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

Tetracycline compounds, processes for their preparation, intermediates for their production and their use as antitumor agents

Technical field

The present invention relates to heterocyclic compounds which have been found to have antitumor activity. In particular, the invention relates to pyrrolo [3,2-b] carbazoles, 1H-benzofuro [3,2-f] indoles and 1H- [1] benzothieno [2,3-f] indoles, a process for their preparation, pharmaceutical compositions containing them and their use as antitumor preparations.

BACKGROUND OF THE INVENTION

Research in the field of cancer chemotherapy has led to the production of many anticancer agents having varying degrees of efficacy. Standard clinically used formulations include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cisplatin, vincristine and vinblastine. However, these currently available antitumor agents are known to have various disadvantages such as healthy cell toxicity and resistance to certain types of tumors.

Thus, there is a continuing need to develop new and improved anticancer agents.

Khoshtariya et al., Khim. Geterotsikl. Soedin. 2, 203-208 (1980) discloses the synthesis of certain indolobenzophenyl] thiophenes.

Khoshtariya et al., Khim. Geterotsikl. Soedin. 10, 1366-1370 (1984) describes the synthesis of some other indolobenzo [b] furans.

Kakhabrishvili et al., Khim. Geterotsikl. Soedin. 3, 355-358 (1985) discloses the synthesis of certain indolobenzo [5,6-d] - and indolo [5,4-d] benzo [b] furans derivatives.

European patent specification no. No. 447,703 discloses the synthesis of some benzo [5,6-b] benzofuran-2-carboxylates.

SUMMARY OF THE INVENTION

We have now found novel compounds which exhibit an antitumor effect on cells and have low toxicity against normal cell lines.

Thus, a first feature of this general formula (I) of the invention provides compounds

in which

represents a group of the formula

represents an oxygen atom, a sulfur atom, a group of formula SO, SO ₂ , CH ₂ , CO or NR ⁷ ,

R is hydrogen, alkyl, aralkyl, aryl, alkenyl,. acyl, alkynyl, sulfonyl or substituted sulfonyl group, is O, S, a group of formula SO, S0 _2, CH _2, CO or NR ^7,

R ¹ is of the formula CONHNR ¹⁰ R ^11, COO (CH _{2) n} NR ¹⁰ R ¹¹ is CONH _2,

COR ⁸ , COOR ⁸

CONHR ¹⁰ ,

CHO, ch ₂ oh, ch ₂ or ⁹

CONR ¹⁰ R ^{1: 1} or

R ⁸ represents a hydrogen atom, an aryl or aralkyl alkyl, aryl, substituted group,

R ⁹ is an acyl or substituted acyl group

R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl or aryl, n is 1 to 4 carbon atoms,

R ² is hydrogen, a group of the formula COOR ^8, an alkyl, aryl or substituted aryl group, or a group of formula _{CH2 CH2 CO2} ^R12,

R is an alkyl or aryl group,

R ³ and R ⁴ are each independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxy or C ₂ r ¹² ,

The

R represents a hydrogen atom, an alkyl group, a substituted alkyl alkyl group, an aralkyl group, a nitro group, an amino group, a halogen atom, a cyano group, a group of formula CHO or COOR ⁸ ,

R ⁶ represents a hydrogen atom, an aryl, alkyl, aralkyl group,

3 is nitro, halogen, CHO or COR;

R ¹³ represents an alkyl or aryl group with the proviso that (i) when R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each represent a hydrogen atom and A represents a group of the formula

where Y is NH and X is O or S, then R ^{1 is} not CO ₂ H or CO ₂ Et, (ii) when R ² , R ³ , R ⁴ , r ⁵ and R ⁶ are each hydrogen and A represents a group of formula

where Y is NH and X is O, then R is not CHO and (iii) Y is not O when X is O, and salts and physiologically functional derivatives thereof.

Yet another aspect of the invention relates to compounds of formula I above wherein:

A represents a group of formula

or

is O, S, a group of formula SO, S0 _2, CH _2, CO or NR ^7,

R ⁷ represents a hydrogen atom, an alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl or sulfonyl group,

Y is O, S, a group of formula SO, S0 _2, CH _2, CO or NR ^7,

R ¹ represents a group of the formula COOR ⁸ , CHO, CH 2 OH, CH 2 OR ⁹ , CONH 2, CONHNR ¹⁰ or CONR ¹⁰ R ¹¹ ,

R ⁸ represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group;

R ⁹ is an acyl or substituted acyl group and

R ¹⁰ and R ¹¹ independently are alkyl or aryl,

R ² is hydrogen, a group of the formula COOR ^8, an alkyl, aryl, substituted aryl, or a group of formula _{CH2 CH2 CO2} ^R12,

R ¹² represents an alkyl or aryl group,

R ³ and R ⁴ are each independently hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxy or C ₂ R ¹² ,

R ⁵ represents a hydrogen atom, an alkyl, substituted alkyl group, an aralkyl group, a nitro group, a halogen atom, a cyano group or a group of formula CHO,

R ⁶ is H, alkyl, aralkyl, nitro, halogen, CHO or a group of formula COR ¹³ and

R is an alkyl or aryl group, with the conditions described above.

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

The acyl groups may be straight or branched and may contain from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of suitable acyl groups include etanoyl and propanoyl groups.

The alkoxy groups may be straight or branched and may contain from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy and the like.

Aryl groups include both carbocyclic aryl groups and heterocyclic aryl groups, typically containing a maximum of 10 ring atoms. Carbocyclic aryl groups include, for example, phenyl and naphthyl and contain at least one aromatic ring. Heterocyclic aryl groups include, for example, a thienyl, furyl, pyridyl, indolyl and quinolyl ring.

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

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

A halogen atom represents a fluorine, chlorine, bromine or iodine atom.

In compounds of formula I

X is oxygen, S or of the formula NR ^7,

R 'represents a hydrogen atom, an alkyl, sulfonyl or toluenesulfonyl group,

Y is preferably NR ⁷ ,

R ¹ is preferably a group of formula COR ⁸ , COOR ⁸ , CH 2 OR ⁹ , CONH 2,

CNHNR ¹⁰ R ^{1, L,} CONHR ^10, CONR ¹⁰ R ^11, COO (CH _{2) n} NR ¹⁰ R ^{and L,}

R ⁸ represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group,

R ⁹ is an acyl or substituted acyl group and

R ¹⁰ and R ¹³ are each independently hydrogen, alkyl or aryl, n is 1 to 4 carbon atoms,

R ^z is preferably COOR, alkyl

Alebo 2 or a group of the formula CH ₂ CH ₂ CO ₂ R,

R ¹² represents an alkyl or aryl group,

R ³ and R ⁴ are each independently hydrogen, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl or carboxy, preferably R 5 is hydrogen or alkyl, and

R is preferably a hydrogen atom, an alkyl or aryl group and salts thereof, or salts and physiologically functional derivatives of the compounds so expressed.

X preferably represents a sulfur atom or a group of formula NH, A preferably represents a group of formula

and Y is preferably NH.

R ¹ preferably represents a group of the formula COOR ⁸ , wherein R ⁸ preferably represents an alkyl or aralkyl group, R ² represents a hydrogen atom or an alkyl group, R ³ preferably represents a hydrogen atom, an alkoxy group or a halogen atom, R ⁴ preferably represents a hydrogen atom or an alkoxy group or halogen, R ⁵ is preferably an alkyl group and R 6 is preferably hydrogen, or is a salt thereof and physiologically functional derivatives of the compounds expressed by the following.

Particularly preferred compounds of the 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-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) 4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), 8-fluoro- 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, ethyl- (8-methoxy-3,4- dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, and benzyl- (8-methoxy-3,4-dimethylpyrolo) [3,2-b] carbazole-2-carboxylate), and their physiologically functional derivatives.

The compounds of formula I were tested against two separately developed cell lines that are clones of the human fibrosarcoma HT1080 cell line. One clone, HT1080scc2, maintains the transformed baseline phenotype, while the other, HT1080C, is a non-tumor-causing morphologically flat revertant.

Thus, the effects of potential antitumor compounds can be evaluated based on their ability to cause detransformation in HT1080scc2 cells.

The compounds of this invention have been found to be particularly effective in this assay system.

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

The compounds also exhibit low toxicity against normal cells.

According to another feature, the present invention also provides a process for the preparation of compounds of formula I which comprises catalyzed ring closure of a compound of formula IV

(IV) in the presence of a strong acid.

The present invention also provides a process for the preparation of compounds of formula IV, which comprises:

a) reacting a compound of formula II with a compound of formula III to form a compound of formula IV, wherein X, Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, according to

followed by catalyzed ring closure.

The reaction is preferably carried out at room temperature in the presence of a strong acid, for example p-toluenesulfonic acid or montmorillonite clay K10 as a catalyst, to form a compound of the invention.

b) Reacting compounds of formula V 0

in which

4 ·

L is a cleavable group, suitable examples of which are -OCOCH ₃ , OEt, -N ⁺ Me ₃ and halogen, with a compound of formula III to give a compound of formula IV, followed by catalyzed ring closure as described under a) .

c) A one-step reaction procedure is carried out in which a compound of formula II is reacted with a compound of formula III in the presence of a catalyst to form a compound of the invention in a single step. A preferred catalyst is montmorillonite clay K10.

The introduction of R ¹ into the ring systems, for example, is that they are

d) carboxylates the polyheterocyclic compound using

i) a carbonyl halide or ii) carbon dioxide, according to known methods (J. March, Advanced Organic Chemistry, 2nd Ed., McGraw Hill, New York, pp. 497-498 (1977)).

e) Alternatively, compounds of formula I wherein R ² is CHO may be prepared by methods known to those skilled in the art, for example by:

i) An appropriate aromatic polyheterocycle can be reacted with a formylating agent, such as those formed by reaction of the tin tetrachloride and the compound of formula C 1 _{2 3} CKD or equivalent reagent.

For example, the procedure of A.

Reiche et al. in Chem. Ber. 93, 88 (1960) or using other standard formulating agents and methods known in the art, such as using the Gatterman-Koch reagent

(CO / HCl / AlCl ₃ / CuCl), Gatterman reaction (HCN / HCl / ZnCl ₂ ) or Vilsmeier reaction agent agent

(POClg / PhN- (Me) CHO or POCl ₃ / Me ₂ NCHO) (J. March, supra, pp. 494-497).

(ii) In a suitable aromatic polyheterocycle containing a suitable functional group, the latter is converted to the aldehyde group by methods known to those skilled in the art. Suitable groups include those of the formula CHBr ₂ , CH ₃ and COR ¹⁴ , wherein R ¹⁴ represents a primary or secondary alkyl group containing from 1 to 6 carbon atoms, COOH or a derivative thereof such as an ester, amide, acid chloride or cyanide.

f) A compound of formula I wherein R ³ is CONHR ¹⁰ may also be prepared by reacting a compound wherein R ¹ is carboxy, or a suitable reactive acid derivative as described in J. March, op. higher. For example, the acid halide can be reacted with a compound of formula NH ₂ R in an inert solvent.

g) Conversion of one compound of formula I to another compound of formula I.

Compounds of this invention wherein R ¹ is a group O of COOR ° and R is, for example, an aralkyl group, can be converted to the free acids wherein R ⁸ is a hydrogen atom by reduction in the presence of hydrogen and palladium as a catalyst, or an alkyl group, by hydrolysis in the presence of a suitable base, for example cesium carbonate.

One skilled in the art can then synthesize the ester and amide compounds within the scope of this invention by converting the free acids obtained by known methods (see J. March, cited above, pp. 363-365).

The compounds of the invention produced as described herein can be converted to other compounds of the invention by electrophilic substitution of R ⁵ and / or R ⁶ , for example to introduce a group of formula NO ₂ halogen atom or a group of formula COR ¹³ , wherein R ¹³ is as defined above. above.

The above methods have been described for compounds wherein Ä is a group of formula

Y

One skilled in the art will appreciate that these methods are also applicable when A is a group of formula

In another aspect, the invention relates to novel intermediates of formula II, III, IV or V.

The compounds of the invention are useful in the treatment of tumors. These compounds can be used for the treatment of various forms of mammalian cancer including carcinomas such as stomach, pancreas, breast, cervix and colon, adenocarcinoma such as lung and colon, sarcomas such as fibrosarcomas, leukemias such as lymphocytic leukemia and lymphomas such as myeloid.

The invention thus further provides a method of treating tumors in a mammal, particularly a human, comprising administering a clinically appropriate amount of a compound of Formula I, or a physiologically acceptable salt thereof, or a physiologically functional derivative thereof in a pharmaceutically acceptable form, once or several times a day or at any time. orally, rectally, parenterally, or administered topically.

, i i

In addition, a further or alternative feature of the invention is provided, a compound of formula I, or a physiologically acceptable salt thereof, or a physiologically functional derivative thereof, for use in therapy, for example, as an antitumor agent.

The amount of the compound of formula I required to produce an effect against the above tumors will, of course, vary and will ultimately depend on the judgment of the physician or veterinarian. Circumstances to be considered include the condition to be treated, the route of administration and the nature of the compositions, the weight of the mammal's body, the surface area, age and general condition, and in particular the compound to be administered. Suitably, the effective anti-tumor dose is in the range of about 0.01 to 100 mg / kg body weight, for example 0.1 to 100 mg / kg body weight, preferably 1 to 30 mg / kg body weight. The total daily dose can be administered as a single dose, a plurality of doses, for example two to six times a day, or by intravenous infusion over a selected duration. For example, for a mammal weighing 75 kg, the dosage range should be from about 8 to 900 mg per day and the usual dose should be about 50 mg per day. If a plurality of separate doses for treatment is given, it should generally be 15 mg of a compound of formula I administered up to four times a day.

While it is possible to administer the active compound alone, it is possible to present the active compound in pharmaceutical compositions. Compositions of the invention for use in medicine include a compound of Formula I or a salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. The carrier (s) should be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The invention thus further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or physiologically functional _T I, compound together with its pharmaceutically acceptable carrier.

The invention also provides a process for the manufacture of a pharmaceutical composition comprising contacting a compound of formula I, or a pharmaceutically acceptable salt thereof, or a physiologically functional derivative thereof, and a pharmaceutically acceptable carrier therefor.

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

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known to those skilled in the art of pharmacy. All methods include the step of bringing into association the active compound with a carrier which constitutes one or more adjuvants added. Generally, the compositions are prepared by uniformly and intimately bringing into association the active compound with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired composition.

Compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges each containing a predetermined amount of the active compound, as a powder or granules, or as a solution or suspension in aqueous or non-aqueous a liquid such as a syrup, elixir, emulsion or syrup medicament.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active compounds in free-flowing form, as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered active compound with any suitable carrier.

A syrup may be prepared by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which any excipients may also be added. Such excipient (s) may include flavoring agents, sugar crystallization preventing agents or solubility enhancers other than polyhydric alcohols such as glycerol or sorbitol.

The compositions for rectal administration may be in the form of suppositories with a conventional carrier such as cocoa butter.

Compositions suitable for parenteral administration typically include sterile aqueous formulations of the active compound, which may preferably be isotonic with the blood of the recipient. Such compositions typically comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of Formula I that is isotonic with the blood of the recipient.

Suitable compositions also include concentrated solutions or solids containing a compound of Formula I which upon dilution with a suitable solvent provides a solution for parenteral administration as described above.

In addition to the above ingredients, the compositions of the present invention may further comprise a single excipient or a plurality of excipients selected from diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). and so on.

Another aspect of the invention relates to the use of the compounds of formula I or their pharmaceutically acceptable salts or physiologically functional derivatives thereof for the manufacture of a medicament for the treatment of tumors.

DETAILED DESCRIPTION OF THE INVENTION

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

All temperatures are in degrees Celsius (° C).

Infrared spectra are recorded on a Perkin-Elemer 257 grid spectrophotometer or a Bruker FS66 spectrophotometer.

Ultraviolet spectra are measured in ethanol using a Unicam SP800 spectrophotometer.

¹ H NMR spectral analyzes are determined on a Bruker WM 360-NMR spectrophotometer at 360 MHz or on a Bruker AC200 spectrophotometer at 200 MHz. J values are given in Hz.

The mass spectrum is obtained on Varian CH5D (EI), Kratos Concept (EI) or Kratos Ms50 (FAB) instruments.

Example 1

Process for preparing intermediates

Process for producing pyrroles

Ethyl (4-acetyl-3,5-dimethylpyrrole-2-carboxylate), benzyl (4-acetyl-3,5-dimethylpyrrole-2-carboxylate) and ethyl (4-acetyl-3-ethyl-5-methylpyrrole) -2-carboxylate) are prepared by the method of AW Johnson et al. in J. Chem. Soc., 4254 (1958).

Method of N-methylation of pyrroles, general procedure i

A mixture of 20 mmol of pyrrole, 50 mmol of methyl iodide and 50 mmol of potassium carbonate is refluxed in 50 ml of methyl ethyl ketone for 8 hours. If thin layer chromatography (toluene / ethyl acetate 3: 1) showed that the reaction was not complete, further 50 mmol aliquots of methyl iodide and 50 mmol potassium carbonate were added and the mixture was refluxed for an additional 6 hours.

After evaporation to dryness under reduced pressure, the residue is taken up in hot water and extracted three times with 50 ml of ethyl acetate each time. The combined extracts were dried (MgSO 4) and evaporated under reduced pressure to give a yellow oil or solid which was crystallized from aqueous ethanol.

Process for the preparation of ethyl (4-acetyl-1,3,5-trimethylpyrrole-2-carboxylate)

The title compound is obtained from ethyl (4-acetyl-3,5-dimethylpyrrole-2-carboxylate) as 2 g white crystals having a melting point of 61-62 ° C. Yield: 41%.

Analysis for ^C 17 ^H I 2 ^{NO 3:} Found: 64.17% C, 7.82% H 6.16% N Found: 64.55% C, 7.68% H, 6.27% N.

¹ H NMR SH ([ ² H 6] -DMSO): 4.25 (2H, q, CH ₂ CH ₃ ), 3.70 (3H, s, 1-CH ₃ ), 2.43 and 2.42 (2 x 3H, 2 xs, 3-CH ₃ and COCH ₃ ), 2.38 (3H, s, 5-CH ₃ ) and 1.29 (3H, t, CH ₂ CH ₃ ) ppm. m / z (%) 224 (MH < ^{+ &gt};, 100),

208 (40), 194 (20), 178 (40) and 133 (20). v _max (KBr roll / cm -1 ⁾

2984, 1691 and 1651.

Process for the preparation of benzyl (4-acetyl-1,3,5-trimethylpyrrole-2-carboxylate)

The title compound is obtained from benzyl (4-acetyl-3,5-dimethyl-2-carboxylate) as white crystals, m.p. 78-79 ° C.

Analysis for ^C 17 ^H 19 ^NO 3 ^: found: 71.30% C, 6.74 % H, 4.79% N, calculated: C, 71.56; 6.71 % H, 4.91% N. ¹ H NMR _8H ^([2 H ₆ J-DMSO): 7.52 - 7.27 (5H, m, ArH), 5.30 (2H, s, CH ₂ Ph), 3.73 (3H, s, 1-) ch ₃ ), 2.42 (6H, s, 3-CH ₃ and COCH ₃ ) a

2.38 (3H, s, _5-CH3) ppm. m / z (%) 285 (76, M < ^{+ >} ), 270 (87), 194 (53), 178 (23), 151 (36), 136 (26) and 91 (100). v _max (KBr roll / cm -1 ⁾

2974, 1693 and 1641.

Process for preparing 5-acetoxymethyl-4-acetylpyrroles, general procedure

To a stirred suspension cooled to 0 ° C containing 0.02 mol of 4-acetyl-5-methylpyrrole in 20 ml of dry diethyl ether was added dropwise over 15 minutes 2.2 ml (1.25 equivalents) of freshly distilled sulfuryl chloride. The reaction mixture is stirred further and the chloromethyl derivative slowly crystallizes. Filtration gave the 5-chloromethyl derivative as colorless crystals. The purity is checked ^{chloromethylpyrrole; H} NMR spectral analysis (90 MHz) and was used directly without recrystallisation.

0.01 mol of the chloromethylpyrrole described above is added to a solution of 3 g of sodium acetate in 50 ml of acetic acid and the mixture is stirred for 2 hours and then poured onto 200 ml of a mixture of ice and water. The resulting solid is washed well with water until it is free of acid and then dried.

Process for the preparation of ethyl (5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate)

The title compound crystallizes from benzene as colorless needles weighing 1.87 g (70%), mp 135.5-138 ° C. Yield: 70%.

Analysis for C ₁₃ H ₁₇ NO _5: Found: 58.6% C, 6.45% H 5.15% N Found: 58.4% C, 6.41% H, 5.24% N.

^X 8 _h NMR (CDC1 _3): 9.57 (1 H, br s, NH), 5.40 (2H, s,

CH ₂ OAc), 4.35 (2H, q, OCH ₂ CH ₃ ), 2.6 (3H, s, 3-CH ₃ ), 2.5 (3H, s,

COCH ₃ ), 2.17 (3H, s, OCOCH ₃ ) and 1.4 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 267 (83, M < ^{+ >} ), 224 (46), 207 (27), 178 (100) and 162 (42).

Process for the preparation of benzyl (5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate)

The title compound crystallizes from methanol as colorless needles, 2.34 g, m.p. 138-141 C. Yield: 71%.

Analysis for ^C 19 ^H i8 ^{NO 5:} Found: 65.8% C, 5.95% H, 4.3% N Found: 65.64% C, 5.81% H, 4.25% N.

1 H NMR δ _H (CDCl ₃ ): 9.44 (1H, broad singlet, NH), 7.49 7.32 (5H, m, ArH), 5.40 (2H, S, CH ₂ OAc), δ 35 (2H, s, _CH2 Ph), 2.62 (3H, s, _3-CH3), 2.49 (3H, s, CH ₃ CO) and 2.14 (3H, s, OCOCH ₃₎ ppm. m / z (%) 329 (9, M < ^{+ >} ), 286 (13), 269 (4), 178 (19) and 91 (100).

In the case of benzyl (5-acetoxymethyl-4-acetyl-3- (2-methoxycarbonylethyl) pyrrole-2-carboxylate), this material does not precipitate when the solution is poured onto ice water. Therefore, the solution was extracted three times with 100 ml of chloroform, dried and the solvent was evaporated under reduced pressure. An oil is obtained which crystallizes from a mixture of benzene and petroleum ether to give colorless needles of the title compound weighing 2.69 g, m.p. 97-100 ° C. Yield: 67%.

Analysis for ^C 21 ^H 23 ^NO 7 ^: found: 62.9% C, 5.9 % calculated: 62.8% C, 5.78 % ^{Τ Η} NMR 6 _h (CDC1 _3): : 9, 15

7.30 (5H, m, Ar H), 5.35 (4 H, _OCH3), 3.37 (2H, t, _{CH2 CH2} CO), _COCH3), and 2.15 (3H, s, OCOCH ₃ ) 268 (6), 250 (60) and 91 (100).

H, 3.45% N,

H, 3.49% N.

(1 H, br s, NH), 7.50 s, CH ₂ Ph, and CH ₂ OAc), 3.63 (3H, s

2.58 (2H, t, _CH2 CO), 2.51 (3H, s, ppm. M / z (%) 401 (4, M ^+), 341 (8),

Process for the preparation of ethyl (5-acetoxymethyl-4-acetyl-1,3-dimethylpyrrole-2-carboxylate)

The title compound crystallizes from a mixture of ethyl acetate and cyclohexane having a melting point of 100-101 ° C. Yield: 61%.

Analysis for C ₁₄ H _ig NO _5:

found: C 59.38, H 6.73, N 4.95, calculated: C 59.78, H 6.81, N 4.98.

^{Τ Η} NMR δΗ ^([2 H 6] -DMSO): 5.30 (2H, s, _CH2 0Ac), 4.29 (2H, q,

CH ₂ CH ₃ ), 3.77 (3H, s, N-CH ₃ ), 2.43 and 2.42 (2 X 3H, 2 xs, 3-CH ₃ and CH ₃ CO), 2.02 (3H , s, OCOCH ₃ ) and 1.31 (3H, t, CH ₂ CH ₃ ) ppm. m / z (%) 281 (34, M < ^{+ >} ), 238 (100), 222 (48) and 192 (52). v _max (KBr kotúčj / ^cm-1 1712 and 1697th

Method of production ^: benzyl (5-acetoxymethyl-4-acetyl-1,3-dimethylpyrrole-2-carboxylate)

The title compound crystallizes from a mixture of ethyl acetate and cyclohexane.

^{Χ Η} NMR δΗ ^([2 H 6] -DMSO): 7.51 to 7.32 (5H, m, Ar H), 5.34 and

5.32 (2 x 2H, 2 xs, CH ₂ Ph and CH ₂ OAc), 3.78 (3H, s, N-CH ₃ ), 2.46 and 2.45 (2 x 3H, 2 xs, 3 -CH ₃ and CH ₃ CO) and 2.04 (3H, s, OCOCH ₃ ) ppm. m / z (%) 343 (5, M < ^{+ >} ), 284 (100) and 91 (95).

Process for the preparation of ethyl (5-acetoxymethyl-4-acetyl-3-ethylpyrrole-2-carboxylate)

The title compound crystallizes from a mixture of ether and perether ether as pale yellow needles having a melting point of 97-98 ° C. Yield: 61%.

Analysis for ^C i4 ^H _ig NO _5: Found: 59.44% C, 6.78% H 4.80% N Found: 59.76% C, 6.81% H, 4.98% N. ¹ H NMR δ _H (CDCl ₃ ): 9.40 (1H, broad singlet, 1-NH), 5.38 (2H, s, _CH2 OAc), 4.38 (2H, q, J = 7 Hz, _{CO2 CH2),} 3.10 (2H, q, J = 7.5 Hz, _3-CH2), 2.54 (3H, s, C0CH _3), 2.18 (3H, s, OCOCH _3),

1.40 (3H, t, J = 7.5 Hz, CO ₂ CH ₃ CH ₃ ), 1.23 (3H, t, J = 7.5 Hz,

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

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

Method for the synthesis of 3- (pyrrolylmethyl) indole, 2- (pyrrolylmethyl) benzofuran and 3- (pyrrolylmethyl) benzothiophene, general procedure

A solution of 1.0 mmol of 5-acetoxymethyl-4-acetylpyrrole and 1.0 mmol of indole in 10 mL of 1,2-dichloroethane is carefully refluxed and stirred with 1 g of montmorillonite clay for 1.5 to 2 hours. After filtering the clay and washing well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give an oil. The oil was flash chromatographed on silica eluting with ethyl acetate in petroleum ether. To give 3- (3'-acetyl-5'-ethoxycarbonyl-4 ^{1-methylpyrrole-2-ylmethyl)} indole, which gave colorless crystals from ethyl acetate and petroleum ether, weighing 0.1465 g, mp: 180 DEG 182 “C. Yield: 45%.

Analysis for ^C 20 ^H ig 2 ^N ° ^3: Found: 70.5% C, 6.25% H 8.65% N Found: 70.4% C, 6.21% H, 8.64% N .

@ 1 H NMR (NH4) 7.45

7-H), 7.25 (1 H,

7.10 (1 H,

2.63 (3H, s, _4'-CH3).

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

8 _hours (CDC1 _3):

(1H, d, J ', J = 7

S, 2-H), 4.45 '

8.78 = 7

Hz, (2H,

2.53 (1 H, s,

HZ, 4-H)

6-H), 7.14 s, 3-CH ₉ ), (3H,

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

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

1650th

1.0 mmol of benzofuran when used in place of indole after chromatography affords 2- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzofuran (0.106 g), m.p. 127 [deg.] C. Yield: 32.6%.

Analysis for ^{C H} ig ig 4 ^N0: Found: 70.1% C, 6.1% H 4.15% N Found: 70.14% C, 5.89% H, 4.31% N.

¹ H NMR δ _H (CDCl ₃ ): 9.25 (1H, s, NH), 7.50 (1H, d, J = 7.3Hz, 4-H), 7.44 (1H, d, J) = 7.3 Hz, 7-H), 7.28-7.18 (2H, m, 6-H and 5-H), 6.57 (1H, s, 3-H), 4.50 (2H , s, 2-CH ₂ ), 4.31 (2H, q,

OCH ₂ CH ₃ ), 2.62 (3H, s, 4'-CH ₃ ), 2.50 (3H, s, CH ₃ CO) and 1.35 (3H, s,

OCH ₂ CH ₃ ) ppm, saturation of 3-H singlets at δ 6.51 increases signals due to 4H at δ 7.50 (2.7%) and 2-CH ₂ at δ 4.50 (0.8%) . m / z (%) 325 (100, M < ^{+ >} ), 310 (4), 279 (29), 264 (17), 251 (59), 236 (27),

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

It further provides 2,3-bis- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzofuran of 0.0238 g, mp 255-257 ° C. Yield 8.94% of theory.

^T H 6 _h NMR (CDC1 ₃₎ (1 H, d. J = 7.7 HZ, (1 H, t, J = 7.7 Hz, ' (2H, with, 2-CH ₂ ), 4.40 (2H, q, OCH ₂ CH ₃ ) 2 2.58 (3H, s, CH ₃ CO); a 1, 31 (3 H, t, OCH 444 ( 9), 397 (6) 162 ( 28). (Found M ' 532. 2209 ϋ.

10.09 (1H, s, NH), 9.95 (1H, s NH) 4-H), 7.27 (1H, d, J = 7.7Hz, 7-H) 6-H), 7.08 (1H, t, J = 7.7Hz, 5-H) (2H, s, 3-CH ₂ ), 4.36 (2H, q, OCH ₂ CH ₃ ) 64 (3H, s, 4 1 -CH ₃ , 2.63 (3H, s,

2.54 (3H, s, CH ₃ CO), 1.39 (3H, t, ₂ CH ₃ ) ppm. m / z (%) 532 (11, M < ^{+ >} ), 100), 282 (18), 278 (27), 236 (20), ⁺ 532.2210 for ^C 30 ^H 32 ^N 2 ° 7 ^z

7.32

7.17

4.45

4.27

-ch ₃ ), ₂ ch ₃ ) 490 (24), 209 (28) and calculated M ⁺

When 1.0 mmol of benzothiophene was used in the same manner as indole, chromatography using a mixture of ethyl acetate and dichloromethane as eluent gave colorless crystals of 3- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) of benzothiophene weighing 0.0963 g and having a melting point of 125 to 128 ° C. Yield: 28.2% of theory.

Analysis for C ^ _3S gHjgNO found: 66.75% C, 5.8 % H, 4,1% N, calculated: 66.84% C, 5.61 % H, 4.10% N. ¹ H NMR 6 _h (CDC1 _3): 8.72 (1 H, broad singlet, 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, -CH ₂ ), 4.23 (2H, q, OCH ₂ CH ₃ ), 2.62 (3H, s, 4'-CH ₃ ), 2.53 (3H, s, CH ₃ CO) and 1.28 (3H, t, OCH ₂ CH ₃ ) ppm, saturation of 3-CH ₂ protons at δ 4.54 increases the signals due to NH at δ 8.72 (3.3%), 4 -H at δ 7.88 (7.7%), 2-H at δ 7.20 (6%), and CH ₃ CO at δ 2.53 (1.3%). m / z (%) 341 (100, M < ^{+ >} ), 326 (9), 298 (6), 295 (20), 230 (39), 267 (46), 252 (32), 224 (27), 194 (26) and 148 (22).

Further, 2,3-bis- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene provides a pale yellow solid of 0.0264 g, mp 206-209 ° C. C. The yield corresponds to 9.6% of theory.

Analysis for ^C 30 ^H 32 ^N 2 ° 6 WITH: found: 65.6% C, 5.8 % H, 5,1% N, calculated: 65.67% C, 5.88 % H, 5.11% N. ¹ H NMR delta _h (CDC1 _3): 9.77 (1 H, broad singlet, NH), 9.43 (1H,

broad singlet, NH), 7.70 (1H, m, 4-H), 7.49 (1H, m, 7-H), 7.26 (2H, m, 6-H and 5-H), 4 55 (2H, s, CH ₂ ), 4.53 (2H, s, CH ₂ ), 4.32 (2H, q, OCH ₂ CH ₃ ), 4.24 (2H, q, OCH ₂ CH ₃ ) , 2.61 (3H, s, CH ₃ 4 ^1), 2.60 (3H, s, _4'-CH3), 2.57 (3H, s, CH ₃ CO), 2.49 (3H, S, CH ₃ CO), 1.35 (3H, t, OCH ₂ CH ₃ ) and 1.28 (3H, t, OCH ₂ CH ₂ ) ppm. m / z (%) 548 (5, M < ^{+ >} ), 530 (11), 340 (100), 294 (27) and 162 (10).

Example 2

Process for the synthesis of 3- (pyrrolylmethyl) benzothiophenes and 3- (pyrrolylmethyl) indoles

I

a) Method for producing 3- (3'-acetyl-5'-benzyloxycarbonyl-4'-methylpyrrol-2'-ylmethyl) benzothiophene

A solution of 0.33 g (1.0 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 0.14 g (1.05 mmol) of benzothiophene in 10 ml of 1,2 dichloroethane is refluxed and stirred with 1 g of K10 montmorillonite clay. for 2.5 hours. After cooling and filtering the clay, which was washed well with 10 ml of 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give an oil. The oil was flash chromatographed on silica eluting with diethyl ether and petroleum ether (1: 2). The title compound is obtained as a colorless solid.

^X 6 H NMR (C): 8.72 (1H, s, NH), 7.92 to 7.84 (1 H, m, 4-H), 7.69 to 7.58 (1 H, m, 7- H), 7.43-7.16 (8H, m, 2-H, 5-H, 6-H, ArH), 5.23 (2H, s, CH 2 Ph), 4.50 (2H, s, 3) -CH 2), 2.61 (3H, s, 4'-CH 3) and 2.50 (3H, s, CH 3 CO) ppm. m / z (%) 403 (M ^< ⁺ &^gt;, 100). max (KBr kotúčj / ^cm-1 3290, 1690 ', and 1659th

b) 3- (3'-Acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -5-cyanindole

A solution of 0.7 g (2.6 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 0.41 g (2.9 mmol) of 5-cyanindole in 50 ml of 1,2-dichloroethane is heated to reflux and stirred with 2. 1 g of K10 montmorillonite clay for 6 hours. After cooling and filtering the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give an orange solid. Crystallization from dichloromethane / ethyl acetate gave a small amount of the analytically pure title compound as cream-colored crystals. The evaporated mother liquors were subjected to flash chromatography on silica eluting with a 9: 1 mixture of dichloromethane and ethyl acetate. An additional 0.65 g of the product is obtained having a melting point of 213-214 ° C. Yield: 71%.

Analysis for ^C 20 ^H 19 ^N 3 ° 3 ^: found: % C, 68.60;% H, 5.46; % N, 1 calculated: H, 5.48; H, 12.03 % N. 1 H NMR _δΗ ([ ² H ₆ ] -DMSO): 12.05 (1H, WITH , 1'-NH), - 11, 38 (1 H, with, 1-NH), 8.20 (1 H, m, 4-H), 7.50 (1 H, d d. J = 0.7 a 8, 5 Hz, 7 -H), 7.39 (1 H, dd , J = 1.7 and 8.5, 6-H), 7, 18 (1H, s, 2-H) F 4.32 (2H, s, 3-CH ₂ ), 4 27 (2H, g, CH ₂ CH ₃ ), 2.33 (3 H, s, 4'- -CH3 ₃ F 2.51 (3H, S, ch ₃ co) and 1.30 (3H, t, CH ₂ CH ₃₎ ppm. m / z (%) 35 O (M ⁺ , 70),

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

c) Preparation of 3- ^(3-acetyl-1 5'-ethoxycarbonyl-4'-methyl- pyrrol-2-ylmethyl) indole-5-carboxylic acid

A solution of 0.74 g (2.8 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 0.5 g (3 mmol) of indole-5- (carboxylic acid in 50 ml of toluene) is stirred at room temperature with 1 g of montmorillonite clay K10 for After cooling and filtering the clay, which was washed well with toluene, the combined filtrates were evaporated under reduced pressure to give an orange solid, which was crystallized from ethyl acetate / cyclohexane to give the title compound as a gray powder of 0.15 mass. m.p. 227 DEG-228 DEG C. The yield corresponds to 15% of theory.

Analysis for ^C 20 ^H 20 ^N 2 ° ^5: Found: 64.96% C, 5.58% H 7.34% N Found: 65.21% C, 5.47% H, 7.60% N .

¹ H NMR SH ([ ² H 6] -DMSO): 12.35 (1H, broad signal, CO ₂ H),

12.04 (1H, S, 1'-NH), 11.17 (1H, s, 1-NH), 8.31 (1H, d, J = 1.6Hz, 4-H), 7.70 (1H, dd, J = 1.6 and 8.7 Hz, 6-H), 7.37 (1H, d, J = 8.7 Hz, 7-H), 6.98 (1H, s, 2H ), 4.36 (2H, s, 3-CH ₂ ), 4.26 (2H, q, CH ₂ CH ₃ ), 2.51 and 2.31 (2 x 3H, 2 xs, 4'-CH ₃₎ and CH ₃ CO) and 1.29 (3H, t, CH ₂ CH ₃ ppm. m / z (%) 369 (22, (M + 1) ⁺ ), 351 (37), 323 (18), 305 ( 19), 232 (19), 208 (60) and 181 (20), 162 (100) in _max (KBr roll) / cm ^-1 1359 and 1676.

d) Method for producing 3- (3'-acetyl-5'-ethoxycarbonyl-4'-methylpyrrole-

2'-ylmethyl) ^{-5-bromoindole}

A solution of 1.3 g (4.9 mmol) of 5-acetoxymethyl-4-acetylpyrrole and 1.09 g (5.6 mmol) of 5-bromoindole in 100 ml of 1,2-dichloroethane is heated to reflux and stirred with 3 g. montmorillonite clay K10 for 5 hours. After cooling and filtering the clay, which was washed well with 1,2-dichloroethane, the combined filtrates were evaporated under reduced pressure to give a yellow solid. Crystallization from a mixture of dichloromethane, petroleum ether and acetone gave the title compound as cream colored crystals (0.33 g), mp 181-183 ° C. Yield: 17%.

Analysis for ^C 19 ^H 19 ^BrN 2 ° 3 ^: found: C 56.24, 4.70 % H, 6.86% N, calculated: C 56.59, 4.75 % H, 6,95% N. ^X H NMR S _H ([ ² H ₆ ] -DMSO): 12 00 (1 H, s, 1'-NH), 11.00 (1H, s, 1-NH), 7.82 (1H, d, J = 1.9) HZ, 4-H), 7.31 (1 H, d, J = 8.6 Hz,

7-H), 7.16 (1H, dd, J = 1.9 and 8.6 Hz, 6-H), 7.02 (1H, s, 2-H), 4.30 (2H, s, 3-CH ₂ ), 4.28 (2H, q, CUHU ₂ CH ₃ ), 2.51 and 2.33 (2 x 3H, 2 xs, 4'-CH ₃ and CH ₃ CO), 1.31 ( 3H, t, CH ₂ CH ₃ ) ppm. m / z (%) 404 and 402 (100, M < ^{+ >} ), 389 and 387 (24), 357 (24), 330 and 328 (32), 206 (36) and 178 (26), respectively. v _max (KBr kotúčj / ^cm-1 3373 and the 1672nd

Example 3

a) Process for the preparation of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

A solution of 0.108 g (0.33 mmol) of 3- (pyrrolylmethyl) indole was cautiously refluxed in 10 ml of 1.2 dichloroethane and stirred with 1 g of Montmorillonite clay K10 for 2 hours. Thin layer chromatography then showed that a single compound had formed and that the reaction was complete. After cooling and filtration from the clay, which was washed well with 1,2-dichloroethane, the combined filtrates evaporated under reduced pressure to give a yellow solid which was crystallized from ¹ ethyl acetate to give pyrrolor3,2-b-carbazole as a yellow crystalline solid, weight 0.076 g, mp 209.5-211 ° C. Yield 75 ° C.

Analysis for ^C i9 i8 ^H 2 ^N ° ^2: Found: 74.6% C, 6.14% H 9.03% N Found: 74.5% C, 5.92% H, 9.14% N .

¹ H NMR _δ Η ⁽⁽² H _6] -DMSO): 11.22 (1H, s, 1-NH), 10.70 (1H, s, 5-NH), 8.06 (1H, d, J = 7Hz, 9-H), 7.85 (1H, s, 10-H), 7.40 (1 H, d, J = 7 Hz, 6-H), 7.35 (1H, t, J = 7Hz, 7-H), 7.08 (1H, t, J = 7 Hz, 8-H), 4.35 (2H, q, OCH ₂ H ₃ ), 2.91 and 2.90 (2 x 3H, 2 xs, 3-CH ₃ and 4-CH ₃ ) and 1.35 (3H, t, OCH ₂ CH ₃ ) ppm. Saturation 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). at _max (CHCl ₃ ) / cm ¹ 3480 and 1700. lambda _max (ethanol) / nm 226, 268, 310 shift, 327 shift, 340, 390 and 410 shift.

b) A process for the preparation of ethyl (3,4-dimethyl-1H-benzofuro [3,2-f] indole-2-carboxylate) mg of p-toluenesulfonic acid is introduced into a solution

0.100 g (0.31 mmol) of 2- (pyrrolylmethyl) benzofuran in 10 ml of toluene and the reaction mixture was refluxed for 3 hours. After cooling, the product crystallized out and was washed with ethanol after filtration. The title compound is obtained as pale yellow crystals weighing 0.084 g and having a melting point of 262-265 ° C. Yield 88.8% of theory.

Analysis for C ₁₇ H _ig NO _3:

Found: C, 74.25; H, 5.55; N, 4.6%. Calculated: C, 74.25; H, 5.56; N, 4.56.

^X δΗ NMR ^([2 H 6] -DMSO): 11.52 (1H, s,

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

1-NH), 8.18 (1 H,

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

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

4.37 (2H, q, OCH ₂ CH ₃ ), 3.14 (3H, s, 4-CH ₃ ), 2.91 (3H, s, 3-CH ₃ ) and 1.39 (3H, t, OCH ₂ H ₃ ) ppm, saturation of 4-CH ₃ at δ 3.14 increases signals due to 5-H at δ 8.18 (4.5%) and 3-CH ₃ at δ 2.91 (2.6)% m / z (%) 307 (53, M < ^{+ >} ), 261 (100), 233 (31) and 205 (9). Ν max (nujol) / cm -1 ¹³⁵⁰ and 1686. λ max (ethanol) / nm 240, 269, 293,

330 and 344.

c) A process for the preparation of ethyl (3,4-dimethyl-1H- [1] benzothieno [3,2-f] indole-2-carboxylate) mg of p-toluenesulfonic acid is added to a solution of 0.100 g (0.29 mmol) 3. - (pyrrolylmethyl) benzothiophene in 10 ml of toluene and the reaction mixture is refluxed for 3 hours. Evaporation of the solvent and washing of the resulting solid with ethanol gave the title compound as a pale yellow material (0.0758 g), m.p. 191-193 ° C. The yield corresponds to 80% of theory.

Analysis for C ₁₇ H _ig NO ₂ S: found: 70.3% C, 5.5% H, 4.2% N Found: 70.6% C, 5.30% H, 4.33% N.

¹ H NMR 8h ([ ² H 6] -DMSO): 11.64 (1H, s, NH), 8.25 (1H, m, 9-H), 8.12 (1H, s, 10-H), 7.95 (1H, m, 6-H), 7.48 (2H, m, 7-H and 8-H), 4.38 (2H, q, OCH ₂ CH ₃ ), 2.87 and 2, 85 (2 x 3H, 2 xs, 3-CH ₃ ) and 1.37 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 323 (53, M < ^{+ >} ), 277 (100), 249 (33) and 221 (15), 139 (7) and 111 (11). v _max (nujol) / cm ^-1 3350 and 1686.

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

d) Preparation of benzyl (3,4-dimethyl-1H- [1] benzothieno [3,2-f] indole-2-carboxylate) mg of p-toluenesulfonic acid is added to a solution of 0.100 g (0.25 mmol) of 3 - (pyrrolylmethyl) benzothiophene in 12 ml of toluene and the reaction mixture is refluxed for 6 hours. Evaporation of the solvent and washing of the resulting solid with ethanol gave the title compound as a pale yellow solid, 0.02 g, mp 203-204 ° C. Yield 20%.

Analysis for ^C 24 ^H 19 ^NO 2 ^S: found: 74.7% C, 4.9% H, 3.6% N Found: 74.8% C, 5.0% H, 3.6% N.

¹ H NMR SH ([ ² H 6] -DMSO): 11.64 (1H, s, NH), 8.27

8.15 (1H, m, 9-H), 8.10 (1H, s, 10-H), 7.90-7.89 (1H, m, 6-H), 7.60 7.30 (1H 7H, m, 7H, 8-H, Ar H), 5.40 (2H, s, _CH2) and 2.87 (6H, s, 2 x _CH3) ppm. m / z (%) 385 (100, M < ^{+ >} ), 277 (89), 248 (25), 221 (15), and

91 (28). the "_ _v (KBr Disc) / ^cm-1 3331 and the 1672nd

llLClX

e) Process for the preparation of ethyl (8-cyano-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

A mixture of 0.6 g (1.7 mmol) of 3- (pyrrolylmethyl) indole and 2 g of Montmorillonite clay K10 in toluene is stirred and refluxed for 24 hours. After cooling and filtering the clay, which was washed well with toluene, the combined filtrates were evaporated under reduced pressure to give a brown solid which was subjected to flash chromatography on silica eluting with cyclohexanone / ethyl acetate 3: 1. Recrystallization from cyclohexane / ethyl acetate gave the title compound as a yellow powder of 0.030 g, m.p. > 240 ° C. The yield corresponds to 5% of theory.

Analysis for ^ 20 ^ 17 ^ 3θ2 '0.2 H ₂ 0: found: 71.54% C, 5.18% H, 12.78 % N, calculated: % C, 71.71;% H, 5.24. 12.54 % N. ¹ H NMR δ _Η (t X 1 -DMSG): 11.39 (1 H, s, 1-NH), 11.29 (1 H, s, 5-NH), 8.65 (1H, d, J = 1.7Hz, 9-H), 8.01 (1 H, s, 10-H), 7.71 (1 H, dd, J = ^: 1.7 and 8.6 Hz, 7-H), 7.50 (1 H, d, J = = 8.6 Hz, 6-H), 4.36 (2 H, q, CH ₂ CH ₃ ), 2.91 and 2.89 (2 x 3H, 2x s, 4-CH ₃ and 3-CH ₃ ) and 1.38 (3H, t, CH ₂ CH ₃ ) ppm. m / z ( % 331 (52, M ⁺ ) 285 (100)

256 (32), 229 (12), 167 (14) and 149 (40). v _max (KBr roll) / cm ¹ 3414, 3550, 12212 and 1664.

f) Method for the preparation of 3,4-dimethyl-2-ethoxycarbonylpyrrolo [3,2-b] carbazole-8-carboxylic acid

A mixture of 0.1 g (0.3 mmol) of 3- (pyrrolylmethyl) indole and 0.34 g of K10 montmorillonite clay in 15 ml of toluene is stirred and refluxed for 6 hours. After cooling and filtering the clay, which was washed well with toluene, the combined filters were evaporated under reduced pressure to give an orange solid, which crystallized from methanol / dichloromethane to give the title compound as a yellow powder, 0.027 g, having a temperature of mp > 260 ° C. Yield: 28%.

Analysis for C q H ₂ O _{2 18} N _4th 0.05 H ₂ O:

found: 68.12% C, 5.19% H, 7.91% N, calculated: 68.39% C, 5.19% H, 7.98% N. ¹ H NMR δ _Η ([ ² H ₆ ] -DMS °): 12 , 42 (1H, broad signal, COOH), 11.30 (1 H, s, 1-NH), 11.09 (1 H, s, 5-NH), 8.68 (1 H, s, 10-H), 8.07 - 7.93 (2H, m, 7H and 9H), 7.45 (1H, d, J = 9Hz, 6-H);

(2H, q, CH ₂ CH ₃ ), 2.94 and 2.90 (2 x 3H, 2 xs, 4-CH ₃ and 3-CH ₃ ) and 1.39 (3H, t, CH ₂ CH ₃ ) ppm. m / z (%) 350 (100, M < ^{+ >} ), 304 (100),

278 (40), 232 (35) and 181 (38). v _max (KBr roll) / cm ^-1 3459, 1697 and 1674.

g) Process for the preparation of ethyl (8-bromo-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

A mixture of 0.3 g (0.74 mmol) of 3- (pyrrolylmethylindole) and 1 g of Montmorillonite clay K10 in toluene was stirred and refluxed for 6 hours. After cooling and filtering the clay, which was well washed with toluene, the combined filtrates were evaporated under reduced pressure to give a brown solid which was subjected to flash chromatography on silica eluting with a 7: 3 mixture of dichloromethane and petroleum ether to give a yellow solid which crystallized from a mixture of cyclohexane and ethyl acetate to give the title compound. Yield: 24% of theory.

Analysis for C ₁₉ H ₁₇ BrN ₂ O ₂ :

found: C 59.17, H 4.43, N 7.30, calculated: C 59.23, H 4.45, N 7.27.

^{Χ Η} NMR δΗ ^([2 H 6] -DMSO): 11.26 (1Η, s, 1-NH), 10.79 (1H, s, 5-NH), 8.30 (1H, d, J = 2 2 Hz, 9-H), 7.92 (1H, s, 10-H), 7.47 (1H, dd, J = 2.2 and 8.8 Hz, 7-H), 7.35 (1H, 1 H, d, J = 8.8 Hz, 6-H), 4.36 (2H, q, CH ₂ CH _3), 2.89 and 2.88 (2 x 3H, 2 x s, 4-CH ₃ and 3-CH ₃ ) and 1.38 (3H, t, CH ₂ CH ₃ ) ppm. m / z (%) 386 and 384 (100, M < ^{+ >} ), 340 and 338 (70), 232 (60) and 181 (50), respectively. v _max (KBr roll) / cm ^-1 3350, 1705 and 1663.

Example 4 ..

Process for preparing pyrrolocarbazoles in one reaction vessel, general procedure

A solution of 1.0 mmol of indole and 1.0 mmol of 5-acetoxymethyl-4-axylpyrrole in 10 mL of 1,2-dichloroethane was gently refluxed and stirred with 1 g of montmorillonite clay K10 for 3-4 hours. The clay color turns to light brown and the reaction is complete by thin layer chromatography. After filtering the clay and washing well with 1,2-dichloroethane, the combined filtrates are evaporated to give pyrrolo [3,2-b] carbazoles, which are obtained as yellow crystals, after crystallization from a mixture of dichloromethane and ethyl acetate.

a) Process for the preparation of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.199 g of the title compound is obtained by reaction of indole and 5-acetoxymethyl-4-acetylpyrrole in a yield corresponding to 65% of theory. This compound is identical in all directions to the pyrrolo [3,2-b] carbazole of Example 1.

b) Method for producing benzyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.179 g of the title compound is obtained by reacting indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 229-232 ° C. Yield 48.8% of theory.

Analysis for ^C 24 ^H 20 ^N 2 ° 2 ^: found: 78.2% C, 5.65 % H, 7.8 % N, calculated: 78.23% C, 5.47 % H, 7.60 % N. ^{Χ Η} NMR S _H ([ ² H ₆ J-DMS °)]: 11 29 (1H, with, 1-NH), 10.65 (1 H, s, 5-NH), 8.08 (1 H, d, H = 8 Hz, 9-H), 7 89 (1H, s, 10-H), 7.56-

7.34 (7Η, m, Ar H, 6-H and 7-H), 7.08 (1H, t, J = 7 Hz, 8-H), 5.42 (2H, s, CH ₂ Ph), and 2.92 (6H, s, _3-CH3 and _4-CH3) ppm. m / z (%) 368 (74, M < ^{+ >} ), 354 (10), 260 (100), 246 (13), 231 (20), and 91 (31).

0.166 g of pyrrolo [3,2-b] carbazole is also obtained by reaction of indole and 4-acetyl-5- (ethoxymethyl) pyrrole. Yield: 45%.

c) Process for the preparation of ethyl (8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reaction

5-methoxyindole; and 5-acetoxymethyl-4-acetylpyrrole. The compound has a melting point of 119-122 ° C.

Analysis for ^C 20 ^H 20 ^N 2 ° 3 ^: found: 71.6% C, 6.0 % H, 8 .05% N, calculated: 71.4% C, 5.99 % H, 8 , 33% N. ^X H NMR 6 _H ( ² H ₆ -DMSO) : 11,20 (1H, s, 1-NH), 10. 38 (1 H, s, 5-NH), 7.85 (1 H, s, 10-H) , 7.62 (LH, d, J) = 2.5 Hz, 9-H), 7.31 (1 H, d, J = 9 Hz, 6-H), 01 (1 H, dd, J = 9 and 2.5 Hz, 7-H), 4.38

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

d) Method for the preparation of benzyl (8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.139 g of the title compound is obtained by reaction of 5-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 212-215 ° C. yield corresponds to 35% of theory.

Analysis for found:

N, 6.95. Found: C, 75.4; H, 5.57; N, 7.03.

^X δΗ NMR ^([2 H 6] -DMSO): 11.29 (1H, s, 1-NH), 10.38 (1H, s, 5-NH), 7.88 (1H, s, 10-H 7.65 (1H, d, J = 2.5Hz, 9-H), 7.58 7.36 (5H, m, ArH), 7.32 (1H, d, J = 9Hz, 6) -H), 7.02 (1H, dd, J = 9 and 2.5 Hz, 7-H), 5.43 (2H, s, CH 2 Ph), 3.88 (3H, s, OCH ₃ ) , 2.92 (3H, s, _4-CH3) and 2.89 (3H, s, _3-CH3) ppm. m / z (%) 398 (73, M < ^{+ >} ), 290 (100), 262 (10), 247 (15), 219 (7) and 91 (17).

e) Process for the preparation of ethyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.131 g of the title compound is obtained by reaction of 5-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound had a melting point of 231-234 C. The yield was 40.5% of theory.

Analysis for ^{C H} ig i7 ^FN 2 ° ^2: Found: 70.5% C, 5.3% H, 8.4% N Found: 70.4% C, 5.28% H, 8.64% N .

^X δΗ NMR ^([2 H 6] -DMSO): 11.27 (1H, s, 1-NH), 10.64 (1H, s,

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

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

f) Method for the preparation of benzyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.155 g of the title compound is obtained from 5-fluoroindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 217-219 ° C. Yield: 40%.

Analysis for C ₂₄ H _ig FN ₂ O _2:

Found:% C, 74.6;% H, 4.95;% N, 7.3. Calculated:% C, 74.6;% H, 4.96;

¹ H NMR SH ([ ² H 6] -DMSO): 11.36 (1H, s, 1-NH), 10.86 (1H, s, 5-NH), 7.94 (1H, dd, J = 9) and 2.5 Hz, 9-H), 7.88 (1H, s, 10-H), 7.56-7.38 (5H, m, ArH), 7.39 (1H, dd, J = 9) and 4 Hz, 6-H), 7.21 (1H, dt, J = 9 and 2.5 Hz, 7-H), 5.42 (2H, s, _CH2 Ph), 2.91 a2.90 (2 x 3H, 2 xs, 3-CH ₃ and 4-CH 3) ppm. m / z (%) 386 (68, M < + >)

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

g) Process for the preparation of ethyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.206 g of the title compound is obtained by reaction of 7-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 230 ° C (decomposition). Yield: 64.4%.

Analysis for ^C 20 ^H 20 ^N 2 ° ^2: Found: 74.9% C, 6.25% H 8.65% N Found: 75.0% C, 6.29% H, 8.74% N .

^X δΗ NMR ^([2 H 6] -DMSO): 11.20 (1H, s, 1-NH), 10.11 (1H, s, 5-NH), 7.89 (1H, d, J = 7 5 Hz, 9-H), 7.84 (1H, s, 10-H), 7.18 (1H, d, J = 7.5, 7-H), 7.01 (1H, t, J = 7.5 Hz, 8-H), 4.37 (2H, q, OCH ₂ CH ₃ ), 2.98 (3H, s, 4-CH ₃ ), 2.91 (3H, s, 3-CH ₃ ), 2.58 (3H, s, 6-CH ₃ ) and 1.34 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 320 (54, M < ^{+ >} ), 274 (100), 246 (30), 230 (5), 137 (9), 123 (7), and 109 (6).

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

0.167 g of the title compound is obtained by reaction of 7-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound had a melting point of 222, yielding 43.7% of theory.

C (decomposition).

Analysis for ^C 25 ^H 22 ^N 2 ° 2 ^: found: 78.5% C, 5.9% H, 7.25% N, calculated: 78.5% C, 5.80% H, 7.33% N. ¹ H NMR S _H ([ ² H ₆ ] -DMSO): 11 .27 (1H, , with, 1-NH), 10.11 (1 H, s, 5-NH), 7.89 (1H, d, J = 7Hz) '· T 9-H), 85 (1H, s, 10-H), 7.56- 7.35 (5 H, m, ArH), 7.18 (1H, d. J = 7 Hz, 7-H), 7 0.08 (1H, t, J, 8-H), 5.43 (2H, s, _CH2 Ph); 2 99 (3H, with, _4-CH3); 2.93 (3H, s,

3-CH3) and 2.59 (3H, s, 6-CH3) ppm. m / z (%) 382 (71, M < ^{+ >} ), 274 (100), 246 (19) and 91 (22).

i) Process for the preparation of benzyl [3- (2-methoxycarbonylethyl) -4-methylpyrrolo [3,2-b] carbazole-2-carboxylate]

0.230 g of the title compound was obtained from indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 211 to 210 ° C. 213 ’C. Yield: 52.3%.

Analysis for ^C 27 ^H 24 ^N 2 ° 4 ^: found: 73.7% C, 5.6% H, 6.2% N, calculated: 73.6% C, 5.49% H, 6.36% N. ^X H NMR δ _Η ([ ² H ₆ ] -DMSO): 11 51 (1H, s) 1-NH), 10.71 (1 H, s, 5-NH), 8.75 (1H, d, J = 7.5Hz, 9-H), 7.92 (1 H, S, 10-H), 7.57- 7.44 (7H, m, ArH, 6-H and 7-H), 7.18 (1 H, t, J = 7.5 Hz, 8-H), 5.43 (2H, s) CH ₂ Ph) 3.63 (3H, s, and ₃ ): 3.59 (2H, , especially bad visible, t, CH ₂ CH ₂ CO ₂ , 2.88 (3H, S, 5 · -CH ₃ ) a 2.65 (2 H, t, CH ₂ CO) ppm. m / z (%) 440 (100, M < ^{+ >)} ), 332 (20), 290 (47) and 91 (57).

j) Process for the preparation of ethyl (3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.140 g of the title compound is obtained by reaction (in the range of 2.65 mmol) of N-methylindole and 5-acetoxymethyl-438

-acetylpyrrolu. The title compound has a melting point of 208 ° C (dec.). Yield 16%.

Analysis for ^C 20 ^H 20 ^N 2 ° 2 ^: found: 75.12% C, 6.40 % H, 8.69% N, calculated: 74.98% C, 6.29 % H, 8.74% N. ¹ H NMR δ _Η ([ ^{1 2} H ₆ ] -DMSO): 11.28 (1 H, S, 1-NH), 8.08 (1H, d, J)

= 7.9 Hz, 9-H), 7.88 (1 H, s, 10-H), 7.44 (2 H, m, 6-H, 7-H), 7.07  7 17 (1H in, 8-H), 4.36 (2 H, q, CH ₂ CH ₃ ), 4.01 (3H, S, _5-CH3); 3.13 (3H, s, _4-CH3); 2.90 (3H, s, _3-CH3) and 1.38 (3H, t, ch ₂ ch ₃ ) ppm. m / z ( 320) (72, M ⁺ ), 274 (100) 245 (16) and 137 (12). in max (KBr Disc) / cm " ¹ 3329 and 1670.

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

0.220 g of the title compound is obtained by reacting N-methylindole and 5-acetoxymethyl-4-acetylpyrrole in toluene at 55 ° C, catalyzed by toluene-4-sulfonic acid.

The compound produced has a melting point of 228-229 ° C. Yield: 57%.

Analysis for ^C 25 ^H 22 ^N 2 ° 2 '°' 33 H ₂ 0 found: 77.17% C, 5.73 % H, 7.09 % N, calculated: 77.31% C, 5.88 % H, 7.21 % N. ^X H NMR 6 _H ^([2 H _6] -DMSO): 11.28 (1H, 1H); - with, 1-NH), 8.03 (LH, d, J) = 7.5 Hz, 9-H), 7.88 (1 H, 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 ) ppm. m / z (%) 382 (72, M < ^{+ >} ), 291 (4), 274 (100) and 91 (34). V _max (KBr disc) / cm -1 ¹³³⁷ and 1674.

1) Process for the preparation of ethyl (1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.060 g of the title compound was obtained by reaction (in the range of 2.5 mmol) of indole and 5-acetoxymethyl-4-acetylpyrrole.

The title compound has a melting point of 188-189 ° C.

Yield: 7%.

Analysis for ^C 20 ^H 20 ^N 2 ° 2 ^: found: H, 6.32; H, 8.65 % N, calculated: H, 6.29; H, 8.74 % N. ¹ H NMR _δΗ ([ ² H ₆ ] -DMSO): 10.66 (1H, ' WITH, 5-NH), 8.14 (1 H, d, J = 7.7 Hz, 9-H), 8.03 (1 H, 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-CH3); 2.91 (3H, s, _4-CH3), 2.83 (3H, s, _3-CH3) and 1.38 (3H, t, ch ₂ ch ₃ ) ppm. m / z (%) 320 (M ^< ⁺ &^gt;, 100) 306 (: 10) 292 (30) , 2471 (8) a 231 (10). In _{m v} (KBr roll) / cm ^-1 1385 ad X 1657 •

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

0.240 g of the title compound is obtained by reaction (2.7 mmol) of indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 186-187 ° C. Yield: 28%.

Analysis for ^C 25 ^H 22 ^N 2 ° ^2: Found: 78.63% C, 5.83% H 7.32% N Found: 78.51% C, 5.80% H, 7.32% N .

¹ H NMR δΗ ([ ² H 6] -DMSO): 10.66 (1H, s, 5-NH), 8.14 (1H, d, J = 7.4 Hz, 9-H), 8.02 ( 1H, s, 10-H), 7.56-7.31 (7H, m, ArH, 6-H, 7-H), 7.06-7.15 (1H, m, 8-H), 5 , 41 (2H, s, _CH2 Ph), 3.98 (3H, s, _1-CH3), 2.90 (3H, s, _4-CH3) and 2.83 (3H, s, 3- _CH3) ppm. m / z (%) 382 (M ^< ⁺ &^gt;, 100), 338 (10), 291 (44), 247 (18) and 231 (10). V _max (KBr roll) / cm ^-1 3343 and 1697.

n) Process for the preparation of ethyl (1,3,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.220 g of the title compound is obtained by reaction (in the range of 2.2 mmol) of N-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 165.5-167 ° C (dec.). The yield corresponds to 30% of theory.

Analysis for ^c 21 ^H 22 ^N 2 ° 2 ^: found: C, 75.50, 6.65 % H, N, 8.30% calculated: 75.47% C, 6.63 % H, 8.38% N. ¹ H NMR δΗ ([ ² H 6] -DMSO): 8.15 (LH, d, J) = 7.5 Hz, 9-H), 8.07 (1H, s, 10-H), 7.50-7.38 (2H, m, 6-H, 7- -H), 7.09-7.19 (1 H, m, 8-H), 4.38 (2H, q, CH ₂ CH ₃ ), 4, , 02 (3H, s, 5-CH ₃ ), 3.96 (3H , with,

1-CH ₃ ), 3.14 (3H, s, 4-CH ₃ ), 2.84 (3H, s, 3-CH ₃ ) and 1.39 (3H, t, CH ₂ CH ₃ ) ppm. m / z (%) 334 (100, M < ^{+ >} ), 306 (18) and 245 (6). v _max (KBr roll) / cm ^-1 1190 and 1528.

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

0.070 g of the title compound is obtained by reaction (in the range of 1.4 mmol) of N-methylindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 196-198 ° C. Yield: 13%.

anal SIS OF ^{for C} 26 ^H 24 ^N 2 ° 2 ^: ná jd INTENDED % H, 6.16;% C, 78.45; 6.94% N F calculated cit. %: 78.76% C, 6.10% H, N, 7.07 • _Δ Η NMR ^([2 H _6] -DMSO): 8.15 (1 H, d, J = 7.8 Hz, 9-H), 8.07 (1 H, with, 10-H), 7.59-7.29 (7H, m, ArH, 6-H, 7-H), 7.20 (1 H, m. 8-H), 5.42 (2H, S, CH2 ₎ Ph), 4.03 (3H, s, _5-CH3); 3.97 (3H, with, _1-CH3), 3.13 (3H, s, 4 CH ₃ ) and 2, 83 (3H, s, _3-CH3) ppm. m / z (% ) 396 (100, M ⁺ ), 305 (38) 245 (16) and 235 (10). in _max (KBr

roll) / cm ¹ 1696 and 1529.

p) Process for the preparation of benzyl (3,4-dimethyl-5- (4-toluenesulfonyl) pyrrolo [3,2-b] carbazole-2-carboxylate)

0.012 g of the title compound is obtained by reacting (in the range of 0.6 mmol), N- (4-toluenesulfonyl) indole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 270 ° C. Yield: 4%.

Analysis for ^C 31 ^H 26 ^N 2 ° 4 ^S: Found: 70.83% C, 5.01% H 5.23% N Found: 71.24% C, 5.01% H, 5.36% N.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.58 (1H, s, NH), 8.28-8.08 (3H, m, 6-H, 9-H, 10-H), 7 , 66 to 7.21 (11 H, m, Ar H, TSH, 7-H, 8-H), 5, 40 (2H, s, _CH2 Ph), 3.04 (3H, s, _4-CH3) , 2.88 (3H, S, 3-CH ₃ ) and 2.20 (3H, s, Ts-CH ₃ ) ppm. m / z (%) 523 (30, (M ⁺ +1)), 446 (20),

367 (30), 348 (56), 33 (100), 295 (30) and 274 (90). v _max (KBr roll) / cm ^-1 3358 and 1666.

q) Process for the preparation of ethyl (7-acetoxy-3,4-dimethyl-6-methoxy-pyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting 6-acetoxy-7-methoxyindole and 5-acetoxymethyl-4-acetylpyrrole. This compound has a melting point of 241-244 ° C. Yield: 7%.

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

4-CH ₃ and ppm. m / z

263 (21) and 87 (73). ^{max (methane} ° l) / ^nm (Found: M ^+, 394, (1 H, br s, NH), 7.76 (1H, s, 10-H), 7.74 (1 H, Hz, H-9 ), 6.88 (1H, d, J = 8Hz, 8-H), 4.44 (2H, q, 4.04 (3H, s, 6-OCH3 ₎ ), 2.96 and 2.92 ( 2 x 3H, 3 xs, 3-CH ₃ ), 2.42 (3H, s, 7-CH ₃ COO) and 1.46 (3H, t, CH ₂ CH ₃ ) (%) 394 (100, M ⁺ ), 352 (47), 348 (33), 306 (87) ^at max (nujol) / cm ^-1 3413, 3341, 1739

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

1529, calcd. For ^C 22 ^H 22 ^N 2 ^O 5 394.1529).

r and 1675.

a 2 26,

(r) Production method of ethyl (9-methoxy-3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reaction of 4-methoxy-1-methylindole and 5-acetoxymethyl-4-acetylpyrrole. This compound has a melting point of 263-266 ° C.

Analysis for ^C 22 ^H 2 R 2 ^N ° ^3: Found: 71.84% C, 6.34% H 7.91% N Found: 71.98% C, 6.33% H, 7.99% N .

^X δΗ NMR ^([2 H 6] -DMSO): 8.60 (1H, br s, NH), 8.15 (1 H, s, 10-H), 7.40 (1H, t, J = 8 Hz 7-H), 6.95 (1H, d, J = 8)

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

4.10 and 4.04 (2 x 3H, 2 xs, N-CH ₃ and OCH ₃ ), 3.19 (3H, S, 4-CH ₃ ),

2.98 (3H, s, -3-CH ₃ ) and 1.46 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 350 (74

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

s) Method for the preparation of benzyl (8-chloro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.069 g of the title compound is obtained by reaction of 5-chloroindole and 5-acetoxymethyl-4-acetylpyrrole. The title compound has a melting point of 215-220 ° C (dec.). Yield: 17%.

Analysis for ^C 24 ^H 19 ^C1N 2 ° ^2: Found: 71.42% C, 4.96% H 7.11% N Found: 71.55 / C, 4.75% H, 6.95% N .

^X H NMR? H ^([2 H 6] -DMS0): 11.39 (1H, s, 1-NH), 10.84 (1H, s, 5-NH), 8.17 (1H, s, 9 H); 7.93 (1H, s, 10-H), 7.54 (1H, J = 7Hz,

7-H), 7.48 to 7.34 (6H, m, Ar-H and 6 H), 5.42 (2H, s, CH ₂ Ph), and 2.88 (6H, s, 3-CH ₃ and _4-CH3) ppm. m / z (%) 402 (30, M < ^{+ >} ), 358 (5),

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

I

The mother liquors from the crystallization were subjected to flash chromatography on silica. Elution with mixtures of ethyl acetate and petroether yields another title compound, which is crystallized from ethyl acetate. 0.030 g of compound is obtained, which corresponds to a yield of 7% of theory, and further

3- (3'-Acetyl-5'-benzyloxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -5-chloroindole as cream colored crystals of a mass

0.152 g, corresponding which has a temperature 36% of theory. mp 141 to 143 C. yield Analysis for C ₂₄ H ₂₁ ClN ₂ O ₃ : found: 68.20% C, 5.18% H, 6.60% N, calculated: 68.49% C, 5.03% H, 6.65% N. ¹ H NMR δΗ ([ ² H 6] -DMSO): δ 72 (1 H, s, 1'-NH), 8.26 (1H, s, 1-NH), 7, 38 (1 H, d, J = 2 Hz) F 4-H), 7.35 (6H, m, Ar H) and 6-H), 7.18 (1 H, dd, J = 8 and 2 Hz, 2 H) , 7.09 (1 H, d, J = 2 Hz, 2-H), 5.23 (2H, s, _CH2 Ph), 4.39 (2H, with, _3-CH2 ), 2.64 (3H, s, 4) -CH ₃ ) a 2.52 (3H, s, CH ₃ CO) ppm. m / z (%) 420 (20, M ⁺ ), 405 (10) 311 (21), 151 (15) a 91 (100). t) Method production of ethyl- (3,4-dimethyl-8-hydroxypyrolo [3,2- b] -kar-

Bazoli-2-carboxylate)

The title compound is obtained by reacting 5-hydroxyindole with 5-acetoxymethyl-4-acetylpyrrole and crystallizing from methanol. Mp 250 ° C (dec.).

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.11 (1H, s, 1-NH), 10.21 (1H, s, 5-NH), 8.83 (1H, S, OH), 7.73 (1H, s, 10-H); 7.37 (1H, d, J =

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

3- (3'-Acetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl) -5-hydroxyindole is also isolated from the reaction mixture. This compound has a melting point of 99-102 ° C.

Analysis for ^C 19 ^H 20 N ₂ ° 4 ^: found: 66,89 % C, 6.17 % H, 8.03% N, calculated: 67.04 % C, 5.92 % H, 8.23% N.

¹ H NMR δΗ ([ ² H 6] -DMSO): 8.84 (1H, s, 1'-NH), 8.14 (1H, s,

1-NH), 7.20

2 H, 6.81

Hz, 6-H),

4.21 (2H,

3'-COCH ₃ )

325 (44), 2

147 (20) and 1

Hz, 7-H),

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

7.10 (1 H, d,

6.79 (1 H, dd,

5-OH), 4.31 s, _4'-CH3).

u) Process for the preparation of benzyl (3,4-dimethyl-7-fluoromethylpyrrolo [3,2-b] carbazole-2-carboxylate) and benzyl (3,4-dimethyl-8-fluoro-pyrrolo [3,2- b] carbazole-2-carboxylate)

The title compounds are obtained as a mixture of isomers by reaction of 6-fluoroindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gives 0.139 g of the [3,2-b] isomer having a melting point of 205 ° C (decomposition) in a yield corresponding to 36% of theory.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.32 (1H, s, 1-NH), 10.85 (1H, s, 5-NH), 8.08 (1H, dd, J = 9) and 6 Hz, 9-H), 7.86 (1H, s, 10-H), 7.57 = 7.35 (5H, m, ArH), 7.12 (1H, dd, J = 10 and 2) Hz, 6-H),

6.90 (1H, dt, J = 9 and 2 Hz, 8-H), 5.43 (2H, s, _CH2 Ph), 2.91 (3H, s, _3-CH3) and 290 (3 H , s, _4-CH3) ppm. m / z (%) 386 (55, M < ^{+ >} ), 342 (5), 295 (4), 278 (100), 249 (45), 236 (20), 222 (25) and 91 (95); found:

MH ^+, 387.1509, for ^C 24 ^H 20 ^FN 2 Calc'd 387.1509 ° 2).

Separation gave the [2,3-b] isomer having a melting point of 190-193 ° C.

^X δΗ NMR ^([2 H 6] -DMSO): 8.54 (1H, br s, NH-1),

8.10 (1H, dd, J = 9 and 6 Hz, 5-H), 7.87 (1H, broad singlet, 9-NH), 7.51-7.34 (5H, m, ArH), 7, 34 (1H, s, 10-H), 7.22 (1H, dd, overlapped by 10-H, 8-H), 6.93 (1H, dt, J = 2 and 9 Hz, 6-H), 5 , 41 (2H, s, _CH2 Ph), 3.20 (3H, s, _4-CH3) and 3.00 (3H, s, 3 _CH3) ppm. m / z (%) 386 (100, M < ^{+ >} ), 295 (12), 278 (96), 250 (27), 236 (7), 222 (8) and 91 (59), (found: M ^< ⁺ &^gt; 386, 1433, calcd. For ^C 24 ^H 19 ^FN 2 ° 2

386.1431).

v) A process for the preparation of ethyl (3,4-dimethyl-7-fluoromethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (3,4-dimethyl-8-fluoropyrrolo [2,3-b] carbazole-2-carboxylate)

The title compounds are obtained as a mixture of isomers by reaction of 6-fluoroindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatography gave the [3,2-b] isomer which was crystallized from dichloromethane. Mp 231-234 ° C.

Analysis for ^{C H} ig i7 ^FN 2 ^{O 2:} Found: 70.45% C, 5.53% H 8.66% N Found: 70.36% C, 5.28% H, 8.64% N .

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

10.82 (1H, broad singlet, 5-NH), 8.90 (1H, dd, J = 9 and 6Hz,

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

6.89 (1H, dt, J = 2 and 9 Hz, 8-H), 4.37 (2H, g, OCH ₂ CH ₃ ), 2.89 (6H, s, 4-CH ₃ ), 1, 39 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 324 (60, M ^+), 278 (100), 250 (34), 222 (10), and 139 (7), (Found: M ^+, 324.1267, ^C 19 to 17 ^{H FN} 2 ° 2 (calc. 324.1274).

Separation further yields the [2,3-b] isomer having a melting point of 262-265 ° C.

NMR δ _Η ([ ² H ₆ ] -DMSO): 11.14 (1H, broad singlet, 1-NH),

11.06 (1H, broad singlet, 9-NH), 8.12 (1H, dd, J = 6 and 9 Hz, 5-H), 7.19 (1H, s, 10-H), 7.15 (1H, dd, J = 10 and 2 Hz, 8-H), 6.92 (1H, dt, J = 2 and 9 Hz, 6-H), 4.36 (2H, q, OCH ₂ CH ₃ ) , 3.13 (3H, s, _4-CH3), 2.93 (3H, s, _3-CH3) and 1.39 (3H, t, OCH ₂ CH ₃₎ ppm. m / z (%) 324 (72, M < ^{+ >} ), 278 (100), 250 (39), 222 (9), 139 (6) and 125 (7), (found: M ⁺ , 324.1280, for C _ig H ₁₇ FN ₂ O ₂ Calc'd 324.1274).

w) Method for the preparation of ethyl (3,4-dimethyl-9-hydroxymethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (3,4-dimethyl-5-hydroxypyrolo [2,3-b] carbazole-2-carboxylate)

The title compounds are obtained as a mixture of isomers by reacting 4-hydroxyindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gives the [3,2-b] isomer, which is crystallized from ethyl acetate / petroleum ether, m.p. 260 DEG-262 DEG C. (decomposition).

NMR δ _H (( ² H ₆ ) -DMSO): 11.13 (1H, s, 1-NH), 10.56 (1H, s, 5-NH), 10.00 (1H, s, OH), 8.02 (1 H, s, 10-H), 7.12 (1 H, t, J =

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

7.5 Hz, 8-H), 4.39 (2H, q, OCH ₂ CH ₃ ), 2.87 (3H, s, 4-CH ₃ ), 2.85 (3H, s, 3-CH ₃₎ ) and 1.38 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 322 (61, M ^+), 276 (100), 248 (20), 219 (5) and 138 (11), (Found: M ^+, 322.1305, for ^C 19 ^H 18 ^N 2 ° 3 (calculated 322.1317).

Separation further affords the [2,3-b] isomer which is crystallized from ethyl acetate and has a melting point of 251-254 ° C (dec.).

¹ H NMR δ (( ² H 6) -DMSO): 10.95 (1H, s, 1-NH), 10.85 (1H, s, 9-H), 9.89 (1H, s, OH), 7.08 (1H, t, J = 7.5Hz, 7-H), 7.07 (1H, s, 10-H), 6.77 (1H, d, J = 7.5Hz, 8-) H, 6.52 (1H, d, J = 7.5)

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

138 (10), and 115 (10), (Found: M ^+, 322.1317, C to H _{ig g} of N ₂ O ₃ Calc'd 322.1317).

x) A process for the preparation of ethyl (6,9-dimethoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (5,8-dimethoxy-3,4-dimethylpyrrolo [2, 3-b] carbazole-2-carboxylate)

The title compounds are obtained as a mixture of isomers by reaction of 4,7-dimethoxyindole with 5-acetoxymethyl-4-acetylpyrrole. Chromatographic separation gives the [3,2-b] isomer having a melting point of 256-258 ° C. Yield 13.7% of theory.

Analysis for ^C 22 ^H 2 R 2 ^N ° ^4: Found: 68.98% C, 6.23% H 7.89% N Found: 68.84% C, 6.05% H, 7.65% N .

^{Χ Η} NMR δΗ ^([2 H 6] -DMSO): 8.58 (1Η, s, br s, NH), 8.08 (1H, s, 10-H), 7.84 (1H, br s, NH 6.82 (1H, d, J = 8Hz, 7-H), 6.50 (1H, d, J = 8Hz, 8-H), 4.43 (2H, q,

OCH ₂ CH ₃ ), 4.05 (3H, s, 9-OCH ₃ ), 3.98 (3H, s, 6-OCH ₃ ), 2.96 (3H, s, 4-CH ₃ ), 2, 92 (3H, s, 3-CH ₃ ) and 1.44 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%) 366 (73, M < ^{+ >} ), 326 (100), 305 (11), 290 (11), 277 (23), 262 (15),

183 (10), 160 (17), 152 (19), and 131 (7). v _max (nujol) / cm ^-1 3474, 3323 and 1674. lambda _max (methanol) / nm 415, 387, 344, 330 (shift),

305 (offset), 266, 246, and 220.

Separation further affords the [2,3-b] isomer having a melting point of 193-195 ° C. Yield: 9.3%.

Analysis for ^C 21 ^H 22 ^N 4 ° ^2: Found: 69.03% C, 6.29% H 7.42% N Found: 68.84% C, 6.05% H, 7.65% N .

¹ H NMR δΗ ([ ² H 6] -DMSO): 8.44 (1H, s, broad singlet, NH) ', 8.10 (1H, broad singlet, NH), 7.06 (1H, s, 10- H), 6.82 (1H, d, J = 8Hz, 7-H), 6.56 (1H, d, J = 8Hz, 6-H), 4.40 (2H, q, OCH ₂ CH) ₃ ), 3.98 (3H, s, OCH ₃ ), 3.97 (3H, s, OCH ₃ ), 3.42 (3H, s, 4-CH ₃ ), 3.00 (3H, s, 3 -CH ₃ ) and 1.43 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%)

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

160 (28), 131 (3). in _max (nujol) / cm ^-1 1357, 3345 and 1660. lambda _max (methanol) / nm 381, 365, 293, 247 and 219.

y) A process for the preparation of ethyl (7-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and ethyl (7-methoxy-3,4-dimethylpyrrolo [2,3-b] carbazole-2-carboxylate)

I

The title compounds are obtained as a mixture of isomers by reaction of 6-methoxyindole with 5-acetoxymethyl-4-acetylpyrrole. Flash chromatography on silica, eluting with ethyl acetate / cyclohexane (1: 1) affords the [3,2-b] isomer, which is crystallized from ethyl acetate / cyclohexane and has a melting point of 239-241 ° C ( dec).

^X δΗ NMR ^([2 H 6] -DMSO): 11.09 (1Η, S, 1-NH), 10.49 (1H, s, 5-NH), 7.91 (1H, d, J = 8 7 Hz, 9-H), 7.73 (1H, s, 10-H), 6.88 (1H, d, J = 2.3Hz, 6-H), 6.68 (1H, dd, J = 8.7 and 2.3 Hz, 8-H),

4.35 (2H, q, OCH ₂ CH ₃ ), 3.84 (3H, S, 7-OCH ₃ ), 2.87 (3H, S,

3-CH ₃ ), 2.86 (3H, s, 4-CH ₃ ) and 1.37 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%)

336 (84, M < ^{+ >} ), 290 (100), 262 (32), 247 (16) and 219 (16). v _max (KBr disc) / cm -1 ¹³⁴² , 1674 and 1628.

Separation further affords the [2,3-b] isomer which is crystallized from ethyl acetate and cyclohexane and has a melting point of 260 ° C (decomposition).

^X δΗ NMR ^([2 H 6] -DMSO): 10.98 (1H, s, 1-NH), 10.74 (1H, s, 9-NH), 8.00 (1 H, d, J = 8 7 Hz, 5-H), 7.13 (1H, s, 10-H), 6.87 (1H, d, J = 2.7Hz, 8-H), 6.70 (1H, dd, J = 8.7 and 2.7 Hz, 6-H),

4.34 (2H, q, OCH ₂ CH ₃ ), 3.83 (3H, s, 7-OCH ₃ ), 3.10 (3H, s,

4-CH ₃ ), 2.91 (3H, s, 3-CH ₃ ) and 1.37 (3H, t, OCH ₂ CH ₃ ) ppm. m / z (%)

336 (56, M < ^{+ >} ), 290 (70), 262 (26), 145 (16), 129 (14). v _max (KBr roll) / cm ^-1 3379, 3339 and 1663.

z) Process for the preparation of ethyl (3-ethyl-4-methylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.956 g of the title compound is obtained by reacting (11 mmol) indole with ethyl (5-acetoxymethyl-4-acetyl-3-ethylpyrrole-2-carboxylate) after recrystallization from toluene. The title compound has a melting point of 248-249 ° C (dec.). Yield: 27%.

Analysis for ^C 20 ^H 20 ^N 2 ° 2 ^: found: 74.93% C, 6.35 % H, 8 60% N, calculated: 74.98% C, 6.29 % H, 8 74% N. ^X H NMR δ _Η ([ ² h ₆ ] -dmso) J 11 27 (1 H, s, N-H), 10.63 (1 H, s 5-NH), 8.09 (1 H, d, J = 8) HZ , 9 H) , 7, 93 (1 H, s, 10-H), 7.31

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

4.40 (2H, q, J = 7 Hz, _{CO2 CH2),} 3.37 (2H, q, J = 7 Hz, _3-CH2).

2.91 (3H, s, 4-CH ₃ ), 1.41 (3H, t, J = 7Hz, CO ₂ CH ₂ CH ₃ ), 1.30 (3Η, t, J = 7.5Hz, 3-CH ₂ CH ₃ ) ppm.m / z (%) 320 (100, M ⁺ ), 274 (96). v ν, _v (KBr disc) / cm ^-1 3344, 3327, 1680, 1664, 1238.

lllcLX

Example 5

Process for preparing pyrrolo [3,2-b] carbazole-2-carboxylic acid, general procedure

To a solution of benzyl (pyrrolo [3,2-b] carbazole-2-carboxylate) in 10 mL of dry tetrahydrofuran was added 50 mg of 10% palladium on carbon. The reaction mixture is hydrogenated at room temperature at 100 kPa. After hydrogen uptake ceased, the catalyst was filtered off through diatomaceous earth (Celite) and washed well with tetrahydrofuran. The combined filtrates were evaporated under reduced pressure. Crystallization of the resulting solid from acetone, methyl ethyl ketone or aqueous methanol affords pyrrolo [3,2-b] carbazole-2-carboxylic acid as yellow crystals.

a) Method for the preparation of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

0.234 g of the title compound of melting point 237 DEG C. (decomposition) is obtained. Yield 84.3% of theory.

-'- H NMR _δ Η ^([2 H ₆ J-DMSO): 12.74 (1H, br s, CO ₂ H);

11.13 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.05 (1H, d, J = 7.5

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

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

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

130 (10) and 117 (25), (found: M ⁺ , 278.1060, calcd for C ₁₇ H ₁₄ N ₂ O ₂ 278.1055).

b) Process for the preparation of 8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

This gives 0.0845 g of the title compound, m.p. 236-239 ° C. Yield 85.6% of theory.

¹ H NMR δΗ ([ ² H 6] -DMSO): 12.80 (1H, broad singlet, CO ₂ H),

11.19 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 7.91 (1H, dd, J = 9 and

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

222 (13), 139 (22), 125 (36) and 111 (28), (found: M ⁺ , 296.0960, calcd for C17H13FN2O2: 296.0961).

c) Method for the preparation of 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

This gives 0.065 g of the title compound having a melting point of 230 ° C (decomposition). Yield: 85%.

Analysis for ^C 16 ^H i8 2 ^N ° ^2: Found: 74.2% C, 5.55% H, 9.4% N Found: 74.0% C, 5.52% H, 9.58% N .

^X δΗ NMR ⁽⁽² H6] -DMSO) 12.80 (1H, br s, CO ₂ H);

11.01 (1H, s, 1-NH), 10.08 (1H, s, 5-NH), 7.90 (1H, d, J = 7.5Hz, 9-H), 7.82 (1H 1H, s, 10-H), 7.16 (1H, d, J = 7.5Hz, 7-H), 7.01 (1H, t, J = 7.5Hz, 8-H), 2 , 97 (3H, s, _4-CH3), 2.92 (3H, s, _3-CH3) and 2.58 (3H, s, _6-CH3) ppm. m / z (%) 292 (72, M < ^{+ >} ), 274 (100), 246 (50), 230 (11), 137 (25), 122 (24) and 109 (30).

d) Process for the preparation of 3- (2-methoxycarbonylethyl) -4-methylpyrrolo [3,2-b] carbazole-2-carboxylic acid

I

This gives 0.0673 g of the title compound which it has

temperature theory. mp 255 ’C (Decomposition). Yield 84.6 Analysis for found: calculated: ^c 20 ^h 68.4 68.6 18 ^N 2 ^O 4 ^: % C, 5.3% C, 5.18 % H, 7.75% % H, 8.00% N, N.

¹ H NMR δΗ ([ ² H 6] -DMSO): 12.88 (1Η, broad singlet, CO ₂ H), 11.34 (1H, s, 1-NH), 10.65 (1H, s, 5- NH), 8.06 (1H, d, J = 7.5Hz, 9-H), 7.88 (1H, s, 10-H), 7.42 (1H, d, J = 7.5Hz) , 6-H),

7.36 (1H, t, J = 7.5Hz, 7-H), 7.07 (1H, t, J = 7.5Hz, 8-H), 3.66 (3H, s, OCH3 ₎ ), 3.63 (2H, partially obscured t, _{CH2 CH2} CO), 2.89 (3H, s, _4-CH3), 2.66 (2H, t, _CH2 CO) ppm. m / z (%) 350 (100, M < ^{+ >} ), 332 (17), 306 (30), 290 (63), 272 (22), 259 (32) and 233 (47).

e) Process for the preparation of 1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

This gives 0.060 g of the title compound, m.p. 215 DEG-216 DEG C. (decomposition). Yield: 44%.

Analysis for ^C IgH ₁₆ N ₂ O _2: Found: 73.69% C, 5.51% H 9.41% N Found: 73.95% C, 5.52% H, 9.58% N.

^ • H-NMR _δ Η ^([2 H ₆ 3-DMSO): 12.94 (1H, br s, COOH).

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

3.99 (3H, s, _1-CH3), 2.91 (3H, s, _4-CH3) and 2.85 (3H, s, 3 _CH3) ppm. m / z (%) 292 (95, M < ^{+ >} ), 275 (10), 247 (40), 232 (30), 180 (100);

135 (100). v _max (KBr roll) / cm ^-1 3375, 2930 and 1709.

f) Process for the preparation of 3,4,5-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

The solid was dried in vacuo giving 0.015 g of the title compound, m.p. 239-240 ° C (dec.). Yield: 18%.

Analysis for ^C 18 ^H 16 ^N 2 ° 2 ^: found: 74.11% C, 5.38 % H, 9.39 % N, calculated: 73.95% C, 5.52 % H, 9.58 % N. ¹ H NMR δ _Η ([ ^2h ₆ ] -D ^MS °) · 11.15 (1 H, . WITH, 1-NH), 8.04 (LH, d, J) = 7.5 Hz, 9-H), 7.88 (1 H, s, 10-H), 7.48 - 7.41 (2H, m, 6 — H,

7-Η), 7.17-7.06 (1Η, m, 8-H), 4.03 (3H, s, 5-CH ₃ ), 3.16 (3H, s, 4-CH ₃ ) and 2.93 (3H, s, 3 _CH3) ppm. m / z (%) 292 (90, M < ^{+ >} ),

274 (75), 232 (70), 197 (35), 181 (60), 149 (30), and 130 (100). V _max (KBr roll) / cm ³ 3454, 2926 and 1670.

g) Process for the preparation of 1,3,4,5-tetramethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

This gives 0.030 g of the title compound, m.p. 215 DEG-217 DEG C. (decomposition). Yield: 32%.

Analysis for ^C i9 i8 ^H 2 ^N ° ^2: Found: 74.44% C, 6.00% H 9.14% N Found: 74.49% C, 5.92% H, 9.14% N .

• H NMR _δ Η ^([2 H _6] -DMSO): 12.98 (1H, br s, COOH).

8.14 (1H, d, J = 7.6Hz, 9-H), 8.04 (1H, s, 10-H), 7.48 = 7.38 (2H, m, 6-H, 7H); -H), 7.18-7.08 (1H, m, 8-H), 4.01 (3H, s,

_5-CH3), 3.97 (3H, s, _1-CH3), 3.12 (3H, s, _4-CH3) and 2.84 (3H, s,

_3-CH3) ppm. m / z (%) 306 (100, M < ^{+ >} ), 279 (25), 232 (38), 197 (34),

181 (80) and 149 (25). in _ffiax (KBr Disc) / cm ^_1 and 1935 1659th

h) A process for the preparation of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid

500 mg (1.6 mmol) of ethyl ester in 15 ml of water and 35 ml of methanol are refluxed and then enough methanol is added to dissolve the solid. To the reaction mixture, 5.32 g (16 mmol) of cesium carbonate was added and the mixture was refluxed under nitrogen for 18 hours. After cooling, the solvent was evaporated under reduced pressure to give approximately 20 ml of a solution which was brought to pH 3 by addition of 0.1 molar hydrochloric acid to precipitate the title compound. Filtration, washing with water and drying under reduced pressure gave 437 mg of analytically pure compound produced, which was spectroscopically identical to the compound obtained in Example 5a. Yield 96%.

Example 6

Process for preparing pyrrolo [3,2-b] carbazole-2-carboxylic acid esters, general procedure

1.0 mmol of pyrrolo [3,2-b] carbazole-2-carboxylic acid and 1.1 mmol of N, N'-carbonyldiimidazole are dissolved in freshly distilled tetrahydrofuran under a nitrogen atmosphere. The resulting suspension was stirred at room temperature for at least 1 hour and the completion of the conversion of the acid to the imidazolide intermediate was verified by thin layer chromatography. Alcohol or phenol is added in a single portion in an amount of 1.5 to 2.0 moles, i.e. in excess, and the resulting mixture is refluxed until thin layer chromatography shows complete consumption of the imidazole intermediate. The title compound was obtained by column chromatography on silica and then recrystallized.

a) Method for the preparation of phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with phenol. Chromatography (eluting with 10% acetone and 90% petroleum ether) followed by recrystallization from acetone / petroleum ether gave an orange crystalline solid of 0.230 g, mp> 230 ° C (dec.). Yield: 65%.

Analysis for _C2 3 H ₁₈ N ₂ O _2: Found: 78.17% C, 5.09% H 7.77% N Found: 77.95% C, 5.12% H, 7.90% N .

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

355 (40, M < ^{+ >} ). v _max (KBr roll) / cm ^-1 3396, 1701 and 1180.

b) Method for producing (2-dimethylamino) ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with (2-dimethylamino) ethanol. Chromatography (eluting with 10% methanol and 90% dichloromethane) gave a yellow solid of 0.350 g. Yield: 99%. Recrystallization of a portion of the product from dichloromethane gave a yellow crystalline solid having a melting point of 174.0 ° C to 175.7 ° C (dec.).

Analysis for ^C 21 ^H 23 ^N 3 ° 2 * 2 ^{0.15 CH} 2 ^C1: Found: 70.46% C, 6.48% H, 11.76% N Found: 70.29% C, 6.45 % H, 11.55% N.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.18 (1H, s, 1-NH) 10.60 (1H, s,

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

4.41 (2H, t, J = 6 Hz, _OCH2), 2.91 (6H, s, _3-CH3 and _4-CH3), 2.69 (2H, t, J = 6.0 Hz , NCH ₂ ) and 2.27 (6H, s, N (CH ₃ ) ₂ ) ppm. m / z (%) 350 (46, M + 1) < ^{+ >} ), 261 (68) and 133 (100). v _max (KBr roll) / cm ^-1 3377, 1661 and 1238.

c) Method for producing (3-dimethylamino) phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with (3-dimethylamino) phenol. Chromatography (eluting with 10% ethyl acetate and 90% toluene) followed by recrystallization from ethyl acetate gave a yellow crystalline solid, 0.272 g, m.p. 240-242 ° C (dec.). Yield: 72%.

Analysis for ^C 25 ^H 23 ^N 3 ° ^2: Found: 75.37% C, 5.71% H, 10.36% N Found: 75.55% C, 5.83% H, 10.57% N .

¹ H NMR δ (( ² H 6) -DMSO): 11.49 (1Η, s, 1-NH), 10.64 (1H, s, 5-NH), 8.08 (1H, d, J = 8) Hz, 9-H), 7.91 (1 H, s, 10-H), 7.34 7.48 (2 H, m, 6-H, 7-H), 7.27 (1 H, t, J = 8 Hz, 5'-H), 7.10 (1H, ddd, J = 8.6, 2 Hz, 8-H), 6.56-6.70 (3H, m, 2'-H, 4 ' -H, 6'-H), 2.96 (3H, s) and 2.94 (9H, s, 3-CH ₃ , 4-CH ₃ , N (CH ₃ ) ₂ ) ppm. m / z (%) 398 (38, (M + 1) < ^{+ >} ), 261 (25), 232 (21) and 217 (100). v _max (KBr roll) / cm ^-1 3350, 1674 and 1610 and 1232.

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

The title compound is obtained by reacting the imidazolide intermediate with 3-hydroxypyridine. Chromatography (eluting with 50% ethyl acetate and 50% petroleum ether) followed by recrystallization from acetone gave a yellow crystalline solid (0.230 g), mp > 270 C (dec.). Yield: 65%.

Analysis for ^C 22 ^H 17 ^N 3 ° 2. 0.2 H ₂ O:

Found: C, 73.88; H, 4.76; N, 11.50. Calculated: C, 73.61; H, 4.89; N, 11.71.

¹ H NMR

5-NH3, 8.63

6'-H), 8.10 δ ₍ ( ² H ₆ ) -DMSO): 11.59 (1H, s, 1-NH), 10.65 (1H, s, (1H, d, J = 2) 2'-H), 8.55 (1H, dd, J = 4.1Hz, (1H, d, J = 8Hz, 9-H), 7.90 (1H, s, 10-H), 7.86 (1H, ddd, J = 8,1,1 Hz, 5'-H), 7,58 (1H, dd, J = 8,5 Hz, 4'H), 7,32-7,45 (2H, m, 6-H, 7-H), 7.09 (1 H, ddd, J = 8.6, 2)

Hz, 8-H) and 2.97 and 2.94 (2 x 3H, 2 x s, _3-CH3 and _4-CH3) ppm. m / z (%) 356 (15, (M + 1) < ^{+ >} ). v _max (KBr disc) / cm -1 ¹³⁷⁷ , 1715 and 1173.

e) Process for preparing 4-carbamoylphenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with 3-hydroxybenzamide. Recrystallization from ethanol gave a yellow powder and a impure residue. This residue was further purified by column chromatography on silica, eluting with a mixture of 5% methanol and 95% dichloromethane and then 10% methanol and 90% dichloromethane, followed by recrystallization from ethanol. 0.262 g of compound is obtained having a melting point of greater than 250 DEG C. (decomposition). Yield: 66%.

Analysis for ^C 24 ^H 19 ^N 3 ° 3 ^{'0.2 H} 2 ^0: Found: 71.72% C, 4.81% H, 10.26% N Found: 71.88% C, 4.88% H, 10.48% N.

^X δΗ NMR ^([2 H 6] -DMSO): 11.56 (1H, s, 1-NH), 10.63 (1H, s, 5-NH), 7.90 to 8.12 (5H, m 9-H, 10-H, 3'-H, 5'-H, amide NH), 7.33-7.49 (5H, m, 6-H, 7-H, 2'-H, 6 ' -H, amide NH), 7.09 (1H, ddd, J = 8.5, 6, 1.5 Hz, 8-H) and 2.95 and 2.93 (2 x 3H, 2 xs, 3- CH ₃ and 4-CH ₃ ) ppm. m / z (%) 398 (10) (M + 1) < ^{+ >} ), 297 (100). v _max (KBr disc / cm ^-1 3423, 1717 and 1695 and 1171).

f) Method for producing (pyridyl-4-methyl) - (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with 4-pyridylcarbinol. Chromatography (eluting with a mixture of ethyl acetate and petroleum ether, gradient of 60%, 80%, 100% ethyl acetate, then a mixture of methanol and ethyl acetate, gradient of 10%, 20%) followed by recrystallization from tetrahydrofuran gave an orange crystalline solid weighing 0.168 g. > 240 ° C (decomposition). Yield: 46%.

Analysis for ^C 23 ^H 19 ^N 3 ° 2 · ^{0/7 H} 2 ^0: Found: 72.16% C, 5.12% H, 10.73% N Found: 72.31% C, 5.38% H, 11.00% N

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.31 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.62 (2H, dd, J = 4) 0.5 Hz, 2'-H, 6'-H), 8.08 (1H, d,

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

3'-H, 5'-H), 7.32-7.43 (2H, m, 6-H, 7-H), 7.07 (1H, ddd, J = 8.5, 1 HZ, 8) -H), 5.45 (2H, s, ArCH ₂ ) and 2.94 and 2.92 (2 X 3 H, 2 X 3 -CH ₃ and 4-CH ₃ ) ppm. m / z (%) 369 (27, (M + 1) < ^{+ >} ), 327 (70) and 295 (100). v _max (KBr roll) / cm ¹ 3400, 1709 and 1232.

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

The title compound is obtained (within 1.5 mmol) by reaction of the imidazolide intermediate with 1,3-dibenzyloxy-2-propanol. Chromatography (eluting with 20% ethyl acetate and 80% toluene followed by 40% ethyl acetate and 60% toluene) followed by recrystallization from ethyl acetate / ether / petroleum ether gave 0.776 g of yellow crystals, which

have a melting point of 97% of theory. 124.8 to 126 ° C (Decomposition). yield Analysis for ^C 34 ^H 32 ^N 2 ^O 4 from found: C, 76.35; 6.07 % H, 5,12% N, calculated: 76.67% C, 6.06 % H, 5.26% N. ^1H NMR 8H ^([2 H 6] - DMSO): 11 18 (1 H, with, 1-NH), 10.60 (1H, s, 5-NH), 8.06 (1 H, d, J) = 7.5 Hz, 9-H), 7 88 (1H, s, 10-H) , 7.22 - 7.42 (12H, m 2 x PhH ₅ , 6-H, 7-H) , .7.07 (1 H, ddd, J = 8, 6.5, 1.5

Hz, 8-H), 5.44 (1H, quintet, J = 5 Hz, 1'-H), 4.60 and 4.53 (2 x 2H, 2 x dd, J = 12 Hz, 2 x PhCH) ₂ O), 3.77 (4H, d, J = 5.5 OCH (CH ₂ ) ₂ ) and 2.91 and 2.89 (2 x 3H, 2 xs, 3-CH ₃ and 4-CH ₃ ) ppm. m / z (%) 532 (50, M < ^{+ >} ), 260 (65) and 91 (100). v _max (KBr disc) / cm -1 ¹³⁵⁸ , 1681 and 1234.

h) Method for preparing 4-methylsulfinylphenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with 4-methylsulfinylphenol. Chromatography (eluting with a mixture of ethyl acetate and petroleum ether, gradient 90%, 95%, 100% ethyl acetate, then 10% methanol in ethyl acetate) followed by recrystallization from tetrahydrofuran gave a yellow powder, 0.261 g, m.p. > 230 ° C ( dec). Yield: 63%.

analysis for ^C 24 ^H 20 ^N 2 ° 3 ^N * ^{0/3 H} 2 ^0: found % C, 68.40;% H, 4.81;% N, 6.44. calculated: H, 4.92; N, 6.64. NMR S _H ([ ² H ₆ ] -DMSO): 11.59 (1H, s, 1-NH) 10.68 (1 H, s, 5-NH), 8.10 (1H, d, J = 8 Hz, 9-H), 7.93 (1H, s, 10-H), 7.82 (2H, d, J = 9.5 Hz, 3'-H, 5'-H), 7.59 (2H, d, J) = 9.5 Hz, 2'-H, 6'-H), 7.33 7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J = 8.6, 2.5 Hz, 8-H) 2.99 and 2.95 (2 * 3H, 2 * s, 3-CH3 ₎ and 4-CH ₃ ) and 2.82 (3H, s, CH ₃ SO) ppm ·. m / z (%) 417 (2 (M + 1) ⁺ ), 261 ( 100) and 233 (75).

^v max ^{(KBr k} kt) / cm ^-1 3427, 3288, 1717 and 1200.

i) Method for the preparation of methyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with methanol. Chromatography (eluting with 30% ethyl acetate in petroleum ether) followed by recrystallization from ethyl acetate gave a yellow powder (0.188 g), mp 211-213 ° C (dec.). Yield: 64%.

Analysis for C ₁₈ H ₁₆ N ₂ O ₂ :

Found: C, 74.06; H, 5.49; N, 9.42. Calculated: C, 73.95; H, 5.52; N, 9.52.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.25 (1H, s, 1-NH), 10.62 (1H, s, 5-NH), 8.08 (1H, d, J = 8) Hz, 9-H), 7.89 (1 H, s, 10-H), 7.33 7.58 (2 H, m, 6-H, 7-H), 7.09 (1 H, ddd, J = 8,6,1 Hz, 8-H), 3,92 (3H, s, OCH ₃ ), 2,92 and 2,91 (2 x 3H, 2 pcs, 3-CH ₃ and 4-CH ₃ ) ppm . m / z (%) 292 (68, M < ^{+ >} ), 260 (100), 232 (39). v _max (KBr) disc / cm ^-1 3342, 1684 and 1236.

j) Method for producing (2-methylsulfonyl) ethyl- (3,4-dimethylpyrrolo [3,2-

b] carbazole-2-carboxylate)

The title compound is obtained by reacting the imidazolide intermediate with (2-methylsulfonyl) ethanol. Chromatography (eluting with a mixture of ethyl acetate and petroleum ether, gradient 30 to 100%) followed by recrystallization from acetone gave fine yellow crystals weighing 0.222 g, m.p. 255-257 ° C (dec.). The yield corresponds to 58% of theory.

Analysis for ^C 20 ^H 20 ^N 2 ° 4 ^S: Found: 62.33% C, 5.25% H 7.08% N Found: 62.48% C, 5.24% H, 7.29% N.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.19 (1H, s, 1-NH), 10.60 (1H, s, 5-NH), 8.09 (1H, d, J = 7) 5 Hz, 9-H), 7.89 (1H, s, 10-H), 7.32 7.45 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J = 7.5, 5.5, 3 Hz, 8-H), 4.69 (2H, t, J = 5.5 Hz, OCH ₂ ), 3.69 (2H, t, J = 5.5) Hz, SO ₂ CH ₂ ), 3.12 (3H, s, SO ₂ CH ₂ ), 2.93 (6H, s, 3-CH ₃ and 4-CH ₃ ) ppm. m / z (%) 384 (17, M < ^{+ >} ), 260 (13), 59 (100). v _max (KBr Disc) / cm ^_1

3387, 1661, 1234.

k) Process for the preparation of tert-butyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate)

0.86 mmol of pyrrolo [3,2-b] carbazole-2-carboxylic acid and 0.91 mmol (1.05 equivalent) of triphenylphosphine are dissolved in freshly distilled tetrahydrofuran under nitrogen. Tert-butanol (2.12 mmol, 2.5 equivalents) was introduced via syringe and 0.95 mmol (1.1 equivalents) of diethyl azodicarboxylate was finally added dropwise over 10 minutes. The resulting suspension was stirred at room temperature for 2 hours, after which time thin layer chromatography indicated complete consumption of the starting acid. The title compound was obtained from the crude reaction mixture in several steps by column chromatography on silica eluting with 20% ether and 80% petroleum ether followed by a mixture of 50% ether and 50% petroleum ether, column chromatography on silica, eluting with silica. of a mixture of 25% ether and 75% petroleum ether and then 40% ether% petroleum ether and finally recrystallization from dichloromethane. A yellow powder of 0.030 g is obtained having a melting point of 187-189 ° C (decomposition). The yield corresponds to 10% of theory.

Analysis for ^C 22 ^H 2 R 2 ^N ° 2 '° / ^{15 CH} 2 ^C' 2 ^s: Found: 73.24% C, 6.53% H 7.93% N Found: 73.18% C, 6 H, 47.07; N, 8.07.

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

2.89 and 2.87 (2 x 3H, 2 xs, 3-CH ₃ and 4-CH ₃ ) and 1.59 (9H, s,

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

126 (32), 91 (78) and 57 (100). v _max (KBr roll) / cm ^-1 3337, 1664,

1240th

Example 7

A process for the preparation of pyrrolo [3,2-b] carbazole-2-carboxylic acid amides

a) Method for the preparation of 3,4-dimethyl-2- (1-imidazolecarbonyl) pyrrolo [3,2-b] carbazole

0.280 g (1.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and 0.164 g (1.0 mmol) of N, N'-carbonyldiimidazole are dissolved in 5 ml of freshly distilled tetrahydrofuran under a nitrogen atmosphere. The resulting suspension was stirred at room temperature for 2 hours, and complete conversion of the acid to imidazolide was verified by thin layer chromatography. The tetrahydrofuran was evaporated and the residue was recrystallized from ethyl acetate. The title compound is obtained as a yellow solid, 0.125 g, m.p. 252 DEG C. (decomposition). Yield: 38%.

Analysis for C ₂₀ H ₁₆ N ₄ O:

Found: C, 73.17; H, 4.87; N, 16.80. Calculated: C, 73.15; H, 4.91; N, 17.06.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.53 (1Η, s, 1-NH), 10.20 (1H, s, 5-NH), 8.30 (1H, s, 2'- H), 8.12 (1H, d, J = 8Hz, 9-H), 7.94 (1H, s, 10-H), 7.79 (1H, s, 5'-H), 33-7.47 (2H, m, 6-H,

7-H), 7.19 (1H, s, 3'-H), 7.09 (1H, ddd, J = 8.6, 2Hz, 8-H), 2.95 (3H, s, 3 -CH ₃ ), 2.73 (3H, s, 4-CH ₃ ) ppm. m / z (%) 261 (40). ^v max ^(KBr Disc) / cm ^_1 3427, 1699 and 1242nd

b) Process for the preparation of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxamide)

0.278 g (1.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid is dissolved in 10 ml of dimethoxyethane to give a yellow solution. To this solution are added 0.260 g (2.0 mmol) of diisopropylethylamine, 0.245 g (3.0 mmol) of elylamine hydrochloride and 0.482 g (1.5 mmol) of tetrafluoroborate salt of O-benzotriazolyl-Ν, Ν, Ν ', N'- tetramethyluronium (TBTU) to give a white suspension in a yellow solution. The reaction mixture was stirred at room temperature for 24 hours, after which time thin layer chromatography showed no acid was left. The solvent was evaporated under reduced pressure to give a tan solid. This was subjected to column chromatography on silica, eluting first with dichloromethane and then with a mixture of 10% ethyl acetate and 90% dichloromethane. The ethyl amide compound is obtained as a yellow solid weighing 0.240 g. Yield: 79%. To remove traces of impurity, some of the material was recrystallized from a mixture of dichloroethane and petroleum ether. An analytically pure compound is obtained as a yellow powder having a melting point of 235 DEG C. (decomposition).

Analysis for and ^C 19 ^H 19 n ₃ o. 0.1 ^C 2 ^H 4 ^C1 2 ^: found: 73.21 % C, 6.10 % H, 13.33 % N, calculated: 73.15 % C, 6.20 % H, 13.32 % N.

¹ H NMR δΗ ([ ² Η6] - DMSO) 10.72 (1H (S, 1-NH), 10.57 (1H, s, 5-NH), 8.09 (1 H, d, J = 8 Hz, 9H), 7.93 (1 H, t, J) = 5 HZ, N-H), 7.83 (1 H, with, 10-H), 7.27 - 7.41 (2H, m, 6-H 7-H), 7.06 (1 H, d, J) = 8 HZ , 8-H), 3.35 (2 H, q, J = 7.5 Hz, GH ₂ CH ₃ ), 2.89 and 2.71 (2 x 3H , 2 x s, 3-CH ₃ and 4-CH ₃ ), 1 18 (3H,

t, J = 7.5, CH ₂ CH ₃ ) ppm. m / z (%) 305 (65, M < ^{+ >} ), 260 (100). V _max (KBr disc) / cm ^_1 3314, 1603 and 1545th

c) A process for the preparation of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxamide

0.556 g (2.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid is dissolved in 20 ml of dimethoxyethane to a yellow solution. To this solution is added _to 0.520 g (4.0 mmol) of diisopropylethylamine, 0.321 g (6.0 mmol) of ammonium hydrochloride, and 0.963 g (3.0 mmol) of tetrafluoroborate salt of O-benzotriazolyl-Ν, Ν, Ν ', N' -tetramethyluronium (TBTU) to give a white suspension in a yellow solution. The reaction mixture was stirred at room temperature for 24 hours, after which time thin layer chromatography showed that no acid was left. The solvent was evaporated under reduced pressure to give a tan solid. This was subjected to column chromatography on silica, eluting with a gradient of ethyl acetate and dichloromethane (gradient from 10 to 30%). The amide compound is obtained as a yellow solid weighing 0.350 g. Yield: 63%. To remove traces of the impurity, a portion of the substance is recrystallized from ethyl acetate / petroleum ether and then purified by preparative high performance liquid chromatography (25 cm long column with 2.12 cm internal diameter, packed with Cg Zorbax), eluting with 5% acetonitrile and 95% water up to 95% acetonitrile in water, with detection at 340 nm). A yellow powder is obtained having a melting point of 240 DEG C. (decomposition).

^X δΗ NMR ^([2 H 6] -DMSO): 10.82 (1H, s, 1-NH), 10.54 (1H, s, 5-NH), 8.08 (1H, d, J = 7 5 Hz, 9-H), 7.84 (1H, s, 10-H), 7.29 7.43 (4H, m, 6-H, 7-H, NH ₂ ), 7.07 (1H , ddd, J = 8, 5.5, 2Hz,

8-H), 2.89 and 2.85 (2 x 3H, 2 X, 3-CH ₃ and 4-CH ₃ ) ppm. m / z (%) 277 (62, M < ^{+ >} ), 260 (100), 232 (44). v _max (KBr roll) / cm ^-1 3317,

1628, 1595, (found: M ⁺ , 277.1205 for ^c 17 ^H 15 ^N 3 ° calculated

277.1215).

d) Process for the preparation of phenyl 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxamide

0.278 g (1.0 mmol) of 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid is dissolved in 10 ml of dimethoxyethane to give a yellow solution. To this solution is added 0.130 g (1.0 mmol) of diisopropylethylamine, 0.190 g (2.0 mmol of aniline and 0.482 g (1.5 mmol) of tetrafluoroborate salt of O-benzotriazolyl-Ν, Ν, Ν ', N'-). tetramethyluronium (TBTU) to give a white suspension in a yellow solution The reaction mixture was stirred at room temperature for 42 hours, after which time thin layer chromatography showed no acid was left, the solvent was evaporated under reduced pressure to give a yellow solid The organic layer was dried over magnesium sulfate, evaporated, and subjected to column chromatography on silica eluting with ethyl acetate and petroleum ether (gradient from 5 to 100%) followed by recrystallization from acetone. The title compound was obtained as a yellow powder (0.10 g), m.p. 260 DEG C. (decomposition), yielding 30% of theory.

Analysis for C ₂₃ H _ig N ₃ O:

found: C 77.79, H 5.26, N 11.64. Calculated: C 78.16, H 5.42, N. 11.89.

¹ H NMR δΗ ([ ² H 6] -DMSO): 11.10 (1H, s, 1-NH), 10.59 (1H, s, 5-NH), 9.96 (1H, s, amide NH) 8.10 (1H, d, J = 7.5Hz, 9-H), 7.89 (1H, s, 10-H), 7.79 (2H, d, J = 9Hz, 2'- H, 6'-H), 7.29 7.45 (4H, m, 6-H, 7-H, 3'-H, 5'-H), 7.00-7.14 (2H, m, 8-H, 4'-H), 2.93 and 2.88 (2 x 3H, 2 xs, 3-CH ₃ ) ppm. m / z (%) 353 (46, M < ^{+ >} ), 260 (100). v _max (KBr roll) / cm ^-1 3310, 1614, 1595 and 1317.

e) Method for preparing 3,4-dimethyl-2- (hydrazinocarbonyl) pyrrolo [3/2-b] carbazole

500 mg of ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and 5 ml of 95% hydrazine are stirred and heated to 120 ° C for 6 hours in a Readi tube. The mixture was allowed to stand overnight, ice-cooled and filtered. The resulting yellow solid was washed thoroughly with water and dried. This gives 350 mg of the title compound. The melting point of this compound is not sharp, but decomposes at 285 ° C. Yield: 73%.

Analysis for C 17 ^ 16 ^ * 4θ ^θ, 2θ ^Χ ^ Found: 69.19% C, 5.57% H, 19.38% N Found: 69.42% C, 5.55% H, 19, 05% N.

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

10.55 (1H, s, exchangeable, NH), 9.20 (1H, s, exchangeable, NH),

8.06 (1H, d, J = 7.5Hz, 9-H), 7.81 (1H, s, 10-H), 7.42-7.28 (2H, m, 6-H and 7) -H), 7.12-7.01 (1H, m, 8-H), 4.5 (2H, broad singlet, exchangeable, NH ₂ ) and 2.4 and 2.3 (2 xs, 4-CH) ₃ and _3-CH3) ppm. m / z 293 [(M + 1) < ^{+ &gt};, FAB].

Example 8

Process for preparing 2-acetyl-3,4-dimethylpyrrolo [3,2-b] carbazole

Stage 1

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

Stage 2

Process for the preparation of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole

To a stirred mixture of 1.0 g 2,4-diacetyl-3,5-dimethylpyrrole, 35 ml dichloromethane and 7.73 g potassium carbonate at 0-5 ° C was added a solution of 0.79 g sulfuryl chloride in 15 ml dichloromethane. The temperature of the mixture is maintained at 0.5 ° C during the addition by external cooling, and then the mixture is stirred at this temperature until it is shown to have been quantitative (by thin layer chromatography, for approximately 2 hours). The mixture was then filtered and evaporated to give crude 2-chloromethyl-3,5-diacetyl-4-methyl-65-pyrrole. This material was dissolved in 10 mL of acetic acid, 1.83 g of sodium acetate was added, followed by an additional 10 mL of acetic acid. The mixture was stirred at room temperature overnight, evaporated under reduced pressure and the residue was stirred with ice water for 2 hours. The solid was collected by filtration and the filtrate was extracted twice with ethyl acetate. The extracts were dried (MgSO4), evaporated and the residue combined with the solid above. This gives the crude material. Silica chromatography, eluting with 1: 1 ethyl acetate: hexane gave 0.075 g of pure compound as an off-white solid, mp 112.5-114.5 ° C.

m / z 238 (M ^@ + +1, FAB). ¹ H NMR δ _H (CDCl ₃ ): 2.16 (3H, s, OCOCH ₃ ), 2.50 (3H, s, CH ₃ ), 2.53 (3H, s, CH ₃ ), 2.62 ( 3H, s, CH ₃ ), 5.38 (2H, s, OCH ₂ ) ppm.

Stage 3

To a solution of 0.200 g of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole and 0.098 g of indole in 90 ml of dichloroethane is added 0.30 g of Montmorillonite clay K10. The mixture is stirred and refluxed for 80 hours. After cooling, the clay was filtered off and the filtrate was evaporated to a volume of approximately 20 ml under reduced pressure. The crude material was filtered off and then chromatographed on silica. Elution with 60: 1 chloroform-methanol gave 0.08 g of the title compound as a yellow solid, mp 258-260 ° C.

m / z (EI) 276 (M < ^{+ >} ). ¹ H NMR δΗ ([ ² Hg] -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 = 8Hz,

9-H), 10.6 (1H, s, NH), 11.17 (1H, s, NH) ppm.

Analysis for ^{C H} i6 i8 ^N ° 2 '0.14 EtOAc: Found: 77.0% C, 5.74% H, 9.76% N. Found: 77.2% C, 5.98% H, 9 , 70% N.

Example 9

Process for the preparation of ethyl 1,5-dihydroindeno [2,1-f] indole-2-carboxylate

Stage 1

Process for the preparation of ethyl (2-azido-3-fluoren-2-ylacrylate)

1.7 equivalents of sodium are introduced with stirring into absolute ethanol under a nitrogen atmosphere at room temperature. When sodium is completely dissolved, the reaction mixture is cooled to -10 ° C and 1 equivalent of fluorene-2-carboxyldehyde and 3 equivalents of ethyl azidoacetate are added dropwise and dissolved in a minimum amount of tetrahydrofuran. The mixture was stirred at -10 ° C for 20 hours and then quenched by the addition of water and dichloromethane. The combined organic extracts were dried (MgSO 4) and evaporated under reduced pressure. Flash chromatography gave the title compound. The yield corresponds to 37% of theory.

_max (CHCl ₃₎ / cm ^_1 2120 and 1765th

Stage 2

Ethyl (2-azido-3-fluoren-2-ylacrylate) suspended in dry toluene was refluxed for 1 hour and the resulting solution was then evaporated to dryness under reduced pressure. The resulting mixture of ethyl (1,5-dihydroindino [2,1-f] indole-2-carboxylate) and ethyl (1,10- * dihydroindino [1,2-g] indole-2-carboxylate) is crystallized from ethanol This removes most of the [1,2-g] isomer and recovered

I title compound which contains approximately 30% of the [1,2-g] isomer in mother liquors which evaporated to dryness.

^X H NMR _H (CDC1 _3): 9.11 (1H, br s, 1-NH), 7.82 7.76 (3H, m), 7.56 to 7.52 (1 H, m), 7 37 (H, dd, J = 1 and 7 Hz), 7.34-7.28 (1H, m), 7.25 (1H, dd, J = 1 and 2 Hz), 4.45 (2H, q, OCH ₂ CH ₃ ), 3.97 (2H, s, CH ₂ ) and 1.46 (3H, t, OCH ₂ CH ₃ ) ppm.

67 Example 10

Effect of Compounds of the Invention on Detection Transformation (Stabilization Assay) Using HT1080scc2 and HT10801C Cell Lines.

Cell lines and culture conditions

The transformed and reverting sub-lines HT1080 as well as HT1080scc2 and HT10801C are obtained from the Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London. These lines are maintained as usual in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 1% penicillin or streptomycin solution containing 10,000 units per ml. All reagents are obtained from Gibco Ltd.

The cells are incubated in tissue culture plastic flasks at 37 ° C, in air containing 5% carbon dioxide.

Compound activity assay

The cell proliferation or cell cytotoxicity assay is performed in a 96-well tissue culture microtiter plate (Costar). Cells in logarithmic growth are added to the plates at a concentration of 1x10 ³ cells per well on day 0 and on day 1 serially diluted compounds are then added. Plates are then incubated at 37 ° C in air containing 5% carbon dioxide for an additional 4 days.

A method for staining biomass with methylene blue is used to determine the amount of cell growth. The values obtained in the test are read on a Multiscan plate at 620 nm. Cell morphology is examined microscopically at phase contrast immediately prior to fixation and staining with methylene blue and after microscopic determination in normal light. IC ₅₀ values for the active compounds are obtained using the GS1 computer program and also plot the dose-response slopes graphically.

The compounds are tested for activity in the colony formation assay, the methods used being identical to those described above, except that the serially diluted compound is added to the slurry agar when the assay is ready to start and replenished at the same concentration on day 7. The test results are subtracted on day 14.

The results

Comparative growth and morphology of HT1080scc2 and HT10801 c

The growth rate with respect to cell number is similar for both lines up to day 4, but then HT1080scc2 cells are persistently divided into richly saturated densities approximately two to three times higher than for HT10801C by day 5.

The phenotypic differences between the two lines are clearly evident. HT10801C cells display much flatter morphology than transformed cells, and only a few mitotic cells show up in confluent areas of culture. However, HT1080scc2 cells continue to divide with a number of mitotic cells visible after overlap.

When growing under conditions independent of capture in soft agar, HT1080scc2 produces several large colonies, while HT10801C cells fail to produce any colonies larger than 0.1 mm in diameter.

Effects of selected compounds

A number of compounds of the invention were evaluated for activity against cell lines.

The compounds of the invention exhibited low toxicity with IC ₅₀ values ranging from 50 to 100 μιηοΐ.

The results of a cell-based detransformation assay of the compounds of the invention are shown below.

b compound Detransformation (μιηοΐ) Example 3 0.04 * Example 4 (a) 0.04 « Example 4 (b) 0.04 Example 4 (f) 0.8 à Example 4 (e) 0.8 Example 4 (h) 25 Example 4 (g) 25

The compounds are effective at achieving detransformation at levels significantly lower than their levels of toxicity.

The same compounds were also tested in human breast cancer cells MCF7, A431 epidermoid carcinoma cells and A285 melanoma cells. In all cases, the compounds were active in the range of 1 to 5 μπιοί.

Claims (10)

A compound of formula I (I) wherein is a group of formula or X is O, S, SO, SO ₂ , CH ₂ , CO or NR ⁷ 7 i, L R is hydrogen, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulfonyl or substituted sulfonyl, is oxygen, sulfur, SO, SO ₂ , CH ₂ , CO or NR ⁷ , - 71 represents a group of the formula conh ₂ , CONHNR ¹⁰ R ¹¹ , COO (CH ₂ ) _n NR ¹⁰ R ¹¹ , COR ⁸ , COOR ⁸ , CHO, CH ₂ OH, CH ₂ OR ⁹ , CONHR ¹⁰ , CONR ¹⁰ R ^{1: L} or R ⁸ represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group, R ⁹ is an acyl or substituted acyl group R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl or aryl, n is 1 to 4 carbon atoms, R ² is H hydroxyalkyl, hydroxybenzyl the formula COOR ^8, an alkyl, aryl or substituted aryl group, or a group of formula _{CH2 CH2 CO2} ^R12, R ¹² represents an alkyl or aryl group, R ³ and R ⁴ independently of one another are hydrogen, hydroxyl, alkyl, haloalkyl, alkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, substituted alkyl, carboxy or a group of CO ₂ R ^12, R ⁵ represents a hydrogen atom, an alkyl group, a substituted alkyl alkyl group, an aralkyl group, a nitro group, an amino group, a halogen atom, a cyano group, CHO or COOR ⁸ , R ⁶ is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or a group of formula COR ¹³ and R ¹³ represents an alkyl or aryl group with the proviso that (i) when R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each represent a hydrogen atom and A represents a group of formula wherein Y 'represents a group of formula NH and X represents an oxygen atom * 1 or a sulfur atom, then R is not a group of formula CO ₂ H or CO ₂ Et, (ii) when R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each represent a hydrogen atom and A represents a group of the formula of formula NH and X is oxygen, Ί _# then R is not CHO and (iii) Y is not oxygen when X is oxygen, and salts and physiologically functional derivatives thereof. A compound according to claim 1, wherein ¹ '7 X is O, S or NR; R ⁷ represents a hydrogen atom, an alkyl, sulfonyl or toluenesulfonyl group, Y is NR ⁷ , R ¹ is COR ⁸ , COOR ⁸ , CH 2 OR ⁹ , CONH 2, CNHNR ¹⁰ R ¹¹ , CONHR ¹⁰ , CONR ¹⁰ R ^{1: L} or COO (CH ₂ ) _n NR ¹⁰ R ^{11 : L} R ⁸ represents a hydrogen atom, an alkyl, aryl, substituted aryl or aralkyl group, R ⁹ represents an acyl or substituted acyl group, R ¹⁰ and R ¹¹ are each independently hydrogen, alkyl * or aryl, n is 1 to 4 carbon atoms R ² represents a group of formula COOR °, an alkyl group or a group of formula CH ₂ CH ₂ CO ₂ R ¹² , R ¹² represents an alkyl or aryl group, R ³ and R ⁴ independently of one another hydrogen, hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl, or carboxy, R ⁵ represents a hydrogen atom or an alkyl group and R represents a hydrogen atom, an alkyl or aryl group, and salts thereof together with their salts to physiologically functional dervates. I A compound according to claim 1 or 2, wherein X is sulfur or NH, Y is NH, - 74 A represents a group of the formula Ί Q Q R represents a group of the formula COOR, wherein R represents an alkyl or aralkyl group, R ² is H or alkyl, R ³ is H, alkoxy or halogen, R ⁴ represents a hydrogen atom, an alkoxy group or a halogen atom, R ⁵ represents an alkyl group, R ⁶ represents a hydrogen atom, or a salt thereof, and physiologically functional derivatives thereof. 4. A compound selected from the group consisting of 3-pyridyl (3,4-dimethyl-pyrrolo [3,2-b] carbazole-2-carboxylate), _F / (3-dimethylamino) phenyl / -3,4-dimethyl-pyrrolo [3,2-b] -karbazol- 2-carboxylate, • benzyl (1,3,4-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), phenyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2- carboxylate), 3,4-dimethyl-2- (1-imidazolylcarbonyl) pyrrolo [3,2-b] carbazole, ethyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl - (3,4-dimethylbenzothieno [4,5-f] indole-2-carboxylate), benzyl (3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), benzyl (8-fluoro) -3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (8-fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), benzyl- (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), ethyl (3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylate), acid 8 -fluoro-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, 3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid, ethyl- (8-methoxy-3) (4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate), 3,4,6-trimethylpyrrolo [3,2-b] carbazole-2-carboxylic acid and benz yl (8-methoxy-3,4-dimethylpyrrolo [3,2-b] carbazole-2-carboxylate) and their salts and their physiologically functional derivatives. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 together with a pharmaceutically acceptable carrier therefor. A compound of formula I according to claims 1 to 4 for use in medicine. Use of a compound of formula I or a pharmaceutically acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumors. 8. A method of treating tumors in an animal comprising administering an effective amount of a compound of formula I or a salt thereof, or a physiologically functional derivative thereof. A process for the preparation of compounds of the formula I according to claim 1, characterized in that it is: a) catalytic ring closure in a compound of formula IV - 76 (IV) in which X, Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, in the presence of a strong acid, or b) converging one compound of formula I to another compound of formula I 10. New intermediates of formula II, III, IV or V.