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

Definitions

• the present invention relates to heterocyclic compounds which have been found to have anti-tumour activity. More specifically, the invention concerns Pyrrolo [3,2-b] carbazoles, IH-Benzofuro [3,2-f.] indoles and 1H-[1] Benzothieno [2,3-f indoles, methods for their preparation, pharmaceutical formulations containing them and their use as anti-tumour agents.
• anti-tumour agents which have differing degrees of efficacy.
• Standard clinically used agents include adriamycin, actinomycin D, methotrex- ate, 5-fluorouracil, ci ⁇ -platinum, vincristine and vinblastine. How ⁇ ever, these presently available anti-tumour agents are known to have various disadvantages, such as toxicity to healthy cells and resistance to certain tumour types.
• EP447,703 discloses the synthesis of certain benzo(5,6-b)benzofuran-2-carboxylates.
• the present invention provides a compound of the general formula (1)
• X is O, S, SO, SO , CH , CO or NR , wherein R is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulphonyl or substituted sulphonyl;
• Y is O, S, SO, SO , CH , CO or NR ;
• R is acyl or substituted acyl
• R 10 and R 11 are independently hydrogen, alkyl or aryl
• n is 1 to 4 carbon atoms
• R is H, COOR , alkyl, aryl, substituted aryl or CH CH CO R
• R is alkyl or aryl
• R and R are independently H,hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkyl amino, dialkyl amino,
• R is H, alkyl, substituted alkyl, aralkyl, nitro, amino,
• R is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or COR wherein R is alkyl or aryl
• X is O, S, SO, SO , CH , CO or NR , wherein R is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl or sulphonyl;
• ⁇ is O, S, SO, SO , CH , CO or NR ;
• R 1 is COOR 8 ,CHO,CH OH, CH OR 9 , CONH , CONHR 10 or CONR ⁇ R 11 ,
• R is H, alkyl, aryl, substituted aryl or aralkyl, R is acyl or substituted acyl, and R and R are independently alkyl or aryl;
• R is H, COOR , alkyl,aryl, substituted aryl or CH CH CO R
• R is alkyl or aryl
• R and R are independently H, hydroxy, alkyl, haloalkyl, alkoxy, halo, cyano, nitro, amino, alkyl amino, dialkyl amino,
• R is H, alkyl, substituted alkyl, aralkyl, nitro, halo, cyano CHO;
• R is H, alkyl, aralkyl, nitro, halo, CHO or COR wherein R is alkyl or aryl with the proviso described above.
• Alkyl groups present in general formula (I) may be straight or branched chain alkyl groups, and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like.
• Acyl groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable acyl groups include ethanoyl and propanoyl groups.
• Alkoxy may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy and the like.
• Aryl includes both carbocyclic aryl groups and heterocyclic aryl groups normally containing a maximum of 10 ring atoms.
• Carbocyclic aryl groups include, eg phenyl and naphthyl and contain at least one aromatic ring.
• Heterocyclic aryl groups include eg thienyl, furyl, pyridyl, indole and quinoline rings.
• An aralkyl group may contain from 1 to 4 atoms in the alkyl portion and the aryl portion may be a carbocyclic or heterocyclic aryl group.
• Substituents which may be present on the alkyl, aryl or acyl groups include alkyl, alkoxy, halo, sulphinyl, amino (optionally substituted by one or two alkyl groups), haloalkyl (eg trifluoromethyl), sulphinyl, sulphonyl and cyano.
• Substituents which may be present on the sulphonyl include alkyl, aryl and aralkyl.
• Halogen represents fluoro, chloro, bromo or iodo.
• X is preferably O, S or NR , wherein R is H, alkyl, sulphonyl or toluene sulphonyl;
• Y is preferably NR ;
• R 1 is preferably COR 8 , COOR 8 , CH OR 9 , CONH , CNHNR ⁇ R 11 , CONHR 10 ,
• R is acyl or substituted acyl, and R and R are independently hydrogen, alkyl or aryl and n is 1 to 4 carbon atoms;
• R is preferably COOR , alkyl or CH CH CO R wherein R is alkyl or aryl;
• R and R represent independently H,hydroxy, alkyl, alkoxy, halogen, cyano, substituted alkyl or carboxyl;
• R is preferably H or alkyl
• R is preferably H, alkyl or aryl and salts and physiologically functional derivatives thereof.
• X preferably represents S or NH
• A is preferably
• Y preferably represents NH.
• R is preferably COOR , witn v. preferably being alkyl or aralkyl.
• R is preferably H or alkyl.
• R is preferably H, alkoxy or Halo.
• R is preferably H, alkoxy or halo.
• R is preferably .alkyl
• Particularly preferred compounds according to the present invention include:
• compounds of the present invention have been found to be effective against MCF7 human breast cancer cells, A431 Epidermoid carcinoma cells and A285 melanoma cells.
• the compounds also exhibit low toxicity against normal cells.
• the present invention also provides a process for preparing compounds of general formula (I), which process comprises catalysed ring closure of compounds of formula (IV) in the presence of a strong acid.
• the present invention also provides for a process for preparing compounds of formula (IV) which process comprises either:
• the reaction is preferably carried out at room temperature in the presence of a strong acid, eg p-toluene sulphonic acid or montmorillo- nite K10 clay as a catalyst to produce a compound of the invention;
• a strong acid eg p-toluene sulphonic acid or montmorillo- nite K10 clay
• L is a leaving group.
• suitable leaving groups include -OCOCH-, OET, -N Me, and halo;
• Insertion of the sub ⁇ tituent R onto the ring system for example: (d) Carboxylation of a polyheterocyclic compound using (i) a carbonyl halide or
• the appropriate aromatic polyheterocycle can be reacted with a formylating agent, such as that generated by the reaction between SnCl and Cl CHOCH or equivalent reagents.
• H_ and a Pd catalyst or where R is, for example, alkyl, by hydrolysis in the presence of an appropriate base e.g. caesium carbonate.
• the invention relates to novel intermediates of the formulae (II), (III), (IV) or (V).
• the compounds of the present invention are useful for the treatment of tumours. They may be employed in treating various forms of cancer of mammals including carcinomas, for instance of the stomach, pancreas, breast, uterus and colon; adenocarcinoma ⁇ , for instance of the lung and colon; sarcomas, for instance fibrosarcoma; leukaemias, for instance lymphocytic leukaemia and lymphoma ⁇ , for instance myeloid lymphoma.
• the invention thus further provides a method for the treatment of tumours in animals, including mammals, especially humans, which comprises the administration of a clinically useful amount of compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative in a pharmaceutically useful form, once or several times a day or in any other appropriate schedule, orally, rectally, parenterally, or applied topically.
• a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for use in therapy for example as an antitumour agent.
• the amount of compound of formula (I) required to be effective against the aforementioned tumours will, of course, vary and is ultimately at the discretion of the medical or veterinary practitioner.
• the factors to be considered include the condition being treated, the route of administration, and nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered.
• a suitable effective anti-tumour dose is in the range of about 0.01 to about 100 mg/kg body weight, eg 0.1 to about 100 mg/kg body weight, preferably 1-30 mg/kg body weight.
• the total daily dose may be given as a single dose, multiple doses, e.g.. two to six times per day or by intravenous infusion for selected duration.
• the dose range would be about 8 to 900 mg per day, and a typical dose could be about 50 mg per day. If discrete multiple doses are indicated treatment might typically be 15 mg of a compound of formula (I) given up to 4 times per day.
• Formulations of the present invention for medical use, comprise a compound of formula (I) or a salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
• the carrier( ⁇ ) 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 present invention therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof together with a pharmaceutically acceptable carrier thereof.
• a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier thereof.
• Formulations according to the present invention include those suitable for oral, topical, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration.
• Preferred formulations are those suitable for oral or parenteral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into desired formulations.
• Formulations of the present 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 a solution or suspension in an aqueous or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active compound with any suitable carrier.
• a syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients.
• a sugar for example sucrose
• accessory ingredients(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredients, such as a polyhydric alcohol for example glycerol or sorbitol.
• Formulations for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter.
• Formulations suitable for parenteral administration conveniently •comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
• Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.
• Useful formulations also comprise concentrated solutions or solids containing the compound of formula (I) which upon dilution with an appropriate solvent give a solution for parenteral administration as above.
• the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
• the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumours.
• IR spectra were recorded on a Perkin-Elmer 257 grating spectrophoto ⁇ meter or a Bruker FS66 spectrophotometer.
• Ethyl 4-acety1-3,5-dimethylpyrrole-2-carboxylate, benzyl 4-acetyl- 3,5-dimethylpyrrole-2-carboxylate and ethyl 4-acetyl-3-ethyl-5-methyl- pyrrole-2-carboxylate) were prepared according to the method of A.W.Johnson et al, J. Chem. Soc. , 4254 (1958).
• Toluene-p-sulfonic acid (45 mg) was added to the solution of the 3-(pyrrolylmethyl)benzothiophene (0.100 g, 0.29 mmol) in toluene (10 cm ) and the reaction mixture was heated under reflux for 3 h. Evaporation of the solvent and washing the resulting solid with ethanol gave the title compound as a pale yellow solid (0.0758 g, 80%), m.p. 191-193 °C (Found: C,70.3; H 5.5; N, 4.2.
• M 2D 2 2 2 requires C, 78.51; H, 5.80; N, 7.32%); ⁇ - H-([ Ho-J-DMSO) 10.66 (1H, s, 5-NH), 8.14 (1 H, d, J7.4, 9-H), 8.02 (1 H, S, 10-H),
• 3,4-Dimethylpyrrolo[3,2-b]carbazole-2-carboxylic acid (0.278 g, 1.0 mmol) was dissolved in dimethoxyethane (10 cm ) to give a yellow solution.
• diisopropylethylamine (0.260 g, 2.0 mmol
• ethylamine hydrochloride 0.245 g, 3.0 mmol
• TBTU 0-benzotriazolyl-N,N,N', N'- tetramethyluronium
• 2,4-Diacetyl-3,5-dimethylpyrrole was prepared from acetylacetone and hydroxylamine-O-sulphonic acid according to the procedure of Y.Tamura, S. Kato and M.Ikeda (Chem & Ind., 1971, 767).
• HT1080 ⁇ cc2 and HT10801c were obtained from the Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London. They were maintained routinely in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% foetal calf serum (FCS) and 1% penicillin/streptomycin solution containing 10,000 units per ml. All reagents were obtained from Gibco Ltd. o Cells were incubated in tissue culture grade plastic vessels at 37 C in 5 percent CO. in air.
• DMEM Dulbecco's Modified Eagle's Medium
• FCS foetal calf serum
• penicillin/streptomycin solution containing 10,000 units per ml. All reagents were obtained from Gibco Ltd. o Cells were incubated in tissue culture grade plastic vessels at 37 C in 5 percent CO. in air.
• Assays for cell proliferation/cytotoxity were carried out in tissue culture grade 96 well microtitre plates (Co ⁇ tar) . Cells in log growth were added to the plates at a concentration of 1x10 cells per well on day 0 and serially diluted compounds were then added on day 1. Plates o were then incubated at 37 C in 5% CO in air for a further 4 days.
• the methylene blue bioma ⁇ s staining method was used, the test being read on a Multiscan plate reader at wavelength of 620nm.
• the morphology of the cells was checked microscopically under phase-contrast immediately before the fixation and staining with methylene blue, and by ordinary light microscopy thereafter.
• IC50 values for active compounds were obtained using the computer programme, GS1 and dose-response slopes were also plotted.
• HT1080 ⁇ cc2 cells continued to divide to reach saturation densities approximately 2 to 3 times higher than HT10801c by day 5. Phenotypic differences between the 2 lines were clearly evident.
• HT10801C cells displayed a much flatter morphology than the transformed cells and only a few mitotic cells were seen in confluent areas of the cultures.
• HTl080 ⁇ cc2 cells however continued to divide with numerous mitotic cells visible after confluence.
• the compounds of the invention exhibited low toxicity with IC50 values in the range 50-100 ⁇ M.
• the compounds are effective at achieving "flattening" ie de-transform ⁇ ation, at levels significantly below their toxicity level.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Public Health (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Plural Heterocyclic Compounds (AREA)

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