 (90, M +), 274 (75), 232 (70), 197 (35), 181 (60), 149 (30) and 130 (100); v _max (KBr tablet) / cm ^_ 1 3454, 2926 and 1670.

g) 1,3,4,5-Tetral1ethylpyrrolo [3,2-b] carbazole-2-carboxyl. acid (0.030 g, 32%); mp 215-217 ° C (decomposition). (Found: C, 74.44; H, 6.00; N, 9.14. C49H18N2O2 requires C, 74.49; H, 5.92; N, 9.14%); (PH ₆ ] -DMSO) 12.98 (1H, br, s, COOH), 8.14 (1H, d, J 7.6, 9-H), 8.04 (1H, s, 10-H), 7.48-7.38 (2H, m , 6-H, 7-H), 7.18-7.08 (1H, t, 8-H), 4.01 (3H, s, 5-CH ₃ ), 3.97 (3H, s, 1-CH ₃ ), 3.12 (3H , s, 4-CH3) and 2.84 (3H, s, 3-CH3); m / z (%) 306 (100, M +), 279 (25), 232 (38), 197 (34), 181 (80) and 149 (25); v _max (KBr tablet) / cm ^_ 1 1935 and 1659.

h) 3,4-Diethylethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

Ethyl ester (500 mg, 1.6 mmol) in water (15 cm ³ ) and methanol (35 cm ³ ) was refluxed and added.

sufficient methanol to dissolve. Cesium carbonate (5.32 g, 16 mmol) was added and the mixture was refluxed under nitrogen for 16 hours. After cooling, the solvent was evaporated in vacuo to leave about 20 cm < ^{3 >} of the solution, which, by adding 0.1M hydrochloric acid, brought to pH 3. The title compound precipitated. Subsequent filtration, washing with water and drying afforded the analytically pure compound (437 mg, 96%), which is spectroscopically identical to the compound obtained in Example 5a.

Example 6

Pyrrolo [3,2-b] carbazole-2-carboxylic acid ester. General method of production

Pyrrolo [3,2-b] carbazole-2-carboxylic acid (1.0 mmol) and N, N -carbonyldiimidazole (1.1 mmol) were dissolved in a nitrogen atmosphere in freshly distilled tetrahydrofuran. The resulting suspension was stirred at room temperature for at least one hour and complete conversion of the acid to an imidazolid intermediate was determined by thin layer chromatography. Alcohol or phenol (1.5-2.0 mmol, ie excess) was added at once and the resulting mixture heated to reflux until thin layer chromatography showed complete consumption of the imidazolid intermediate. The final compound was obtained by column chromatography on silica gel, followed by recrystallization.

a) Phenyl 3, 4-dimethylpyrrolo [3 _g 2-b] carbazole-2-carboxylate was obtained by reacting the imidazolid intermediate with phenol. Chromatography (eluting with 10% acetone / 90% gasoline) followed by recrystallization from acetone-gasoline gave orange crystals (0.230 g, 65%), mp> 230 ° C (decomposition). (Found: C, 78.17; H, 5.09; N, 7.77. C 23 H ₁₈ O ₂ requires C, 77.95; H, 5.12; N, 7.90%); §H (pH ₆ ] -DMSO) 11.55 (1H, s, 1-NH), 10.64 (1H, s, 5-NH),

8.10 (1H, d, J 7.5, 9-H), 7.94 (1H, s, 10-H), 7.30-7.58 (7H, m, PhH, 6H, 7-H), 7.09 (1H, ddd, J 7.5 , 5.5, 2, 8-H), and 2.97 and 2.95 (2 x 3H, 2 x s, 3-CH3 and 4-CH3); m / z (%) 355 (40, M +); v _max (KBr tablet) / spg1 3396.1701 and 1180.

b) [(2-Diethylamino) ethyl] -3,4-dimethylpyrrolo [3.2-b] carbazole-2-carboxylate was obtained by reacting the imidazolid intermediate with (2-dimethylamino) ethanol. Chromatography (eluting with 10% methanol / 90% dichloromethane) gave a yellow solid (0.350 g, 99%). Recrystallization of a portion of it from dichloromethane gave yellow crystals with a melting point of 174-175.7 ° C (decomposition). (Found: C, 70.46; H, 6.48; N, 11.76. C21H23N3O2.O.I5CH2Cl2 requires C, 70.29; H, 6.45; N, 11.55%); 5H ^([2 H _6] -DMSO) 11.18 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.07 (1H, d, J 8, 9-H), 7.89 (1H, s, 10-H), 7.30-7.43 (2H, t, 6-H, 7-H), 7.09 (1H, ddd, J 8, 6, 2.5, 8-H), 4.41 (2H, t, J 6 , OCH ₂ ), 2.91 (6H, s, 3-CH 3 and 4-CH 3), 2.69 (2H, t, J 6.0, NCH ₂ ) and 2.27 (6H, s, N (CH ₃ ) ₂ ); m / z (%) 350 (46, (M + 1) +), 261 (68) and 133 (100); ν chess (KBr tablet) / cm'1 3377, 1661 and 1238.

c) [(3-Dimethylamino) phenyl] -3 ₍ 4-dimethylpyrrolo [3.2-b] carbazole-2-carboxylate) was obtained by reacting the imidazolid intermediate with (2-dimethylamino) phenol with respect to 0.95 mmol. (eluting with 10% ethyl acetate / 90% toluene), followed by recrystallization from ethyl acetate,

receive yellow crystals (0.272 g, 72%) with a melting point of 240-242 ° C (decomposition). (Found: C, 75.37; H, 5.71; N, 10.36. C25H23N3O2 requires C, 75.55; H, 5.83; N, 10.57%); bn ([ ² Nb] DMSO) 11.49 (1H, s, 1-NH), 10.64 (1H, s, 5-NH), 8.08 (1H, d, J 8.9H), 7.91 (1H, s, 10- H), 7.34-7.48 (2H, m, 6-H, 7-H), 7.27 (1H, t, J 8, 5'-H), 7.10 (1H, ddd, J 8, 6, 2, 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 ); m / z (%) 398 (38, (M + 1) +), 261 (25), 232 (21) and 217 (100); v _max (KBr tablet ^ spg ¹ 3350,1674,1610 and 1232.

d) (3-Pyridyl) -3,4-dimethylpyrrolo [3.2-b] carbazole-2 carboxylate was prepared by reacting the imidazolid intermediate with 3-hydroxypyridine. Chromatography (eluting with 50% ethyl acetate / 50% gasoline) followed by recrystallization from acetone gave yellow crystals (0.230 g, 65%) with a melting point of> 270 ° C (decomposition). (Found: / C, 73.88; H, 4.76; N, 11.50. C 22 H ₁₇ N ₂ O ₂ .0.2H ₂ O requires C, 73.61; H, 4.89; N, 11.71%); 5h ([2H ₆ ] -DMSO) 11.59 (1H, s, 1-NH), 10.65 (1H, s, 5-NH), 8.63 (1H, d, J 2, 2'-H), 8.55 (1H. dd, J 4, 1, 6'-H), 8.10 (1H, d, J 8, 9-H), 7.90 (1H, s, 10-H), 7.86 (1H, ddd, J 8, 3, 1 , 5'-H), 7.58 (1H, dd, J 8, 5, 4'-H), 7.32-7.45 (2H, t, 6-H, 7-H), 7.09 (1H, ddd, J 8, 6, 2, 8-H), 2.97 and 2.94 (2 x 3H, 2 x s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 356 (15, (M + 1) +); v _max (KBr tablet) / cm-1 3377, 1715 and 1173.

e) (4-Carbamoylphenyl) -3 ₍ 4-dimethylpyrrolo [3,2-b] carbazole-2 carboxylate was obtained by reacting the imidazolid intermediate with 3-hydroxybenzamide. Recrystallization from ethanol gave a yellow powder and the impure residue. further by column chromatography (eluting with 5% methanol / 95% dichloromethane and then with 10% methanol / 90% dichloromethane) followed by recrystallization from ethanol to give (0.262 g, 66%), mp> 250 ° C (dec.) (Found: C, 71.72; H, 4.81; N, 10.26. C24H ₁₉ N ₃ O ₃ .0.2H ₂ O requires C, 71.88; H, 4.88; N, 10.48%);

(PH ₆ ] -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, amide NH), 7.33-7.49 (5H, m, 6-H, 7H, 2'-H, 6'-H, amide NH), 7.09 (1H, ddd, J 8.5, 6, 1.5. 8-H) and 2.95 and

2.93 (2 x 3H, 2 x s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 398 (10, (M + 1) +), 279 (100); v _max (KBr tablet) / spn1 3423, 1717,1695 and 1171.

f) (Pyridyl-4-methyl) h _g 4-dil1etilpirolo [H _g 2-b] carbazole-2-carboxylate was prepared by the reaction of the imidazolide intermediate with 4-pyridylcarbinol. Chromatography (eluting with ethyl acetate / gasoline at a gradient of 60%, 80%, 100% ethyl acetate followed by methanol / ethyl acetate at a gradient of 10%, 20%) followed by recrystallization from tetrahydrofuran gave orange crystals (0.168 g, 46% ) with a melting point> 240 ° C (decomposition). (Found: C, 72.16; H, 5.12; N, 10.73. C ^ H ^ OO. OR requires C, 72.31; H, 5.38; N, 11.00%); 5H ^([2 H _6] -DMSO) 11.31 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.62 (2H, dd, J 4.5, 0.5, 2'-H, 6 ' -H), 8.08 (1H, d, J 7.5, 9-H), 7.89 (1H, s, 10-H), 7.53 (2H, d, J 5, 5, 3'-H, 5'-H) , 7.327.43 (2H, m, 6-H, 7-H), 7.07 (1H, ddd, J 8, 5, 1, 8-H), 5.45 (2H, s, ArCH ₂ ) at 2.94 in 2.92 ( 2 x 3H, 2 xs, 3-CH _{3 in} 4-CH ₃ ); m / z (%) 369 (27, (M + 1) +), 327 (70) in 295 (100); v _max (KBr tablet) / cm-1 3400, 1709 at 1232.

g) (L3-Dibenzyloxypropyl ~ 2) D4-dimethylpyrrolo [3 _f 2 -bJ. carbazole-2-carboxylate was prepared by the reaction calculated with respect to 1.5 mmol of the imidazolid intermediate with (1,3-dibenzoxy-250 propanol). Chromatography (eluting with 20% ethyl acetate / 80% toluene followed by 40% ethyl acetate / 60% toluene) followed by recrystallization from ethyl acetate-ether-gasoline gave yellow crystals (0.776 g, 97%), mp> 124.8-126 ° C (decomposition). (Found: C, 76.35; H, 6.07; N, 5.12. C34H32N2O4 requires C, 76.67; H, 6.06; N, 5.26%); bd (PH ₆ ] DMSO), 11.18 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.06 (1H, d, J 7.5, 9-H), 7.88 (1H, s. 10-H), 7.2-7.42 (12H, m, 2 x PhH ₅ , 6-H, 7-H), 7.07 (1H, ddd, J 8, 6.5, 1.5, 8-H), 5.44 (1H, quintet) , J 5, GN), 4.60 and 4.53 (2 x 2H, 2 x dd, J 12, 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 x s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 532 (50, M +), 260 (65) and 91 (100); v _max (KBr tablet) / cm ^-1 3358, 1681 and 11234.

h) (4-Methylsulfinyl) phenyl] -3,4 ~ dimegpylpyrrolo [3,2-b] carbazole-2-carboxylate was obtained by reacting the imidazolid intermediate with 4-methylsulfinylphenol. Chromatography (eluting with ethyl acetate / gasoline at a gradient of 90%, 95%, 98%, 100% echylacetate, followed by 10% methanol / ethyl acetate) followed by recrystallization from tetrahydrofuran gave a yellow powder (0.261 g, 63% ) with a melting point> 230 ° C (decomposition). (Found: C, 68.40; H, 4.81; N, 6.44. C 24 H ₂ o N ₂ O ₃ S.0.3H ₂ O requires C, 68.32; H, 4.92; N, 6.64%); bd (PH ₆ ] -DMSO) 11.59 (1H, s, 1-NH), 10.68 (1H, s, 5-NH), 8.10 (1H, d, J 8, 9-H), 7.93 (1H, s. 10-H), 7.82 (2H, d, J 9.5, 3'-H, 5'-H), 7.59 (2H, d, J 9.5, 2'-H, 6'-H), 7.33-7.45 (2H , t, 6-H, 7-H), 7.09 (1H, ddd, J 8, 6,

2.5, 8-H), 2.99 and 2.95 (2 x 3H, 2 x s, 3-CH ₃ and 4-CH ₃ ) and 2.82 (3H, s, CH ₃ SO); m / z (%) 417 (2, (M + 1) +), 261 (100) and 233 (75); v _max (KBr tablet ^ st ¹ 3427,3288,1717 and 1200.

i) Methyl 3, 4-methylphenol [3 _f 2 -b] capanOA-2-carboxylic acid was obtained by reacting the imidazolid intermediate with methanol. Chromatography (eluting with 30% ethyl acetate / 70% gasoline) followed by recrystallization from ethyl acetate gave a yellow powder (0.188 g, 64%), mp> 211-213 ° C (decomposition). (Found: C, 74.06; H, 5.49; N, 9.42. C ₁₈ Hi ₆ N ₂ O ₂ requires C, 73.95; H, 5.52; N, 9.58%); 6h ([2H ₆ ] -DMSO) 11.25 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.08 (1H, d, J 8, 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, 8-H), 3.92 (3H, s, OCH ₃ ) at 2.92 at 2.91 (2 x 3H, 2 xs, 3-CH _{3 in} 4-CH ₃ ); m / z (%) 292 (68, M +), 260 (100), 232 (39); v _max (KBr tablet) / cm ^_ 1 3342, 1684 u 1236.

j) [(4-methylsulfonyl) ethyl] -3 _f 4-dimethylpyrrolo [H _g 2-b] carbazole-2-carboxylate was prepared by the reaction of the imidazolide intermediate with (2-methylsulphonyl) ethanol. Chromatography (eluting with ethyl acetate / gasoline at a gradient of 30% - 100%) followed by recrystallization from acetone gave yellow crystals (0.222 g, 58%) with a melting point of 255257 ° C (decomposition). (Found: C, 62.23; H, 5.25; N, 7.08. C 1 H 2 N 4 S requires C, 62.48; H, 5.24; N, 7.29%); δπ ^([2 H _6] DMSO) 11.19 (1H, s, 1-ΝΗ), 10.60 (1H, s, 5-NH), 8.09 (1H, d, J 7.5, 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, 8-H), 4.69 (2H, t, J 5.5). OCH ₂ ), 3.69 (2H, t, J 5.5, SO ₂ CH ₂ ), 3.12 (3H, s, SO ₂ CH ₂ ) in 2.93 (6H, s, 3-CH 3 in 4-CH ₃ ); m / z (%) 384 (17, M +), 260 (13) in 59 (100); v _max (KBr tablet) / cm-1 3387,1661u1234.

k) Tert-Butyl 34-Riethylpyrrolo [3.2-b] carbazole-2carboxylate

Pyrrolo [3,2-b] carbazole-2-carboxylic acid (0.86 mmol) and triphenylphosphine (0.91 mmol, 1.05 equiv) were dissolved

α.

ί nitrogen atmosphere in freshly distilled tetrahydrofuran. Tertiary butanol (2.12 mmol, 2.5 eq) was added with a syringe and diethyl azodicarboxylate (0.95 mmol, 1.1 eq) was added dropwise over 6 minutes. The resulting suspension was stirred for 2 hours at room temperature, during which time thin layer chromatography showed complete consumption of the starting acid. The title compound was isolated from the crude reaction mixture in several steps: silica gel column chromatography eluting with 20% ether / 80% gasoline and then with 50% ether / 50% gasoline; silica gel column chromatography eluting with 25% ether / 75% gasoline and then with 40% ether / 60% gasoline; and, finally, recrystallization from dichloromethane gave a yellow powder (0.030 g, 10%), mp 187-189 ° C (decomposition). (Found: C, 73.24; H, 6.53; N, 7.93. C2iH22N ₂ O2.0.1 ^ CH ₂ a2 requires C, 73.Ϊ8; H, 6.47; N / 8.07%) ; bd (PH ₆ ] -DMSO) 10.95 (1H, s, 1-ΝΉ), 10.57 (1H, s, 5-NH), 8.05 (1H, d, J 8, 9-H), 7.88 (1H, s. 10-H), 7.29-7.43 (2H, m, 6-H, 7-H), 7.05 (1H, ddd, J 8,6,1,8-H), 2.89 and 2.87 (2 x 3H, 2 x s, 3-CH ₃ and 4-CH ₃ ) and 1.59 (9H, s, C (CH ₃ ) ₃ ); m / z (%) 355 (62, M + 1 +), 278 (90), 233 (38), 126 (32), 91 (78) and 57 (100); v _max (KBr tablet) / cm ^-1 3337, 1664 and 1240.

Example 7

Pyrrolo [3,2-b] carbazod-2-carboxylic acid amides

a) 3D-Dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3.2-b] carbazole

3,4-Dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.280 g, 1.0 mmol) and N, N-carbonyldiimidazole (0.164 g, 1.0 mmol) were dissolved in a nitrogen atmosphere in freshly distilled tetrahydrofuran (5 cm ³ ). The resulting slurry was stirred for 2 hours at room temperature, and the whole was determined by thin layer chromatography. conversion of the starting acid to imidazolid. The tetrahydrofuran was removed and the residue was recrystallized from ethyl acetate to give a yellow solid (0.125 g, 38%), mp 252 ° C (decomposition). (Found: C, 73.17; H, 4.87; N, 16.80. C20H16N4O requires C, 73.15;

H, 4.91; N, 17.06%); bn (PH ₆ ] -DMSO) 11.53 (1H, s, 1-NH), 10.20 (1H, s, 5-NH), 8.30 (1H, s, 2 ^f -H), 8.12 (1H, d, J 8 , 9-H), 7.94 (1H, s,

10-H), 7.79 (1H, s, 5'-H), 7.33-7.47 (2H, m, 6-H, 7-H), 7.19 (1H, s, 3'H), 7.09 (1H, ddd , J 8, 6, 2, 8-H), 2.95 (3H, s, 3-CH3), 2.73 (3H, s, 4CH3); m / z (%) 261 (40); v _max (KBr tablet) / cm ^-1 3427, 1699 and 1242.

b) Ethyl 3,4-dimethylpyrrolo [3 ₁ 2-b] carbazole-2-carboxamide

3,4-Dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.278 g, 1.0 mmol) was dissolved in dimethoxyethane (10 cm ³ ) to give a yellow solution. To this were added diisopropylethylamine (0.260 g, 2.0 mmol), ethylamine hydrochloride (0.245 g, 3.0 mmol) and the tetrabluoroborate salt of Obenzotriazolyl-N, N-N-tetramethyluronium (TBTU) (0.482 g,

I. 5 mmol) to give a white suspended in yellow liquid. The reaction mixture was stirred for 24 hours at room temperature, after which time thin-layer chromatography showed no residual acid. The solvent was removed in vacuo to give a tan solid. It was subjected to silica gel column chromatography eluting with 10% ethyl acetate / 90% dichloromethane. The ethylamide compound was obtained as a yellow solid (0.240 g, 79%). To remove traces of impurities, a portion of the substance was recrystallized from dichloroethane / gasoline to give an analytically pure compound as a yellow powder, mp 235 ° C (decomposition). (Received: C,

73.21; H, 6.10; N, 13.33. C ₁₉ H ₁₉ N ₃ O.0.1C ₂ H2C12 requires C, 73.15; H, 6.20; N, 13.32%); (PH ₆ ] -DMSO) 10.72 (1H, s, 1-NH), 10.57 (1H, s, 5-NH), 8.09 (1H, d, J 8, 9-H), 7.93 (1H, t, J 5, amide NH), 7.83 (1H, s, 10-H), 7.27-7.41 (2H, m, 6-H, 7-H), 7.06 (1H, d, J8, 8-H), 3.35 ( 2H, q, J 7.5 CH ₂ CH ₃ ), 2.89 u 2.71 (2 x 3H, 2 xs, 3-CH ₃ and 4-CH ₃ ) u

1.18 (3H, t, J 7.5, CH 2 CH 3); m / z (%) 305 (65, M +), 260 (100); v _max (KBr tablet) / item “1 3314,1603 at 1545.

c) 3 _f 4-Dimethylpyrrolo [3 _f 2-b] carbazole-2-carboxamide

3,4-Dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.556 g, 2.0 mmol) was dissolved in dimethoxyethane (20 ml) to give a yellow solution. To this was added diisopropylethylamine (0.520 g, 4.0 mmol), ammonium hydrochloride (0.321 g, 6.0 mmol) and tetrabluoroborate salt of Obenzotriazolyl-N, N-N-tetramethyluronium (TBTU) (0.963 g, 3.0 mmol), receives white suspended in yellow liquid substance. The reaction mixture was stirred for 24 hours at room temperature, during which time thin-layer chromatography showed no residual acid. The solvent was removed in vacuo to give a tan solid. It was subjected to silica gel column chromatography eluting with ethyl acetate / dichloromethane at a gradient of 10% -30%.

The amide compound was obtained as a yellow solid (0.350 g, 63%). To remove impurities, a portion of the substance is recrystallized from ethyl acetate / gasoline and then purified by preparative HPLC (column size 25 cm x 2.12 cm internal diameter filled with ί i

Cg Zorbax, elution gradient: 5% acetonitrile / 95% water to 95% acetonitrile / water; reading at 340 µm) to give a yellow powder with a melting point of 240 ° C (decomposition). Hm (PH ₆ ] -DMSO) 10.82 (1H, s, 1-NH), 10.54 (1H, s, 5-ΝΉ), 8.08 (1H, d, J 7.5, 9-H), 7.84 (1H, s. 10-H), 7,297.43 (4H, m, 6-H, 7-H, NH ₂ ), 7.07 (1H, ddd, J 8, 5.5, 8-H), 2.89 and 2.85 (2 x 3H, 2 x s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 277 (62, M +), 260 (100), 232 (44); v _max (KBr tablet) / cm ' ¹ 3317, 1628 and 1595. (Found: M +, 277.1205. C ₁₇ Hi ₅ N ₃ O requires 277.1215.)

d) F. < RTI ID = 0.0 > nil-3 < / RTI >

3,4-Dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.278 g, 1.0 mmol) was dissolved in dimethoxyethane (10 ml) to give a yellow solution. To this were added diisopropylethylamine (0.130 g, 1.0 mmol), aniline (0.190 µg, 2.0 mmol) and the tetrafluoroborate salt of O-benzotriazolyl, Ν, Ν, Ν-tetramethyluronium (TBTU) (0.482 g, 1.5 mmol). receives white suspended in yellow liquid substance. The reaction mixture was stirred for 42 hours at room temperature, after which time thin-layer chromatography showed no residual acid. The solvent was removed in vacuo to give a yellow solid which was dissolved in ethyl acetate and the resulting solution was washed with water. The organic layer was dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography eluting with ethyl acetate / gasoline at a gradient of 5% 100% followed by recrystallization from acetone to give the phenylamide compound as a yellow powder. g, 30%) with a melting point of 260 ° C (decomposed) (Found: C, 77.79; H, 5.26; N, 11.64. C23H19N3O requires C, 78.16; H, 5.42; N, 11.89%); 8H (PH 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 7.5, 9- H), 7.89 (1H, s, 10-H), 7.79 (2H, d, J 9, 2'H, 6'-H), 7.29-7.45 (4H, m, 6-H, 7-H, 3 1 -H, 5'-H), 7.00-7.14 (2H, tn, 8H, 4'-H), 2.93 at 2.88 (2 x 3H, 2 xs, 3-CH ₃ ); m / z (%) 353 (46, M +), 260 (100); v _max (KBr tablet) / cm ^-1 3310, 1614, 1595 and 1317.

e) 3 _{g of} 4-Dimethyl-2- (hydrazinocarbonyl) pyrrolo [3 _is 2-b] -carbazole2-carboxamide

Ethyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate (500 mg) and 95% hydrazine (5 cm ³ ) were stirred and heated at 120 ° C for 6 h in a Readi dish. The mixture was allowed to stand overnight, cooled in ice and filtered. The resulting yellow solid was washed thoroughly with water and dried. The title compound (350 mg, 73%) was obtained which did not have a pronounced melting point but decomposed at 285 ° C. (Found: C, 69.19; H, 5.27; N, 19.38. C17H16N4O.O.IH2O requires C, 69.42; H, 5.55; N, 19.05%); 5H (pHfiJ-DMSO) 10.80 (1H, s, variable, NH), 10.55 (1H, s, variable, NH), 9.20 (1H, s, variable, NH), 8.06 (1H, d, J 7.5, 9H) , 7.81 (1H, s, 10-H), 7.28-7.42 (2H, m, 6-H, 7-H), 7.12-7.01 (1H, m,

8-H), 4.5 (2H, br, s, variable, NH ₂ ) 2.4 and 2.3 (2 x s, 4-CH ₃ and 3CH ₃ ); m / z (%) 293 (M + 1) +, FAB).

Example 8

2-Acetyl-3,4-dimethylpyrrolo [3,2, b] carbazole

Grade 1

2,4-Diacetyl-3,5-dimethylpyrrole was obtained from acetylacetone and hydroxylamine-O-sulfonic acid by the method of Y. Tamura, S. Kato and M. Ikeda (Chem & Ind., 1971, 767).

Grade 2

_{2-Atsetoksimetid-3>} 5-diatsep1iA-4-.mstidpirod

I f

To a stirred mixture of 2,4-diacetyl-3,5-dimethyl pyrrole (1.0 g), dichloromethane ( ^{3 5} cm ³ ) and potassium carbonate (7.73 g) at 0-5 ° C was added a solution of sulfuryl chloride (0.79 g) in dichloromethane (15st ³ ). By external cooling during the addition, the temperature was maintained at 0.5 ° C and the mixture was stirred at this temperature until the reaction was judged complete by thin layer chromatography (about 2 hours). The mixture was then filtered and evaporated to give crude 2-chloromethyl-3,5-diacetyl-4-methylpyrrole. The latter was dissolved in acetic acid (10 cm ³ ), sodium acetate (1.83 g) was added followed by more acetic acid (10 cm ³ ). The mixture was stirred overnight at room temperature, evaporated in vacuo and the residue was stirred with ice-cold water for 2 hours. The solid was filtered off and the filtrate washed twice with ethyl acetate. The extracts were dried (MgSO4), evaporated with C and the residue added to the solid obtained by filtration. The crude compound is thus obtained. Chromatography on silica gel eluting with ethyl acetate-hexane (1: 1) gave the pure compound as an off-white solid with a melting point of 112.5114.5 ° C; m / z 238 (M + 1) +, FAB); 8H (COCl ₃ ) 2.16 (3H, s, OCHOS 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 ).

Degree

To a solution of 2-acetoxymethyl-3,5-diacetyl-4methylpyrrole (0.200 g) and indole (0.098 g) in dichloromethane (90 cm ³ ) was added montmorillonite clay K 10 (0.30 g). The mixture was stirred and refluxed for 80 hours. After cooling, the clay was removed by filtration and the filtrates were concentrated in vacuo to a volume of 20 cm ³ . The crude product was isolated by filtration and chromatographed on silica gel. Elution with chloroformmethanol (60: 1) afforded 0.08 g of the title compound as a yellow solid, mp 258-260 ° C; m / z (EI) 276 (M +); (pH ₆ ] -DMSO) 2.58 (3H, s, OCHOS ₃ ), 2.88 (3H, s, CH ₃ ), 2.92 (3H, s, CH ₃ ), 7.05 (1H, t, 8-H),

7.38 (2H, m, 6-H, 7-H), 7.85 (1H, s, 10-H), 8.08 (1H, J 8 Hz, 9-H), 10.6 (1H, s, NH), 11.17 ( 1H, s, NH). (Found: C, 77.0; H, 5.74; N, 9.76. Ci ₈ Hi ₆ N ₂ O.0.14EtAc requires C, 77.2; H, 5.98; N, 9.70%.) Example 9

Ethyl 1,5-dihydroindeno [2 _> 1-1] 1dol = 2-carboxylate Grade 1

Ethyl-2-azido-3-fluoro-2-ylacrylate /

Sodium (1.7 equiv.) Was added to the absolute alcohol, stirred under nitrogen at room temperature. When dissolution is complete, the reaction mixture is cooled to -10 ° C and fluorene-2carboxaldehyde (1 eq) and ethyl azidoacetate (3 eq) dissolved together in a minimum amount of tetrahydrofuran are added dropwise. The mixture was stirred for 20 hours at -10 ° C, after which the reaction was quenched by the addition of water and dichloromethane. The combined organic extracts were dried (MgSO4) and evaporated in vacuo. Flash chromatography afforded the pure compound (37%), v _max (CHCl ₃ ) / cm-1 2120 and 1765. Step 2

Ethyl-2-azido-3-fluorene-2-ylacrylate suspended in dry toluene was refluxed for 1 hour and the resulting solution was evaporated in vacuo. The resulting mixture of ethyl-1,5-dihydroindino [2,1-b] indole-2-carboxylate and ethyl-1,10-dihydroindino [2,1-d] indole-2-carboxylate was recrystallized from ethanol, which separated ( 1.2 g) isomer, and the title compound (contaminated with about 30% [1,2-μ] isomer) remains in the mother liquors which are evaporated to dryness. 8Hz (CDCI3)

9.11 (1H, s, bg, 1-ΝΉ), 7.82-7.76 (3H, m), 7.56-7.52 (1H, m), 7.37 (H, dd, J 1 and 7), 7.34-7.28 (1H, m ), 7.25 (1H, dd, J 1 and 2), 4.45 (2H, q, OCH ₂ CH ₃ ), 3.97 (2H, S, CH ₂ ) and 1.46 (3H, t, CH ₂ CH ₃ ).

Example 10

Evaluation of the effect of the compounds of the invention in reverse transformation (alignment) assay using HT1080scc2 and HT 10801c cell lines.

Cell lines and culture conditions

Transformed and reverted HT1080 cell lines, HT1080scc2 and HT 10801c cell lines were obtained from the Cancer Research Institute, Chester Beatty Laboratories, Fulham Road, London. They are stored routinely in Dulbecco's Modified Eagle's Medium (DMEM) with 10% cow embryonic serum (FCS) and 1% penicillin / streptomycin added to the solution containing 10,000 units per ml. All reagents were obtained from Gibco Ltd. The cells were incubated in tissue culture vessels at 37 ° C in air with 5% CO ₂ content.

Activity analysis

Proliferation / cytotoxicity assays were performed in microtiter plates with tissue culture wells, brand 96 (Costar). The growing cells were placed in the plates at a concentration of 1 x 10 ³ cells

socket on day Ou on day ί were added diluted to a series of compounds. Then, for the next 4 days, the plates were incubated at 37 ° C in air with 5% CO2- |

The method of biomass staining with methylene blue was used to quantify cell growth using the Multiscan plate reader at a wavelength of 620 pt. Cell morphology was examined microscopically by contrast between the phases immediately prior to fixation and staining with methylene blue and then with a conventional light microscope. The IC50 values of the active compounds were obtained using a computer program. GS1 curves and corresponding doses were also obtained.

When the compounds were tested for their activity by colony formation assay, the methods used were identical to those described above except that, at the beginning of the assay, a successively diluted compound was added to the slope agar and the concentration was restored on the seventh day to the initial value. The test results were reported on day 14. Results

Comparison of growth and morphology of HT1080scc2 and HT10801C

The rate of increase in number of cells is the same in both lines until the fourth day, after which the HT1080scc2 cells continue to divide. They reach a saturation density of approximately 2 to 3 times greater than that of HT10801c on the fifth day.

the phenotypic differences between the two lines are obvious.

HT10801c cells exhibit much smoother morphology than the transformed cells and only a few mitotic cells can be seen in the fusion regions of the cultures. However, HT1080scc2 cells continue to divide by multiple mitotic cells visible after fusion.

Grown on soft agar under conditions independent of the site of placement, HT1080scc2 cells produce several long colonies, whereas HT10801c cells do not produce colonies larger than 0.1 m in diameter. The effectiveness of certain compounds

A number of compounds of the invention have been evaluated for cell lines.

SCC2 Equalization (µM)

0.04

0.04

0.04

0.8

0.8

The compounds of the invention show low toxicity with IC50 values in the range of 50-100 μΜ.

I The results of the equalization assay "for the compounds of the invention are shown below.

Compound

Example 3

Example 4 (a)

Example 4 (b)

Example 4 (f)

Example 4 (e)

Example 4 (h)

Example 4 (g)

The compounds are effective in achieving equalization, "i.e. reverse transformation, at a concentration significantly lower than their toxic concentration.

The same compounds were also tested for use in the analysis of human breast carcinogenic cells

MCF7, epidermoid carcinoma cells A431 and melanoma cells A285. In all cases, the compounds are effective in the range of 1-5 µM.

Claims (10)

CLAIMS 1. Compound of Formula (I) ί ί (I) and its salts and physiologically active derivatives, where A is R ¹ R ² R ¹ LZH R ² R ² γ R ² ' X is O, S, alkyl, aralkyl, substituted sulfonyl; Y is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ ; j R1 e COR ^8, COOR ^8, CHO, CH2OH, CH2OR ^9, CONH2, CONHNRIORH, CONHR10, CONR10RH , COO (CH _{2) n} NR10RH, F where R ⁸ is H, alkyl, aryl, substituted aryl or aralkyl, R ⁹ is acyl or substituted acyl, R ¹⁰ and R ¹¹ are independently hydrogen, alkyl or aryl and n is 1 to 4; R ² is hydrogen, COOR ⁸ , alkyl, aryl, substituted aryl or CH ₂ CH ₂ CO ₂ R ¹² , where R ¹² is alkyl or aryl; R ³ and R ⁴ are independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxyl or CO ₂ R ¹² ; R ⁵ is hydrogen, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano, CHO, COOR ⁸ ; R ¹ * SO, SO ₂ , CH ₂ , aryl, alkenyl, R ¹ CO or NR ⁷ wherein R ⁷ is H, acyl, alkynyl, sulfonyl or R ⁶ is hydrogen, alkyl, aralkyl, nitro, halogen, CHO, COR ¹³ , where R ¹³ is alkyl or aryl, provided that | (i) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is R 'where Y is ΝΉ and X is O or S, then R ¹ is not CO ₂ H or CO ₂ Et; and (ii) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is where Y is NH and X is O or S, then R ¹ is not CHO; and (iii) Y is not O when X is O. A compound according to claim 1, wherein X is O, S or NR ⁷ , wherein R ⁷ is H, alkyl, sulfonyl or toluenesulfonyl; Ye NR ⁷ ; R 1 is COR ⁸ , COOR ⁸ , CH ₂ OR 9, CONH ^ CONHNR10RH, © CONHR10, CONR10RH, 000 ((¾ ^ NR10R11, where R8 is H, alkyl, aryl, substituted aryl or aralkyl, R ⁹ is acyl or substituted acyl, R ¹⁰ and RH are each independently hydrogen, alkyl or aryl, and n is from 1 to 4 carbon atoms; R ² is COOR ⁸ , alkyl or CH ₂ CH ₂ CO ₂ R ¹² , where R ¹² is alkyl or aryl; R ³ and R ⁴ are independently hydrogen, hydroxy, alkyl, alkoxy, halo, cyano, substituted alkyl, or carboxyl; R ⁵ is hydrogen or alkyl; R ⁶ is hydrogen, alkyl or aryl; together with their salts and physiologically acceptable derivatives. A compound according to claims 1 and 2, wherein 4-- X is S or NH; YeNH; A is I R ¹ is COOR ⁸ , wherein R ⁸ is alkyl or aralkyl. R ² is H or alkyl. R ³ is H alkoxy or halogen. R ⁴ is H, alkoxy or halogen. R ⁵ is alkyl and R ⁶ eH; as well as their salts and physiologically active derivatives. 4. Compound selected from 3-Pyridyl-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate; [(3-Dimethylamino) phenyl] -3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate; 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-Scarbazole-2-carboxylate; Ethyl, 3,4-dimethylbenzothieno [4,5-cyndol-2-carboxylate; Benzyl, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate; Benzyl, 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate; Ethyl, 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate; Benzyl, 3,4,6-trimethylpyrrolo [3,2-Scarbazole-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-2carboxylate; 3,4,6-Trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and Benzyl, 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate; as well as their physiologically functional derivatives. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, together with pharmaceutically acceptable carriers. A compound of formula (I) according to claims 1 to 4 for use in medicine. Use of a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for the manufacture of agents for the treatment of tumors. 8. A method for treating tumors comprising an effective amount of a compound of formula (I) or a salt thereof or a physiologically functional derivative. A process for the preparation of compounds of formula (I) as described in claim 1, characterized in that it comprises: (a) in the catalytic ring closure of a compound of formula (IV) in the presence of a strong acid. drug in animals, submitting (1¼ where X, Y, Rl, R ^2, R ^3, R ⁴ u R ⁵ are as defined definitions; or (b) converting a compound of formula (I) into another compound of formula (I ). 10. New intermediates of formula (II), (III), (IV) or (V). 4D REG.1P 99359 By letter: dated 2 August 1994 Revised pages according to Art. 34 EPC Thus, on the one hand, the present invention f-4Z A provides a compound of general formula (I) (I) and its salts and physiologically active derivatives, where A is R ¹ R ¹ OR R ² R? R ¹ X is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ , where R ⁷ is H, C 1-10 alkyl, aralkyl containing from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety , aryl containing up to 10 carbon atoms, alkenyl, C 1-10 acyl, alkynyl or sulfonyl optionally substituted with C 1-3 alkyl, aryl containing up to 10 carbon atoms or aralkyl containing from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety; Y is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ ; R ¹ is COR ^8, COORS, CHO, CH2OH, CH2OR9, CONH2, CONHNR10RH, CONHR _{^10, CONR10RH, COO (CH2) n} NRi0RH, wherein R ⁸ is H, Cj.jo alkyl, aryl containing go 10 carbon atoms and substituted optionally with C 1-3 alkyl, C 1-3 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-3 alkyl groups), haloalkyl, sulfonyl or cyano, or aralkyl containing from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety, R ⁹ is C 1-6 acyl optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-6 alkyl groups), haloalkyl, sulfonyl or cyano, R10 and RH are unsaturated independently of one another, hydrogen, C1-10 alkyl or aryl containing up to 10 carbon atoms and n being from 1 to 4 carbon atoms; R ² is H, COOR ⁸ , C 1-10 alkyl, aryl containing 10 carbon atoms and optionally substituted with C 1-10 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-10. (alkyd groups), haloalkyl, sulfonyl or cyano or CH ₂ CH ₂ CO2R ¹² , wherein R ¹² is C 1-10 alkyl or aryl containing up to 10 carbon atoms; R ³ and R 4 are independently H, hydroxy, C 1-10 alkyl, haloalkyl, C 1-3 alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl substituted with C 1-3 alkyl, C 1-3 alkoxy, halo , sulfinyl, amino (optionally substituted by two C1-10 alkyl groups), haloalkyl, sulfonyl or cyano, carboxyl or CO ₂ R ¹² ; R ⁵ is H, C 1-10 alkyl optionally substituted with C 1-10 alkyl, C 1-3 alkoxy, halo, sulfinyl, amino (optionally substituted with two C 1-12 alkyl groups), haloalkyl, sulfonyl or cyano, aralkyl containing from 1 to 4 carbon atoms in the alkyd moiety and up to 10 carbon atoms in the aryl moiety, nitro, amino, halo, cyano, CHO, COOR ⁸ ; R ⁶ is H, C 1-10 alkyl, aralkyl containing up to 10 carbon atoms or aralkyl containing from 1 to 4 carbon atoms in its alkyd moiety and up to 10 carbon atoms in its aryl moiety, nitro, halogen, CHO, COR ¹³ , wherein R ¹ is C 1-3 alkyl or (i) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is where Y is NH and X is O or S, then R 1 is not CO ₂ H or CO ₂ Et; and (i) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is where Y is ΝΉ and X is O or S, then R 1 is not CHO; and (iii) Y is not O when X is O. On the other hand, the invention provides a compound of the above general formula (I) wherein A is R X is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ , where R ⁷ is H, C 1-4 alkyl, aralkyl containing from 1 to 4 carbon atoms in its alkyl moiety and up to 10 carbon atoms in its aryl moiety , aryl containing up to 10 carbon atoms, alkenyl, C140 acyl, alkynyl or sulfonyl; Y is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ ; R 1 is COOR 8, CHO, CH ₂ OH, CH ₂ OR ⁹ , CONH ₂ , CONHR10, id _and CONR10RH, where R ⁸ is H, C 1-10 alkyl, aryl containing up to 10 carbon atoms and optionally substituted with C 1-12 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-10 alkyl groups), haloalkyl, sulfonyl or cyano, or aralkyl containing from 1 to 4 carbon atoms in their alkyl moiety and up to 10 carbon atoms in the aryl moiety, R ⁹ is C 1-10 acyl optionally substituted by C 1-10 alkyl, C 1-12 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-10 alkyl groups), haloalkyl, sulfinyl or cyano, R ¹⁰ and R ¹¹ are independently one of another hydrogen, C1-10 alkyl or aryl containing up to 10 carbon atoms; R ² is H, COOR ⁸ , C 14Q alkyl, aryl containing up to 10 carbon atoms and optionally substituted with C 1-10 alkyl, C 1-4 alkoxy, halo, sulfinyl, amino (optionally substituted with one or two C 1-10 alkyl groups), haloalkyl , sulfonyl or cyano or CH ₂ CH ₂ CO ₂ R ¹² , wherein R ¹² is C 1-10 alkyl or aryl containing up to 10 carbon atoms; R ³ and R 4 are independently H, hydroxy, C 1-10 alkyl, haloalkyl, C 1-12 alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl substituted with C 1-10 alkyl, alkoxy, halo, sulfinyl, amino ( optionally substituted by two C1-10 alkyl groups), haloalkyl, sulfonyl or cyano, carboxyl or CO ₂ R ¹² ; R ⁵ is H, C 1-10 alkyl optionally substituted with C 1-10 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted with two C 1-10 alkyl groups), haloalkyl, sulfonyl or cyano, aralkyl containing from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety, nitro, amino, halo, cyano, CHO; R ⁶ is H, C 1-6 alkyl, aralkyl containing from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in its aryl moiety, nitro, halo, CHO, COR ¹³ , where R ¹³ is C 1-6 alkyl or aryl containing up to 10 carbon atoms under the conditions described above. The alkyd groups present in the general formula (I) may be straight or branched, and preferably contain from 1 to 6 carbon atoms. Examples of such alkyd groups include methyl, ethyl, t-butyl and the like. The acyl groups may be straight and branched, and suitably contain from 1 to 6 carbon atoms. Examples of such acyl groups include ethanoyl and propanoyl groups. The alkoxy groups may be straight and branched, and suitably contain from 1 to 6 carbon atoms. Examples of such alkoxy groups include methoxy, ethoxy and the like. Aryl groups also include carbocyclic aryl silly and heterocyclic aryl groups. Carbocyclic aryl groups include, for example, phenyl and naphthyl and contain at least one aromatic ring. Heterocyclic aryl groups include, for example, thienylene, furylene, pyridylene, indole and quinoline rings. An aralkyl group may contain from 1 to 4 atoms in its alkyl moiety, and the aryl moiety may be a carbocyclic or heterocyclic aryl group. Halogen is fluorine, chlorine, bromine or iodine. In the compounds of formula (I) X is preferably O, S or NR ⁷ , wherein R ⁷ is H, C 1-10 alkyl, sulfonyl or toluenesulfonyl; Y is preferably NR ⁷ ; R1 preferably is COR ^8, COOR ^8, CH2OR ^9, CONH2, CNHNRIORH, CONHR10, CONR10RH , COO (CH _{2) n} NR10RH, wherein R ⁸ is H, Cj.jq alkyl, aryl containing go 10 carbon atoms and substituted optionally with C 1-12 alkyl, C 1-3 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-12 alkyl groups), haloalkyl, sulfonyl or cyano, or aralkyl containing from 1 to 4 carbon atoms in the alkyd up to 10 carbon atoms in the aryl moiety, R ⁹ is C 1-10 acyl optionally substituted by C 1-10 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-10 alkyl groups ), haloalkyl, sulfonyl or cyano, R ¹⁰ and R ¹¹ c and independently of one another hydrogen, C 1-12 alkyl or aryl containing up to 10 carbon atoms; R ² is preferably COOR ⁸ , C 1-10 alkyl or CH ₂ CH ₂ CO ₂ R ¹² , wherein R ¹² is C 1-10 alkyl or aryl containing up to 10 carbon atoms; R ³ and R ⁴ are independently hydrogen, hydroxy, C 1-10 alkyl, C 1-4 alkoxy, halogen, cyano substituted with C 1-10 alkyl, C 1-3 alkoxy, halo, sulfinyl, amino (optionally substituted with two C 1-10 alkyd groups), haloalkyl, sulfonyl or cyano or carboxyl; R ⁵ is preferably H or C 1-10 alkyl; R ⁶ is preferably H, C 1-10 alkyl or aryl containing up to 10 carbon atoms, as well as their salts and physiologically active derivatives. X is preferably S or ΝΉ and A is preferably where Y is preferably NH. R 1 is preferably COOR ⁸ , wherein R ⁸ is preferably C 1-10 alkyl or aralkyl containing from 1 to 4 carbon atoms in the alkyd moiety and up to 10 carbon atoms in the aryl moiety. R ² is preferably hydrogen or C 1-10 alkyl. R ³ is preferably hydrogen, C 1-10 alkoxy or halogen. R ⁴ is preferably hydrogen, C 1-10 alkoxy or halogen. R ⁵ is preferably C 1-10 alkyl and R ⁶ is preferably H as well as their salts and physiologically active derivatives. I PAINT CLAIMS A compound of formula (I) (I) and its salts and physiologically active derivatives, wherein A is X is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ , where R ⁷ is H, C 1-10 alkyl, aralkyl containing from 1 to 4 carbon atoms in its alkyl moiety and up to 10 carbon atoms in its aryl moiety , aryl containing up to 10 carbon atoms, alkenyl, C 1-10 acyl, alkynyl or sulfonyl optionally substituted by C 1-10 alkyl, aryl containing up to 10 carbon atoms or aralkyl containing from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety; Y is O, S, SO, SO2, CH ₂ , CO or NR ⁷ ; R1 is COR8, COOR8, CHO, CH ₂ OH, CH ₂ OR9, CONH2, CONHNR10RH, CONHR10, CONR10RH, COO (CH ₂ ) _n NR10RH, where R ⁸ is H, C 1-10 alkyl, aryl containing up to 10 carbon atoms and optionally substituted with C1-10 alkyl, C10 alkoxy, halo, sulfinyl, amino (optionally substituted with one or two C1-6 alkyl groups), haloalkyl, sulfonyl or cyano, or aralkyl having from 1 to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety, R ⁹ is C 1-10 acyl optionally substituted with C 1-10 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted with one or two C 1-3 alkyl groups), haloalkyl , sulfonyl or cyano, FBO and RH are despite this, hydrogen, S1_yu alkyl or aryl containing up to 10 carbon atoms, and η is from 1 to 4 carbon atoms; R ² is H, COOR ⁸ , C 1-10 alkyl; aryl containing up to 10 carbon atoms and optionally substituted with S1_yu alkyl S1_yu alkoxy, halo, sulphinyl, amino (optionally substituted by one or two S1_yu alkyl groups), haloalkyl, sulfinyl or cyano or CH2CH2CO2R ^12, wherein R ¹² is S1_yu alkyl or aryl containing up to 10 carbon atoms; R ³ and R ⁴ are independently H, hydroxy, C 1-12 alkyl, haloalkyl, C 1-10 alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl substituted with C 1-10 alkyl, C 1-3 alkoxy, halo, sulfinyl, amino (optionally substituted by two C1-10 alkyl groups), haloalkyl sulfonyl or cyano, carboxyl or CO ₂ R12; R ⁵ is H, C 1-10 alkyl optionally substituted by C 1-10 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted by two C 1-10 alkyl groups), or cyano, aralkyl containing from 1 to 4 carbon atoms up to 10 carbon atoms in the aryl moiety, nitro, amino, halo, cyano, CHO or COOR ⁸ ; R ⁶ is H, C 1-10 alkyl, aralkyl containing up to 10 carbon atoms or aralkyl containing from 1 to 4 carbon atoms in its alkyd moiety and up to 10 carbon atoms in its aryl moiety, nitro, halogen, CHO, COR ¹³ , wherein R ¹³ is C 1-10 alkyl or aryl containing up to 10 carbon atoms; provided that (i) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is where Y is NH and X is O or S, then R ¹ is not CO ₂ H or CO ₂ Et; and (i) when all the radicals R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are H and A is 2 where Y is NH and X is O or S, then R ¹ is not CHO; and (iii) Y is not O when X is O. A compound according to claim 1, wherein X is O, S or NR ⁷ , where R ⁷ is H, C 1-10 alkyl, sulfonyl or toluenesulfonyl; Ye NR ⁷ ; Rl is COR ^8, COOR8, CHO, CH2OH, CH2OR9, CONH2, CONHNR10RH, CONHR10 , CONR ^{10 _{R n, COO (CH2) n}} NR10RU, wherein R ⁸ is H, Cj-jq alkyl, aryl containing go 10 carbon atoms and optionally substituted with C 1-10 alkyl, C 1-10 alkoxy, halo, sulfinyl, amino (optionally substituted with one or two C 1-10 alkyl groups), haloalkyl, sulfonyl or cyano, or aralkyl containing from 1 to 4 carbon atoms in the alkyd and up to 10 carbon atoms in the aryl moiety, R ⁹ is C 1-6 acyl optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, halo, sulfinyl, amino (optionally substituted by one or two C 1-6 alkyl). jq alkyl groups), haloalkyl, sulfonyl or cyano, R ¹⁰ and R ¹¹ are independently independently of one another hydrogen, C1-10 alkyl or aryl containing up to 10 carbon atoms and n being from 1 to 4 carbon atoms; R 2 is COOR ⁸ , C _1-10 alkyl or CH ₂ CH ₂ CO ₂ R 4 where R 12 is C 1-10 alkyl or aryl containing up to 10 carbon atoms; R ³ and R ⁴ are independently H, hydroxy, C 1-10 alkyl, C 1-3 alkoxy, halo, cyano, alkyl substituted with C 1-3 alkyl, C 1-3 alkoxy, halo, sulfinyl, amino (substituted by choice with two C1-10 alkyl groups), haloalkyl, sulfonyl, cyano or carboxyl. R ⁵ is H or C 1-10 alkyl; R ⁶ is H, C 1-10 alkyl or aryl containing up to 10 carbon atoms; together with their salts and physiologically acceptable derivatives. A compound according to claims 1 and 2, wherein X is S or NH; YeNH; Ah R1 is COORS, where R ⁸ is Cj.jo alkyl or aralkyl having from 1 to 4 carbon atoms in the alkyl part and up to 10 carbon atoms in the aryl part ,. And! R ² is H or C 1-10 alkyl. R ³ is H C 1-10 alkoxy or halogen. R 4 is H, C 1-10 alkoxy or halogen. R ⁵ is C 1-10 alkyl and R6eH; I as well as their salts and physiologically active derivatives. 4. Compound selected from 3-Pyridyl-3,4-dimethylpyrrolo [3,2b] carbazole-2-carboxylate; [(3-Dimethylamino) phenyl] -3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylapz Benzyl, 1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate; phenyl, 3,4-dimethylpyrrolo [3,2-Scarbazole-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-N] indole-2-carboxylate; Benzyl, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate; Benzyl, 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate; Ethyl, 8-fluoro-3,4-dimethylpyrrolo [3,2-H] carbazole-2carboxylate; Benzyl, 3,4,6-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-2carboxylapz 3,4,6-Trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and Benzyl, 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2carboxylate; * i as well as their physiologically functional derivatives. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, together with pharmaceutically acceptable carriers. A compound of formula (I) according to claims 1 to 4 for use in medicine. Use of a compound of formula (I) or | R a pharmaceutically acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumors. 8. A method for treating tumors in animals comprising administering to an animal an effective amount of a compound of formula (I) or a salt thereof or a physiologically functional derivative. A process for the preparation of compounds of formula (I) as described in claim 1, characterized in that it comprises: (a) in the catalytic ring closure of a compound of formula (IV) in the presence of a strong acid. (IV) wherein X, Υ, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined; or (b) converting a compound of formula (I) into another compound of formula (I). 10. Novel Intermediates of formula (IV) (IV) wherein X, Y, Rl, R ^2, R ^3, R ⁴ and R ⁵ are-as defined in claim 1.