SI9300390A - Pyrolo :3,2-b: carbazones, 1h benzofuro :3,2-f: indoles and 1h-:1: benzothieno :2,3-f: indoles and their use as anti-tumour agents - Google Patents

Abstract

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

Description

1. THE WELLCOME FOUNDATON LIMITED

2. UNIVERSITY COLLEGE CARDIFF CONSSULTANTS LIMITED

Pyrrolo [3,2-b] carbazoles, 1H-benzofuro [3,2-f] indoles and 1H- [1] benzothieno [2,3-findoles, useful as antitumor agents

The present invention relates to heterocyclic compounds found to have antitumor efficacy More specifically, the present invention relates to pyrrolo [3,2-b] carbazoles, ΙΗ-benzofuro [3,2-f] indoles and lH- [l] benzothieno [2,3-f] indoles, processes for their preparation, pharmaceutical compositions containing them and their use as antitumor agents.

Research into cancer chemotherapy has made it possible to produce a variety of anticancer agents that have varying degrees of efficacy. Standard clinical agents used include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cis-platinum, vincristine and vinblastine. However, these antitumor agents, now available, are known to have various disadvantages, such as e.g. 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.Geterotsikl. Soedin (1980), (2) 203-8, describe the synthesis of certain and indolobenzo [b] thiophenes.

Khoshtariya et al, khim Heterotsikl Soedin (1984), (10) 1366-70 describe the synthesis of certain indolobenzo [b] furans.

Kakhabrishvili et al, khim Heterotsikl Soedin (1985), (3) 355-8 describe the synthesis of certain derivatives of indolo [5,6-d] and indolo [5,4-d] benzo [b] furans.

EP 447,703 describes the synthesis of certain benzo (5,6-b) benzofuran-2carboxylates.

We have now discovered new compounds that have antitumor cellular efficacy with low toxicity against normal cell lines.

From the first aspect, the present invention provides a compound of general formula (I)

and its salts and physiologically functional derivatives, wherein A

X R or

X is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ , wherein R ^{7 is} H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulfonyl or substituted sulfonyl;

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

R ¹ is COR ⁸ , COOR ⁸ , CHO, CH 2 OH, CH 2 OR ⁹ , CONH 2, CONHNR ¹⁰ R ⁿ , CONHR ¹⁰ , CONR ¹⁰ R ⁿ , COOtCH ^ NR ^ R ¹¹ , 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 represents 1 to 4 carbon atoms;

R ² is H, 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 H, hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkyl amino, dialkyl amino, substituted alkyl, carboxyl or CO ₂ R ¹² ;

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

R ⁶ is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or COR ¹³ wherein R ^{13 is} alkyl or aryl with the proviso that (i) if R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} all H and is A .1

where Υ is NH and X is X or S, then R ¹ is not CO.H ah CO ₂ Et;

and (ii) if R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} all H and A is

where Υ is NH, and XO is then R ¹ is not CHO;

and (iii) Y is not O if X is O.

In a further aspect, the present invention provides a compound of general formula (I) above, wherein A

or

R

X is O, S, SO, SO ₂ , CH ₂ , 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 ;

R ¹ is COOR ⁸ , CHO, C1 12 OH, CH 2 OR ⁹ , CONH 2, CONHR ¹⁰ or CONR ¹⁰ R ⁿ , where R ^{8 is} H, alkyl, aryl, substituted aryl or aralkyl, R ⁹ is acyl or substituted acyl, and R ¹⁰ and R ^{11 is} independently alkyl or aryl;

R ² is H, COOR ⁸ , alkyl, aryl, substituted aryl or CF 3 CH 2 O ¹² where R ^{12 is} alkyl or aryl;

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

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

R ⁶ is H, alkyl, aralkyl, nitro, halo, CHO or COR ¹³ wherein R ^{13 is} alkyl or aryl with the proviso described above.

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

The acyl groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable acyl groups include ethanoyl and propanoyl groups.

Alkoxy groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy, and the like.

Aryl groups include both carbocyclic aryl groups and heterocyclic aryl groups normally containing a maximum of 10 ring atoms. Carbocyclic aryl groups include e.g. phenyl and naphthyl and containing at least one aromatic ring. Heterocyclic aryl groups include e.g. thienyl, furyl, pyridyl, indole, and quinoline rings.

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

Substituents which may be present on alkyl, aryl or acyl groups include alkyl, alkoxy, halogen, sulfinyl, amino (optionally substituted with 1 or 2 alkyl groups), halo alkyl (e.g. trifluoromethyl), sulfinyl, sulfonyl and cyano.

Substituents which may be present on sulfonyl include alkyl, aryl and aralkyl.

Halogen represents 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 toluene sulfonyl;

Y is preferably NR ⁷ ;

R ¹ is preferably COR ⁸ , COOR ⁸ , CH ₂ OR ⁹ , CONH 2, CNHNR ¹⁰ R ⁿ , CONHR ¹⁰ , CONR ¹⁰ R ⁿ , COO (CH ₂ ) _n ¹⁰ NR ¹⁰ R ¹¹ , 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 represents 1 to 4 carbon atoms;

R ² is preferably COOR ⁸ , alkyl or CH ₂ CH ₂ CO ₂ R ¹² wherein R ^{12 is} alkyl or aryl;

R ³ and R ⁴ independently represent H, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl or carboxyl;

R ⁵ is preferably H or alkyl;

R ⁶ is preferably H, alkyl or aryl and their salts and physiologically functional derivatives.

X is preferably S or NH, A is preferred

and Y preferably represents NH.

R ¹ is preferably COOR ⁸ , wherein R ^{8 is} preferably alkyl or aralkyl.

R ² is preferably H or alkyl.

R ³ is preferably H, alkoxy or halogen.

R ⁴ is preferably H, alkoxy or halogen.

R ⁵ is preferably alkyl and

R ⁶ is preferably H and its salts and physiologically functional 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-2-carboxylate benzyl 1,3, 4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate phenyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate

3,4-dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3,2-b] carbazole ethyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate, ethyl 3,4-dimethylbenzothieno [4,5- f] indole-2-carboxylate benzyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate, benzyl 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate ethyl 8 -fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate benzyl 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate ethyl 3,4,6-trimethylpyrrolo [3 , 2-b] carbazole-2-carboxylate 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

3,4-Dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid ethyl 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate, 3,4,6-trimethylpyrrolo [3,2 -b] carbazole-2-carboxylic acid and benzyl 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate and their physiologically functional derivatives.

Compounds of general formula (I) were tested against two specially developed cell lines, which are clones of the human fibro sarcoma cell line, ΗΊΊ080. One HT1080 clc2 clone retains the transformed original lineage phenotype, while the other HT10801 c is a morphologically level non-tumorigenic reverse mutant.

Therefore, the effects of potent antitumor compounds can be determined on the basis of their ability to induce detransformation in HT1080 scc2 cells. The compounds of the present invention have been found to be particularly effective in this experimental system.

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

The compounds also have low toxicity to normal cells.

According to a further aspect, the present invention also provides a process for the preparation of compounds of general formula (I), comprising catalyzed closure of a ring of compounds of formula (IV) in the presence of a strong acid.

The present invention also provides a process for the preparation of compounds of formula (IV) comprising either:

(a) reacting a compound of formula (II) with a compound of formula (III) to form a compound of formula (IV) wherein Χ, Υ, Κ ¹ , R ² , R ³ , R ^4, and R ⁵ are as defined after:

followed by catalytic ring closure.

The reaction is preferably carried out at room temperature in the presence of a strong acid, e.g. p-toluene sulfonic acid or montmorillonite K10 clay as a catalyst to form the compound of the invention;

(b) reaction of a compound of formula (V) with a compound of formula (III) to form a compound of formula (IV), followed by as in (a), catalyzed ring closure.

where L is a leaving group. Examples of suitable leaving groups include -OCOCH ₃ , OET, -N ⁺ Me ₃ and halogen;

(c) a one-step reaction process wherein the compound of formula (II) is reacted with a compound of formula (III) in the presence of a catalyst to form the compound of the invention in a single step. Preferred catalysts are montmorillonite K10 clay;

Integration of the substituent R ¹ into the ring system eg:

(d) carboxylation of the polyheterocyclic compound using (i) carbonyl halide or (ii) carbon dioxide.

According to known methods (J. March, Advanced Organic Chemistry, Second Edition, McGraw Hill, New York, 1977, pp. 497-498).

(e) Alternatively, compounds of formula (I) may be made, wherein R ^{2 is} CHO, by methods known to one skilled in the art, e.g.

(i) by reaction of a suitable aromatic polyheterocycle with a formyl agent, such as e.g. those produced by the reaction between SnCl ₄ and C1 ₂ CHOCH ₃ or equivalent reagents.

E.g. according to the procedure of A. Reiche et al, Chem. Ber. 93, 88 (1960), or by other standard formulating reagents / methods known in the art, e.g. with the Gatterman-Koch reaction (CO / HC1 / A1C1 ₃ / CuC1), the Gatterman reaction (HCN / HCl / ZnCl ₂ ), and the Vilsmeier reaction (POCl ₃ / PhN- (Me) CHO or POCl ₃ / Me ₂ NCHO) (J March, see above, pp. 494-497); or by reaction (ii) of a suitable aromatic polyheterocycle bearing a suitable functional group, wherein said group is converted into an aldehyde group by methods known to one skilled in the art. Suitable functional groups include CHBr ₂ , CH ₃ , COR ¹⁴ , where R ^{14 is a} primary or secondary C ₁₆ -alkyl group, COOH or derivatives thereof, such as e.g. esters, amides, acid chlorides or CNs; or (f) compounds of formula (I) wherein R ^{1 is} CONHR ¹⁰ may also be prepared by reaction of a compound wherein R ^{1 is} COOH or a suitable reactive acid derivative thereof, as shown in J. March, see above. For example, an acid halide may be reacted with the compound NH ₂ R ¹⁰ in an inert solvent.

(g) Conversion of one compound of formula (I) into another compound of formula (I).

The compounds of the invention wherein R ^{1 is} COOR ⁸ and R ⁸ is e.g. aralkyl can be converted to free acids, where R ^{8 is} H, by reduction in the presence of H ₂ and Pd catalyst, or where R ⁸ , e.g. alkyl, by hydrolysis in the presence of a suitable base, e.g. of cesium carbonate.

Thus, it is possible for those skilled in the art to synthesize ester and amide compounds within the scope of the present invention by converting the free acids obtained by known methods (See J. March, see above, pp. 363-365).

The compounds of the invention made as described herein can be converted to other compounds of the invention by electrophilic substitution on R ⁵ and / or R ⁶ to introduce, e.g. NO ₂ , halogen and COR ¹³ , wherein R ^{13 is} as defined herein.

The above procedures are described for compounds wherein A

Those skilled in the art will appreciate that they are equally useful if A / </ '

In another aspect, the present invention relates to novel intermediates of formulas (II), (III), (IV) or (V).

The compounds of the invention are useful for the treatment of tumors. They can be used in the treatment of various cancers in mammals including cancers, e.g. stomach, pancreas, breast, uterus and colon; adenocarcinoma, e.g. lungs and colon; sarcoma, e.g. fibrosarcoma; leukemia, e.g. lymphocytic leukemia and lymphoma, e.g. myeloid lymphoma.

The present invention therefore further provides a method for treating tumors in creatures, including mammals, especially humans, comprising administering a clinically useful amount of a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative in a pharmaceutically useful form once or several times a day or any other appropriate schedule, oral, rectal, parenteral or topically administered.

Additionally provided as a further or alternative aspect of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof useful in therapy, e.g. as an antitumor agent.

The amount of a compound of formula (I) required to be effective against said tumors naturally varies and is ultimately within the discretion of the physician or veterinarian. Factors to consider include the condition being treated, the route of administration and the nature of the formulation, body weight, effective surface area, age and general condition of the mammal, and in particular the particular compound administered. A suitable effective antitumor dose is in the range of about 0.01 to about 100 mg / kg body weight, e.g. 0.1 to about 100 mg / kg body weight, preferably 1-30 mg / kg body weight. The whole daily dose can be administered as a single dose, a multiple dose, e.g. 2 to 6 times a day or with an intravenous infusion for the selected duration. E.g. for a 75 kg mammal, the dose is in the range of about 8 to 900 mg per day and the typical dose may be about 50 mg per day. If separate multiple doses are prescribed, treatment can typically be carried out with 15 milligrams of the compound of formula (I) administered up to 4 times daily.

While it is possible to administer the effective compound alone, it is preferred that it is present in the pharmaceutical formulation. The formulations of the present invention for medical use comprise a compound of formula (I), or a salt thereof, together with one or more pharmaceutically acceptable carriers and, where appropriate, other therapeutic ingredients. The carrier (s) should be pharmaceutically acceptable in the sense that it is compatible with the other ingredients of the formulation and does not harm its recipient.

The present invention therefore further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a physiologically functional derivative thereof together with a pharmaceutically acceptable carrier thereof.

Also provided is a process for the preparation of a pharmaceutical formulation comprising, combining a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier thereof.

The formulations of the present invention include those suitable for oral, topical, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred formulations are those suitable for oral or parenteral administration.

The formulations are conveniently present in a unit dosage form and can be prepared by any method well known in the pharmaceutical art. All processes involve the step of combining an effective compound with a carrier comprising one or more additional ingredients. Generally, formulations are prepared by uniformly and thoroughly combining the effective compound with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, forming the product into the desired formulations.

The formulations of the present invention suitable for oral administration may be present as separate units, such as e.g. capsules, tablets or lozenges, each containing a predetermined amount of the effective compound; as powders or granules; or solutions or suspensions in aqueous or non-aqueous liquids, such as e.g. syrups, elixirs, emulsions or doses of liquid medicine.

The tablets may be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in suitable machines, effective free-flowing compounds such as e.g. powdered or granular, optionally mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersing agent. The formulated tablets can be made by molding, in suitable machines, a mixture of the powdered effective compound with any suitable carrier.

Syrups can be made by adding an effective compound to a concentrated aqueous sugar solution, e.g. sucrose, to which any additional ingredients can be added. Such additional ingredient (s) may include flavoring agents, sugar crystallization retaining agents, or solubility enhancers of any other ingredients, such as e.g. polyvalent alcohol, e.g. glycerol or sorbitol.

Formulations for rectal administration may be present as suppositories with a conventional carrier, such as e.g. with coconut butter.

Formulations suitable for parenteral administration typically comprise a sterile aqueous preparation of an effective compound, which is preferably isotonic with the recipient's blood. Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of formula (I) which is isotonic with the recipient's blood.

Useful formulations also include concentrated solutions or solids containing a compound of formula (I), which, upon dilution with an appropriate solvent, provides a solution for parenteral administration as described above.

In addition to the ingredients mentioned above, the formulations of the invention may further include one or more additional ingredients selected from diluents, buffers, flavoring agents, binders, surfactants, thickening agents, lubricants, safeners (including antioxidants) and the like.

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

The present invention is illustrated by the following examples, but which are not limiting.

All temperatures are in degrees Celsius (° C).

IR spectra were recorded with a Perkin-Elmer 257 mesh spectrophotometer or a Bruker FS66 spectrophotometer.

U. V. spectra are measured in ethanol on a Unicam SP800 spectrophotometer.

^X H NMR spectra were obtained with a Bruker WM 360-NMR spectrophotometer at 360 MHz or a Bruker spectrophotometer AC200 at 200 MHz. J values are given in Hz.

The mass spectra are obtained with the following instruments: Varian CH5D (EI), Kratos Concept (El) or Kratos Ms50 (FAB).

EXAMPLE 1

Preparation of intermediates

Preparation of pyrrole

Ethyl 4-acetyl-3,5-dimethylpyrrole-2-carboxylate, benzyl 4-acetyl-3,5-dimethylpyrrol-2-carboxylate and ethyl 4-acetyl-3-ethyl-5-methylpyrrole-2-carboxylate) were prepared according to the procedure of A.W. Johnson et at, J. Chem. Soc., 4254 (1958).

N-methylation of pyrrole - general procedure

A mixture of pyrrole (20 mmol), methyl iodide (50 mmol) and potassium carbonate (50 mmol) was refluxed in methyl ethyl ketone (50 ml) for 8 h. If TLC (toluene / ethyl acetate 3: 1) indicates that the reaction is incomplete, further aliquots of methyl iodide (50 mmol) and potassium carbonate (50 mmol) are added and the mixture is refluxed for a further 6 h. After evaporation in vacuo to dryness, the residue was taken up in warm water and extracted with ethyl acetate (3 x 50 ml). The combined extracts were dried over magnesium sulfate and evaporated in vacuo to leave a yellow oil or solid which was crystallized from aqueous ethanol.

Ethyl 4-acetyl-1,3,5-trimethylpyrrole-2-carboxylate

Obtained from ethyl 4-acetyl-3,5-dimethylpyrrole-2-carboxylate as white crystals (2g; 41%) of m.p. 61-62 ° C (Found: C 64.17; H 7.82; N 6.16 C ₁₂ H _1? NO ₃ calc .: C 64.55; H 7.68; N 6.27%) 5 _h ^([2 H6] DMSO) 4.25 (2H, q, C ^ CH), 3.70 (3H, s, 1-CH3), 2.43 and 2.42 (2 x 3H, 2 xs, 3-CH3 and COCH3), 2.38 (3H, s, 5 · ^ and 1.29 (3H, t, CH2CH3); m / z (%) 224 (MH ⁺ , 100), 208 (40), 194 (20), 178 (40) and 133 (20) (FAB); vmax (KBr Disc) / CM ⁴ 2984,1691 and 1651.

Benzyl 4-acetyl-1,3,5-trimethylpyrrole-2-carboxylate

Obtained from benzyl 4-acetyl-3,5-dimethyl-2-carboxylate as white crystals of the soil. 78-79 ° C (Found: C 71.30; H 6.74; N 4.79; C ₁ H ₁₉ NO ₃ calcd: C71.56; H 6.71; N 4.91%); _δ Η ^([2 H6] DMSO) 7.52 to 7.27 (5H, m, ArH), 5.30 (2H, s ^ Ph), 3.73 (3H, s, 1-CH3), 2 , 42 (6H, s, 3-CH3 and COCH3) and 2.38 (3H, s, 5-CH3); m / z (%) 285 (76, M ⁺ ), 270 (87), 194 (53), 178 (23), 151 (36), 136 (26) and 91 (100); vmax (KBr Disc) / cm ⁴ 2974, 1693 in

1641.

Preparation of 5-acetoxymethyl-4-acetylpyrrole - general procedure

Freshly distilled sulfuryl chloride (2.2 cm ³ ) was added dropwise to a cooled and mixed suspension of 4-acetyl-5-methylpyrrole (0.02 mol) in dry diethyl ether (20 cm ³ ).

1.25 eq.). The reaction mixture was further stirred and the chloromethyl derivative slowly crystallized; Filtration gives the 5-chloromethyl derivative as colorless crystals. The purity of chloromethylpyrrole was verified by * H NMR spectroscopy (90 MHz) and used directly without recrystallization.

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 h and poured into ice-water (20 cm ³ ). The resulting solid was washed thoroughly with water to give it acid free before drying.

Ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate

Crystallizes from benzene as a colorless needle (1.87 g, 70%) of soil. 135.5-138 ° C (found: C 58.6; H 6.45; N 5.15. C ₁₃ H ₁₇ NO ₅ calculated: C 58.4; H 6.41; N 5.24% ); δ _Η (CDC1 ₃ ) 9.57 (1H, br s, NH), 5.40 (2 H, s, CE ^ 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 ) and 1.4 (3H, t, OCH ₂ CH ₃ ); m / z (%) 267 (83, M ⁺ ), 224 (46), 207 (27), 178 (100) and 162 (42).

Benzyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate

Crystallized from methanol as a colorless needle (2.34 g, 71%) of soil. 138-141 ° C (Found: C 65.8; H 5.95; N 4.3 C _J8 H ₁₉ NO ₅ Calc .: C 65.64; H 5.81; N 4.25%); δ _Η (CDCl ₃ ) 9.44 (1H, br with NH); 7.49-7.32 (5 H, m, ArH), 5.40 (2H, s, CH ₂ OAc), 5.35 (2H, s, CH ₂ Ph), 2.62 (3H, s. 3-CH ₃ ), 2.49 (3H, s, CH ₃ CO) and 2.14 (3H, s, OCOCHg): m / z (%) 329 (9, M ⁺ ), 286 (13), 269 (4), 178 (19) and 91 (100).

In the case of benzyl 5-acetoxymethyl-4-acetyl-3- (2-methoxycarbonylethyl) -pyrrole-2carboxylate, there is no precipitation when the solution is poured into ice-water. Extraction with chloroform (3 x 100 cm ³ ), drying and solvent removal under reduced pressure gave an oil which was crystallized from benzene-light petroleum to give colorless needles (2.69 g, 67%) of the soil. 97-100 ° C (Found: C 62.9; H 5.9; N 3.45. C ^ H ^ NO? Calc: C 62.8; H 5.78; N 3.49%); δ _Η (CDCl ₃ ) 9.15 (1H, br s, NH), 7.50-7.30 (5H, m, ArH), 5.35 (4H, s,

CH ₂ Ph and CH ₂ OAc), 3.63 (3H, s, OCH ₃ ), 3.37 (2H, t, CH ₂ CH ₂ CO), 2.58 (2H, t, CH ₂ CO), 2 , 51 (3H, 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-acetyl-1,3-dimethylpyrrole-2-carboxylate

Crystallized from ethyl acetate / cyclohexane (61%); m.p. 100-101 ° C. (Found: C 59.38; H 6.73; N 4.95. C ₁₄ H ₁₉ NO ₅ calc. C 59.78; H 6.81; N 4.98%); 5 _h ^([2 H6] DMSO) 5.30 (2H, s, CH2OAc), 4.29 (2H, q, CH2CH3), 3.77 (3H, s, N-CH3), 2.43 and 2, , 42 (2 χ 3H, 2 xs, 3-CH3, and CH3CO), 2.02 (3H, s, OCOCH3) and 1.31 (3H, t, Cl ^ CH ^; m / z (%) 281 ( 34, M ⁺ ), 238 (100), 222 (48), and 192 (52); vmax (KBr Discj / cm ' ¹ 1712 and 1697).

Benzyl 5-acetoxymethyl-4-acetyl-1,3-dimethylpyrrole-2-carboxylate

Crystallizes from ethyl acetate / cyclohexane. δ _Η ( ² [H] ₆ -DMSO) 7.51-7.32 (5H, m, ArH), 5.34 and 5.32 (2 χ 2H, 2 xs, CH ₂ Ph and CH ₂ OAc), 3.78 (3H, s, N-CH ₃ ), 2.46 and 2.45 (2 χ 3H, 2 xs, 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-acetoxymethyl-4-acetyl-3-ethylpyrrole-2-carboxylate

Crystallizes from ether / petroleum as yellowish brown needles (61%) from the ground. 97-98 ° C (found: C 59.44; H 6.78; N 4.80. C ₁₄ H ₁₉ NO ₅ calc. C 59.76; H 6.81; N 4.98%); δ _Η (CDCl ₃ ) 9.40 (1H, br s, 1-NH), 5.38 (2H, s, CH ₂ OAc), 4.38 (2H, q, J 7, CC ^ CH ^, 3 , 10 (2H, q, J 7.5, 3- (¾ 2.54 (3H, s, COCH ₃ ), 2.18 (3H, s, OCOCH ₃ ), 1.40 (3H, t, J 7 , 5, CO ^ I ^ CH ^ l ^ (3H, t, J 7.5, 3- (¾¾ m / z (%) 281 (42, M ⁺ ), 238 (61), 221 (89), 206 (58), 192 (92), 175 (95), 160 (81), 147 (59), 43 (100); in _max (KBr disc) / cm ⁴ 3277,1738,1674,1657.

Synthesis of 3- (pyrrolylmethyl) indole, 2- (pyrrolylmethyl) benzofuran and 3- (pyrrolylmethyl) benzothiophene - general procedure

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) for 1.5-2 h . After filtration from clay and a good washing with 1,2-dichloroethane by evaporation of the combined filtrates under reduced pressure, an oil is obtained. This oil was flash chromatographed on silica eluting with ethyl acetate in light petroleum to give 3- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) indole. Light petroleum ethyl acetate gave colorless crystals (0.1465 g, 45%), m.p. 180-182 ° C (Found: C 70.5; H 6.25; N 8.65. Calc .: C 70.4; H 6.21; N 8.64%); δ _Η (CDC1 ₃ )

8.78 (1H, s, pir-NH), 8.27 (1H, s, ind-NH), 7.45 (1H, d, J7, 4-H) 7.42 (1H, d, J7) , 7-H),

7.25 (1H, t, J7, 6-H), 7.14 (1H, t, J7, 5-H), 7.10 (1H, s, 2-H), 4.45 (2H, s , 3 - (^), 4.22 (2H, q, OCH ₂ CH ₃ ), 2.63 (3H, s, 4'-CH ₃ ), 2.53 (3H, s, CH ₃ CO) and 1 , 25 (3H, t, OCH ^ CH3); m / z (%) 324 (100, M ⁺ ) 309 (48), 277 (25), 263 (54), 250 (38), 235 (30). 207 (48), 139 (24), 130 (30), 117 (67) and 90 (16); _Vmax (CHCl ^ / crn ¹ 3490, 3430, 1680 and 1650.

If benzofuran (1.0 mmol) is used instead of indole, chromatography is obtained

2- (3′-acetyl-5′-ethoxycarbonyl-4′-methylpyrrol-2′-ylmethyl) benzofuran (0.106 g, 32.6%), m.p.

124- 127 ° C (Found: C 70.1; H 6.1; N 4.15 C ₁₉ H ₁₉ NO ₄ calculated: C 70.14; H 5.89; N 4.31%); δ _Η (CDCl ₃ ) 9.25 (1H, s, NH), 7.50 (1H, d, J7.3, 4-H) 7.44 (1H, d, J7.3, 7-H) 7.287 , 18 (2H, m, 6-H and 5-H), 6.57 (1H, s, 3-H), 4.50 (2H, s, 2-0 ^), 4.31 (2H, q , OCH ₂ CH ₃ ) 2.62 (3H, s, 4'-CH ₃ ) 2.50 (3H, s, CH ₃ CO) and 1.35 (3H, t, OCH ₂ CH ₃ ); saturation of the 3-H singlet at δ 6.51 increases the signals due to 4H at δ 7.50 (2.7%) and 2-CH ₂ at δ 4.50 (0.8%); m / z (%) 325 (100, M ⁺ ), 310 (4), 279 (29), 264 (17), 251 (59), 236 (27), 208 (19), 193 (9), 131 (7) and 118 (7); and 2,3-bis (3'-acetyl-5'-ethoxycarbonyl-4'methylpyrrol-2'-ylmethyl) benzofuran (0.0238 g, 8.94%) m.p. 255-257 ° C; δΗ (CDCl 3) 10.09 (1H, s, NH) 9.95 (1H, s, NH), 7.32 (1H, d, J7,7,4-H), 7,27 (1H, d. J7.7, 7-H), 7.17 (1H, t, J7.7, 6-H), 7.08 (1H, t, J7.7, 5-H) 4.45 (2H, s. 2-CH2), 4.40 (2H, s, 3-CH2), 4.36 (2H, q, OCH2CH3), 4.27 (2H, q, OCH2CH3), 2.64 (3H, s, 4 ^ O ^), 2.63 (3H, s, 4'-CH3), 2.58 (3H, s, CH3CO), 2.54 (3H, s, CH3CO), 1.39 (3H, t, OCH2CH3) and 1.31 (3H, t, OCH2CH3); 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.C3QH ₃₂ N ₂ O ₇ calc .: M, 532.2209).

Using benzothiophene (1.0 mmol) in the same manner as indole by chromatography using ethyl acetate in dichloromethane as eluent to give colorless crystals of 3- (3'acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene (0.0963 g, 28.2%) m.p.

125- 128 ° C (Found: C 6675; H 5.8; N 4.1 C ₁₉ H ₁₉ NO ₃ S calculated: C 66.84; H 5.61; N 4.10%); δ _Η (CDCl ₃ ) 8.72 (1H, br, s, NH), 7.88 (1H, m, 4-H), 7.63 (1H, m, 7-H), 7.37 (2H , m, 6-H and 5-H), 7.20 (1H, s, 2-H), 4.54 (2H, s, 3-0 ^), 4.23 (2H, q, OCH ₂ CH ₃ ), 2.62 (3H, s, 4'-CH ₃ ), 2.53 (3H, s, CH ₃ CO) and 1.28 (3H, t, OCH ^ H ^; saturation of 3-CH ₂ protons at δ 4.54 increases signals due to NH at δ 8.72 (3.3%), 4-H at δ 7.88 (7.7

%), 2-H at δ 7.20 (6%) and CH ₃ CO at δ 2.53 (1.3%); m / z (%) 341 (100, M ⁺ ), 326 (9), 298 (6), 295 (20), 230 (39), 267 (46), 252 (32), 224 (27), 194 (26) and 148 (22); and 2,3-bis (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene as a pale yellow solid (0.0264 g, 9.6%), mp.206-209 ° C (found: C 65.6; H 5.8; N 5.1 C ₃₀ H ₃₂ N ₂ O ₆ S calculated: C 65.67; H 5.88; N 5.11%), δ _Η (CDCl ₃ ) 9.77 (1H, br, s, NH), 9.43 (1H, br, s, NH), 7.70 (1H, m, 4-H), 7.49 (1H, m, 7-H), 7.26 (2H, m, 6-H and 5-H), 4.55 (2H, s, CH ^, 4.53 (2H, s, CH _2), 4.32 (2H, q, OCH ₂ CH ₃ ), 4.24 (2H, q, OCH ₂ CH ₃ ), 2.61 (3H, s, 4'-CH ₃ ), 2.60 (3H, s, 4 ' -CH ₃ ), 2.57 (3H, s, CH ₃ CO) 2.49 (3H, s, CH ₃ CO), 1.35 (3H, t, 00¾¾) 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

Synthesis of 3- (pyrrolylmethyl) benzothiophenes and 3- (pyrrolylmethyl) indoles

a) 3- (3'-acetyl-5 ^, -benzyloxycarbonyl-4 ^, -methylpyrrol-2 ^, -ylmethyl) benzothiophene

A solution of 5-acetoxymethyl-4-acetylpyrrole (0.33 g; 1.0 mmol) and benzothiophene (0.14 g; 1.05 mmol) in 1,2-dichloroethane (10 cm ³ ) was heated at reflux and stirred with montmorillonite K10 clay (1 g) 2.5 h. After cooling and filtration from well-washed clay with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to leave a yellow oil. Flash chromatography on silica eluting with diethyl ether / light petroleum (1: 2) gave the title compound as a colorless solid.

δ _Η (CDCl ₃ ) 8.72 (1H, s, NH), 7.92-7.84 (1H, m, 4-H), 7.69-7.58 (1H, m, 7-H) , 7,437.16 (8H, m, 2-H, 5-H, 6-H, ArH), 5.23 (2H, s, CH ₂ Ph), 4.50 (2H, s, 3-CH ₂ ) , 2.61 (3H, s, 4'-CH ₃ ) and 2.50 (3H, s, CH ₃ CO); m / z (%) 403 (M ⁺ , 100); p _fflax (KBr Disc / cm ⁴ 3290, 1690 and 1659.

b) 3- (3 ^, -acetyl-5 ^, -ethoxycarbonyl-4 ^, -methylpyrrol-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 heated at reflux and stirred with montmorillonite K10 clay (2.1 g) for 6 h. After cooling and filtering from well-washed clay with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to leave an orange solid. Crystallization from dichloromethane / ethyl acetate yielded a small amount of analytically pure title compound as cloudy yellow crystals. The evaporated mother liquors were flash chromatographed on silica eluting with dichloromethane / ethyl acetate (9: 1) to give a further product (0.65 g, 71%). 213-214 ° C (Found: C 68.60; H 5.46; N 11.99. Calc .: C 68.75; H 5.48; N

12.03%) S _h ([ ² H 6] -DMSO) 12.05 (1H, s, 1'-NH), 11.38 (1H, s, 1-NH), 8.20 (1H, m, 4-H), 7.50 (1H, dd, 10.7 and 8.5, 7-H), 7.39 (1H, dd, JI, 7 and 8.5.6-H), 7.18 (1H, s, 2-H), 4.32 (2H, s, 3-CH2 4.27 (2H, q, CH2CH3), 2.33 (3H, s, 4'-CH3), 2.51 ( 3H, s, CH 3 CO) and 1.30 (3H, t, CH 2 CH 2); m / z (%) 350 (M ⁺ , 70), 302 (16), 279 (18), 237 (35), 208 (100) and 181 (20); vmax (KBr Disc / cm ⁴ 3309,2218 and 1665.

c) 3- (3 ^, -acetyl-5 ^, -ethoxycarbonyl-4 ^, -methylpyrrol-2 ^, -ylmethyl) indole-5-carboxylic acid

A solution of 5-acetoxymethyl-4-acetylpyrrole (0.74 g, 2.8 mmol) and indole-5-carboxylic acid (0.5 g, 3 mmol) in toluene (50 cm ³ ) was stirred at room temperature with montmorillonite K10 clay (1 g) 10 days. After cooling and filtration from the well-washed clay with toluene, the combined filtrates were evaporated under reduced pressure to leave an orange solid. Crystallization from ethyl acetate / cyclohexane gave the title compound as a gray powder (0.15 g, 15%). 227-228 ° C (Found: C 64.96; H 5.58; N 7.34.

^C 20 ^H 20 ^N 2 ° 5 ^Calc. - ^{C 65 '21} ; ^{H 5} ' ⁴⁷ ' ^{N 7 '60%} )' ^S h ([ ² H 6] -DMSO) ^{12 '35} ( ^1H ' ^br 'CO2H) 12.04 (1H, s, Γ-ΝΗ), 11.17 (1H , s, 1-NH), 8.31 (1H, d, JI, 6, 4-H), 7.70 (1H, dd, JI, 6 and 8.7, 6-H), 7.37 ( 1H, d, J8.7, 7-H), 6.98 (1H, s, 2-H), 4.36 (2H, s, 3-CH ₂ ),

4.26 (2H, q, CH ₂ CH ₃ ), 2.51 and 2.31 (2 χ 3H, 2 xs, 4′-CH ₃ and CH ₃ CO) and 1.29 (3H, t, CH ₂ CH ₃ ); m / z (%) 369 (22 (M + 1) ⁺ ), 351 (37), 323 (18), 305 (19), 232 (19), 208 (60) and 181 (20), 162 (100) ); in _max (KBr Disc) / cm ⁴ 3359 and 1676.

d) 3- ^{(3-acetyl-5-ethoxycarbonyl 4> -metilpirol-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 ) was heated at reflux and stirred with montmorillonite K10 clay (3 g) 5 h. After cooling and filtering from well-washed clay with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to leave a yellow solid. Crystallization from light petroleum / acetone dichloromethane gave the title compound as cloudy yellow crystals (0.33 g, 17%). 181-183 ° C (Found: C 56.24; H 4.70; N 6.86. C 19 H 19 BrN 2 O 3 calculated: C 56.59; H 4.75; N 6.95%); δΗ ^([2 H6] -DMSO) 12.00 (IH, s, l'-NH), 11.00 (IH, s, 1-NH), 7.82 (IH, d, JI, 9, 4- H, 7.31 (1H, d, J8.6, 7-H), 7.16 (1H, dd, JI, 9 and 8.6, 6-H), 7.02 (1H, s, 2 -H), 4.30 (2H, s,

3- 0¾). 4.28 (2Η, q, 0 ^ 0 ^), 2.51 and 2.33 (2 χ 3H, 2 xs, 4'-CH ₃ and CH ₃ C0) 1.31 (3H, t, CH ^ CHj ) m / z (%) 404 and 402 (100 M ⁺ ), 389 and 387 (24), 357 (24), 330 and 328 (32), 206 (36) and 178 (26); in _max (KBr Disc / cm ¹ 3373 and 1672.

EXAMPLE 3

a) Ethyl 3,4-dimethylpyrrolo [3,2-bicarbazole-2-carboxylate

A solution of 3- (pyrrolylmethyl) indole (0.108 g, 0.33 mmol) was heated at gentle reflux in 1,2-dichloroethane (10 cm ³ ) and stirred with montmorillonite K10 clay (1 g) for 2 h. TLC shows that a single compound is formed and the reaction is complete. Filtration from clay and washing with 1,2-dichloroethane by evaporation of the combined filtrates under reduced pressure gave a yellow solid which was recrystallized from ethyl acetate to give pyrrolo [3,2-b] -carbazole as yellow crystals (0.076 g; 75%), mp 209.5-211 ° C (found: C 74.6; H 6.14; N 9.03. C19 H11 N2 O2 calcd: C 74.5; H 5.92; N 9 , 14%); 5h ^[2 HJ-DMSO) 11.22 (IH, s, 1-NH), 10.70 (IH, s, 5-NH), 8.06 (IH, d, J7, 9-H), 7, 85 (1H, s, 10-H), 7.40 (1H, d, J7, 6-H), 7.35 (1H, t, J7, 7-H), 7.08 (1H, t, J7 , 8-H), 4.35 (2H, q, OCH2CH ₃ ) 2.91 and 2.90 (2 χ 3H, 2 xs, 3-CH ₃ and 4-CH ₃ and 1.35 (3H, t, OCH ₂ CH ₃ ) .Saturation of 10-H at δ 7.85 increases singlets due to 1-NH 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) and 130 (26); vmax (CHCl ⁴ / cm ⁴ 3480 and 1700; kmax (EtOH) / nm 226, 268, 310sh, 327sh, 340, 390 and 410sh.

b) Ethyl 3,4-dimethyl-1H-benzofuroyl 3,2-flindole-2-carboxylate

Toluene-p-sulfonic acid (50 mg) was added to a solution of 2- (pyrrolylmethyl) benzofuran (0.100 g 0.31 mmol) in toluene (10 cm ³ ) and the reaction mixture was refluxed for 3 h. After cooling, the product crystallizes out and after filtration and washing with ethanol, the title compound is obtained as light yellow crystals (0.084 g, 88.8%), m.p. 262-265 ° C (Found: C 74.25; H5.55; N 4.6 C19H1? NO3 calcd: C 74.25; H 5.56; N 4.56%); 6h ([ ² H 6] -DMSO) 11.52 (1H, s, 1-NH). 8.18 (1H, d, J7.5.5-H), 7.62 (1H, d, J7.5, 8-H), 7.46 (1H, t, J7.5, 7-H) , 7.38 (1H, t, J7.5, 6-H), 7.38 (1H, s, 10-H), 4.37 (2H, q, OCH / DK,), 3.14 (3H , s,

4- CH ₃ ), 2.91 (3H, s, 3-CH ₃ ) and 1.39 (3H, t, 00d ₂ 01 ₃ ); saturation of 4-CH ₃ at δ 3.14 increases the signals due to 5-H at δ 8.18 (4.5%) and 3-0¾ at δ 2.91 (2.6%); m / z (%) 307 (53, M ⁺ ), 261 (100), 233 (31) and 205 (9); vmax (nujol / cm ¹ 3350 and 1686; Xmax (EtOH) / nm 240, 269, 293, 330 and 344.

c) Ethyl 3,4-dimethyl-1H-rylbenzothieno 2,3-flindole-2-carboxylate

Toluene-p-sulfonic acid (45 mg) was added to a solution of 3- (pyrrolyl) benzothiophene (0.100 g, 0.29 mmol) in toluene (10 cm ³ ) and the reaction mixture was refluxed for 3 h. Evaporation of the solvent and washing of the resulting solid with ethanol gave the title compound as a pale yellow solid (0.0758 g, 80%), m.p. 191-193 ° C (Found: C 70.3; H 5.5; N 4.2; C 19 H 17 NO 2 S calcd: C 70.6; H 5.30; N 4.33%); 5h ([ ² HJ-DMSO) 11.64 (1H, s, NH), 8.25 (1H, m, 9-H), 8.12 (1H, s, 10-H), 7.95 (1H , m, 6-H), 7.48 (2H, m, 7-H and 8-H), 4.38 (2H, q, OCH2CH ₃ ), 2.87 and 2.85 (2 χ 3H, 2 xs, 3-CH ₃ ) and 1.37 (3H, t, OCH ₂ CH ₃ ): m / z (%) 323 (53, M ⁺ ), 277 (100), 249 (33), 221 (15) , 139 (7) and 111 (11); vmax (nujol / cm ⁴ 3350 and 1686; Xmax (EtOH) / nm 240,269,293,330 and 344.

d) Benzyl 3,4-dimethyl-1H-ylbenzothieno [2,3, -f] indole-2-carboxylate

Toluene-p-sulfonic acid (40 mg) was added to a solution of 3- (pyrrolyl) benzothiophene (0.100 g, 0.25 mmol) in toluene (12 cm ³ ) and the reaction mixture was refluxed for 6 h. Evaporation of the solvent and washing of the resulting solid with ethanol gave the title compound as a pale yellow solid (0.02 g, 20%) of the soil. 203-204 ° C (Found: C 74.7; H 4.9; N 3.6; C ^ H ^ NC ^ S calculated: C 74.8; H 5.0; N 3.6%) ; δΗ ^([2 H6] -DMSO) 11.64 (IH, s, NH), 8.27 to 8.15 (IH, m, 9-H), 8.10 (IH, s, 10-H), 7 , 90-7.89 (1H, m, 6-H), 7.607.30 (7H, m, 7-H, 8-H, ArH), 5.40 (2H, s, C ^) and 2.87 (6H, s, 2 x CH ₃ ); m / z (%) 385 (100, M ⁺ ), 277 (89), 248 (25), 221 (15) and 91 (28); in _max (KBr Disc / cm ' ¹ 3331 and 1672.

e) Ethyl 8-cyano-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate

A mixture of 3- (pyrrolylmethyl) indole (0.6 g, 1.7 mmol) and montmorillonite K10 clay (2 g) in toluene was stirred and refluxed for 24 h. After cooling and filtration from well washed with toluene, the combined filtrates were evaporated under reduced pressure to leave a brown solid which was flash chromatographed on silica eluting with cyclohexane / ethyl acetate (3: 1) to give a yellow solid. Crystallization from cyclohexane / ethyl acetate gave the title compound as a yellow powder (0.030 g, 5%). Tal. &Gt; 240 ° C (Found: C 71.54; H 5.18; N 12.78, Ό ^ Η ^ Ν ^ .Ο, ΖΗ /) Calcd .: C 71.71; H, 5.24; N 12.54 (%) _H ^([2 H _6] -DMSO) 11.39 (IH, s, 1-NH), 11.29 (lH, s, 5-NH), 8.65 (IH, d, JI, 7, 9-H), 8.01 (1H, s, 10-H), 7.71 (1H, dd, JI, 7 and 8.6, 7-H), 7.50 (1H , d, J8,6, 6-H), 4.36 (2H, q, CE ^ CH ^, 2.91 and 2.89 (2 χ 3H, 2 xs, 4-CH 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) and 149 ( 40);

in _max (KBr Disc) / cm ⁴ 3414,3550,2212 and 1664.

f) 3,4-Dimethyl-2-ethoxycarbonylpyrrolo [3,2-b] carbazole-8-carboxylic acid

A mixture of 3- (pyrrolylmethyl) indole (0.1 g, 0.3 mmol) and montmorillonite K10 clay (0.34 g) in toluene (15 cm ³ ) was stirred and refluxed for 6 h. After cooling and filtering from the well-washed clay with toluene, the combined filtrates were evaporated under reduced pressure to leave an orange solid. Crystallization from methanol / dichloromethane gave the title compound as a yellow powder (0.027 g, 28%). > 260 ° C (Found: C 68.12; H 5.19; N 7.91 C H H N N.0.0.05H2 O calc .: C 68.39; H 5.19; N 7.98% ); δΗ ( ² [H] 6-DMSO) 12.42 (1H, br, COOH), 11.30 (1H, s, 1-NH), 11.09 (1H, s, 5-NH), 8.68 (1H, s, 10-H), 8.07-7.93 (2H, m, 7-H and 9-H), 7.45 (1H, d, J9, 6-H), 4.38 ( 2H, q, CH ₂ CH ₃ ), 2.94 and 2.90 (2 χ 3H, 2 xs, 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) and 181 (38); _Vfflax (KBr Disc) / cm ⁴ 3459, 1697 and 1674.

g) Ethyl 8-bromo-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate

A mixture of 3- (pyrrolylmethyl) indole (0.3 g, 0.74 mmol) and montmorillonite K10 clay (1 g) in toluene was stirred and refluxed for 6 h. After cooling and filtration from well-washed clay with toluene, the combined filtrates were evaporated under reduced pressure to leave a brown solid which was flash chromatographed on silica eluting with dichloromethane / light petroleum (7: 3) to give a yellow solid. Crystallization from cyclohexane and ethyl acetate gave the title compound as a yellow powder (0.070 g, 24%). M.p .: 204-205 ° C (dec) (Found: C 59.17; H 4.43; N 7.30. C ₁₉ H ₁₇ BrN ₂ O ₂ calc. C 59.23; H 4.45 N, 7.27%; 6 _h ([ ² H 6] -DMSO) 11.26 (1H, s, 1-NH), 10.79 (1H, s, 5-NH), 8.30 (1H, d, J2.2, 9- H), 7.92 (1H, s, 10-H), 7.47 (1H, dd, J2.2 and 8.8, 7-H), 7.35 (1H, d, J8.8, 6 -H), 4.36 (2H, q, CH2CH3), 2.89 and 2.88 (2 χ 3H, 2 xs, 4-CH3 and 3-0¾) and 1.38 (3H, t, CT ^ CH ^; m / z (%) 386 and 384 (100, M ⁺ ), 340 and 338 (70), 232 (60) and 181 (50); vmax (KBr Disc) / cm ⁴ 3350,1705 and 1663.

EXAMPLE 4

Synthesis of pyrrolocarbazoles in the same container - general procedure

A solution of indoles (1.0 mmol) and 5-acetoxymethyl-4-acetylpyrrole (1.0 mmol) in 1,2 dichloroethane (10 cm ³ ) was heated at gentle reflux and stirred with montmorillonite

Κ10 clay (1 g) 3-4 h. The color of the clay changes to light brown and the reaction is followed until complete with TLC. Filtration from clay and washing with 1.2dichloroethane, evaporation of the combined filtrates afforded pyrrolo [3,2-b] carbazoles, which were recrystallized from dichloromethane or ethyl acetate to give yellow crystals.

a) Ethyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate (0.199 g, 65%) was obtained by the reaction of indole and 5-acetoxymethyl-4-acetylpyrrole. The flight is identical in all respects to 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 reaction between indole and 5-acetoxymethyl-4-acetylpyrrole and m.p. 229-232 ° C (Found: C 78.2; H 5.65; N 7.8 Calcd .:

C, 78.23; H, 5.47; N, 7.60%; S _H [ ² H ₆ ] -DMSO-d ₆ ) 11.29 (1H, s, 1-NH), 10.65 (1H, s, 5-NH), 8.08 (1H, d, J8, 9) -H), 7.89 (1H, s, 10-H), 7.56-7.34 (7H, m, ArH,

6- H and 7-H), 7.08 (1H, t, J7, 8-H), 5.42 (2H, s.CEL.Ph) and 2.92 (6H, s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 368 (74, M ⁺ ), 354 (10), 260 (100), 246 (13), 231 (20) and 91 (31).

Pyrrolo [3,2-b] carbazole (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-bicarbazole-2-carboxylate

Obtained by reaction of 5-methoxyindole and 5-acetoxymethyl-4-acetyl pyrrole, m.p. 119-122 ° C (found: C 71.6; H 6.0; N 8.05. C ₂₀ H ₂₀ N ₂ O ₃ calculated: C 71.4; H 5.99; N 8.33% ); S _h ^([2 H ₆ DMSO) 11.20 (IH, s, 1-NH), 10.38 (IH, s, 5-NH), 7.85 (IH, s, 10-H), 7 , 62 (1H, d, J2.5, 9-H), 7.31 (1H, d, J9, 6-H), 7.01 (1H, dd, J9 and 2.5,

7- H), 4.38 (2H, q, OCH ₂ CH ₃ ), 3.88 (3H, s, OCHj), 2.89 and 2.87 (2 χ 3H, 2 xs,

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 [2,3-bicarbazole-2-carboxylate (0.139 g, 35%) was obtained by reaction of 5-methoxyindole and 5-acetoxymethyl-4acetylpyrrole and having a m.p. 212-215 ° C (Found: C 75.4; H 5.55; N 6.95. C 22 H 27 N 4 O 4 Calc .: C 75.4; H 5.57; N 7.03%); 5 _h ([ ² H ₆ ] -DMSO) 11.29 (1H, s, 1-NH),

10.38 (1H, s, 5-NH), 7.88 (1H, s, 10-H), 7.65 (1H, d, J2.5, 9-H), 7.58-7.36 (5H, m, ArH), 7.32 (1H, d, J9, 6-H), 7.02 (1H, dd, J9 and 2.5, 7-H), 5.43 (2H, s. CH ^ Ph), 3.88 (3H, s, OCH _3), 2.92 (3H, s, 4-CH ₃₎ and 2.89 (3H, s, 3-CH); m / z (%) 398 (73, M +), 290 (100), 262 (10), 247 (15), 219 (7) and 91 (17).

e) Ethyl 8-fluoro-3,4-dimethylpyrrolor3 _< 2-b] carbazole-2-carboxylate (0.131 g, 40.5%) was obtained by the reaction of 5-fluoro-indole and 5-acetoxymethyl-4acetylpyrrole and had m.p. 231-234 ° C (found: C 70.5; H 5.3; N 8.4. C ₁₉ H ₁₇ FN ₂ O ₂ calc .:

C, 70.4; H, 5.28; N, 8.64%; 5 _h [ ² H ₆ ] -DMSO) 11.27 (1H, s, 1-NH), 10.64 (1H, s, 5-NH), 7.93 (1H, dd, J9 and 2.5, 9-H), 7.88 (1H, s, 10-H), 7.36 (1H, dd, J9 and 6.6-H), 7.19 (1H, dt, J9 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-3,4-dimethylpyrrolo [2,3-b] carbazole-2-carboxylate (0.155 g, 40%) was obtained from 5-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole and had m.p. 217-219 ° C (Found: C 74.6; H 4.95; N 7.3. C 16 H 16 FN 4 O requires: C 74.6; H 4.96; N 7.25); 5 _h [ ² H ₆ ] -DMSO) 11.36 (1H, s, 1-NH), 10.86 (1H, s, 5-NH), 7.94 (1H, dd, J9 and 2.5, 9-H), 7.89 (1H, s, 10-H), 7.56-7.38 (5H, m, ArH), 7.39 (1H, dd, J9 and 4.6-H), 7.21 (1H, dt, J9 and 2.5, 7-H), 5.42 (2H, s, CH ₂ Ph), 2.91 and 2.90 (2 χ 3H, 2 xs, 3-0¾ and 4-0 ^); m / z (%) 386 (68, M ⁺ ), 278 (100), 249 (22) and 91 (43).

g) Ethyl 3,4,6-trimethylpyrrolo [2,3-b] carbazole-2-carboxylate (0.206 g, 64.4%) is obtained by the reaction of 7-methylindole and 5-acetoxymethyl-4-acetylpyrrole and has m.p. 230 C (dec) (found: C 74.9; H 6.25; N 8.65.C ₂₀ H _{2 ()} N ₂ O ₂ calculated: C 75.0; H 6.29; N, 8.74%; 5 _h ([ ² HJ-DMSO) 11.20 (1H, s, 1-NH), 10.11 (1H, s, 5-NH), 7.89 (1H, d, J7.5, 9-H) ), 7.84 (1H, s, 10-H), 7.18 (1H, d, J7.5, 7-H), 7.01 (1H, t, J7.5.8-H), 4 , 37 (2H, q, OCH ₂ CH ₃ ), 2.98 (3H, s,

4- CH ₃ ), 2.91 (3H, s, 3-CH ₃ ), 2.58 (3H, s, 6-CH ₃ ) and 1.34 (3H, t, OCH ₂ CH ₃ ); 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-bicarbazole-2-carboxylate (0.167 g, 43.7%) is obtained by the reaction of 7-methylindole and 5-acetoxymethyl-4acetylpyrrole and has a mp of 222 DEG C. (dec.) (Found: C78.5; H 5.9; N 7.25. C ^ H ^^ CL calc .:

C, 78.5; H, 5.80; N, 7.33%; 5 _h ([ ² HJ-DMSO) 11.27 (1H, s, 1-NH), 10.11 (1H, s, 5-NH), 7.89 (1H, d, J7.9-H). 7.85 (1H, s, 10-H), 7.56-7.35 (5H, m, ArH), 7.18 (1H, d, J7, 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, 3-CH ₃ ) and 2 , 59 (3H, s, 6-CH ₃ ); m / z (%) 382 (71, M ⁺ ) 274 (100), 246 (19) and 91 (22).

i) Benzyl 3- (2-methoxycarbonylethyl) -4-methylpyrrolo [2,3-b] carbazole-2-carboxylate (0.230 g, 52.3%) is obtained from indole and 5-acetoxy-methyl-4-acetylpyrrole and has m.p. 211-213 ° C (Found: C 73.7; H 5.6; N b ^ C ^ N ^ Calc: C 73.6; H 5.49; N 6.36%); 5 _h ^([2 H _6] -DMSO) 11.51 (IH, s, 1-NH), 10.71 (IH, s, 5-NH), 8.75 (IH, d, J7,5,9 -H), 7.92 (1H, s, 10-H), 7.57-7.44 (7H, m, ArH, 6-H and 7-H), 7.18 (1H, t, J7, 5, 8-H), 5.43 (2H, s, CH ₂ Ph), 3.63 (3H, s, OCH ₃ ), 3.59 (2H, partially obscured 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 3A5-trimethylpyrrolo [2,3-b] carbazole-2-carboxylate (0.140 g, 16%) was obtained by reaction (amount 2.65 mmol) between 1-methylindole and 5-acetoxymethyl-4-acetylpyrrole and m.p. 208 ° C (dec) (found: C 75.12; H 6.40; N 8.69; C ^ N ^ calc: C 74.98; H 6.29; N 8.74%); 5 _h ([ ² H 6] DMSO) 11.28 (1H, s, 1-NH), 8.08 (1H d, J7.9, 9-H), 7.88 (1H, s, 10-H). , 7.44 (2H, m, 6-H, 7-H), 7.07-7.17 (1H, m, 8-H), 4.36 (2H, q, CH2CH3), 4.01 ( 3H, s, 5-CH3), 3.13 (3H, s, 4-CH3), 2.90 (3H, s, 3-CH3), and 1.38 (3H, t, CH2CH3); m / z (%) 320 (72, M ⁺ ), 274 (100), 245 (16), 149 (28) and 137 (12); vmax (KBr Disc / cm ' ¹ 3329 and 1670.

k) Benzyl 3,4,5-trimethylpyrrolo [3,2-b1carbazole-2-carboxylate (0.220 g, 57%) was obtained by reaction between N-methylindole and 5-acetoxymethyl-4acetylpyrrole in toluene at 55 ° C catalyzed by toluene- 4-sulfonic acid and has a melting point of 228-229 ° C (found C 77.17; H 5.73; N 7.09 C _{2 S} H ₂₂ N ₂ O ₂ .0.33 H ₂ O calcd .: C, 77.31; H, 5.88; N, 7.21%; S _h ^([2 H _6] -DMSO) 11.28 (IH, s, l-NH), 8.03 (IH, d, J7.5, 9-H), 7.88 (IH, s, 10 -H), 7.56-7.34 (7H, m, ArH, 6-H,

7-H), 7.15-7.07 (1H, m, 8-H), 5.40 (2H, s, CH ₂ Ph), 4.02 (3H, s, 5-CH ₃ ), 3 , 14 (3H, s, 4-CH ₃ ) and 2.91 (3H, s, 3-CH ₃ ); m / z (%) 382 (72, M ⁺ ), 291 (4), 274 (100) and 91 (34); in _max (KBr Disc) / cm ⁴ 3337in 1674.

l) Ethyl 1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate (0.060 g, 7%) is obtained by the reaction (amount of 2.5 mmol) between indole and 5-acetoxymethyl-4-acetylpyrrole and has m.p. . 188-189 ° C (Found C 74.86; H 6.32; N 8.65), calcd C 75.98; H, 6.29; N, 8.74%; 5 _h ^([2 H _6] DMSO)

10.66 (1H, s, 5-NH), 8.14 (1H, d, J7.7.9-H), 8.03 (1H, s, 10-H), 7.45-7.31 (2H, m, 6-H, 7-H), 7.06-7.15 (1H, m, 8-H), 4.38 (2H, q, CH ₂ CH ₃ ), 3.98 (3H , s, 1-CH ₃ ), 2.91 (3H, s, 4 - (^), 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); in _max (KBr Disc / cm ⁴ 3385 and 1657);

m) Benzyl 1,3,4-trimethylpyrrolo [3,2-bicarbazole-2-carboxylate (0.240 g, 28%) is obtained by the reaction (amount of 2.7 mmol) between indole and 5-acetoxymethyl-4-acetylpyrrole and has m.p. . 186-187 ° C (Found: C 78.63; H 5.83; N 7.32.0 ^^ 02 calculated: C 78.51; H 5.80; N 7.32%); 5 _h ([ ² H 6] -DMSO) 10.66 (1H, s, 5-NH), 8.14 (1H, d, J 7.4, 9-H), 8.02 (1H, s, 10- H), 7.56-7.31 (7H, m, ArH, 6-H, 7-H), 7.06-7.15 (1H, m, 8-H), 5.41 (2H, s , O ^ Ph), 3.98 (3H, s, 1-CH3), 2.90 (3H, s, 4-CH3) and 2.83 (3H, s, 3-CH3); m / z (%) 382 (M ⁺ , 100), 338 (10), 291 (44), 247 (18) and 231 (10); pmax (KBr Disc / cm ⁴ 3443 and 1697.

n) Ethyl 1,3,4,5-tetramethylpyrrole 3,2-b] carbazole-2-carboxylate (0.220 g, 30%) was obtained by reaction (2.2 mmol amount) between 1-methylindole and

5-acetoxymethyl-4-acetylpyrrole and has a m.p. 165.5-167 ° C (dec) (Found: C, 75.50; H, 6.65; N, 8.30; C, H, H3 N3OH requires: C, 75.47; H, 6.63; N, 8; , 38%); 5 _h ^([2 H _6] DMSO) 8.15 (IH, d, J7.5, 9-H), 8.07 (IH, s, 10-H), 7.50 to 7.38 (2H , m, 6-H, 7-H), 7.09-7.19 (1H, m, 8-H), 4.38 (2H, q, 0 ^ 0¾). 4.03 (3H, s,

3.96 (3H, s, 1 - (^), 3.14 (3H, s, 4-CH ₃ ), 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); p _max (KBr Disc / cm ⁴ 1690 and 1528).

o) Benzyl 1,3,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylate (0.070 g, 13%) was obtained by reaction (1.4 mmol amount) between 1-methylindole and 5-acetoxymethyl- 4-acetylpyrrole and has a m.p. 196-198 ° C (Found: C 78.45; H 6.16; N 6.94; Calc .: C 78.76; H 6.10; N 7.07%); 5 _h ^([2 H _6] DMSO)

8.15 (1H, d, J7.8, 9-H), 8.07 (1H, s, 10-H), 7.59-7.29 (7H, m, ArH, 6-H, 7- H), 7.10-7.20 (1H, m, 8-H), 5.42 (2H, s, CH ₂ Ph), 4.03 (3H, s, 5-0¾). 3.97 (3H, s, 1-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); in _max KBr Disc / cm ¹ 1696 and 1529.

p) Benzyl 3,4-dimethyl-5- (4-toluenesulfonyl) pyrrolo [2,3-b] carbazole-2-carboxylate (0.012 g, 4%) is obtained by reaction (0.6 mmol) between N- (4toluenesulfonyl) indole and 5-acetoxymethyl-4-acetylpyrrole and has a m.p. 270 ° C (Found: C 70.83; H 5.01; N 5.23; C 16 H 16 N 4 S calcd. C 71.24; H 5.01; N 5.36%); S _h ^([2 H _6] -DMSO) 11.58 (IH, s, NH), 8.28 to 8.08 (3H, m, 6-H, 9-H, 10-H), 7.66 -7.21 (11H, m, ArH, TsH, 7-H, 8-H), 5.40 (2H, s, O ^ Ph), 3.04 (3H, s.

4- CH ₃ ), 2.88 (3H, s, 3-0¾) 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); in _max (KBr Disc / cm ¹ 3558 and 1666.

q) Ethyl 7-acetoxy-3,4-dimethyl-6-methoxypyrrolo [3,2-b] carbazole-2-carboxylate (7%) was obtained by the reaction between 6-acetoxy-7-methoxyindole and

5- acetoxymethyl-4-acetylpyrrole and has a m.p. Mp 241-244 ° C. δ _Η (CDC1 ₃ ) 8.59 (1H, s, br, NH), 7.78 (1H, s, br, NH), 7.76 (1H, s, 10-H), 7.74 (1H , d, J8, 9-H), 6.88 (1H, d, J8, 8-H), 4.44 (2H, q, CH ₂ CH ₃ ), 4.04 (3H, s, 6-OCH) ₃ ), 2.96 and 2.92 2 x 3H, 2 xs, 4-CH ₃ and 3-0 ^), 2.42 (3H, s, 7-CH ₃ COO) and 1.46 (3H, t , CH ₂ CH ₃ ); m / z (%) 394 (100, M ⁺ ), 352 (47), 348 (33), 306 (87), 263 (21) and 87 (73); vmax (nujol) / cm ⁴ 3413,3341,1739 and 1675; vmax (MeOH) / nm 405,386,339, 325, 305, 269,240 and 226. (Found: M ⁺ , 394.1529.C ₂₂ H ₂₂ N ₂ O ₅ calc .: 394.1529).

r) Ethyl 9-methoxy-3A5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate

Obtained by reaction between 4-methoxy-1-methylindole and 5-acetoxymethyl-4acetylpyrrole and having a m.p. 263-266 ° C (Found C 71.84; H 6.34; N 7.91.

^Calc'd - ^{: C 71 '98} )' ^{H 6 '33; N 7 '99 5} h (CDCl ₃ ) 8.60 (1H, s, br, NH), 8.15 (1H, s, 10-H), 7.40 (1H, t, J8.7-H) , 6.95 (1H, d, J8.6-H), 6.66 (1H, d, J8.8-H), 4.43 (2H, q, OCH ₂ CH ₃ ), 4.10 and 4 , 04 (2 χ 3H, 2 xs, N-CH ₃ and OCH ₃ ), 3.19 (3H, s, 4- (¾ 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 [2,3-b] carbazole-2-carboxylate (0.069 g; 17%) was obtained by reaction between 5-chloroindole and 5-acetoxymethyl-4acetylpyrrole and m.p. Mp 215-220 ° C. (breakup). (Found) C 71.42; H, 4.96; N, 7.11; C ₂₄ H ₁₉ C1 N ₂ O ₂ Calc .: C 71.55; H, 4.75; N, 6.95%; δ _Η (2 [H] ₆ -DMSO) 11.39 (1H, s, 1-NH), 10.84 (1H, s, 5-NH), 8.17 (1H, s, 9H), 7. 93 (1H, s, 10-H), 7.54 (1H, d, J7, 7-H), 7.48-7.34 (6H, m, ArH and 6-H), 5.42 (2H , s, CH ₂ Ph) and 2.88 (6H, s, 3-CH ₃ and 4-CH ₃ ); m / z (%) 402 (30, M ⁺ ), 358 (5), 294 (65), 267 (25) and 91 (100). The crystallized liquids were flash chromatographed on silica. Elution with ethyl acetate / light petroleum gave the further title compound, which was crystallized from ethyl acetate (0.030 g; 7%) and 3- (3'-acetyl5 ^, -benzyloxycarbonyl-4 ^, -methylpyrrol-2 ^, -ylmethyl) -5- chloroindole as cloudy yellow-colored crystals (0.152 g; 36%) m.p. 141-143 ° C (Found: C 68.20; H 5.18; N 6.60; C 1-6 CINH requires: C 68.49; H 5.03; N 6.65); δ _Η (CDC1 ₃ ) 8.72 (1H, s, Γ-ΝΗ), 8.26 (1H, s, 1-NH), 7.38 (1H, d, J2, 4-H), 7.35 (6H, m, ArH and 6-H), 7.18 (1H, dd, J8 and 2, 2-H), 7.09 (1H, d, J2, 2-H), 5.23 (2H, s, CH ₂ Ph), 4.39 (2H, s, 3- (¾ 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).

t) Ethyl 3,4-dimethyl-8-hydroxypyrrolo [3,2-b] carbazole-2-carboxylate

Obtained by reaction between 5-hydroxyindole and 5-acetoxymethyl-4-acetylpyrrole and crystallized from methanol from the ground. 250 ° C (decomposition) e _H [ ² H 6] -DMSO) 11.11 (1H, s, 1-NH), 10.21 (1H, s, 5-NH), 8.83 (1H, s, OH) ), 7.73 (1H, s, 10-H), 7.37 (1H, d, J2.5, 9-H), 7.21 (1H, d, J8, 6-H), 6.87 (1H, dd, J8 and 2.5, 9-H), 7.21 (2H, q, 0 (¾¾ 2.87 (3H, s, 4-CH3), 2.84 (3H, 8.3- 0¾) and 1.38 (3H, t, OCHjCHg); m / z (%) 322 (69, M ⁺ ), 276 (100), 248 (24), 220 (3) and 138 (15); .: M ⁺ 322. 1 322 C19H _lg N ₂ O ₃ calcd .: M, 322. 1317). from the reaction mixture, isolating the 3- ^{(3-acetyl-5-ethoxycarbonyl 4>} -metilpirol-2'- ylmethyl) -5hydroxyindole with mp 99-102 ° C (Found: C 66.89; H 6.17; N 8.03. C _ig H ₂₀ N ₂ O ₄ Calc .: C 67.04; H 5, 92; N 8.23%) δ _Η (CDCl ₃ ) 8.84 (1H, s, 1'-NH), 8.14 (1H, s,

1-NH), 7.20 (1H, d, J8, 7-H), 7.10 (1H, d, J2.5, 2-H), 6.81 (1H, d, JI, 5 4- H), 6.79 (1H, dd, JI, 5 and 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 '- ^), 2.48 (3H, s, 3'-COCH ₃ ) and 1.27 (3H, t. OCH ^ CHj); m / z (%) 340 (100, M ⁺ ), 325 (44), 293 (21), 279 (35), 266 (35), 251 (31), 223 (25), 196 (5), 147 (20) and 133 (36).

u) Benzyl 3,4-dimethyl-7-fluoropyrrolo [3,2-bicarbazole-2-carboxylate and benzyl

3,4-Dimethyl-8-fluoro-pyrrolo [2,3-bicarbazole-2-carboxylate is obtained as a mixture of isomers by reaction between 6-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation yielded the [3,2blizomer (0.139 g, 36%), tal.205 ° C (dec.) For 8 _h ^([2 H _6] -DMSO) 11.32 (IH, s, 1-NH), 10 , 85 (1H, s, 5-NH), 8.08 (1H, dd, J9 and 6, 9-H), 7.86 (1H, s, 10-H), 7.57-7.35 ( 5H, m, ArH), 7.12 (1H, dd, J10 and 2, 6-H), 6.90 (1H, dt, J9 and 2,

8-H), 5.43 (2H, s, CH ₂ Ph), 2.91 (3H, s, 3-0 ^ 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 ^ h ^ FN / ^ calc .: 387.1509); and i2,3-blizomer mp. 190-193 ° C for 5 _h (CDC1 ₃₎ 8.54 (IH, s, br, l-NH), 8.10 (1H, dd, J9 and 6, 5-H), 7.87 (1H, s, br, 9-NH), 7.51-7.34 (5H, m, ArH), 7.34 (1H, s, 10-H), 7.22 (1H, dd, obscured by 10-H, 8-H), 6.93 (1H, dt, J2 and 9, 6-H), 5.41 ( 2H, s, CH ₂ Ph), 3.20 (3H, s, 4-0 ^) 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 ^ H ^ FN ^, calc .: 386.1431).

v) Ethyl 3,4-dimethyl-7-fluoropyrrolo [3,2-b] carbazole-2-carboxylate and ethyl

3,4-dimethyl-8-fluoropyryr2,3-b] carbazole-2-carboxylate

It is obtained as a mixture of isomers by reaction between 6-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation afforded [3,2blizomer, which was crystallized from dichloromethane, m.p. 231-234 ° C (Found: C 70.45; H 5.53; N 8.66; C ₁₉ H _1? FN ₂ O ₂ calculated: C 70.36; H 5.28; N 8.64 %); S _h ([ ² H 6] -DMSO) 11.27 (1H, s, br, 1-NH), 10.82 (1H, s, br, 5-NH), 8.90 (1H, dd, J9 and 6, 9-H), 7.85 (1H, s, 10-H), 7.12 (1H, dd, J10 and 2,6-H) 6.89 (1H, dt, J2 and 9, 8- H) 4.37 (2H, q, OCH 2 CH 3), 2.89 (6H, s, 4-CH 3), 1.39 (3H, 1 OCH 2 CH 3); m / z (%) 324 (60, M ⁺ ), 278 (100), 250 (34), 222 (10) and 139 (7); (found); M ⁺ , 324.1267. C19H ₁₇ FN ₂ O ₂ Calcd.: 324.1274); and the [2,3-mercury meter]. Mp 262-265 ° C; 3 _h ([ ² H ₆ ] -DMSO) 11.14 (1H), s, br, 1-NH), 11.06 (1H, s, br.

9-ΝΗ), 8.12 (1H, dd, J6 and 9, 5-H), 7.19 (1H, s, 10-H), 7.15 (1H, dd J10 and 2, 8-H) , 6.92 (1H, dt, J2 and 9, 6-H), 4.36 (2H, q, OCH ₂ CH ₃ ), 3.13 (3H, s, 4-0 ^), 2.93 ( 3H, s, 3-0¾) and 1.39 (3H, t, OCH ₂ CH ₃ ); m / z (%) 324 (72, M ⁺ ), 278 (100), 250 (39), 222 (9), 139 (6) and 125 (7); (Found: M ⁺ , 324.1280. C ₁₉ H ₁₇ FN ₂ O ₂ calc .: 324.1274).

w) Ethyl 3,4-dimethyl-9-hydroxypyrrolo [3,2-bicarbazole-2-carboxylate and ethyl

3,4-Dimethyl-5-hydroxypyrrolo [2,3-b] carbazole-2-carboxylate is obtained as a mixture of isomers by reaction between 4-hydroxyindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation afforded the [3,2b] isomer, which was crystallized from ethyl acetate / light petroleum, m.p. 260-262 ° C (dec) S _d ([ ² H 6] -DMSO) 11.13 (1H, s, 1-NH), 10.56 (1H, s, 5-NH), 10.00 (1H , s, OH), 8.02 (1H, s, 10-H), 7.12 (1H, t, J7.5, 7-H), 6.83 (1H, d, J7.5, 6- H), 6.48 (1H, d, J7.5, 8-H), 4.39 (2H, q, OOi2CH3), 2.87 (3H, s, 4-CH,), 2.85 (3H) , s, 3-0¾) and 1.38 (3H, t, OOECHJ: m / z (%) 322 (61, M ⁺ ), 276 (100), 248 20), 219 (5) and 138 (11) ; (Found: M ⁺ , 322.1305. C ₁₉ H ₁₈ N ₂ O ₃ calc .: 322.1317); and a 2,3-b] isomer crystallized from ethyl acetate, m.p. 251-254 ° C (dec) 5 _h ([ ² H 6] -DMSO) 10.95 (1H, s, 1-NH), 10.85 (1H, s, 9-H), 9.89 (1H , s, OH), 7.08 (1H, t, J7.5, 7-H), 7.07 (1H, s, 10-H), 6.77 (1H, d, J7.5.8- H), 6.52 (1H, d, J7.5.7-H), 4.32 (2H, q, OCH2CH3), 3.44 (3H, s, 4-0¾ ^ 2.92 (3H, s , 3-CH3) and 1.37 (3H, t, OCH2CH3); m / z (%) 322 (65, M ⁺ ), 276 (100), 248 (88), 219 (15), 205 (10) , 191 (10), 178 (5), 165 (5), 138 (10), 115 (10); (found .: M ⁺ 3221317.C19H _lg N ₂ O ₃ calcd .: 322.1317).

x) Ethyl 6,9-dimethoxy-3,4-dimethylpyrrole [3.2-b] carbazole-2-carboxylate and ethyl

5,8-Dimethoxy-3,4-dimethylpyrrolo [2,3-b] carbazole-2-carboxylate is obtained as a mixture of isomers by reaction between 4,7-dimethoxyindole and 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation afforded [3.2 lblisomer (13.7%), m.p. 256-258 ° C. (Found: C 68.98; H 6.23; N 7.89. Ο ₂ ΗΗ22 ^Ν 2 ° 4 Calc .: C 68.84; H 6.05; N 7.65%), SH (CDC13) 8.58 (1H, s, br, NH), 8.08 (1H, s, 10-H), 7.84 (1H, s, br, NH), 6.82 (1H, d, J8, 7 -H), 6.50 (1H, d, J8, 8-H), 4.43 (2H, q, OCH2CH3), 4.05 (3H, s, 9-OCH3), 3.98 (3H, s , 6-OCH3), 2.96 (3H, s, 4-CH3), 2.92 (3H, s, 3-CH3) and 1.44 (3H, t, OCH2CH3); m / z (%) 366 (73, M ⁺ ), 326 (100), 305 (11), 290 (11), 277 (23), 262 (15), 183 (10), 160 (17), 152 (19) and 131 (7); vmax (nujol / cm ¹ 3474, 3323 and 1674; X _max (MeOH) / nm 415, 387, 344, 330 (sh), 305 (sh), 266, 246 and 220, and [2.3-proximity meter (9.3% ) mp 193-195 ° C. (found: C 69.03; H 6.29; N 7.42 calc. C

68.84, H 6.05; N, 7.65%; δ _Η (CDCl ₃ ) 8.44 (1H, s, br, NH), 8.10 (1H, s, br, NH), 7.06 (1H, s, 10-H), 6.82 (1H , d, J8, 7-H), 6.56 (1H, d, J8, 6-H), 4.40 (2H, q, OCKjCHg), 3.98 (3H, s, OCH ₃ ), 3. 97 (3H, s, OCH ₃ ), 3.42 (3H, s, 4-CH ₃ ), 3.00 (3H, s, 3-0¾) 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), 131 (3); _Vmax (nujol) / cm ⁴ 3457,

3345 and 1660; \ _max (MeOH) / nm 381,365,293,247 and 219.

y) Ethyl 7-methoxy-3,4-dimethylpyrrole [3.2-b] carbazole-2-carboxylate and ethyl 7-methoxy-3,4-dimethylpyrrole [2,3-b] carbazole-2-carboxylate are obtained as a mixture of isomers by reaction between 6-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. Flash chromatography on silica eluting with ethyl acetate / cyclohexane (1: 1) afforded the [3,2-b] isomer crystallized from ethyl acetate / cyclohexane, m.p. 239-241 ° C (dec.) Δ _Η ([ ² Η6] DMSO) 11.09 (1H, s, 1-NH), 10.49 (1H, s, 5-NH), 7.91 (1H. d, J8.7,9-H), 7.73 (1H, s, 10-H), 6.88 (1H, d, J2.3, 6-H), 6.68 (1H, dd, J8 , 7 and 2,3,8-H), 4,35 (2H, q, OCH2CH3), 3,84 (3H, s, 7-OCH3), 2,87 (3H, s, 3-CH3), 2 , 86 (3H, s, 4- (¾) and 1.37 (3H, t, OCH2CH3); m / z (%) 336 (84, M ⁺ ), 290 (100), 262 (32), 247 ( 16) and 219 (16); vmax (KBr Disc) / cm ⁴ 3342, 1674 and 1628; and the [2,3-b] isomer crystallized from ethyl acetate / cyclohexane, mp 260 ° C (dec.) δΗ ([ ² Η6] DMSO) 10.98 (1H, s, 1-NH), 10.74 (1H, s, 9-NH), 8.00 (1H, d, J8.7, 5-H) , 7.13 (1H, s, 10-H), 6.87 (1H, d, J2.7.8-H), 6.70 (1H, dd, J8.7 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, OC ^ CH ^; m / z (%) 336 (56, M ⁺ ), 290 (70), 262 (26), 145 (16). 129 (14); p _max (KBr Disc) / cm ⁴ 3379.3339 and 1663.

z) Ethyl 3-ethyl-4-methylpyrrolo [2,3-b] carbazole-2-carboxylate (0.956 g, 27%) was obtained by reaction (11 mmol amount) between indole and ethyl 5-acetoxymethyl-4-acetyl-3-ethylpyrrol-2 -carboxylate after recrystallization from toluene and having a soil. 248-249 ° C (dec.) (Found: C 74.93; H 6.35; N 8.60. (¾¾¾¾ ^{calc. <: C 74 '98; H 6} ' ²⁹ ' ^{N 8} ' ⁷⁴ Sh ([ ² H6] -DMSO) ^{n '27} ( ^1H > s, 1-NH), 10.63 (1H, s, 5-NH), 8.09 (-H, d, J8, 9-H), 7. 93 (1H, s, 10-H), 7,317.47 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J8, 5.5, 2, 8-H), 4 , 40 (2H, q, J7,

CO ₂ CH ₂ ), 3.37 (2H, q, J 7, 3-CH ₂ ), 2.91 (3H, s, 4-CH ₃ ), 1.41 (3H, t, J 7, CO ₂ CH ₂ CH ₃ ), 1.30 (3H, t, J 7.5, 3-CH ₂ CH ₃ ); m / z (%) 320 (100, M ⁺ ) 274 (96); in _max (KBr disc) / cm ⁴ 3344, 3327,1680,1664,1238.

EXAMPLE 5

Pyrrolo [3,2-b] carbazole-2-carboxylic acids. General procedure

To a solution of benzyl pyrrolo [3,2-b] carbazole-2-carboxylate in dry tetrahydrofuran (THF) (10 cm ³ ) was added 10% Pd on carbon (50 mg). The reaction mixture was hydrogenated at a pressure of 1.01 χ 10 ⁵ Pa and at room temperature. When the uptake of H ₂ ceases, the catalyst is removed by filtration through celite and washed well with THF and the combined filtrates evaporated under reduced pressure. Crystallization of the resulting solid from acetone, methylethylketone or aqueous methanol gives pyrrolo [3,2-b] carbazole-2carboxylic acids as yellow crystals.

a) 3,4-dimethylpyrrolo [3.2-bicarbazole-2-carboxylic acid (0.234 g, 84.3%) mp 237 ° C (dec); 5 _h ([ ² H 6] -DMSO) 12.74 (1H, br, s, CO2H), 11.13 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8 , 05 (1H, d, J7.5, 9-H), 7.87 (1H, s, 10-H), 7.42 (1H, d, J7.5, 6-H), 7.36 ( 1H, t, J7.5, 7-H), 7.08 (-H, t, J7.5, 8-H), 2.92 and 2.91 (2 χ 3H, 2 xs, 3-CH3 and 4-CH3); m / z (%) 278 (30, M ⁺ ) 260 (39), 234 (100), 218 (19), 204 (8), 167 (8), 149 (16), 130 (10) and 117 ( 25) (Found: M ⁺ , 278.1060. C17H ₁₄ N ₂ O ₂ calc .: M 278.1055).

b) 8-Fluoro-3,4-dimethylpyrrolo [3.2-b] carbazole-2-carboxylic acid (0.0845 g, 85.6%) m.p. 236-239 ° C, S _h ([ ² H 6] -DMSO) 12.80 (1H, br, s, CO2H), 11.19 (1H, s, 1-NH), 10.60 (1H, s. 5-NH), 7.91 (1H, dd, J9 and 2.5, 9-H), 7.86 (1H, s, 10-H), 7.37 (1H, dd, J9 and 4.6 -H), 7.20 (1H, dt, J9 and 2.5, 7-H) and 2.89 (6H, s, 2 x CH3); 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. C17H ₁₃ FN ₂ O ₂ calc .: M 296.0961).

c) 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.065 g, 85%) m.p. 230 C (dec) (found: C 74.2; H 5.55; N 9.4 C _lg H ₁₆ N ₂ O ₂ calculated: C 74.0; H 5.52; N 9.58 %); _δ Η ^([2 H _6] -DMSO) 12.80 (IH, br, s, CO ₂ H), 11.01 (IH, s, 1-NH), 10.08 (IH, s, 5-NH ), 7.90 (1H, d, J7.5, 9-H), 7.82 (1H, s, 10-H), 7.16 (1H, d, J7.5, 7-H), 7 01 (IH, t, J7.5, 8-H), 2.97 (3H, s, 4-0 ^), 2.92 (3H, s, 3-CH ₃₎ and 2.58 (3H, s, 6-CH ₃ ); m / z (%) 292 (72, M ⁺ ), 274 (100), 246 (50), 230 (11), 137 (25), 122 (24) and 109 (30).

d) 3- (2-Methoxycarbonylethyl) -4-methylpyrrolo [2,3-b] carbazole-2-carboxylic acid (0.0673 g, 84.6%) m.p. 255 ° C (decomp.) (Found .: C, 68.4; H, 5.3; N, 7.75. C ₂₀ H _lg N ₂ O ₄ Calcd .: C, 68.6; H 5.18; N 8, 00%); 5 _h ^([2 H _6] -DMSO) 12.88 (lH, br, s, CO ₂ H), 11.34 (IH, s, 1-NH), 10.65 (IH, s, 5-NH), 8.06 (1H, d, J7.5, 9-H), 7.88 (1H, s,

10-H), 7.42 (1H, d, J7.5, 6-H), 7.36 (1H, t, J7.5, 7-H), 7.07 (1H, t, J7.5) , 8-H), 3.66 (3H, s, OCH ₃ ), 3.63 (2H, partially obscured t, CH ₂ CH ₂ CO), 2.89 (3H, s, 4CH ₃ ), 2.66 (2H, t, Cl ^ CO); m / z (%) 350 (100, M ⁺ ), 332 (17), 306 (30), 290 (63), 272 (22), 259 (32) and 233 (47).

e) 1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.060 g, 44%) m.p. 215-216 ° C (decomp.) (Found .: C, 73.69; H, 5.51; N, 9.41; C _lg H ₁₆ N ₂ O ₂ Calcd .: C, 73.95; H, 5.52; N 9.58); 5 _h ([ ² H 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 (2H, m, 6-H, 7-H), 7.14-7.04 (1H, m, 8 -H), 3.99 (3H, s, 1-CH3), 2.91 (3H, s, 4-CH3) and 2.85 (3H, s, 3-CH3); m / z (%) 292 (95, M ⁺ ), 275 (10), 247 (40), 232 (30), 180 (100) and 135 (100); vmax (KBr Disc) / cm ⁴ 3375,2930 and 1709.

f) 3,4,5-trimethylpyrrolo [3,2-bicarbazole-2-carboxylic acid (0.015 g, 18%) mp.239-240 ° C (dec) (found: C 74.11; H 5, 38; N 9.39; C ₁₈ H ₁₆ N ₂ O ₂ calculated: C 73.95; H 5.52; N 9.58; 5 _h ([ ² H 6] -DMSO) 11.15 (1H, s , 1-NH), 8.04 (1H, d, J7.5, 9-H), 7.88 (1H, s, 10-H), 7.48-7.41 (2H, m, 6- H, 7-H), 7.17-7.06 (1H, m, 8-H), 4.03 (3H, s, 5-CH3), 3.16 (3H, s, 4-CH3) and 2.93 (3H, s, 3-CH3); m / z (%) 292 (90, M ⁺ ), 274 (75), 232 (70), 197 (35), 181 (60), 149 (30 ) and 130 (100); vmax (KBr Disc) / cm ⁴ 3454,2926 and 1670.

g) 1,4,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.030 g, 32%), mp 215-217 ° C (dec) (found: C 74, 44; H 6.00; N 9.14;

C ₁₉ H ₁₈ N ₂ O ₂ Calc .: C 74.49; H, 5.92; N, 9.14); S _h ([ ² H 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, m, 8-H), 4.01 (3H, s, 5 -OH), 3.97 (3H, s, 1-CH3), 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); vmax (KBr Disc) / cm ⁴ 1935 and 1659.

h) 3,4-dimethylpyrrolo [3,2-bicarbazole-2-carboxylic acid

Ethyl ester (500 mg, 1.6 mmol) in water (15 cm ³ ) and methanol (35 cm ³ ) was heated at reflux and additional methanol was added to dissolve. Celsius carbonate (5.32 g; 16 mmol) was added and the mixture was refluxed under nitrogen for 18 h. After cooling, the solvent was removed in vacuo to leave about 20 cm ^{3 of the} solution, which was adjusted to pH 3 with the addition of 0.1 M hydrochloric acid, and then the title compound precipitated. Filtration, washing with water and drying under vacuum afforded an analytically pure product (437 mg; 96%) that is spectroscopically identical to that obtained in Example 5a.

EXAMPLE 6

Pyrrolo [3.2-b1carbazole-2-carboxylic acid esters - general procedure

Pyrrolo [3,2-b] carbazole-2-carboxylic acid (1.0 mmol) and Ν, Ν′-carbonyl diimidazole (1.1 mmol) were dissolved in freshly distilled tetrahydrofuran under a nitrogen atmosphere. The resulting suspension was stirred at room temperature for at least 1 hour and complete conversion of the acid to the imidazolid intermediate was confirmed by TLC. Alcohol or phenol (1.5-2.0 mmol, i.e. excess) was added in one portion and the resulting mixture was heated at reflux until again TLC showed complete consumption of the imidazolid intermediate. The product was obtained by column chromatography on silica followed by recrystallization.

a) Phenyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate is obtained by reaction of the imidazolid intermediate with phenol. Chromatography (eluting with 10% acetone / 90% petroleum) followed by recrystallization from acetone / petroleum gave orange crystals (0.230 g, 65%) m.p.> 230 ° C (dec) (found: C 78.17; H 5.09; N Ί, ΊΊ. ^ Η ₁₈ Ν ₂ Ο ₂ Calc .: C 77.95; H 5.12; N 7.90%); 5 ^([2 H _6] -DMSO) 11.55 (IH, s, 1-NH), 10.64 (IH, s, 5-NH), 8.10 (IH, d, J7.5, 9 H), 7.94 (1H, s, 10-H), 7.30-7.58 (7H, m, PhH, 6-H, 7-H), 7.09 (1H, ddd;

J7.5, 5.5, 2, 8-H) and 2.97 and 2.95 (2 χ 3H, 2 xs, 3-CH ₃ and 4-CH ₃ ); m / z (%) 355 (40, M ⁺ ); _Vmax (KBr Discj / cm ¹ 3396.1701 and 1180.

b) [(2-dimethylamino) ethyl] 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate is obtained by reaction of the imidazolid intermediate with (2-dimethylamino) ethanol. Chromatography (eluting with 10% methanol / 90% DCM) gave a yellow solid (0.350 g, 99%). Recrystallization of the portion from DCM yields yellow crystals from the ground. 174.0-175.7 ° C (dec) (found C 70.46; H 6.48; N 11.76. ^ Η ^ Ν ^ .Ο, ΙδΟΗ ^ calc .: C 70.29; H, 6.45; N, 11.55%; S _h ([ ² H] DMSO) 11.18 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.07 (1H, d, J8, 9-H), 7. 89 (1H, s, 10-H), 7.30-7.43 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J8, 6, 2.5, 8- H), 4.41 (2H, t, J6, OCH2), 2.91 (6H, s, 3-CH3 and 4-CH3), 2.69 (2H, t, J6.0, NCH2 and 2, respectively). 27 (6H, s, N (CH3) 2); m / z (%) 350 (46, (M + 1) ⁺ ), 261 (68) and 133 (100); vmax (KBr Disc / cm ¹ 3377, 1661 and 1238.

c) [(3-dimethylamino) phenyl] -3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate is obtained from an amount of 0.95 mmol by reaction of an imidazolid intermediate with (3dimethylamino) phenol. Chromatography (eluting with 10% ethyl acetate / 90% toluene) followed by recrystallization from ethyl acetate gave yellow crystals (0.272 g, 72%) m.p. 240-242 ° C (dec.) (Found: C 75.37; H 5.71; N 10.36. C 22 H 28 N 4 O 4 calc .: C 75.55; H 5.83; N 10. 57%; δ _Η ([ ² H6] -DMSO) 11.49 (1H, s, 1-NH), 10.64 (1H, s, 5-NH), 8.08 (1H, d, J8, 9 -H), 7.91 (1H, s, 10-H), 7,347.48 (2H, m, 6-H, 7-H), 7.27 (1H, t, J8, 5'-H). 7.10 (1H, ddd, J8, 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-CH3,4-CH3, N (CH3) 2); m / z (%) 398 (38, M + 1) ⁺ , 261 (25) , 232 (21) and 217 (100); vmax (KBr Disc) / cm ⁴ 3350,1674,1610 and 1232.

d) (3-Pyridyl) 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate is obtained by reacting the imidazolid intermediate with 3-hydroxypyridine. Chromatography (eluting with 50% ethyl acetate / 50% petroleum) followed by recrystallization from acetone gave yellow crystals (0.230 g, 65%) from m.p. > 270 ° C (dec) (Found: C 73.88; H 4.76; N 11.50. C ₂₂ H ₁₇ N ₃ 0 ₂ .0.2H ₂ 0 Calc .: C 73.61; H 4.89; N, 11.71%; 5 _h ([ ² H 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, J4, 1, 6'-H), 8.10 (1H, d, J8,

9-H), 7.90 (1H, s, 10-H), 7.86 (1H, ddd, J8, 3, 1, 5'-H), 7.58 (1H, dd, J8, 5; 4'H), 7.32-7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J8, 6.2, 8-H) and 2.97 and 2 , 94 (2 χ 3H, 2 xs, 3-CH ₃ and 4-CH ₃ ); m / z (%) 356 (15, (M + 1) ⁺ ). in _max (KBr Disc / cm ⁴ 3377.1715 and 1173.

e) (4-Carbamoylphenyl) 3,4-dimethylpyrrolo [3,2-bicarbazole-2-carboxylate is obtained by reaction of an imidazolid intermediate with 3-hydroxybenzamide. Recrystallization from ethanol gives a yellow powder and an impure residue. The latter was further purified by silica column chromatography (eluting with 5% methanol / 95% DCM then 10% methanol / 90% DCM) followed by recrystallization from ethanol. (0.262 g, 66%) m.p. &Gt; 250 ° C (dec) (Found: C 71.72; H 4.81; N 10.26. C ^ OjAZH /) calcd: C 71.88; H, 4.88; N, 10.48%; 5 _h ([ ² H 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, 7-H, 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 χ 3H, 2 xs, 3-CH3 and 4-CH3) ; m / z (%) 398 (10, (M + 1) ⁺ ), 279 (100); vmax (KBr Disc) / cm ⁴ 3423.1717.1695 and 1171.

f) (Pyridyl-4-methyl) 3,4-dimethylpyrrolo [3.2-bicarbazole-2-carboxylate is obtained by reacting the imidazolid intermediate with 4-pyridylcarbinol. Chromatography (eluting with ethyl acetate / petroleum, gradient 60%, 80%, 100% ethyl acetate, then methanol / ethyl acetate, gradient 10%, 20%) followed by recrystallization from tetrahydrofuran gave orange crystals (0.168 g, 46% ) from the ground. &Gt; 240 ° C (dec) (Found: C 72.16; H 5.12; N 10.73. CfH ^^ O ^ O calc .: C 72.31; H 5.38; N 11 , 00%); 5 _h ([ ² H 6] -DMSO 11.31 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.62 (2H, dd, J4.5, 0.5 , 2'-H, 6'-H), 8.08 (1H, d, J7,5,9-H), 7,89 (1H, s, 10-H), 7,53 (2H, d. J5.5, 3'-H, 5'-H), 7,327.43 (2H, m, 6-H, 7-H), 7.07 (1H, ddd, J8, 5, 1, 8-H) , 5.45 (2H, s, ArCH2) and 2.94 and 2.92 (2 χ 3H, 2 x 3-CH3 and 4-CH3); m / z (%) 369 (27, (M + 1)) ⁺ ), 327 (70) and 295 (100); vmax (KBr Disc) / cm ⁴ 3400,1709 and 1232.

g) (1,3-Dibenzyloxypropyl-2) 3,4-dimethylpyrrolo [3,2-bicarbazole-2-carboxylate is obtained from 1.5 mmol by reacting the imidazolid intermediate with (1,3dibenzyloxy-2-propanol). Chromatography (eluting with 20% ethyl acetate / 80% toluene then 40% ethyl acetate / 60% toluene) followed by recrystallization from ethyl acetate-ether-petroleum gave yellow crystals (0.776 g, 97%) of m.p. 124.8-126 ° C (dec) (Found: C 76.35; H 6.07; N 5.12. ^ Η ₃₂ Ν ₂ Ο ₄ Calc .: C 76.67; H 6.06; N, 5.26%; 5 _h ([ ² HJ-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), 7.22-7.42 (12H, m, 2 x PhH5, 6-H, 7-H), 7.07 (IH, ddd, J8, 6.5, 1.5, 8-H), 5.44 (1H, quintet, J5, ΓΗ), 4.60 and 4.53 (2 χ 2H, 2 x dd, J12 , 2 x PhCHjO), 3.77 (4H, d, J5.5, OCH (CH2) 2) and 2.91 and 2.89 (2 χ 3H, 2 xs, 3-CH3 and 4-CH3); m / z (%) 532 (50, M ⁺ ), 260 (65) and 91 (100); vmax (KBr Disc) / cm ⁴ 3358.1681 and 1234.

h) (4-Methylsulfinylphenyl) 3,4-dimethylpyrrolo [3.2-bicarbazole-2-carboxylate is obtained by reaction of the imidazolid intermediate with 4-methylsulfinylphenol. Chromatography (eluting with ethyl acetate / petroleum, gradient 90%, 95%, 98%, 100% ethyl acetate followed by 10% methanol / ethyl acetate) followed by recrystallization from tetrahydrofuran gave a yellow powder (0.261 g, 63%) m.p. > 230 ° C (dec) (found: C 68.40; H 4.81; N 6.44. C ^ H ^ N ^ SO ^ O calc .: C 68.32; H 4.92; N 6.64% _h ^([2 H6] -DMSO) 11.59 (IH, s, 1-NH), 10.68 (IH, s, 5-NH), 8.10 (IH, 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. J9.5,2'-H, 6'-H), 7.33-7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J8, 6, 2, 5, 8-H), 2.99 and 2.95 (2 χ 3H, 2 xs, 3-CH3 and 4-CH3) and 2.82 (3H, s, CH3SO); m / z (%) 417 ( 2, M + 1 ⁺ ), 261 (100) and 233 (75); vmax (KBr Disc / cm ⁴ 3427, 3288.1717 and 1200.

i) Methyl 3,4-dimethylpyrrolo [3,2-bicarbazole-2-carboxylate is obtained by reaction of imidazolid intermediate with methanol. Chromatography (eluting with 30% ethyl acetate / petroleum) followed by recrystallization from ethyl acetate gave a yellow powder (0.188 g, 64%) from m.p. 211-213 ° C (decomp.) (Found .: C 74.06, H 5.49, N 9.42, C _lg H ₁₆ N ₂ O ₂ Calcd .: C, 73.95; H, 5.52; N 9.58%); 5 _h ([ ² H 6] -DMSO) 11.25 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.08 (1H, d, J8, 9-H) , 7.89 (1H, s, 10-H), 7.33-7.58 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J8, 6, 1, 8 -H), 3.92 (3H, s, OCH3), 2.92 and 2.91 (2 χ 3H, 2 xs, 3-CH3 and 4-CH3); m / z (%) 292 (68, M ⁺ ), 260 (100), 232 (39); vmax (KBr disc) / cm ⁴ 3342, 1684 and 1236.

j) [(2-Methylsulfonyl) ethyl 3,4-dimethylpyrrolo [3,2-bicarbazole-2-carboxylate is obtained by reaction of imidazolid intermediate with (2-methylsulfonyl) ethanol. Chromatography (elution gradient with ethyl acetate / petroleum, 30% - 100%), followed by recrystallization from acetone yielded fine yellow crystals (0.222 g, 58%) from m.p. 255-257 ° C (dec) (Found: C 62.23; H 5.25; N 7.08. Calc .: C 62.48; H 5.24; N 7.29%); S _h [ ² HJ-DMSO 11.19 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.09 (1H, d, J7.5.9-H). 7.89 (1H, s, 10-H), 7.32-7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J7.5, 5.5). 3, 8-H), 4.69 (2H, 1.15.5,00 ^), 3.69 (2H, t, J5.5, SC ^ Cl · ^), 3.12 (3H, s. SC ^ CH2, 2.93 (6H, s, 3-CH3 and 4-CH3); m / z (%) 384 (17, M ⁺ ), 260 (13), 59 (100); vmax (KBr discj / cm ' ¹ 3387.1661.1234.

k) Tert-Butyl 3,4-dimethylpyrrolo [3.2-bicarbazole-2-carboxylate

Pyrrolo [3,2-b] carbazole-2-carboxylic acid (0.86 mmol) and triphenylphosphine (0.91 mmol, 1.05 eq) were dissolved in freshly distilled tetrahydrofuran under a nitrogen atmosphere. Tertiary butanol (2.12 mmol, 2.5 eq) was added by injection and finally diethyl azodicarboxylate (0.95 mmol, 1.1 eq) was added dropwise over 10 minutes. The resulting suspension was stirred at room temperature for 2 hours, showing complete consumption of starting acid by TLC. The title compound is obtained from the crude reaction mixture in various steps: silica column chromatography eluting with 20% ether / 80% petroleum followed by 50% ether / 50% petroleum; silica column chromatography (eluting with 25% ether / 75% petroleum then 40% ether / 60% petroleum); and final recrystallization from DCM to give a yellow powder (0.030 g, 10%), m.p. 187189 ° C (dec) (Found: C 73.24; H 6.53; N 7.93.C ₂₁ H ₂₂ N ₂ O ₂ .0.15CH ₂ Cl ₂ calc .: C 73.18; H 6.47; N 8.07%; 5 _h ([ ² H 6] -DMSO) 10.95 (1H, s, 1-NH), 10.57 (1H, s, 5-NH), 8.05 (1H, d, J8, 9-H) , 7.88 (1H, s, 10-H), 7.29-7.43 (2H, m, 6-H, 7-H), 7.05 (1H, ddd, J8, 6.1, 8 -H), 2.89 and 2.87 (2 χ 3H, 2 xs, 3-CH3 and 4-CH3) and 1.59 (9H, s, C (CH3) 3); m / z (%) 355 (62, M + 1 ⁺ ), 278 (90), 233 (38), 126 (32), 91 (78) and 57 (100); vmax (KBr Discj / cm ⁴ 3337.1664 and 1240.

EXAMPLE 7

The pyrrole 3,2-b1carbazole-2-carboxylic acid amides

a) 3,4-dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3,2-bicarbazole

3,4-Dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid (0.280 g, 1.0 mmol) and NJT-carbonyldiimidazole (0.164 g, 1.0 mmol) were dissolved in freshly distilled tetrahydrofuran (5 cm ³ ) at the nitrogen atmosphere. The resulting suspension was stirred at room temperature for 2 hours and complete conversion of the acid to imidazolid was confirmed by TLC. THF was removed and the residue was recrystallized from ethyl acetate to give the product as a yellow solid (0.125 g, 38%) of soil. 252 ° C (dec) (Found: C 73.17; H 4.87; N 16.80; C ^ H ^ O calc .: C 73.15; H 4.91; N 17.06%) ; 5h ^([2 H6] -DMSO) 11.53 (IH, s, 1-NH), 10.20 (IH, s, 5-NH), 8.30 (IH, s, 2'-H), 8 , 12 (1H, d, J8, 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, J8, 6, 2, 8-H), 2.95 (3H , s, 3-CH ₃ ), 2.73 (3H, s, 4-CH ₃ ); m / z (%) 261 (40); in _max (KBr Disc) / cm ⁴ 3427, 1699 and 1242.

b) Ethyl 3,4-dimethylpyrrolo [3,2-bicarbazole-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 was added diisopropylethylamine (0.260 g, 2.0 mmol), ethylaminhydrochloride (0.245 g, 3.0 mmol) and the tetrafluoroborate salt of O-benzotriazolyl-NNN ^ NLtetramethyluronium (TBTU) (0.482 g, 1.5 mmol) to give white suspension in yellow solution. The reaction mixture was stirred at room temperature for 24 h and after that time TLC showed no acid remaining. The solvent was removed in vacuo to give a yellow-brown solid. The column was chromatographed on silica eluting first with DCM and then with 10% EtOAc / 90% DCM to give the ethylamide product as a yellow solid (0.240 g, 79%). To remove traces of impurities, the portion was recrystallized from dichloroethane / petroleum to give the compound analytically pure as a yellow powder from the ground. 235 ° C (dec) (Found: C 73.21; H 6.10; N 13.33. C ₁₉ H ₁₉ N ₃ O.0, l calc .: C 73.15; H

6.20; N, 13.32%; 5 _h ^([2 H _6] -DMSO) 10.72 (IH, s, 1-NH), 10.57 (IH, s, 5-NH), 8.09 (IH, d, J8, 9-H ), 7.93 (1H, t, J5, amide NH), 7.83 (1H, s, 10-H), 7.27-7.41 (2Η, m, 6-H, 7-H), 7.06 (1H, d, J8, 8-H), 3.35 (2H, q, J7.5, CI ^ CRj), 2.89 and 2.71 (2 x 3H, 2 xs, 3-CH) _{3 in} 4-CH ₃ ), 1.18 (3H, t, 17.5,0¾¾)} m / z (%) 305 (65, M ⁺ ), 260 (100); in _max (KBr Disc) / cm ⁴ 3314.1603 and 1545.

c) 3,4-dimethylpyrrolo [3,2-bicarbazole-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 were added diisopropylethylamine (0.520 g, 4.0 mmol), ammonium hydrochloride (0.321 g, 6.0 mmol) and the tetrafluoroborate salt of O-benzotriazolyl-N, N, N ', N'tetramethyluronium (TBTU) (0.963 g, 3 , 0 mmol) to give a white suspension in a yellow solution. The reaction mixture was stirred at room temperature for 24 h and then time indicated by TLC that there was no residual acid. The solvent was removed in vacuo to give a yellow-brown solid. The column was chromatographed on silica (eluting with ethyl acetate / DCM, gradient 10% -30%) to give the amide product as a yellow solid (0.350 g, 63%). To remove traces of impurities, the portion was recrystallized from ethyl acetate / petroleum and then purified by preparative HPLC (25 cm x 2.12 cm inner diameter filled with C _g Zorbax, elution gradient: 5% acetonitrile / 95% water to 95% acetonitrile / water; detected at 340 nm) to give a yellow powder from the ground. 240 ° C (dec.) 5 _h ^([2 H _6] -DMSO) 10.82 (IH, s,

1-NH), 10.54 (1H, s, 5-NH), 8.08 (1H, d, J 7.5, 9-H), 7.84 (1H, s, 10-H), 7.297 , 43 (4H, m, 6-H, 7-H, NH4, 7.07 (1H, ddd, J8, 5.5, 2, 8-H), 2.89 and 2.85 (2 x 3H) , 2 xs, 3-CH ₃ and 4-CH ₃ ); m / z (%) 277 (62, M ⁺ ), 260 (100), 232 (44); vmax (KBr disc) / cm ⁴ 3317, 1628 , 1595; (found .: M ^+, 277.1205, C17H ₁₅ N ₃ O calcd .: 277.1215).

d) Phenyl 3,4-dimethylpyrrolo [3,2-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 ml) to give a yellow solution. To this were added diisopropylethylamine (0.130 g, 1.0 mmol), aniline (0.190 g, 2.0 mmol) and the tetrafluoroborate salt of O-benzotriazolyl-N, N.N'.N'-tetramethyluroniia (TBTU) (0.482 g, 1 , 5 mmol) to give a white suspension in a yellow solution. The reaction mixture was stirred at room temperature for 42 hours and after that time TLC showed no acid remaining. 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 MgSO ₄ , concentrated and column chromatographed on silica eluting with EtOAc / petroleum (5% -100% elution gradient) followed by recrystallization from acetone to give the phenylamide product as a yellow powder (0.10 g, 30%) ) from the ground. 260 ° C (dec) (Found: C 77.79; H 5.26; N 11.64. C ₂₃ H ₁₉ N ₃ O calc .: C 78.16; H 5.42; N 11.89 %); 5 _h ([ ² H 6] -DMSO) 11.10 (1H, s, 1-NH), 10.59 (1H, s, 5-NH), 9.96 (1H, s, amide NH), 8. 10 (1H, d, J 7.5, 9-H), 7.89 (1H, s, 10-H), 7.79 (2H, d, J9, 2'-H, 6'-H), 7.29-7.45 (4H, m, 6-H, 7-H, 3'-H, 5'-H), 7.00-7.14 (2H, m, 8-H, 4'H ), 2.93 and 2.88 (2 χ 3H, 2 xs, 3-CH3); m / z (%) 353 (46, M ⁺ ), 260 (100); vmax (KBr discj / cm ' ¹ 3310,1614,1595 and 1317.

e) 3,4-dimethyl-2- (hydrazinocarbonyl) pyrrolo [3,21carbazole

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 Readi vials. The mixture was allowed to stand overnight, cooled in ice and filtered. The resulting yellow solid is gently washed with water and dried. The title compound is 350 mg (73%), no sharp melting point, but decomposes at 285 ° C. (Found: C 69.19; H 5.57; N 19.38. Analysis for C13H16N4O.0, H2O calcd .: C 69.42; H 5.55; N 19.05%); 5h [ ² HJ-DMSO) 10.80 (1H, s, converted NH), 10.55 (1H, s, converted NH), 9.20 (1H, s, converted NH), 8.06 ( 1H, d, J7.5, 9-H), 7.81 (1H, s, 10-H), 7.42-7.28 (2H, m, 6-H and 7-H), 7.12 -7.0- (1H, m, 8-H, 4.5 (2H, br, s, convert NH2), and 2.4 and 2.3 (2 xs, 4-CH ₃ and 3-CH ₃ ), m / z 293 (M + 1) ⁺ , FAB)].

EXAMPLE 8

2-acetyl-3,4-dimethylpyrrolo [3,2-bicarbazole

Tier 1

2,4-Diacetyl-3,5-dimethylpyrrole was prepared from acetyl acetone and hydroxylamine-sulfonic acid according to the procedure of Y. Tamura, S. Kato and M.Ikeda (Chem & Ind., 1971,767).

Tier 2

2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole

To a mixed mixture of 2,4-diacetyl-3,5-dimethylpyrrole (1.0 g), dichloromethane (35 cm ³ ) and potassium carbonate (7.73 g) at 0-5 ° C was added a solution of sulfuryl chloride (0.79 g ) in dichloromethane (15 cm ³ ). The temperature of the mixture was maintained at 0.5 ° C during addition with external cooling, and then the mixture was stirred at this temperature until the reaction was judged complete by TLC (approximately 2 h). The mixture was then filtered and evaporated to give crude 2-chloromethyl-3,5-diacetyl4-methylpyrrole. This material was dissolved in acetic acid (10 cm ³ ), sodium acetate (1.83 g) was added, and then more acetic acid (10 cm ³ ) was added. The mixture was stirred overnight at room temperature, evaporated in vacuo and the residue was stirred with ice-cold water for 2 h. The solid was collected by filtration and the filtrate was extracted 2 times with ethyl acetate. The extracts were dried (MgSO4), evaporated and the residue was combined with the above solid to give the crude product. Flash chromatography eluting with ethyl acetate-hexane (1: 1) gave 0.075 g of the pure product as a gray-white solid from the ground. 112.5-114.5 ° C; m / z 238 (M ⁺ + 1, FAB), δΗ, CDCl ₃ ) 2.16 (3H, s, OCOCH ₃ ), 2.50 (3H, s, CH ₃ ), 2.53 (3H, s. CH ₃ ), 2.62 (3H, s, CH ₃ ), 5.38 (2H, s, OCH,).

Tier 3

To a solution of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole (0,200 g) and indole (0.098 g) in dichloroethane (90 cm ³ ) was added montmorillonite K10 clay (0.30 g). The mixture was stirred and refluxed for 80 h. After cooling, the clay was removed by filtration and the filtrate was concentrated to about 20 cm ³ in vacuo. The crude product was removed by filtration and then chromatographed on silica. Elution with chloroform-methanol (60: 1) gave 0.08 g of the title compound as a yellow solid from the ground. 258-260 ° C, m / z (El) 276 (M ⁺ ) δΗ ([ ² Η6] DMSO) 2.58 (3H, s, COCH ₃ ), 2.88 (3H, s, CH ₃ ), 2 , 92 (3H, s, CH ₃ ), 7.05 (1H, m, 8-H), 7.38 (2H, m, 6-H, 7-H), 7.85 (1H, s, 10 -H), 8.08 (1H, J 8 Hz, 9-H), 10.6 (1H, s, NH), 11.17 (1H, s, NH). (Found: C 77.0; H 5.74; N 9.76; ^C i8 ^H i6 ^N 2 ° · ^{0 '14} EtOAc calc .: C 77.2; H 5.98; N 9.70%) .

EXAMPLE 9

Ethyl 1,5-dihydroindenoyl, 1,2-indole-2-carboxylate

Tier 1

Ethyl 2-azido-3-fluoren-2-ylacrylate

Sodium (1.7 eq) was added to absolute ethanol, which was stirred under nitrogen at room temperature. When completely dissolved, the reaction mixture was cooled to -10 ° C and fluorene-2-carboxaldehyde (1 eq) and ethyl azidoacetate (3 eq) were added dropwise, which were together dissolved in a minimal amount of tetrahydrofuran. The mixture was stirred at -10 ° C for 20 h and then quenched by the addition of water and dichloromethane. The combined organic extracts were dried (MgSO ₄ ) and evaporated in vacuo. Flash chromatography afforded the pure product (37%) in _max (CHCl ₃ ) / cm ⁴ 2120 and 1765.

Tier 2

Ethyl 2-azido-3-fluoren-2-ylacrylate suspended in dry toluene was refluxed for 1 h and the resulting solution was then evaporated to dryness in vacuo. The resulting mixture of ethyl 1,5-dihydroindino [2, 1f] indole-2-carboxylate and ethyl 1,10-dihydroindino [1,2-g] indole-2-carboxylate was crystallized from ethanol to remove most of [1, 2-g] isomer and the title compound (contaminated with about 30% [1,2 g] isomer) remains in mother liquors which are evaporated to dryness. δ _Η (CDCl ₃ ) 9.11 (1H, s, br, 1-NH), 7.82-7.76 (3H, m), 7.56-7.52 (1H, m), 7.37 (H, dd, JI and 7), 7.34-7.28 (1H, m), 7.25 (1H, dd, Jl and 2), 4.45 (2H, q, OCH ₂ CH ₃ ), 3.97 (2 ^, 0¾) and 1.46 (3H, t, OCH ₂ CH ₃ ).

EXAMPLE 10

Effects of the compounds of the invention in the detransformation (alignment) experiment using HT1080scc2 and HT10801c cell lines.

Cell line and culture conditions

Transformed and reverted HT1080, HT1080scc2, and HT10801c sublinas are obtained from the Institute of Cancer Research, Cheser Beatty Laboratories, Fulham Road, London. They are properly maintained in Eagle's Dulbecco modified medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 1% penicillin / streptomycin solution containing 10,000 units per ml. All reagents are obtained from Gibco Ltd.

The cells were incubated in tissue culture plastic containers under an atmosphere of air with 5% CO _{2 at} 37 ° C.

Experiments on compound efficacy

Cell proliferation / cytotoxicity experiments were performed in tissue culture on 96-well microtiter plates (Costar). Cells in the logarithmic growth phase were placed on plates at a concentration of 1 χ 10 ³ cells per well on day 0 and then serially diluted compounds were added on day 1. The plates were then incubated at 37 ° C in an air atmosphere with 5% CO _{2 for a} further 4 days.

To assess the amount of cell growth, a biomass staining procedure with methylene blue was used, reading the assay with a Multiscan plate reader at 620 nm. Cell morphology was examined microscopically at phase contrast just before fixation and staining with methylene blue and then by ordinary optical microscopy. IC ₅₀ values for effective compounds are obtained using the GS1 computer program and also a graphical representation of the steep dose response.

If compounds are tested for efficacy in a column experiment, procedures identical to the one described above are used except that the batch diluted compound is added to the wet agar when the test is started and replenished at the same concentration on day 7. The test results are read out on day 14.

Results

Comparative growth and morphology of HT1080scc2 and HT10801c

The growth rate expressed by the number of cells is similar for both lines on day 4, but then HT1080scc2 cells continue dividing to reach a saturation density of about 2 to

3 times greater than HT10801c on day 5.

The phenotypic differences between the two lines are clearly visible. HT10801c cells show much more even morphology than transformed cells, and only a few mitotic cells are visible in the grown culture surfaces. HT1080scc2 cells continue to divide many mitotic cells visible after growth.

Growing under uncoated conditions in HT1080scc2 soft agar produces a variety of large colonies, with HT10801c cells producing no colonies larger than 0.1 mm in diameter.

Effects of selected compounds

Numerous compounds of the invention are evaluated for cell lines.

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

The results of the alignment experiment for cell compounds of the invention are shown below:

Compound SCC2 Leveling (uM)

Example 3 0.04

Example 4 (a) 0.04

Example 4 (b) 0.04

Example 4 (f) 0.8

Example 4 (e) 0.8

Example 4 (h) 25

Example 4 (g) 25

The compounds are effective in achieving equilibration, i.e., detransformation, at levels well below their toxic levels.

The same compounds were also tested in assays using human breast breast MCF7 cells, A431 epidermoid carcinoma cells, and A285 melanoma cells. In all cases, the compounds are effective in the range of 1-5 μΜ.

Claims (9)

Claims and its salts and physiologically functional derivatives, wherein A X is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ , wherein R ^{7 is} H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulfonyl or substituted sulfonyl; Y is O, S, SO, SO ₂ , 0¾ CO or NR ⁷ ; R ¹ is COR ⁸ , COOR ⁸ , CHO, CH 2 OH, CH 2 OR ⁹ , CONH 2, CONHNR ¹⁰ R ⁿ , CONHR ¹⁰ , CONR ¹⁰ R ^H , COOlOH ^ NR ^ R ¹¹ , 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 H, COOR ⁸ , alkyl, aryl, substituted aryl or CH ² , C ¹ -C 4 CO ¹² where R ^{12 is} alkyl or aryl; R ³ and R ⁴ are independently H, hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkyl amino, dialkyl amino, substituted alkyl, carboxyl or CO ₂ R ¹² ; R ⁵ is H, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano, CHO, or COOR ⁸ ; R ⁶ is H, alkyl, aryl, aralkyl, nitro, halogen, CHO or COR ¹³ wherein R ^{13 is} alkyl or aryl with the proviso that (i) if R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} all 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 (ii) if R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} all H and A 1 - k ¹ \ _{Y r} 2 where Y is NH, and XO then R ¹ is not CHO; and (iii) Y is not O if 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 toluene sulfonyl; Y is NR ⁷ ; R ¹ is COR ⁸ , COOR ⁸ , CH 2 OR ⁹ , CONH 2, CONHNR ¹⁰ R ⁿ , CONHR ¹⁰ , CONR ¹⁰ R ⁿ , COOtCH ^ NR 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 hydrogen, alkyl or aryl and n represents 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 H, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl or carboxyl; R ⁵ is H or alkyl; R ⁶ is H, alkyl or aryl; together with its salts and physiologically functional derivatives. A compound according to claim 1 or 2, characterized in that X is SaliNH; Y is NH; Aye R ¹ is COOR ⁸ , where 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; R ⁶ is hydrogen and its salts and its physiologically functional derivatives. 4. A compound characterized in that it is selected from the group consisting of it 3-Pyridyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate [(3-dimethylamino) phenyl] 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate benzyl 1,3,4 -trimethylpyrrolo [3,2-b] carbazole-2-carboxylate phenyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate 3,4-dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3,2-b] carbazole ethyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate, ethyl 3,4-dimethylbenzothieno [4,5-f ] indole-2-carboxylate benzyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate, benzyl 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate ethyl 8- fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate benzyl 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate ethyl 3,4,6-trimethylpyrrolo [3, 2-b] carbazole-2-carboxylate 8-Fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid ethyl 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate, 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and benzyl 8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate and its salts and physiologically functional derivatives . 5. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 together with a pharmaceutically acceptable carrier thereof. 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 thereof, or a physiologically functional derivative thereof, for the manufacture of a medicament for the treatment of tumors. A process for the preparation of compounds of general formula (I) as described in claim 1, characterized in that it comprises: (a) catalyzed ring closure of compounds of formula (IV) in the presence of a strong acid (IV) wherein Χ, Υ, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as previously defined; or (b) conversion of one compound of formula (X) to another compound of formula (I). 9. New intermediates of formulas (II), (III), (IV) or (V).