NZ254207A

NZ254207A - Tetracyclic derivatives antitumour medicaments and intermediate compounds (x and y are each s, c, o or n)

Info

Publication number: NZ254207A
Application number: NZ254207A
Authority: NZ
Inventors: Karl Witold Franzmann; Jeremy Nigel Stables; Patrick Vivian Richard Shannon; Nagaraja Kodanda Ranganath Rao; Laddawan Chunchatprasert
Original assignee: Wellcome Found; Univ Cardiff
Priority date: 1992-07-20
Filing date: 1993-07-19
Publication date: 1997-03-24
Also published as: CZ14995A3; FI950229A; GB9215361D0; HUT76787A; FI950229A0; HU9500171D0; CA2140662A1; EP0651750A1; SI9300390A; JPH08502037A; KR950702563A; IL106385A0; NO950202D0; MX9304355A; PL307169A1; YU50293A; SK7595A3; HRP931066A2; CN1088209A; RU95104939A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £54207 New Zealand No. 254207 International No. PCT/GB93/01512 Priority Date(«): | Gompk>t« Specification Fii«d: ' &,,.. $r&}. D.yx>7l.QWt.CQia&SiS/Gty f&j<Xmuc&(c&lCQ7 MM.D r.O. Journal Mo: .Mb NO DRAMS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Tetracyclic compounds process and intermediates for their preparation and their use as antitumour agents Name, address and nationality of applicant(s) as in international application form: THE WELLCOME FOUNDATION LIMITED, a British company of Unicorn House, 160 Euston Road, London NW1 2BP, England; UNIVERSITY COLLEGE CARDIFF CONSULTANTS LIMITED, of Tower Building, Park Place, Cardiff CF31 3XR, Wales Oi lAKs Co^pQ"^ (FOLLOWED BY PAGE 1A) 254207. WO 94/02483 A PCT/GB93/01512 ~ 1 A* TETRACYCLIC COMPOUNDS PROCESS AND INTERMEDIATES FOR THEIR PREPARATION AND THEIR USE AS ANTITUMOUR AGENTS The preaant invantion ralataa to hatarooyelie compound* which nave baan found to hava anti-tumour activity. Mora specifically, tha invantion concerns Pyrrolo [3,2-fc] carbazoles, lH-Benzofuro [3,2-Xl indolaa and 1H-[1] Benzothieno [2,3-j£] indolaa, methods for thair preparation, pharmaceutical fomulationa containing than and their uaa as anti-tumour agenta. Research in tha area of cancer chemotherapy has produced a variety of anti-tumour agents, which have differing dagraea of efficacy. Standard clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cla-platinum, vincristine and vinblaatina. However, theaa preaantly available anti-tumour agenta are known to have various diaadvantagaa, such as toxicity to healthy calls and raaiatance to certain tumour typaa. There thua axiata a continuing need to develop naw and improved anti-tumour aganta. Xhoahtariya at al, khim. Gatarotaikl. soadin (I960), (2) 203-8, disclose tha synthesis of certain indolobanzo[b) thiophanaa. Xhoahtariya at al, khim Geterotaikl Soadin (1984), (10) 1366-70 diacloaa tha ayntheaia of certain indolobenzofb] furana. Kakhabrishvili at al, khim Geterotaikl Soadin (1985), (3) 355-8 diaclosa tha synthesis of certain derivatives of indolo(5,6-d] and indole (5,4-d) benzofb] furana Tha patent apacification IP447,703 diacloaas the ayntheaia of certain P , banco(5,6-fe)benxofuran-2-carboxylataa. There have now been discovered novel compounds which exhibit anti-tumour call activity with low toxicity against normal call linaa. 7 25420 Thus, in a first aspect the present invention provides a compound of the general formula (I) X is O, S, SO, SO2, CH2, CO or NR7, wherein R7 is H, C^.^o alkyl, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, aryi containing up to 10 carbon atoms, alkenyl, Cx-io acyl. alkynyl, or sulphonyl optionally substituted by Ci_jo alkyl, aryl containing up to 10 carbon atoms or aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 Carbon atoms in the aryl portion; Y is O, S, SO, SO2, CH2, CO or NR7; Rl is COR8, COOR8, CHO, CH2OH, CH0OR9, CONH2, CONHNR^R*1, CONHR10, CONR^rI 1, COO(CH2)qNR^®R* wherein R8 is H, Calkyl, aryl containing up to 10 carbon atoms and optionally substituted by Cj.io alkyl, Ci_io alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C140 alkyl groups), haloalkyl, sulphonyl or cyano, or aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, R9 is Cj.^q acyl optionally substituted by Ci.jq alkyl, Ci_io alkoxy, halo, sulphonyl, amino (optionally substituted by one or two Ci.jq alkyl groups), haloalkyl, sulphinyl or cyano, R^ and R^ are independently hydrogen, Cj.io alkyl or aryl containing up to 10 carbon atoms, and n is 1 to 4; R^ is H, COOR8, Ci_io alkyl, aryl containing up to 10 carbon atoms, optionally substituted byCM0 alkyl, C1.10 alkoxy, halo, sulphinyl, amino (optionally substituted by one or two 6 wherein A is R 1 3 FEB 1997 3 Cj_io alkyl groups), haloalkyl, sulphonyl or cyano, or CH2CH2CO2R12 wherein R12 is C j. 10 alkyl or aryl containing up to 10 carbon atoms; R) and R4 are independently H, hydroxy, Cj.io alkyl, haloalkyl, C i_io alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl substituted by C[.iq alkyl, Ci.jo alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C1 _iq alkyl groups), haloalkyl, sulphonyl or cyano, carboxyl or CO2RI2; R^ is H, C1 _io alkyl, optionally substituted by Ci_io alkyl» alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C,.,0 alkyl groups), haloalkyl, sulphonyl or cyano, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, nitro, amino, halo, cyano, CHO, COOR8; R^ is H, aryl containing up to 10 carbon atoms, Cj.^q alkyl, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, nitro, halogen, CHO or CORlS wherein R1^ is Ci-io alkyl or aryl containing up to 10 carbon atoms; with the proviso thnt (i) whenR2, R^, r4, r5 r6 are all Hand A is wherein Y is NTH and X is O or S, then R* is not CO2H or C02Ht; (ii) whenR2, R3,R4(R5an(iR6areaUHan(iAis 1 3 FEB 1997 (iii) 4 Y is not O when X is 0; 254207 (iv) when R2 to R6 are all H, A is wherein X is S and Y is NH, then R1 is not CHO; (v) when R2 to R6 are all H, and A is 2 wherein X and Y are both NH, then R1 is not C02H or C02Et ; (vi) when R2 to R6 are all H, and A is t 3 FEB 1997 254207 wherein X is CH2 or CO and Y is NH, then Rl is not C02H or C02Et; (vii) when R2 to R6 are all H, and A is 2 wherein X is S or O and Y is NH, then R1 is not C02H or C02Et. l j 1 3 FEB 1997 4b 25420? In yet a further aspect the present invention provides a compound of the general formula (1) above, wherein A is X is O, S, SO, SO2, CH2, CO or NR7, wherein R7 is H, Ci_io alkyl, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, aryl containing up to 10 carbon atoms, alkenyl, Cj.io acyl, akynyl or sulphonyl; Y is O, S, SO, S02, CH2, CO or NR7; Rl is COOR8, CHO, CH2OH, CH20R9, CONH2, CONHRlO OR CONRlORl 1, wherein R8isH,Ci_io alkyl, aryl containing up to 10 carbon atoms, optionally substituted by Cj_ 10 alkyl, Ci_io alkoxy. halo, sulphinyl, amino (optionally substituted by one or two Cj.io alkyl groups), haloalkyl, sulphonyl or cyano or aralkyl Containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, R^ is Cj.^o acyl optionally substituted by Ci_io alkyl, Ci_io alkoxy, halo, sulphinyl, amino (optionally substituted by one or two Ci_io alkyl groups), haloalkyl, sulphinyl or cyano, and R^ and Rl 1 are independently Ci_io alkyl or aryl containing up to 10 carbon atoms; R2 is H, COOR8, Ci_io alkyl, aiyl containing up to 10 carbon atoms, optionally substituted by C1 _ 10 alkyl, Ci_io alkoxy, halo, sulphinyl, amino (optionally substituted by one or two Ci_io alkyl groups), haloalkyl, sulphonyl or cyano or CH2CH2C02R12 wherein R^2 is Ci_io alkyl or aryl containing up to 10 carbon atoms; R^ and R^ are independently H. hydroxy, Ci_jo alkyl, haloalkyl, C^jo alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl substituted by Cj.io alkyl, C[.io alkoxy, halo, sulphinyl. amino (optionally substituted by one or two C i_io alkyl groups), haloalkyl, sulphonyl or cyano, carboxyl orC02R*2; or R- is H. C 1.10 alkyl. optionally substituted by Cj.io alkyl, C j _ i o alkoxy, halo, sulphinyl. amino (optionally substituted by one or two Cj.io alkyl groups), haloalkyl, sulphonyl or cyano, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, nitro. halo, cyano CHO: R6 is H, Ci_io alkyl, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, nitro. halo, CHO or COR.13 wherein Rl3 is Cj.io alkyl or aryl containing up to 10 carbon atoms with the proviso described above. Alkyl groups present in general formula (I) may be straight or branched chain alkyl groups, and suitably contain 1-6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like. Acyl group may be straight or branched and suitably contain 1-6 carbon atoms. Examples of suitable acyl groups include ethanoyl and propanoyl groups. Alkoxy may be straight or branched and suitably contain 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. Carbocyclic aryl group include, eg phenyl and naphthyl and contain at least one aromatic ring. Heterocyclic aryl group includr. 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 porti may be a carbocyclic or heterocyclic aryl group. Halogen represents fluoro, chloro, bromo or iodo. In the compounds of formula (1) X is preferably O, S or NR7, wherein R7 is H, Ci_jo alkyl, sulphonyl or toluene sulphonyl; Y is preferably NR7; Rl is preferably COR8, COOR8, CH2OR9. CONH2, CNHNR^R11, CONHRlO, CONR10Rl!, COOCCHj^NR^Rl!, wherein R8 is H, Cj.io alkyl' ^ containing up to 10 carbon atoms, optionally substituted by Cj.io alkyl, Ci„io alkoxy, halo, sulphinyl, 6 254207 amino (optionally substituted by one or two Calkyl groups), haloalkyl, sulphonyl or cyano or aralkyl containing I to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, R9 is Cj.iq acyl optionally substituted by Ci_io alkyl, Ci.jq alkoxy, halo, sulphinyl. amino (optionally substituted by one or two Cj.jo alkyl groups), haloalkyl, sulphonyl or cyano and RlO and Rl 1 are independently hydrogen, Ci_jo alkyl o aryl containing up to 10 carbon atoms and n is 1 to 4; R2 is preferably COOR^, Ci_io alkyl or CH2CH2CO2RI2 wherein Rl2 is Cj.^q alkyl or aryl containing up to 10 carbon atoms; R3 and R4 represents independently H, hydroxy, Cj.io alkyl, Cl-10 alkoxy, halogen, cyano, alkyl substituted by Ci.jo alkyl, Ci_io alkoxy, halo, sulphinyl, amino (optionally substituted by one or two Cj.^o alkyl groups), haloalkyl, sulphonyl or cyano or carboxyl; R5 is preferably H or Ci_io alkyl; R6 is preferably H, alkyl or aryl containing up to 10 carbon atoms and salts and physiologically functional derivatives thereof. X preferably represents S or NH, A is preferably and Y preferably represents NH. Rl is preferably COOR8, with R8 preferably being Ci_io alkyl or aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl protion. R2 is preferably H or C i_io alkyl. R3 is preferably H, Cj.io alkoxy or halo. R4 is preferably H, Ci_iq alkoxy or halo. R5 is preferably C i_io alkyl and I I 3 FEB 7 25420 R.6 is preferably H and salts and physiologically functional derivatives thereof. Particularly preferred compounds according to the present invention include: 3-Pyridyl 3,4-dimethylpyrrolo [ 3,2-b J carbazole-2-carboxylate [ (3-Dimethylamino) phenyl ] 3,4-dimethylpyrrolo [ 3,2-fe] carbazole-2-carbo- xylate Benzyl 1,3,4-trimethylpyrrolo( 3,2-fe)carbazole-2-carboxylate Phenyl 3,4-dimethylpyrrolo(3,2-fe] carbazole-2-carboxylate 3,4-Dimethyl-2- (1-imidazolylcarbonyl) pyrrolo (3,2-fe] carbazole Ethyl 3, 4-dimethylpyrrolo (3,2,-&]carbazole-2-carboxylate; Ethyl 3,4-dimethylbenzothieno [ 4,5-£] indole-2-carboxylate; Benzyl 3,4-dimethylpyrrolo[ 3,2-fe] carbazole-2-carboxylate; Benzyl 8-fluoro-3,4-dimethylpyrrolo[ 3,2-b)carbaxole-2-carboxylate; Ethyl 8-f luoro-3,4-dimethylpyrrolo [3,2-b)caxbazole-2-carboxylate Benzyl 3,4,6-trimethylpyrrolo[ 3,2-b]carbazole-2-carboxylate; Ethyl 3,4,6-trimethylpyrrolo [ 3,2-|>) 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-tnethoxy-3,4-dimethylpyrrolo(3,2-b)carbazole-2-carboxylate; and physiologically functional derivatives thereof 1 3 FEB 1997 WO 94/02483 8 PCT/GB93/01S1 ** Compounds of tha general formula (X) hava baan taatad againat two apacially developed call linaa which are clonaa of tha human flbroaarooma cell-line, HT10B0. Ona clone, HT1080acc2, rataina tha tranaformed phanotypa of tha parental Una, whllat tha other, HT10801C, la a morphologically flat, non-tumouriganlc, ravartant. Thus, tha affacta of potantlal anti-tumour compounds can ba evaluated on tha baala of thalr ability to affact datranaformation in HT1080aec2 calla. Compounda of tha praaant Invantion hava baan found to ba particularly affactiva in thia aaaay ayatam. Zn addition, compounda of tha praaant invantion hava baan found to ba affactiva againat MCF7 human braaat cancar calls, A431 Epidermoid carcinoma calla and A285 malanoma calls. Tha compounda alao exhibit low toxicity againat normal calla. According to a further aapect, tha praaant invantion alao providea a procaaa for preparing compounda of general formula (X), which proceaa compriaaa catalyaed ring closure of compounda of formula (XV) in tha praaanee of a atrong acid. Tha praaant invention alao provides for a procaaa for preparing compounda of formula (XV) which procasa compriaaa eithert <• (a) Reaction of a compound of the formula (XX) with a compound of the formula (XXX) to produce a compound of the formula (XV), wherein X,Y,R1>R2,R3,R4 and R5 are aa defined hereint- - 9 - 254207 AcO (II) (III) followed by catalysed ring closure. (IV) The reaction is preferably carried out at room temperature in the presence of a strong acid, eg p-toluene sulphonic acid or montmorillonite K10 clay as a catalyst to produce a compound of the invention; (b) Reaction of a compound of the formula (V) with a compound of the formula (III) to produce a compound of the formula (IV) followed as in (a) by catalysed ring closure. - 9a - 254207 wherein L is a leaving group. Examples of suitable leaving groups include -OCOCH3, OET, -N+Me3 and halo; (c) A one step reaction procedure, reacting a compound of the formula (II) with a compound of the formula (III) in the presence of a catalyst, to produce a compound of the invention in a single step. The preferred catalyst is montmorillonite K10 clay; Insertion of the substitutent R1 onto the ring system for example: WO 94/02483 10 - PCT/GB93/015* (d) Carboxylation of a polyheteroeyclic compound using (i) a carbonyl halida or (ii) carbon dioxida According to known procedural (J. March, Advanced Organic Chemistry, 2nd ad, MoOraw Hill, Naw York, 1977, p 497-498). (a) Alternatively one oan produce compounds of the formula (Z) wharain R2 ia CHO by nathoda known to thoae akillad in the art, for examplest- (i) Tha appropriate aromatic polyheterocycle can be reacted with a formylating agent, such aa that generated by the raaction batwaan SnCl^ and Cl^CHOCH^ or equivalent reagents. For axample, according to the method of A. Raiche at al, chem. Bar. 93, 88 (I960), or with other standard formylating reagents/procedures known in tha art, for example, the Gatterman-Koch raaction (CO\HCl\AlCl^\CuCl), the Gatterman raaction (HCNXHClXZnCl^) t and the Vilsmeier reaction (POCl3\PhN-(Me)CHO or POCl3\Me2KCHO) (J. March, Vide Supra, p 494-497); or (ii) The appropriate aromatic polyheterocycle, carrying a suitable functional group, said group being converted to an aldehyde group by methods known to those skilled in the art. Suitable 14 14 functional groups include CHBr^, CH^, COR , wharain R ia a primary or secondary C, alkyl group, COOB or a derivative 1",6 thereof such as an eatar, aaide, acid chloride or CM; or (f) Compounds of the formula <X> wherein R1 is COHHR10 may also be preducad by the reaction of a compound wherein R1 is CC&H or a suitable reactive acid derivative thereof aa outlined in J. Karch, Vida supra. For example an acid halide can ba reacted with a compound 3H2R10 in an inert aolvant. 25420 (9) conversion of on* compound of formula (I) into another compound of formula (I). 1 8 8 Compound* of th* Invantion wharain R ia COOR and R ia, for example, O aralkyl can b* converted to fr** acida wharain R ia H by reduction in g the pr***nc* of H2 and a Pd catalyat, or where R ia, for axample, alkyl, by hydrolyaia in the presence of an appropriate baae e.g. caeaium carbonate. It ia thereafter poaaible for the skilled man to ayntheaiae eater and amide compounda within the acope of the invention by converaion of the free acida obtained, by known procedurea. (See J. March, Vide Supra, p363-365). Compounda of the invention produced aa daacribed herein can ba converted to other compounda of the invention by electrophilic 5 6 aubatitution at R and/or R , to introduce, for axample, NO^, halogen and COR13 wharain R13 ia aa defined herein. Th* abov* proceaaea have been decribed for compounda wherein X ia The akilled man will appreciate that these are squally applicable whan ✓ ft5- rx. In another **p*ct th* invantion r*lat*a to novel int*ra*diat* compounds of the formula (IV). A ia II T*. « * 1 3 FEB 1997 - 12 Th* compound* of th* praaant Invantion u«e£ul for tha treatment of tumours. They may be employed in treatJ.10 various fonts of cancer of manuals including carcinomas, for inst»c*0* of the stomach, pancreas, breast, uterus and colon; adenoearclno0%*» for instance of the lung and colon; sarcomas, for instance fibrosarcoma; leukaemias, for instance lymphocytic leukaemia and lytfPbOw*s, for instance myeloid lymphoma. In addition# there is provided * further aspect of the invention, a compound of formula (X) or a pharmaceutical^ acceptable salt or physiologically functional derivative thereof for use in therapy, for example as an antit\U*oU£ agent. The amount of compound of formula (I) r«4\ii>r*d to be effective against the aforementioned tumours will, of coulter vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition b'ing treated, the route of administration, and nature of the formulation, the mammal's body weight, surface arsa, age and general Condition, and the particular compound to be administered. A suitable ftffactive anti-tumour dose is in the range of about 0.G1 to about 100 tn9/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 singl* dose, multiple dosss, £*£., two to six times per day or by intra^%noue infusion for selected duration. For example, for a 75 kg manmal* the dose range would be about 8 to 900 mg per day, and a typical could be about SO mg per day. If discrete multiple doaee are indicated treatment might 1 3 FEB 1997 C 94/02483 - 13 - PCT/GB93/01512 typically tw IS ng of a compound of formula (X) given up to 4 tinea per day. Whilst It la poaalble foe the active compound to toe administered alone, it la preferable to praaant tha active compound In a pharmaceutical formulation. Formulations of the preaent Invention, for medleal uaa, compriee a compound of formula (X) or a aalt thereof together with one or more pharmaeeutieally acceptable carriera and optionally other therapeutic lngredienta. The carrier(a) ahould be pharmaeeutieally acceptable in tha aenaa of being compatible with tha other lngredlenta of the formulation and not deleterloua to the recipient thereof. The praaant Invantion, therefore, further providea a pharmaceutical formulation comprising a compound of formula (X) or a pharmaceutically acceptable aalt or physiologically functional derivative thereof together with a pharmaeeutieally acceptable carrier thereof. There ia alao provided a method for the preparation of a pharmaceutical formulation coaprlalng bringing Into aaaociation a compound of formula (X) or a pharmaeeutieally acceptable aalt or physiologically functional derivative thereof, and a pharmaeeutieally acceptable carrier thereof. Formulations according to tha praaant Invention include thoaa suitable for oral, topical, rectal or parenteral (including eubeutaneoua, intraauacular and lntravanoua) admlniatration. Preferred formulations are thoaa suitable for oral or parenteral admlniatration. Tha formulationa any conveniently be preaanted in unit dosage form and may be prepared by any of tha methoda well known In tha r art of pharmacy. All methoda Include the step of bringing the active compound into aaaociation with a carrier which eonatitutea one or more aeeeaaory lngredlenta. In general, the formulationa are prepared by uniformly and intimately bringing tha active compound into aaaociation O 94/02483 14 - PCT/GB93/015* with a liquid carrier or a finely divided aolid carrier or both and then, if nacaaaary, ahaping the product into deairad formulationa. rornulationa of the preaant invention auitable for oral adminiatration may be preeented aa diacreta unita auch aa capaulea, cachet a, tablata or loaangaa, each containing a predetermined amount of the active compound? aa a powder or granulaaj or a eolution or auepenaion in an aquaoua or non-aqueous liquid auch aa a ayrup, an elixir, an enuleion or a draught. X tablet may be made by oompraeaion or moulding, optionally with one or more accaaaory ingredienta. Compreaaed tablata may be prapared by eompreaaing in a auitable machine the active compound in a free-flowing form auch aa a powder or granulea, optionally mixed with a binder, lubricant, inert diluent, surface active or diapersing agent. Moulded tablata My ba made by moulding in a auitable machine a mixture of the powdered active compound with any auitable carrier. X ayrup may be made by adding tha active compound to a concentrated, aquaoua aolution of a augar, for exampla aucroae, to which nay alao be added any accaaaory ingredienta. Such accaaaory ingredienta(a) may include flavouringa, an agent to retard cryatalliaation of the augar or an agent to inereaae the aolubility of any other ingredienta, auch aa a polyhydric alcohol for example glycerol or aorbitol. * Formulationa for rectal adminiatration may be preaented aa a auppoaitory with a conventional carrier auch aa cocoa butter. Formulationa auitable for parenteral adminiatration conveniently •compriee a aterile aquaoua preparation of the active compound which ia preferably iaotonic with the blood of the recipient. Such formulationa auitably ccmpriae a aolution of a pharmaeeutieally and pharmacologically acceptable acid addition aalt of a compound of the formula (I) that ia iaotonic with the blood of the recipient. 25420 Uaaful formulationa alao compriaa concantratad solutions or solids containing tha compound of formula (I) which upon dilution with an appropriate aolvant giva a aolution for parantaral adminiatration as above. In addition to tha aforamantionad ingredients, tha formulationa of thia invantion may furthar ineluda ona or mora accaaaory ingredient(a) aalaetad from diluents, buffara, flavouring aganta, bindara, aurfaca activa aganta, thickanara, lubricanta, preservatives (including antioxidant*) and tha lika. In a furthar aapact tha praaant invantion providas tha usa of a compound of formula (I), including the disclaimed compound of disclaimer (iv) to (vii), or a pharmaeeutieally acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumours. Tha invantion will now ba illuatratad by tha following non-limiting Examples: Ml tamparaturaa ara in dagraaa Celsius (°C) IR apactra were racordad on a Parkin-Elmer 257 grating apactrophoto-matar or a Brukar FS66 apactrophotomatar. U.V. apactra wara maaaurad in athanol on a Unicaa SP800 apactrophotomatar. 1H NKR apactra wara obtainad on a Brukar WM 360-NKR spectrophotometer at 360 KHz, or on a Brukar AC200 apactrophotomatar at 200 MHz. J values ara given in Hz. Masa apactra wara obtainad on Varian CHSD(EI), Kratoa Concept (EI) or Kr&toe Ma50(FAB) inatrumants. f ' .V. ■ • ; 1 3 FEB 199? WO 94/02483 - 16 - PCT/GB93/015'~ Bmnmlt I Pranaratlan of Tnffdlif Pftaritlon af Pvrrolaa Cthyl 4-acatyl-3,5~dijnathylpyrrola-2-carbaxylata, banayl 4-acetyl-3,5-din*thylpyrxol»-2-oarboxylat« and athyl 4-aeatyl-3-athyl-5-nathyl- pyrrola-2-carboxylata) tiara praparad according to tha mathod of A.W.Johnaon at al, J. Chan. Soe., 4254 (1958). N-Mathvlatlon of Pvrrolaa - Qanaral Procadura A nixtura of tha pyrrola (20 nnol) mnthyl iodlda (50 mnol) and potaaaiun eaxbenata (50 nnol) waa haatad to raflux in nathyl athyl Katona (50 ml) for 8 h. If TIC (toluana/athyl aeatata 3tl) indicatad inecnplnta raaction, furthar aliquota of mathyl iodida (50 nnol) and potaaaiun carbonata (50 nnol) wara addad and tha nixtura haatad to raflux for a furthar 6 h. Aftar avaporation in vacuo to drynaaa, tha raaidua waa takan up in warn watar and nxtractad with athyl aeatata (3x50 nl). Tha eenbinad axtraeta wara driad ovar magnaaium aulphata and avaporatad in vacuo to laava a yallow oil or aolid which waa cryatalliaad fron aquaoua athanol. Ethyl 4-actvl-l. 3. S-l-rinafhylayggol—2-earboxvlata Obtainad frcai athyl 4-aeatyl-3,5-dinathylpyrrola-2-earboxylata aa whita cryatala (2g; 41%) n.p. 61-62°C (Founds C, 64.17; H, 7.82; N 6.16 C ■ "Oj C, 64.55; H, 7.68; N, 6.27%) 5R([2&6)-DMSO) 4.25 (2H, q, 3.70 (3H, a, 1-CH3), 2.43 and 2.42 (2 x 3H, 2 X a, 3-CHj and OOCH3), 2.38 (3H, a, 5-CH3) and 1.29 (3B, t, CH2CH3); n/s (%)'224(MB*, 100), 208(40), 194(20), 178(40) and 133(20) (FAB); (KBr DiaO/CM-1 2984, 1691 and 1651. -®WO 94/02483 - 17 - PCT/GB93/01512 Ban«vl 4-«ctvl-1.3.8-<TlmathvlPvrrola-2-carboxvl«ta Obtainad 2 ran bantyl 4-aoaty 1-3,5-dimathyl-2-carboxy lata aa whita eryatala a.p. 78-79°C (rounds Cf 71.30; a, 6.74; N, 4.79; c17H19N03 raquiraa C, 71.86; 8, 6.71; M, 4.91%); 5fl ((2H6)-DMSO) 7.52-7.27 (SB, a, ArH), 8.30 (2H, •# ffljPh), 3.73 (3H, a, 1-CHj), 2.42 (6H, a, 3-CB3 and COCH-) and 2.38 (3B, a, B-C8,); m/z (%) 285(76, M+), 270(87), 194 -1 (S3), 178(23), 151(36), 136(26) and 91(100); (KBr Disc)/cm 2974, 1693 and 1641. PrtPtritlgn <st tht 5-lrett«nrfflrthYl-4-ag«*YlPYggpltf =—gtntgtl procidun. To a eoolad (0°C) and atirrad auapanaion of tha 4-aoatyl-5-mathylpyrrola (0.02 nol) in dry diathyl athar (20 en ) waa addad, dropwiaa ovar 15 min, fraahly diatillad sulfuryl ehlorida (2.2 cm3, 1.25 aquiv.). Tha raaction mixtura waa atirrad furthar and tha chloroaathyl darivativa cryatalliaad out slowly, filtration gava tha 5-ehloroowthyl darivativa aa colourlaas eryatala. Tha purity of tha chloroawthylpyrrola waa ehaekad by MKR apactroaeopy (90 MH ) and it 2 waa uaad diractly without racryatalliiation. Tha abova chlorcoathylpyrrola (0.01 nol) waa addad to a aolution of a odium aeatata (3 g) in aeatic acid (50 ca3), tha mixtura atirrad for 3 2 h and pourad into ica-watar (200 cm ). Tha raaulting aolid waa waahad wall with watar until acid-fraa bafora drying. BthYl 5-icitMY«fthYl-4-icitY3L-a-at*hYlmgglt-2-gagbCTYli*i cryatalliaad freai bansana aa colourlaas naadlaa (1.87 g, 70%) m.p. 135.5-138 °C (rounds C, 58.6; B, 6.45; N, 5.15.CI3H17MOg raquiraa C, 58.4; H, 6.41; K, 5.24%); 6B(CDC13) 9.57 (1 H, br a, NH), 5.40 (2 B, a, CB2OAc), 4.35 (2 B, q, OCB2C83), 2.6 (3H, a, 3-CB3) 2.5 (3 B, a, WO 94/02483 - 18 - PCT/GB93/0151 * COCH3), 2.17 (3B, a, OCOCHj) and 1.4 (3B, t, OCB2CB3)> «*/* («) 267(83,M+), 224(46), 207(27), 178(100) and 162(42). Bangvl S—eatoxvmathvl-A->eatvl-3-«athvlpvrrol>-5-earbQ}tvlata cryatalliaad from aathanol at colourlaaa naadlaa (2.34 g, 71%) a.p. 138-141 °C (Founds C, 65.8; B, 5.95; N, 4.3 C^B^NOg raquiraa C, 65.64; H, 5.81; N, 4.25%); ^(CDClj) 9.44 (1 H, br a NH), 7.49-7.32 (5 H,rn,ArH), 5.40 (2H,a,GB20Ae), S.35 (2H,a,£H2Ph), 2.62 (3H,a,3-CH3), 2.49 (3H,a,CH3CO) and 2.14 (3H,a,OOOCH3); m/x (%) 329 (9,M+), 286 (13), 269(4), 178(19) and 91(100). In tha eaaa of bansyl 5-acatoxyaathyl-4-acatyl-3-(2-aathoxycarbonyl- ■thyl) -pyrrola-2-carboxylatc, thara waa no precipitation whan tha aolution waa pourad into iea-watar. Extraction with chloroform (3 x 3 100 cm ), drying and rwooval of aolvant undar raducad praaaura gava an oil which waa cryatalliaad from bansana-light patrolaua to yiald colourlaaa naadlaa (2.69g, 67%) a.p. 97-100°C (Found C, 62.9; H 5.9; N 3.45. C21R23NO? raquiraa C,62.8; H, 5.78; N, 3.49%); dH(CDCl3) 9.15 (1H, br a,NH), 7.50-7.30 (SB, a, ArH), 5.35 (4 H, a, CfljPh and CHjOAc), 3.63 (3 H, a, OCH3), 3.37 (2 H, t, C^CHjCO), 2.58 (2 H, t, CH2CO), 2.51 (3 H,»,C»CH3) and 2.15 (3 H,a,OCOCH3); a/s(%) 401(4,M+), 341(8), 268(6),250(60) and 91(100). Bthvl S-acatoxvmathvl-4-aeatvl-l. 3-dimathvlpvrrola-2-carboxvlata Cryatalliaad from athyl acatata/cyclohaxana (61%) a.p. 100-101°C. (Found: C, 59.38; H, 6.73; N, 4.95. raquiraa C, 59.78; H, 6.81; H, 4.98%); b„{ t2B,]-DKSO) 5.30 (2H, a, <$.OAc), 4.29 (2H, q, no 2 C^CBj), 3.77 (3H, a, M-CH3), 2.43 and 2.42 (2 x 3B, 2 x a, 3-CH3 and CH.CO), 2.02 (3B, a, OCOC8.) and 1.31 (3B, t, CH.CH,); a/sp(%) 281 4- -1 (34,M ), 238(100), 222(48) and 192(52); v (KBr Diac)/ca 1712 and aax 1697. Bantvl 5-acatoxvnathvl-4-aeatvl-l. 3-diinathvlpvrrola-2-carboxvlat* WO 94/02483 19 - PCT/GB93/01512 2 Cryatalliaad from . athyl aoatata/oyelohaxana. $H ( [HJg-DMSO) 7.51-7.32 (5H, m, ArH), 8.34 and 5.32 (2 2L, 2 x a, Q^Ph and CH2OAo), 3.78 (3H, a, M-CHg), 2.46 and 2.4S (2 x 3H, 2 x a, 3-CH3 and CH3CO) and 2.04 (3H, a, OCOCH3); m/s (%) 343*5, M+), 284(100) and 91 (95). athvl S-aoetoxvniathvl"4—acetyl—3—athvltrvrrola—2—carboxvlata Cryatalliaad from fcther/patrol aa fawn naadlaa (61%) with m.p. 97-9B°c (Pounds c, 59.44; H, 6.78; N, 4.80. C,.H..NO, raquiraai C, 59.76; H, 14 19 5 6.81; N, 4.98%); 6u {CDCl^) 9.40 (1H, br a, 1-HH), 5.38 (2H, a, CH2OAc), 4.38 (2H, q, J 7, COjCHj), 3.10 (2H, q, J 7.5, 3-cH2), 2.54 (3H, a, COCH3), 2.18 (3B, a, OCOCH3), 1.40 (3H, t, J 7.5, C02CH2CH3), 1.23 (3H, t, J 7.5, 3-CH2C&3); m/z (%) 281 (42, M+), 238(61), 221(89), 206(58), 192(92), 175(95), 160(81), 147(59), 43(100); (KBr disc)/cm"1 3277, 1738, 1674, 1657. Svnfchaale of tha >Indole. 2-1Pyrrolvlmethvllbenzo- furan and 3-/PvrgolvlinafchvHber>»afchlophene - Oeneral procedure. A aolution of tha 5-acatoxymathyl-4-acatylpyrrola (1.0 nmol) and indola (1.0 naol) in l,2-dichloro«thana (10 cm3) waa haatad at gentle raflux and atirrad with Montaorillonita clay (1 g) for 1.5-2 h. Aftar filtration from clay and washing wall with 1,2-dichloroathana, evaporation of tha coobinad flitrataa undar raduoad praaaura gava an oil. Thia oil waa aubmittad to flaah chromatography on ailica, aluting with athyl aeatata in light petroleum to giva 3-(3'-aeetyl-5'-ethoxycarbonyl-4'-methylpyrrol-2'-ylmethyl)indole. It gava colourlaaa eryatala from ethyl acetate-light petroleum (0.1465 g, 45%). m.p. 180-182°C (rounds C,70.5; H, 6.25; W, »,«55. C19H20N2°3 r*^uir** c' 70.4; H, 6.21; N, 8.64%); fiH(CDCl3) 8.78 (1H, a, pyr-HH), 8.27 (1 H, a, ind-HH), 7.45 (1H, d, J7,4-H) 7.42 (1H, d, J7, 7-H), 7.25 (1H, t, J7, 6—H), 7.14 (1H, t, J7, 5-H), 7.10 (1H, a, 2-H), 4.45 (2H, a, 3-CH2), 4.22 (2H, q, OC^CH^, 2.63 (3H, a, 4'-C»3) 2.53 (3H, a, CB3CO) and 1.25 (3 H, t, OCH2C83); m/z (%) 324(100,M*) 309(48), WO 94/02483 20 PCT/GB93/0151 "* 277(25), 263(54), 250(38),235(30),207(48), 139(24),130(30),117(67) and 90(16)1 l» (CHCl.j/ca"1 3490, 3430, 1680 and 1650. IHIX J Bansofuran (1.0 naol) whan used inataad of indela, aftar chromatography, gava 2-(3'-aeatyl-5'-athoxycarbonyl-4'-»athylpyrrol-2'-ylaathyl)bansofuran (0.106 g, 32.6%), m.p. 124-127°C (roundt C, 70.1; H, 6.1; N, 4.15 c19B19H04 requires C, 70.14; H, 5.69; N, 4.31%); 6n(CDCl-) 9.25 (1 H, a, KB), 7.50(1 H, d, J7.3, 4-H) 7.44 (1H, d, H 3 J7.3, 7—B) 7.28-7.18 (2 H, m, 6-H and 5-H), 6.57 (1 H, s, 3-H), 4.50 (2 H, s, 2—CHj), 4.31 (2 H, q, OCftgCH^ 2.62 (3 H, a, 4'-CH3) 2.50 (3 H, s, CH3CO) and 1.35 (3 H, t, OCH2^3); saturation of tha ainglat 3-H at 5 6.51 anhancad tha aignals dua to 4H at 57.50 (2.7%) and 2-CH^ at 5 4.50 (0.8%); m/z (%) 325(100,M+), 310(4),279(29), 264(17), 251(59), 236(27), 208(19), 193(9), 131(7) and 118(7); and tha 2,3-bis (3' -aeatyl-5' -athoxycarbonyl-4' -mathylpyrrol-2' -ylmathyl) banzof uran (0.0238 g, 8.94%) m.p. 25S-257°C; 6_ (CDC1,) 10.09 (1 B, a, NH) 9.95 B 3 (1H, s, NH), 7.32 (1H, d, J7.7, 4-H), 7.27 (1 H, d, J7.7, 7-B), 7.17 (1 H, t, J7.7, 6-H), 7.08 (1 H, t, J7.7, 5-H) 4.45 (2 H, S, 2-CH2), 4.40 (2 B, a, 3-CH2), 4.36 (2B, q, , 4.27 (2 ' H,q,0^2CH3), 2.64(3 H,a,4'-CH3), 2.63(3H,S,4'-CB3), 2.58 (3H, a, CH3CO), 2.54 (3 B, a, CB3CO), 1.39 (3B, t, OCHjCH^ and 1.31 (3 H, t, OCH2CH3); m/z (%) 532(11,M*), 490(24), 444(9), 397(6), 324(100), 282(16), 278(27), 236(20), 209(28) and 162(28) (Founds M+,532.2210. c30H32N2O7 raquiras M, 532.2209). When benxothiophene (1.0 onol) was uaad in tha aame way as indole, chromatography using ethyl acetate in dichloromethane aa eluent gave colourless crystala of 3-(3'-acety1-5'-athoxycarbonyl-4'-methyl-pyrrol -2 '-ylmethyl ) benxothiophene (0.0963g, 28.2%) s.p.i25-128°C (Founds C, 6675; H, 5.8; >1,4.1 CjjH^liOjS r«qui.rea C, 66.84; H, 5.61; N, 4.10%); 2B(CDC13) 8.72 (IB, br, a, NH), 7.88 (1 H, m, 4-H), 7.63 (1 H, m, 7-H), 7.37 (2 H, n, 6-H and 5-H), 7.20 (1 H, a, 2-B), 4.54 (2 H, s, 3-CHj), 4.23 (2 H, q, OC^CH^, 2.62 (3 H, s, 4'-CH3), 2.53 (3 H, s, CHjCO) and 1.28 (3 H, t, OCB^Cg^t saturation of the 3-CH2 protona at 6 4.54 anhancad the aignala due to NH at 6 8.72 (3.3%), 4-H WO 94/02483 - 21 - PCT/GB93/01512 at 5 7.88 (7.7%), 2-B at 5 7.20(6%) and CB3CO at 5 2.S3 (1.3%); m/z (%) 341(100,M*), 326(9), 298(6), 295(20), 230(39), 267(46), 252(32), 224(27), 194(26) and 148(22); and tha 2,3-bia (3'-aeatyl-5'■-athoxy-carbony 1-4' ■■ttaylpyrrol-2' -ylnafchyl)banaothiophana aa a pal* yallow •olid (0.0264 g, 9.6%), m.p. 206-209°C (Founds C, 65.6; H, 5.8; N 5.1 °30H32N2°68 r**uir** C' fi5.67; H, 5.88; N, 5.11%), 6B(CDC13) 9.77 (1H, br, s, NB), 9.43 (IB, br, a, NH), 7.70 (1 H, m, 4-H), 7.49(1 H, m, 7—H), 7.26 (2 H, a, 6-H and 5-H), 4.55 (2 H, a, CH2), 4.53(2 H, a, CHj), 4.32 (2 R, q, OCHjCH^, 4.24 (2 H, q, OCB2CH3), 2.61 (3 H, a, 4'-CH3), 2.60 (3 H, a, 4'-CH3), 2.57 (3H, a, CH3C0) 2.49 (3 H, a, CH3C0), 1.35 (3R,t,0CH2Ca3) and 1.28 (3H H,t,0CH2CB3) ;«/*(%) 54^(5,M+), 530(11), 340(100), 294(27) and 162(10). BXMIPtt 2 SYfltrttili Qf 3-fPvrgolvlmathvl i hanzothionhanaa ind 3-(PYfg9lYl- mat hv1\Indolaa a) 3-f3'-Aeafcvl-5 '-b«n«vloitve*gbonvl-4'-mathvlPVgrol-2 '-vlmathVll frintgthlgphqnc A aolution of tha 5-acatoxyaathyl-4-acatylpyrrol« (0.33g; 1.0 naol) and bcnzothiophana (0.14 9; 1.05 nmol) in 1,2-dichloro-athana (10 cm3) waa haatad at raflux and atirrad with Montaiorillonite K10 clay (1 g) for 2.5 h. Aftar cooling and filtration from tha clay, which waa waahad wall with 1,2-dichlorathana, tha combined filtrataa wara avaporatad undar reducad praaaura to leave a yallow oil. Flaah chromatography on ailica, aluting with diathyl athar/light patrolaum (li2) gava tha titla eoopound aa a colourlaaa aolid. c 6h(CDC13) 8.72 (1H, a, KB), 7.92-7.84 (1H, m, 4-H), 7.69-7.58 (1H, m, 7-H), 7.43-7.16 (8H, m, 2-H, 5-H, 6-H, ArH), 5.23 (2H, a, CHjFh), 4.50 (2H, a, 3-CH2), 2.61 (3H, a, 4'-CH3) and 2.50 WO 94/02483 - 22 PCT/GB93/015* "* (3H, a, CH3CO); m/z (%) 403 (M+, 100)/ (KBr Disc)/em"1 3290, 1690 and 16S9. b). 3-13' -Aetvl-S'-efcho»ve«rhonvV-4' -methvlt»vr«-ol-2 '-vlmthvl 1 -B-evanolndole A aolution of tha 5-aeetoxymethyl-4-aeetylpyrrole (0.7 g, 2.6 naol) and 5-cyanoindole (0.41 g, 2.9 nnol) in 1,2-dichloroethana (50 can3) waa haatad at raflux and atirrad with Montaorillonite K10 clay (2.1 g) for 6 h. After cooling and filtration from tha clay, which waa waahad wall with 1,2-dichloroethana, tha combined filtrataa wara evaporated under reduced preaaure to leave an orange eolid. Cryetalliaation from dichloromethane/ ethyl acetate yielded a small amount of analytically pure title compound aa cream eryatala. Tha evaporated mother liquors were aubmitted to flash chromatography on silica, eluting with diehlorooethane/ethyl acetats (9:1) to give furthar product (0.65g, 71%). m.p. 213«214°C (Found: C, 66.60; H, S.46; N, 11.99. C2qH19N303 requires C, 68.75; H, 5.48; N, 12.03%) £„((2H..}-DKSO) 12.05 (IB, s, l'-NH), 11.38 (1H, a, 1-NH), 8.20 H © (1H, m, 4-H), 7.50 (1H, dd, JO.7 and 8.5, 7-H), 7.39 (IK, dd, J1.7 and 8.5, 6-H), 7.18 (IB, s, 2-H), 4.32 (2H, s, 3-CHj 4.27 (2H, q, 2.33 (3H, a, 4'-CH3), 2.51 (3H, s, CH3CO) and 1.30 (3H, t, CH2Ca3); m/r («) 350(M+, 70), 302(16), 279(18), 237(35), 208(100) and 181(20); v (KSr Diac)/cm"1 3309, 2218 mix and 1665. c) 3-(3'-Agftvl-5 '-rthOTYglrt9IlYl-4 • -nttthYlFYgggl-2 '-YlffifthYl) indole—S—carboatvlle acid A aolution of tha 5-acetoxymethyl-4-acetylpyrrole (0.74g, 2.8 naol) and indole-5-carboxylic acid (0.5g, 3 nnol) in toluene (50 3 cm ) waa atirrad at room temperature with Montmorillonite K10 elay (1 g) for 10 days. After cooling and filtration from the clay, which was washed well with toluene, the combined filtrataa WO 94/02483 23 PCT/GB93/01512 vara evaporated undar raduoad preasure to laava an orange aolld. Cryatalliaation fro® athyl aeefcate/eyclohaxane yialdad tha titla compound aa a gray powder (O.lSg, 1S«). m.p. 227-228°C (round< C, 64.96; B, 5.58; N, 7.34. C20H20H2°5 raquiraa C, 6S.21; H, 5.47; H, 7.60%); 5R([2R6)->DM80) 12.35 (IB, br, OOjB) 12.04 (1H, a, l'-HH), 11.17 (IB, a, 1-HH), 8.31 (IB, d, J1.6, 4-H), 7.70 (lHr dd, J1.6 and 8.7, 6-H), 7.37 (1H, d, J8.7, 7-H), 6.98 (1H, а, 2-H), 4.36 (2B, a, 3-CBg), 4.26 (2H, q, CBgCBj), 2.51 and 2.31 (2 x 3H, 2 x a, 4'-CH3 and CH3CO) and 1.29 (3B, t,CH2CH3); m/z (%) 369(22(M+1)+), 351(37), 323(18), 305(19), 232(19), 208(60) and 181(20), 162(100); v (KBr DiscJ/cm"1 3359 and ffliy 1676. d) 3—( 3' -Acetvl-S' -ethoxvcagbonvl-^ • -methvlpvrrol-2'-vlmathvl) -5-broroolndola A solution of tha 5-acatoxyaathyl-4-acatylpyrrola (1.3g, 4.9 naol) and 5-brocnoindole (l.09g, 5.6 nmol) in 1,2-dichloroathana (100 cm ) waa haatad at raflux and atirrad with Montraorillo-nita K10 clay (3 g) for 5 h. Aftar cooling and filtration from tha clay, which waa waahad wall with 1,2-dichloroathana, tha combined filtrataa were evaporated under reduced pressure to leave a yellow solid. . Cryatalliaation from dichloromsthane/ light petroleum/acetone yielded the title compound as cream crystals (0.33 g, 17%). m.p. 181-183°C (Found: C, 56.24; H, 4.70; N, 6.86. C19H19Br!l203 requires C, 56.59; H, 4.75; N, б.95%); 8 ([^B_ J—DHSO) 12.00 (1H, s, l'-NH), 11.00 (1H, a, H O 1-HH), 7.82 (1H, d, J1.9, 4-H), 7.31 (1H, d, J8.6, 7-H), 7.16 (IB, dd, J1.9 and 8.6, 6-H), 7.02 (1H, a, 2-H), 4.30 (2H, a, 3-CH2), 4.28 (2H, q, C0BU2CH3),2.51 and 2.33 (2 x 3H, 2 x S, 4'-CH3 and CH3C0) 1.31 (3B, t, CB2CH3) m/x (%) 404 and 402(100 M+), 389 and 387(24), 357(24), 330 and 328(32), 206(36) and 178(26); y^tKBr Disc)/cm"1 3373 and 1672. WO 94/02483 - 24 PCT/GB93/015'" BKMPlt 3 • ) Kthvl 3.4-d< mefhvl nvrrolof3.2. -b 1 carha»ole-2-carboxvlats A aolution of tha 3-(pyrrolylmethyl)indola (0.108 g 0.33 naol) 3 was hnatad at gantla raflux in 1,2-dichloroethane (10 en ) and stirred with Montmorillonita K10 clay (1 g) for 2 h. TLC than ■howad a aingla compound had baan formed and that reaction was complete. After filtration from clay and washing well with 1,2-dichloroethane, evaporation of the combined filtrataa under redueed pressure gave a yellow solid which crystallised from ethyl acetate to give the pyrrolo(3,2-fe]-carba*ole as yallow crystals (0.076 g; 75%), m.p. 209.5-211°C (Pound: C, 74.6; H, 6.14; N, 9.03. C,_H,_N_0_ requires C.74.5; H, 5.92; N, 9.14%); 2 19 IB 2 2 2„( H.)-DMS0) 11.22 (1H, s, 1-HH), 10.70 (1 H, s, 5-NH), 8.06 H © (1H, d, J7, 9-H), 7.85 (1H, S, 10-H), 7.40 (IB, d. J7, 6-H), 7.35 (1H, t, J7, 7-H), 7.08 (1H, t, J7, 8-H), 4.35 (2H, q, OCQgCH^ 2.91 and 2.90 (2 x 3H, 2 x 8, 3-CH3 and 4-CH3 snd 1.35 (3 H, t, OCH2CH3)• Saturation of tha 10-H at 6 7.85 enhanced the singlats due to 1-NH at 5 11.22 (3%) and 9-H at 6 8.06 (4%); m/s(%) 306(56,M*), 260(100), 323(39), 205(15), 140(18) and 130(26); v (CHCl-)/cm~1 3480 and 1700; X (ItOH)/nm 226, 268, my • 3 intx 310sh, 327sh, 340, 390 and 410sh. b) Ethvl 3.4-dlmathvl-lH-bengofurof3.2.-f 1 indole-2-carboxvlate Toluene-p-sulfonic acid (50 mg) was addad to a solution of ths 2-(pyrrolylmethyl)bansofuran (0.100 g 0.31 nnol) in toluene (10 cm ), and tha raaction mixtura waa haatad undar raflux for 3 h. On cooling, tha product crystallisad out, and after filtration and waahing with athanol gava tha title compound as pala yallow crystals (0.084 g, 88.8%), m.p. 2t2-265°C (Pound: C, 74.25; H, 5.55; N, 4.6 c19H17N03 requires C. 74.25; H, 5.56; N, 4.56%); WO 94/02483 25 - PCT/GB93/01512 5 (t2H.)-DK»0) 11.52 (1 H, a, 1-HH). 8.18 (1 H, d, J7.5, 5-H), n p 7.62 (1 H, d, J7.5, 8-H), 7.46 (1 H, t, J7.5, 7-H), 7.38 (1H, t, J7.5, 6-H) 7.36 (1 H, S, 10-H), 4.37 (2 H, q, OCJ^CS^), 3.14 (3 H, 4-CH3), 2.91 (3 H, s, 3-CH3) and 1.39 (3 H, t, OC^CH^; saturation pf tha 4-CH3 at 6 3.14 enhanced th* signals dua to S-H at 6 8.18 (4.8%) and 3-CH3 at 6 2.91 (2.6%); n/s (%) 307 (53,M*), 261(100), 233(31) and 205(9); K^CNujol)/cm"1 3350 and 1686; X|M]C(KtOH)/iHi 240, 269,293,330 and 344. c) Ethvl 3.4—dimethyl-lH-f 11 beniothl.nof2.3-fllndole-2-oagboxvlate Toluene-p-sulfonie acid (45 mg) wae added to the solution of the 3-(pyrrolylmethyl)bensothiophene (0.100 q, 0.29 onol) in toluene (10 cm3) and the reaction mixture wae heated under reflux for 3 h. Evaporation of tha solvent and washing the resulting solid with ethanol gava tha title eompound as a pale yallow solid (0.0758 g. 80%), m.p. 191-193 °C (Founds C,70.3; H 5.5; N, 4.2. C19H17IK>28 r*?uirM c' 70*6» B, 5.30; N, 4.33%); 6fi( [2H6]-DM80) 11.64 (1 H, s, NH), 8.25(1 H, a, 9-H), 8.12 (1 H, a, 10-H) 7.95 (1 H, m, 6-H), 7.48 (2 H, m, 7-H and 8-H), 4.38 (2 H, q, OC^CHj), 2.87 and 2.85 (2 x 3H, 2 x 8, 3-CH3) and 1.37 (3 H, t, OCH2Cfl3); m/* (%) 323(53,M+), 277(100), 249(33), 221(15), 139(7) and 111(11); i» (HuJol^/esT1 3350 and 1686; X (BtOH)/ na wmX BIX 240,269,293,330 and 344. d) Benzvl 3.4-dlmathvl-lH-flIbensothienof2.3-f 1 indole-2-caghoxvlats Toluana-p-aulphonic acid (40 mg) was addad to the solution of tha 3-(pyrrolylmethy 1)benaothiophene (0.100 g, 0.25 nnol) in toluana (12 cm3) and tha raaction hsatad undar raflux'for 6 h. Evaporation of tha solvent and waahlng tha rasultant solid with ethanol gava tha title compound as a pala yallow aolid (0.02 g, 20%) a.p. 203-204°C (Founds C, 74.7; H, 4.9; N, 3.6; C^H^llOjS require# C, 74.8; H, 5.0; H, 3.6%); 6„ ((2H.]-DMSO) 11.64 (1H, H © WO 94/02483 - 26 - PCT/GB93/015' " a, MB) S.27-8.15 (1H, a, 9-B), 8.10 (1H, a, 10-H), 7.90-7.89 (IB, m, 6-H). 7.60-7.30 (7B, m, 7-H, 8-H, ArH), 5.40 (2H, ■, CH. and 2.87 (6B, ■, 2 k CH,); m/s («) 385(100, M+), 277(89), -1 248(25), 221(18) and 91(28); f (KBr Diac/cm 3331 and 1672. a) Kthvl 8-evinfrai^-rfj-athvlpygrelof3.2-ble«rb.«o 1—2-earboxvlata A nixtura of tha 3-(pyrrolylmethyl)indole (0.6 9, 1.7 nnol) and Montmorillonite K10 clay (2 g) in toluana waa atirrad and haatad at raflux for 24 h. Aftar cooling and filtration from tha clay, which waa waahad wall with toluana, tha conbinad filtrataa wara avaporatad undar raduead praaaura to leave a brown solid which was submitted to flaah chromatography on silica, aluting with eyelohaxana/athyl aeatata (3:1) to giva a yallow solid. Crystallisation from cyelohaxana/athyl aeatata yialdad tha tltla Q compound as a yallow powdar (0.030 g, 5%). m.p. >240 C (Founds C, 71.54; B, 5.18; M, 12.78, c20H17K302*0*aH20 ca^uiral C' 71.71; H, 5.24; N, 12.54%) £n((2H.]-DMS0) 11.39 (1H, a, 1-NH), O D 11.29 (IB, a, 5-MB), 8.65 (IB, d, J1.7, 9-H), 8.01 (IB, a, 10—B), 7.71 (1H, dd, J1.7 and 8.6, 7-H), 7.50 (IB, d, J8.6, 6-H), 4.36 (2H, q, CHjCHj), 2.91 and 2.89 (2 x 3H, 2 x a, 4-CH3 and 3-CH3) and 1.38 (3H, t, CB2Cfl3)> m/s (%) 331 (52,M+) 285(100), 256(32), 229(12), 167(14) and 149(40); v^jKBv Disc)/cm"1 3414, 3550, 2212 and 1664. f) ,1.4-l?lmtthvl-2-ithQKYCtrbOTvlpyrrglQf 3,2-bl cagbisolf-8-fiisteesclic-icU A mixtura of tha 3- (pyrrolylmethyl)lndola (O.lg, 0.3 nmol) and Montmorlllonita K10 clay (0.34 g) in toluana (15 cm3) was atirrad and haatad at raflux for 6 h. Aftar coofing and filtration from tha clay, which waa washad wall with toluana, tha combined filtrataa wara evaporated undar raduead preeaure to leave an orange aolid. Cryatalliaation from methanol/dichloro-mathana yialdad tha title compound aa a yellow powder (0.027 g. WO 94/02483 - 27 - PCT/GB93/01512 28%). m.p. >2«0°C (Found I C, 68.12) H, 8.19; N, 7.91 C20H18M2°4*°' 0SH2° r<V>lrai c' 6S-39' H' 5.19; N, 7.98%); dR ( [H]6-DMSO) 12.42 (1H, br, COOH), 11.30 (1H, ■, 1-MH), 11.09 (1H, a, 5-HH), 8.68 (IB, s, 10-H), 8.07-7.93 (2H, n, 7-H and 9-H), 7.45 (1H, d, J9, 6-H), 4.38 (2H, g, , 2.94 and 2.90 (2 x 3H, 2 x a, 4-CH^ and 3-CHj) and 1.39 (3H, t, CH^CQ^); m/s (%) 350(100, H+), 304(100), 278(40), 232(35) and 181(38); p_mm (KBr DiaO/cm"1 3459, 1697 and 1674. 9) Bthvl 8-brono-3.4-dlmathvlpvrrolof3.2-b 1 earbagola-2-carboxvlata A nixtura of tha 3-(pyrrolylmathyl)indola (0.3g, 0.74 nnol) and Montaorillonita K10 clay (1 g) in toluana waa atirrad and haatad at raflux for 6 h. Aftar cooling and filtration from tha clay, which waa waahad wall with toluana, tha caoibinad filtrataa wara avaporatad undar raduead praaaura to laava a brown aolid which waa aubaiittad to flaah chromatography on ailica, aluting with dichlorooMthana/light patrolaum (7:3) to giva a yallow aolid. Cryatalliaation from cyclohaxana/athyl aeatata yialdad tha titla o compound aa a yallow powdar (0.070 g, 24%). m.p. 204-205 C (daeomp.) (round: C,S9.17; H, 4.43; N, 7.30. ci9Hi7BrH2°2 raquiraa C, 59.23; H, 4.45; N, 7.27%); ((2H.]-DMSO) 11.26 (1H, n o a, 1-MH), 10.79 (1H, a, 5-HH), 8.30 (1H, d, J2.2, 9-H), 7.92 (IB, a, 10-H), 7.47 (1H, dd, J2.2 and 8.8, 7-H), 7.35 (1H, d, J8.8, 6-H), 4.36 (2H, q, CHjCH^, 2.89 and 2.88 (2 x 3H, 2 x a, 4-CH3 and 3-CH3) and 1.38 (3H, t, CH2CB3); m/s (%) 386 and 384(100, H*), 340 and 338(70), 232(60) and 181(50); "Bax<KBr DiaO/cm'1 3350, 1705 and 1663. WO 94/02483 - 28 - PCT/GB93/015 BXUBPll 4 on—note gynthaala of tha Pvgrolocagh»tola« - Oanaral cfocadura. A aolution of indola (1.0 amol) and tha 5-acatoxy«athyl-4- 3 aoatylpyrrola (1.0 naol) ia 1,2-dichloroathana (10 ea ) waa haatad undar gantla raflux and atirrad with Montooorillonita K10 clay (1 g) for 3-4 h. Tha colour of elay turnad light brown and tha raaction waa followad to completion by TLC. Aftar filtration froa clay and washing wall with 1,2-diehloroathana, a vapor at ion of tha coabinad filtrataa gava tha pyrrolo[3,2-fe]earbatolaa which wara obtainad as yallow eryatala aftar cryatalliaation froa dichloromathana or athyl aeatata. a) Bthvl 3.4-rt<mathvlnvrrolof3■2.-b1 carbaaola-2-earboxvlata (0.199 g, 65%) waa obtainad froa tha raaction of indola and tha 5-acatoxyaathyl-4-acatylpyrrola. Zt waa idantical in all raapacta to tha pyrrolof 3,2-fe] carbaaola froa axarapla 1. b) Ban«vl 3.4-ri\mafchvlpyrrolof3.2-b 1 carbanol—2-carboKvlata (0.179 g, 48.8%) was obtainad froa tha raaction batwaan indola and tha 5-acatoxyaathyl-4-acatylpyrrola, it had a.p. 229-232°C (Foundt C, 78.2; H, 5.65; N, 7.8. C24H20N2°2 ra^u^ru c' 7B*23; H, 5.47; N, 7.60%); 5H(2H6)-DM80-d6) 11.29 (1 H, a, 1-HH), 10.65 (1 H, a, 5—NR) ,8.08 (1 H, d, J8, 9-H), 7.89 (1 H, a, 10-H), 7.56-7.34 (7 H, a, ArH, 6-H and 7-H), 7.08 (1 H, t, J7, 8-H), 5.42 (2 H, a, ffljPh) and 2.92 (6H, a, 3-C«3 and 4-CH3); m/z (%) 368(74,M*), 354(10), 260(100), 246(13), 231(20) and 91(31). Tha pyrrolof3,2-fe)carbasola (0.166 g, 45%) was alao obtainad from tha raaction of indola and tha 4-acatyl—5—(athoxyvathyl) -pyrrola. WO 94/02483 - 29 - PCT/GB93/01512 ¥ c) IthYt 9-MthMY-a.4-dl—thYUYCTQlPf3.2-fa 1 B>rtHfllf-2-Btfl»XYlltl Mas obtainad froa tha raaction of 5-aathoxyindola and tha 5-aeatoxyaethyl-4-aeatyl pyrrola, it had a.p. 119-122°C {roundi C,71.6; R, 6.0; It, 8.OS. C2QU20n2°3 sai>li£ai C' 71*4' H' 5,M' M, 8.33%); 6h((2H6-DMS0) 11.20 (1 H, s, 1-HH), 10.38 (1 8, a, 5-NB), 7.88(1 H, S, 10-H), 7.62 (1 H, d, J 2.8, 9-H), 7.31 (1 H, d, J9, 6-H), 7.01 (1 E, dd, J9 and 2.8, 7-H), 4.38 (2 H, q, OCBgCHj), 3.88 (3 H, S, OCBj), 2.89 and 2.87 (2 X 38, 2 X 8, 3-CH3 and 4-CH3) and 1.39 (3 H, t, OCH2CB3); m/s («) 336(60,M*), 290(100), 275(5), 262(4), 247(23), 219(8) and 148(9). d) B.ntvl B-m^fchoxv-3 i-rt4^hyit>vrrolof3■ 2-b1c»rba»ol«-2-carboxv- (0.139 g, 35%) was obtainad froa tha raaction of 5-aathoxy indola and tha S-aeatoxyaathyl-4-acetylpyrrola, it had a.p. 212-215°C (roondt C, 75.4; H, 5.55; N, 6.98. C25R22N203 r**ulr*s C, 75.4; H, 5.57; N, 7.03%); &g((2H6)-DMSO) 11.29 (1 H, a, 1-NH), 10.38 (1H ,a,5-MH), 7.88 (1 H,a,10-H), 7.68 (1 H, d, J2.5, 9-H), 7.58-7.36 (SH. a, ArH), 7.32 (IB, d, J9, 6-H), 7.02 (1 H, dd, J9 and 2.5, 7-H), 5.43 (2 H, a, fSjPh), 3.88 (3 H, a, OCH ), 2.92 (3 H, s, 4-CH.) and 2.89 (3H, a, 3-CB.); a/s (%) ■f 398(73,M ), 290(100), 262(10), 247(15), 219(7) and 91(17). •) *»>wl ^ryifolof3.2-b 1 e»rb»»ol>-i-eirbe«vlif (0.131 g, 40.5%) waa obtainad froa tha raaction of 5-fluoro-indola and tha 5-acatoxyathy 1-4-acatylpyrrola, it had a.p. 231-234°C (roondt C, 70.5; B, 5.3; K, 8.4. C^H^ntjOj raquiraa C, 70;4; ,B,8.28; N, 8.64%); 6B(2B6]-DMSO) 11.27 (1 B, a,' 1-MB), 10.64 (IB, a, 5-HH), 7.93 (1 B, dd, J9 and 2.5, 9-B), 7.88 (1 B, a, 10—B), 7.36(1 B, dd, J9 and 6,6-B), 7.19 (1 B, dt, J9 and 2.5, 7-B), 4.36 (2 B, «, OC^CHj), 2.88 (6 B, a, 3-CB3 and WO 94/02483 - 30 - PCT/GB93/015 4-CH3) and 1.37 (3 H, t, 0G82CB3)) m/s (%) 324(50,8") 278(100), 250(31), 220(10), 139(8), 125(7) and 111(8) f) Bansvl ■-fluora-3, \-A «-afhYlpvrrol° f3-2-tal o*gba»ole-2-aarhn»v-lltl (0.188 g, 40%) was obtainad from B-fluoroindole and tha 5- aeatoxymathy1-4-aeaty lpyrrola, it had m.p. 217-219°C (rounds C, 74.6; R, 4.95; N, 7.3. r,<Julr#B c' 74,6' H' *'96' N' 7.25); 5„(2Ht)-DKIO) 11.36 (1 H, s, 1-HH), 10.86 (1 H, a, B-HH), H O 7.94 (1 H, dd, J9 and 2.8, 9-H), 7.89 (1 H, a, 10-H), 7.56-7.38 (5 H, m, ArH), 7.39 (1 H, dd, J9 and 4,6-H), 7.21 (1 H, dt, J9 and 2.5, 7-H), 5.42 (2 H, a, CHjPh), 2.91 and 2.90 (2 x 3H, 2 x 8, 3-CHj and 4-CHj); »/s (») 386(68,H+), 278(100), 249(22) and 91(43). g) thy! 1 A. ft-f fehvlnygrolo 13.2-bI eirtiiol-2-earboxvlat:a (0.206 g, 64.4%) waa obtainad from tha raaction of 7-wathylln- Q dole and tha S-aeatoxymathyl-4-acatylpyrrola, it had m.p. 230 C (dacomp.) (rounds C, 74.9; H, 6.25; N, 8.65. C20H20N2°2 ra^u^r" C, 78.0; H, 6.29; N, 8.74%); [2H6J-DMIO) 11.20 (1 H, a,1-HR), 10.11 (1 H, a, 5-HH), 7.89(1 H, d, J7.5, 9-H), 7.84 (1 H, a, 10-H), 7.18 (1 «t, d, J7.5, 7-H), 7.01 (1 H, t, J7.5, 8-H), 4.37 (2 B, q, OC^CHj), 2.98 (3 H, s, 4-CH3), 2.91 (3 H, a, 3-CHj), 2.58 (3 H, a, 6-GR3) and 1.34 (3 H, t, OCH2CH3); m/s (%) 320(54,M*), 274(100), 246(30), 230(5), 137(9), 123(7) and 109(6). h) —nzvl 3.4, ^-tTfl«tt)Yliaiy*">lor 3- 2-hlc»gba«ol»-:g-carhoxvlata / * (0.167 g. 43.7%) waa obtainad from tha raaction of 7 mathylln- o dole and tha 5-acatoxymathyl-4-acatylpyrrola, it had m.p. 222 C (daccmp.) (rounds C, 78.5; H, 5.9; N.7.25. C25H22*2°2 r*9uir** C, 78.5; H, 5.80; N, 7.33%); 6R([2H6)-DNSO) 11.27 (1 H, a, 094/02483 - 31 - PCT/GB93/0I512 l-HB), 10.11 (1 B, a, B-HH), 7.89 (1 8, d, J7, 9-H), 7.85 (1 H, a, 10-8), 7.56-7.35 (5 8, m, ArH), 7.18 (18, d, J7, 7-H), 7.08 (IB, t, J, 8-H), 5.43 (2B, •, fl^ii), 2.99 (3B, a, 4-CH3), 2.93 (3 H, •, 3-CBj) and 2.89 <3 H, a, 6-CH3); a/a (%) 382(71,K+) 274(100), 2.48(19) and 91(22). i) —«i«vl 3-1 a—fcteMtvcagtoonvlathvl \ -4—thvlnvgrolof 3.2-b1 carh— mtrt'blrtwyuti (0.230 g, 52.3%) waa obtainad from Indola and tha 5-aeatoxy-aathy 1-4-aeaty lpyrrola, it had m.p. 211-213°C (founds C, 73.7; H, 5.6; N, 6.2. C27R24N2°4 ra4uir*a c» 73-6' H' 5,49; N' 6.36%); 5h([2H6J-DK,°) 11.51 (1 B, a, 1-NH), 10.71 (1 H, a, 5-HH), 8.75 (1 B, d, J7.5, 9-H). 7.92 (1 H, a, 10-H), 7.S7-7.44 (7 H, a, AxB, 6-H and 7-H), 7.18 (1 B, t, J7.5, 8-H), 5.43 (2 H, a, C&gMi), 3.63 (3 H,a,OCB3), 3.89 (2 H, partially obaeured, t, CBjCB^CO), 2.88 (3 B, a, 4-CHj) and 2.65 (2 H, t, CHjCO); m/s(%) 440(100,M*), 332(20), 290(47), and 91(57). j) athvl 3.4. a a-»>1 .-^-r.rhnrvl«»« (0.140 9, 16%) was obtainad froa tha raaction (2.65 aaol soala) batwaan N-aathylIndola and tha 5-aeatoxymathy1-4-aeatylpyrrola, it had m.p. 208°C (daeeap.) (found: C, 75.12; B, 6.40; H, 8.69, C»0U20n2°2 ******** c' 74.98; B, 6.29; H, 8.74%); $H((2H6]-DKSO) 11.28 (IB, ■, 1-NH), 8.08 (IB d, J7.9, 9-H), 7.88 (IB, a, 10-H), 7.44 (2 B, a, 6-H, 7-H), 7.07-7.17 (1 H, a, 8-H), 4.36 (2 H, q, CH2CB3), 4.01 (3H, a, 5-CB3), 3.13 (3H, a, 4-CHjJ, 2.90 (3H, a, 3-CB3), and 1.38 (3B, t, CB2CB3); a/a (%) 320(72,M*), 274(100), 245(16), 149(28) and 137(12); KBr Disc)/en"*1 3329 and 1670. ' r k) —n«vl 3.4| 1 3.2-blearba«Bl»-2-cagbo«vlata (0.220 g, 57%) waa obtainad froa tha raaetion batwaan N-aathyl indola and tha 5-aeatoxyaathyl-4-aeetylpyrrola in toluana at WO 94/02483 - 32 - PCT/GB93/015^ 55°c, catalyaad by toluana-4-aulphonic acid, it had m.p. 228-229°C (Foondt C, 77.17| B, 5.73; H, 7.09. C2BH22N2°2*0*33 H20 raquiraa C, 77.31; H, 5.88; N, 7.21%); 5H([2HftJ-DM*0) 11.28 (IB, a, 1-HH), 8.03 (IB# d, J7.S, 9-H), 7.88 (IB, a, 10-H), 7.56-7.34 (7B, m, ArH, 6-H, 7-H), 7.1B-7.07 (IB, n, 8-H), 5.40 (2B,a, OgPh), 4.02 (3B, a, 5-CH.), 3.14 (SB, a, 4-CHj) and 2.91 (3H, a, 3-CB3); a/a («) 382(72,N ), 291(4), 274(100) and 91(34); v (KBr Disc) /on"1 3337 and 1674. 1) Ethyl 1.3.4-terlaathvlcvggQlo f 3.2-b 1e*gb»«al«-2-cagboitvlata (0.060 g, 7%) waa obtainad from tha raaction (2.5 nrnol acala) batwaan indola and tha 5-aeatoxymathyl-4-aeatylpyrrola, it had m.p. 188-189°C (roondt C, 74.86; H, 6.32; N, 8.65), c20H2oN2°2 raquiraa C, 75.98; H, 6.29; N, 8.74%); 6„( ^H.J-DMSO) 10.66 (1 H © H, a, 5-MB), 8.14 (1 B, d, J7.7, 9-H), 8.03 (1H, a, 10-H), 7.45-7.31 (2B, m, 6-H, 7-H), 7.06-7.15 (1 H, m, 8-H), 4.38 (2 H, q, C%2CB3), 3.98 (3B, a, 1-CH3), 2.91 (3B, a, 4-CHj), 2.83 (3B, a, 3-CB3) and 1.38 (38, t, CBjCHj); m/s (») 320(M*,100), 306(10), 292(30), 247(8) and 231(10); P_(KBr DisO/cm"1 3385 and 1657. m) Banavl 1.3 »hvlpyggalaf3.2-b1carba«Bla-2-eagbagvlat< (0.240 g, 28%) waa obtainad from tha raaction (2.7 naol acala) batwaan indola and tha 5-acatoxyaathy1-4-aeaty lpyrrola, it had m.p. 186—187°C (Found: C, 78.63; H, 5.83; N, 7.32, C25R22N202 raquiraa C, 78.51; H, 5.80; N, 7.32%); 5R((2B6)-DNSO) 10.66 (IB, a, 5-HH), 8.14 (IB, d, J7.4, 9-H), 8.02 (IB, a, 10-H), 7.56-7.31 (7B, m, ArH, 6-B, 7-H), 7.06-7.15 (1 H, m, 8-H), 5.41 (2B, JffljPh), 3.98 (3H, a, 1-CB3), 2.90 (3B, a, 4-CB3) and 2.83 (3B, a, 3-CB3); m/s (%) 382(M*,100), 338(10), 291(44), 247(18) and 231(10); ¥ .(KBr DiacJ/cm"1 3443 and 1697. n) Kthvl 1.3.4, n-rntr—^hvlwrrelo f 3.2-b 1 carbaaole-2-carbo«vlata WO 94/02483 - 33 - PCT/GB93/01512 (0.220 g, 30%) waa obtainad from tha raaetion (2.2 naol aeala) batwaan N-mathylindola and tha S-acetoxymathyl-4-acetylpyrrola, it had m.p. 165.5-167°C (daoomp.) (Founds C, 78.50* H, 6.65; N, 8.30, c21H22W2°2 c' 75.47; H, 6.63; N, S.38%); 6H([2H6)-DM»0 8.15 (1 H, d, J7.5, 9-H), 8.07 (1H, a, 10-H), 7.50-7.38 (2H, m, 6-H, 7-H), 7.09-7.19 (1 H, m, 8-H), 4.38 (2 H, q, CBgCHj), 4.03 (3H, a, 5-CHj), 3.96 (3H, a, 1-CH3), 3.14 (3H, a, 4-CH3), 2.84 (3H, a, 3-CHj) and 1.39 (3H, t, CH^CQ.); m/a (%) 334(100,M+), 306(18) and 245(6); y (KBr DiaeJ/em" 1690 and imx 1528. o) Bansvl 1. a. 4. S-fctrmathvlpyggolo f 3.2-hi earhaaal»-2-cagho«vlat* (0.070 g, 13%) waa obtainad from tha raaction (1.4 nmol aeala) between N-aathylindola and tha S-acatoxymathyl-4-aoatylpyrrola, it had m.p. 196-198°C (Founds C, 78.45; H, 6.16; N, 6.94, C26H24N2°2 r*«ulr** C» H, 6.10; N, 7.07%); 8H([2H6)-DM80) 8.15 (1 H d, J7.8, 9-H), 8.07 (1 H, a, 10-H), 7.59-7.29 (7H, m, ArH, 6-H, 7-H), 7.10-7.20 (1 H, m, 8-H), 5.42 (2H, a, CH^Ph), 4.03 (3H, a, 5-CH3), 3.97 (3H, a, 1-CH3), 3.13 (3H, a, 4-CH3) and 2.83(3H, a, 3-CH,); m/s (%) 396(100,H+), 305(38), 245(16) j -1 and 235(10) tv KBr Diac)/cm 1696 and 1529. bix P) Banal 3.4-dlmathvl-S-14-toluaneaulnhonvl \ wrrolo 13.2-b 1 carba- % (0.012 g, 4%) waa obtained from tha reaction (0.6 onol aeala) between N-(4- tolueneaulphonyl)indole and tha 5-aeetoxymethyl-4-acetylpyrrola, it had m.p. 270°C (Founds C, 70.83; H, 5.01; N, 5.23, C31H26H2048 raquiraa C, 71.24; H, 5.0T; N, 5.36%); 6 H(l2H6)-DMSO) 11.58 (1H, a, H-H), 8.28-8.08 l m, 6-H, 9-H, 10-H), 7.66-7.21 (11H, m, ArH, TaH, 7-H, 8-H), 5.40 (2H, a, CH2Ph), 3.04 (3H, a, 4-CH3), 2.88 (3H, a, 3-CH3) and 2.20 (3H, a, Ta-CH3); m/s (%) 523(30,(K+l), 446(20), 367(30), 348(56), 33(100), 295(30) and 274(90); v (KBr DiaO/cm"1 3558 and 1666. IHIX WO 94/02483 - 34 - PCT/GB93/015,'> q) Sfehvl 7.ierta«v.3 - 4-d < lefrhvl -ft-methoxvpvrrolo f3.2-b 1 ClfbllQlt -2-gjgbflyylitt (7%) obtained froa tha reaction batwaan 6-acatoxy-7-methoxy- indola and tha 5-aoetoxymethyl-4~ac«:ty lpyrrola, it had m.p. 241-244°C. (COCl3) 6.59 (IB, a, br, MB), 7.76 (IB, a, br, NB), 7.76 (IB, a, 10-H), 7.74 (IB, d, J8, 9-H), 6.88 (IB, d, J8, 8-h), 4.44 (2B, q, CBgCBj), 4.04 (3B, a, 6-ochj), 2.96 and 2.92 (2 x 3H, 2 x a, 4-CB3 and 3-CB3), 2.42 (3B, a, 7-CH3COO) and 1.46 (3B, t, CH,CH,)/ m/s (%) 394 (100, M*), 352 (47), 348 (33), -1 306 (87), 263 (21) and 87 (73); V (Nujol)/em * 3413, 3341, max 1739 and 1675; V (MaOB)/nm 405, 386, 339, 325, 305^ 269, 240 and 226. (Founds N , 394, 1529. C22H22M2°5 r*4uiras 394.1529). r) ttthvl 9-methoxv-a. 4. m^hylpvrrolor 3.2-b 1 carbaxole-2-car- obtained from tha reaction between 4-mathoxy-l-methylindola and the S-acatoxyaMthyl-4-aeatylpyrrola, it had m.p. 263-266°C (Found! C, 71.84; B, 6.34; N, 7.91. c2iH22N2°3 raquir*> C' 71.98; H, 6.33; N, 7.99%; (CDCl3) 8.60 (IB, •, br, HH), 8.15 (IB, a, 10-H), 7.40 (IB, t, JB, 7-H), 6.95 (IB, d, J8, 6-H), 6.66 (IB, d, J8, 8-H), 4.43 (2B, q, OC^CH^, 4.10 and 4.04 (2 x 3B, 2 x a, N-CB3 and OCB3), 3.19 (3B, a, 4-CB3), 2.98 (3H, a, 3-CB3) and 1.46 (3B, t, OCB2<^3); m/s (%) 350 (74, X*), 304 (100), 276 (17), 223 (10) and 152 (19). s) Banavl B-ehloro-3 n Jp-i-twlpvrrolo f 3.2-b 1 earbasola-2-carboxv- •' <• (0.069 gt 17%) waa obtained from the reaction between 5-chloroIndole and the 5-aeatoxymethyl-4-acatylpyrrola, it had m.p. 215-220°C. (decoop.). (Founds C, 71.42; H, 4.96; N, 7.11, 0 94/02483 - 35 - PCT/GB93/01512 C24H19C1»202 r*<Iuir*B c» 71.55; H, 4.75; N, 6.95%); 6^ ( [H)6-DMS0) 11.39 (1H, s, 1-NH), 10.84 (1H, a, 5-HH), 8.17 (1H, а, 9H), 7.93 (IB, a, 10-H), 7.54 (IB, d, J7, 7-H), 7.48-7.34 (6H, a, ArH and 6-H), 5.42 (2H, a, C^Ph) and 2.88 (6H, a, 3-CH3 and 4-083); m/a <%) 402 (30, a+), 358(5), 294 (65), 267 (25) and 91 (100). Tha eryatalllaatlon iiquora wara aubaittad to flaah chromatography on ailioa. tlution with athyl aeatata/light patrolaua yialdad furthar titla eonpound which waa cryatalliaad froa athyl aeatata (0.030g; 7%) and a-1a'-acatvl-5*-bentvioxv- CagbanYl-4' -MthVlPYriral-2' -ViWthYl)-5-ChlgfglndPl« " cream coloured eryatala (0.152g; 36%) m.p. 141-143°C (Pound: C, 68.20; H, 5.18; N, 6.60; C24H21C1H2°3 ra<luiraB c' 68.49; H, 5.03; N, б.65); (C0C13) 8.72 (1H, a, l'-NH), 8.26 (IK, a, 1-NH), 7.38 (1H, d, J2, 4-H), 7.35 (6H, m, ArH and 6-H), 7.18 (1H, dd, J8 and 2, 2-H), 7.09 (1H, d, J2, 2-H), 5.23 (2H, a, Cfl^h), 4.33 (2H, a, 3-CH2), 2.64 (3H, a, 4'-CH3) and 2.52 (3H, a, CH3CO); m/a (%) 420 (20, M*), 405 (10), 311 (20), 151 (15) and 91 (100). t) «thvl 3.4-dimathvl-B-hvdroxvpygrolof 3.2-bl carbaaole-2-carboxv-ili* Obtainad froa tha raaction batwaan 5-hydroxyindola and tha 5-aoatoxyaathyl-4-aoatylpyrrola and cryatalliaad froa methanol, it had a.p. 250°C (deeoap.) &H[2H6]-DMSO) 11.11 (1H, a, 1-NH), 10.21 (1H, a, S-HH), 8.83 (1H, a, OH), 7.73 (1H, a, 10-H), 7.37 (1H, d, J2.5, 9-H), 7.21 (1H, d, JB, 6-H), 6.87 (1H, dd, J8 and 2.5, 9-H), 7.21 (2H, q, OC^CH^, 2.87 (3H, a, 4-CH3), 2.84 (3H, a, 3-CH.) and 1.38 (3H, t, OCH.CH ); m/z (%) 322 (69, M*), 276 + (100), 248 (24), 220(3) and 138 (15); (Pound: M , 322. 1322 C19H18*2°3 r*3u*-raa x* 322. 1317). Alao iaolated from tha raaction waa 3-13'-acatvl-5' -etho«vcarbnnvl-4' —>athvlP*ggol-2' -vlmathvl>-5-hvdroKvindola.It had m.p. 99-102°C (Pound: C, 66.89; H, 6.17; H, 8.03. c19H2QH204 raquiraa C, 67.04; H, 5.92; N, 8.23%) 6_(CDC1-) 8.84 (1H, B, l'-NH), 8.14 (1H, a, 1-NH), 7.20 h 3 (1H, d, J8, 7-H), 7.10 (1H, d, J 2.5, 2-H), 6.81 (1H, d, J1.5, WO 94/02483 - 36 - PCT/GB93/015* 4-H), 6.79 (1H, dd, J1.5 and 8, 6-H), 5.60 (1H, ■, br, 5-OH), 4.31 (2H, a, CH2), 4.21 (2B, q, OCJ^CHg), 2.58 (3H, a, 4'-CH3) 2.48 (3H, a, 3'-COCH3) and 1.27 (3H, t, OCHjCflj); m/s (%) 340 (100, M*), 325 (44), 293 (21), 279 (35), 266 (35), 2S1 (31), 223 (25), 196 (5), 147 (20) and 133 (36). u) —n«yj 3 , .7.»1.,n^mryn1of 1. 9-h tr.rh»n)..?-g,rho>v. lafca and Banayl jhl^ngtW-fl-f^rr^-irr^lflf ?r CUfeBBYlltl obtainad aa a mixture of isomera from tha reaction between 6-fluoroindole and tha 5-acetoxynethyl-4-aeatylpyrrole. Chromatographic aaparation yialtivd tha r 3.2-b i leaner (0.139g, 36%) m.p. 205°C (decomp.) 5H((2Hfi]-DHSO) 11.32 (1H, a, 1-HH), 10.85 (1H, a, 5-HH), 8.08 (IB, dd, J9 and 6, 9-H), 7.86 (1H, a, 10-H), 7.57-7.35 (5H, m, ArH), 7.12 (1H, dd, J10 and 2, 6-H), 6.90 (1H, dt, J9 and 2, 8-H), 5.43 (2H, a, C^Ph), 2.91 (3H, a, 3-CH3) and 2.90 (3H, a, 4-CH3); m/s (%) 38£ (55, M+), 342(5), 295 (4), 278(100), 249(45), 236(20), 222 (25) and 91 (95); (roundt MH*, 387. 1509. 387.1509); and the f 2.3—b 1 learner m.p. 190-193°C 6H(CDC13) 8.54 (1H, B, br, 1-HH), 8.10 (1H, dd, J9 and 6, 5-H), 7.87 (1H, a, br, 9-HH), 7.51-7.34 (5H, m, ArH), 7.34 (IB, a, 10-H), 7.22 (1H, dd, concealed by 10-H, 8-H), 6.93 (1H, dt, J2 and 9, 6-H), 5.41 (2H, a, C^Ph), 3.20 (3H, s, 4-CH3) and 3.00 (3H, a, 3-CH3); m/s («) 386 (100, M+), 295 (12), 278 (96), 250 (27), 236 (7), 222(8) and 91 (59); (round* M+, 386.1433. C24Hi9***202 386.1431). v) gthvi 3.4-fl inttttiyl -''-f ^"tirmrrn'"!f * - *-K 1 and Ethvl frOXYlitt r obtained aa a mixture of iaoaera from the reaction between 6-fluoroindole and the 5-acatoxymethyl-4-acetylpyrrole. Chromatographic aaparation yialdad the r3.2-biiecwer which waa WO 94/02483 - 37 PCT/GB93/01512 crystallised froa dlchloromathana, m.p. 231-2S4°C (Foundx C, 70.48; H, 5.S3; B, 8.66. r«quir«« C, 70.36, H, 5.28; N, 8.64%); $H([2H6]-DNSO) 11.27 (1H, a, br, 1-nh), 10.82 (IB, a, br, 5-MB), 8.90 (IB, dd, J9 and 6, 9-H), 7.85 (IB, a, 10-H), 7.12. (IB, dd, J10 and 2, 6-H) 6.89 (IB, dt, J2 and 9, 8—B), 4.37 (2B, q, OCBgCBj) 2.89 (6B, s, 4-CBj), 1.39 (3B, t, OCB.CQ,); m/s (%) 324 (60, H+), 278 (100), 250 (34), 222 (10) and 139 (7); (round; H , 324.1267a C19H17**2°2 324.1274); and tha r2.3-b11«a—r m.p. 262-265°C; 5R(I2H6l-DMSO) 11.14 (IB, s, br, 1-MH), 11.06 (1H, a, br, 9-NB), 8.12 (1H, dd J 6 and 9, 5-H), 7.19 (IB, a, 10-H), 7.15 (IB, dd J10 and 2, 8-H), 6.92 (IB, dt, J2 and 9, 6-H), 4.36 (2B, q, OC^CH^, 3.13 (SB, s, 4-CHg), 2.93 (3H, a, 3-CH.j) and 1.39 (3H, t, OCH2CH3)/ «/* (%) 324 (72, M+), 278 (100), 250 (39), 222 (9), 139(6) and 125(7); (Found: M+, 324.1280. C2gHi7rN2°2 r*(Iu^rB* 324.1274). Ethvl 3.4-rt1mft,hYl-?-hYdrg?yYPYcrolgf 3,2-blcarbnQlf-2-cigfaPny- lata and Bfchvl 3.4-dlaatehvl-S-hvdromrpvrrolof3.2-b1carbaaola-2- earboitvlafea obtainad aa a mixtura of isomara from tha raaction batwaan 4-hydroxyindola and tha 5-acatoxymathyl-4-acatylpyrrola. Chromatographic aaparation yialdad tha f3.2-blisomar which was cryatallisad from athyl acatata/light patrolaum, m.p. 260-262°C (dacoap.) 5d((2B6]-DMSO) 11.13 (IB, a, 1-NH), 10.56 (IB, a, 5—MB), 10.00 (IB, s, OH), 8.02 (1H, s, 10-H), 7.12 (IB, t, J7.5, 7-H), 6.83 (1H, d, J7.5, 6-H), 6.48 (IB, d, J7.5, 8-H), 4.39 (2H, q, QfiHjCB^, 2.87 (SB, a, 4-CH3), 2.85 (3B, a, 3-CH3) and 1.38 (SB, t, OCHjffl^; m/s (%) 322 (61, li**), 276 (100), 248 (20), 219 (5) and 138 (11); (Found: M+, 322.1305. C^B^N^ raquiraa 322.1317); and tha f2.3-b1iaomar which waa cryatalliaad from athyl aeatata, m.p. 251-254°C (dacomp.) 6 ([2B.)-DMSO) IS D 10.95 (IB, a, 1-MB), 10.85 (IB, a, 9-H), 9.89 (IB, a, OH), 7.08 (IB, t, J7.5, 7-H), 7.07 (IB, a, 10-H), 6.77 (IB, d, J7.5, 8-H), 6.52 (IB, d, J7.5, 7-H), 4.32 (2B, q, OCJ^CB^, 3.44 (3H, a, WO 94/02483 - 38 PCT/GB93/015 * ^ 4-CH3), 2.92 (3B, a, 3-CH3) and 1.37 (3H, t, 0CH2CH3); »/* (%) 322(65, M+), 276 (100), 248 (88), 219 (15), 205(10), 191 (10), 178 (5), 165 (5), 138 (10) and 115 (10); (FoundiH+f 322.1317. C19H18N2°3 322*1317). x) 'thvl 6.9-dlathMv-a. 4—dlm«fchvlpvrgol« f 3.2-b 1 earbaaola-2- eaghmtvlata and Kfehvl |iiMlrt,ho«v-3.4-<|)f»t«>1«wrralBH.3-b1 B«rt»aMl»-2-g»gbo«vlafca obtainad aa a mixtura of iaomara from tha raaction batwaan 4,7-dimathoxyindola and tha 5-aeatoxyoathy 1-4-aeaty lpyrrola. Chromatographic aaparation yialdad tha r3.2-bllaomar (13.7%) m.p. 256-258°C. (Founds C, 68.98} H, 6.23; N, 7.89. C21H22N2°4 raquiraa C, 68.84; H, 6.05; N, 7.65%). (C0C13) 8.58 (1H, ■, br, NH), 8.08 (1H, a, 10-H),7.84 (1H, a, br, NH), 6.82 (1H, d, J8, 7-H), 6.50 (1H, d, J8, 8-H), 4.43 (2H, q, OCJ^CBg), 4.05 (3H, a, 9-OCH3), 3.98 (3H, a, 6-OCH3), 2.96 (3H, a, 4-CH3), 2.92 (3H, a, 3-CH3) and 1.44 (3H, t, OCH2QH3); 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 _ (Nujol)/em"1 3474, 3323 and mix 1674; X (MaOB)/nm 415, 387, 344, 330(ah), 305(ah), 266, 246 MX and 220; and tha f2.3-bllaonar (9.3%) m.p. 193-195°C. (Founds C, 69.03; H, 6.29; N, 7.42. C21H22M2°4 raquiraa C, 68.84, H, 6.05; N, 7.65%); (CDC13) 8.44 (IB, a, br, NH), 8.10 (1H, a, br, NH), 7.06 (IB, a, 10-H), 6.82 (1H, d, J8, 7-H), 6.56 (1H, d, JB, 6-B), 4.40 (2B, q, OC^CB^, 3.98 (3H, a, OCB3), 3.97 (3B, a, 0CB3), 3.42 (3H, a, 4-CB3), 3.00 (3H, a, 3-CBa) and 1.43 (3B, t, OCB2CS3); B/S (%) 366 (100, M+>, 320 (82), 292 (20), 277 (24), 262 (10), 183 (14), 160 ( 28), 131 (3); V _ (NujoD/cnf1 3457, IBIX 3345 and 1660; X (M0B)/nm 381, 365, 293, 247 and 219. (huc r y) Kthvl 7-mathoxv-3. »wipygrolT 3.2-bl earbazola-2-carboxv- lafca and gthvl 7—athoxv-3.4-dimathvH>vrrolaf2.3-b1carbazola-2-CtTfrOTYlltl WO 94/02483 - 39 - PCT/GB93/01512 oLtainad as a mixtura of isomers from tha raaetion batwaan 6-mathoxyIndola and tha S-aeatoxymathyl-4-aeaty lpyrrola. Flaah chromatography on ailiea, aluting with athyl aeatata/cyclohaxana (111) yialdad tha f which waa cryatalliaad from o *2 athylacatata/cyclohaxana, m.p. 239-241 C (daeoop.) 6g([ Hg)- DM80) 11.09 (1H, ■, 1-MB), 10.49 (1H, a, 5-HH), 7.91 (1H, d, J 8.7, 9-H), 7.73 (1H, a, 10-H), 6.88 (IB, d, J2.3, 6-H), 6.68 (IB, dd, J 8.7 and 2.3, 8-H), 4.35 (2H, q, OC^CH^, 3.84 (3B, a, 7-OCH3), 2.87 (3H, a, 3-CB3), 2.86 (3H, a, 4-CH3) and 1.37 (3H, t, OCH2CH3); m/s («) 336 (84, M+), 290 (100), 262 (32), 247 (16) and 219 (16); v ' (KBr Disc)/cm"1 3342, 1674 and 1628; and tHIX tha f2.3-bliaomag which waa cryatalliaad from athyl aeatata/cyclohaxana, m.p. 260°C (dacomp.) [2Hg]-DMSO) 10.98 (IB, a, 1-HH), 10.74 (IB, a, 9-NH), 8.00 (1H, d, J8.7, S-H), 7.13 (1H, a, 10-H), 6.87 (1H, d, J2.7, 8-H), 6.70 (1H, dd, J8.7 and 2.7, 6-H), 4.34 (2B, q, OCHjCH^, 3.83 (3H, a, 7-OCH3), 3.10 (3H, a, 4-CH3), 2.91 (3H, a, 3-CB3) and 1.37 (3H, t, OCT.^); m/s («) 336 (56, M+), 290 (70), 262 (26), 145 (16), 129 (14); v (KBr Disc)/cm"1 3379, 3339 and 1663. BUX s) Ethvl 3-athvl-4-mathvlpvrrolof3■ 2-blcarba»ol—2-carboxvlata (0.956g, 27%) waa obtainad from tha raaction (11 mmol acala) batwaan indola and tha athyl 5-acatoxymathyl-4-acatyl-3-athyl-pyrrola-2-carboxylata, aftar raeryatalliaation from toluana, it had m.p. 248-249°C (dacomp.) (Founds C, 74.93; H, 6.35; N, 8.60. C20H20H2°2 c' 74.98; H, 6.29; N, 8.74%); $B((2H6J- DMSO) 11.27 (1H, a, 1-HH), 10.63 (1H, a, 5-NH), 8.09 (1H, d, J 8, 9-H), 7.93 (IB, a, 10-H), 7.31-7.47 (2H, m, 6-H, 7-H), 7.09 (1H, ddd, J 8, 5.5, 2, 8-H), 4.40 (2H, q, J 7, COgCHg), 3.37 (2H, q/ J 7, 3-CH2), 2.91 (3H, a, 4-CH3), 1.41 (3H, *, J 7, C02CH2CB3), 1.30 (3H, t, J 7.5, 3-CH,CH3)» m/s (%) 320(100, M+), 274(96); v (KBr disc)/cm"1 3344, 3327, 1680, 1664, 1238. bmx WO 94/02483 - 40 - PCT/GB93/0151 ftlffiPlt 8 Pvrrolof3.2-b1cagbagala-2-eag>MMtvllc Acida Oanaral uroeidugt. To a ■olutlon of tha toansyl pyrrolo [3,2-b] carbaaola-2-carboxylata in dry tatrahydrofuran (TBT) (10 n^) waa addad 10% Pd-on-C (SO ng). Tha raaction nixtura waa hydroganatad at ona ataoa. praaaura and roon taaparatura. Xftar uptaka of had caaaad, tha catalyat waa ranoyad by filtration through Callta and waahad trail with THT, and tha eonbinad filtrataa tiara avaporatad undar raduoad praaaura. Cryatalliaation of tha raaulting aolid from acatona, nathyl athyl katona or aquaoua mathanol gava tha pyrrolo(3,2-b)carbazola-2-carboxylie acida aa yallow eryatala. a) 3.4-Piffi«thYiPYrrglgf3.2-b1gigbMgli-2-gtgbgxyllg tsld (0.234 g, 84.3%) n.p. 237°C (dacomp.); 6„([2H,J-DMSO) 12.74 (1 a o H, br, a, COgH), 11.13 (1 H, a, 1-NH), 10.60 (1 H, a, 5-NH), 8.05 (1 H, d, J7.5, 9-H), 7.87 (1 H, a, 10-H), 7.42 (1 H, d, J7.5, 6-H), 7.36 (1 H, t, J7.5, 7-H), 7.08 (1 H, t, J7.5, 8-H), 2.92 and 2.91 (2 x 3H, 2 x S, 3-CH3 and 4-CH3); m/x(%) 278(30,K*) 260(39), 234(100), 218(19), 204(8), 167(8) 149(16), 130(10) and 117(25) (Pounds H*, 278.1060.raquiraa M,278.1055). b) 8-Tluoro-3.4-rtimathvlnvTrolof3.2-b 1 carbatola-2-cagboxvllc acid (0.0845 g, 85.6%) m.p. 236-239 °C, d_([2Hc]-DHSO) 12.80 (1 H, n d br, a, C02H), 11.19 (1 H, a, 1-NH), 10.60 (1 H, a, 5-NH), 7.91 (1 H, dd, J9 and 2.5, 9-H), 7.86 (1 H, a, 10-H), 7.37 (1 H, dd, J9 and'4,6-H), 7.20 (1 H, dt, J9 and 2.5, 7-H) and 2.89 f6 H, a, 2XCH3); m/r (%) 296(51,H+), 278(71), 252(100), 250(37), 236(19), 222(13), 139(22), 12!i(36) and 111(28) (Pounds M*, 296.0960. C17H13n,2°2 rw^uir•■ M» 296.0961) WO 94/02483 - 41 PCT/CJB93/01512 c) 3.4.6-TrijMfehvlPvrrolof3.2-b1eagbagpla-2-B»rbpitvlic acid (0.065 g, 88%) a.p. 230°C (dacomp.) (Pound< C,74.2; H,5.55; N,9.4 C1BH16N2°2 C, 74.0; H, 8.52; N, 9.58%); dB((2H6)-DK8°) 12.80 (1 8, br, a, COjH), 11.01 (1 H, a, 1-NH), 10.08 (1 H, a# 5-NH), 7.90 (1 H, d, J7.5, 9-H), 7.82 (1 H, a, 10-H), 7.16 (1 I'., d, J7.5, 7-H), 7.01 (1 H, t, J7.5, 8-H), 2.97 (3 H, a, 4-CH3), 2.92 <3H, a, 3-C»3) and 2.58 (3 H, a, 6-CH3); m/«(%) 292(72,M+), ?74(100), 246(50), 230(11),137(25), 122(24) and 109(30). d) 3-12-Mathoxvearbonvlatehv 1 \ -4-aathvlpyrrolo f 3. 2-bl earh»*ol—2-ca- rboxvllc add (0.0673 g, 84.6%) a.p. 2BS°C (dacomp.) (Foundt C, 68.4; H,5.3; N,7.75.C2QH18N204 raquiraa C, 68.6; H,5.18; N, 8.00%); aH([2H6)-DM80> 12.88 (1 H, br, a, C02H), 11.34 (1 H,a,1-NH), 10.65 (1 H, a, 5-NH), 8.06 (1 H, d, J 7.5, 9-H), 7.88 (1 H, a, 10-H), 7.42 (1 H, d, J 7.5, 6-H), 7.36 (1 H, t, J7.5, 7-H) 7.07 (1 H, t, J7.5, 8-H), 3.66 (3 H, a, OCH3), 3.63 (2 H, partially obacurad ^q^O^CO), 2.89 (3 H, a, 4-CH3), 2.66 (2 H, t, CH2C0); m/s(%) 350(100,M*), 332(17), 306(30), 290(63), 272(22), 289(32) and 233(47). a) 1.3.4-TriaathvlPvrrolof3.2-b1cagbagol«-2-carboxvlic acid (0.060 g, 44%) a.p. 215-216°C (dacomp.) (Foundt C, 73.69; H, 5.51; N, 9.41; c^gHx6N2°2 r**uirM c' 73.95; H, 5.52; N, 9.58); 5r([2H6)-DK8°) 12.94 (1H, br, a, COOH), 10.63 (1H, a, 5-NH), 8.13 (1H, d, J 7.9, 9-H), 8.00 (1H, a, 10-H), 7.45-7.30 (2H, m, 6-H, 7-H), 7.14-7.04 (1H, a, 8-H), 3.99 (3B, a, 1-CHp, 2.91 (3H, a, 4—CHj) and 2.88 (3H, a, 3-CH3); m/s (%) 292(95.M+). 275(10), 247(40), 232(30), 180(100) and 135(100); y^(KBr Disc)/cm"1 3375, 2930 and 1709. WO 94/02483 - 42 - PCr/GB93/015,"» f) 3.4. B-Trlmthvlpyrrolot3.2-bl eagb»«ol—2-eagboxvlic acid (0.01S g, 18%) m.p. 239-240°C (dacomp.) (Founds C, 74.11; B, 8.38; N, 9.39; C28BKM2°2 ra4u^ral c' 73.98; B, 8.82; N, 9.88; iH( (2H6)-DM*°) 11.18 (IB, ■, 1-NH), 8.04 (IB, d, J 7.S, 9-H) 7.88 (IB, ■, 10-H), 7.48-7.41 (2B, m, 6-H, 7-H), 7.17-7.06 (IB, m, 8-H), 4.03 (3H, a, 5-CH3), 3.16 (3H, a, 4-CBj) and 2.93 (SB, а, 3-CH3); m/a (%) 292(90,M+), 274(78), 232(70), 197(38), 181(60), 149(30) and 130(100); v^fKBr DiacJ/cm"1 3484, 2926 and 1670. g) 1.3.4. S-Tatrimthvlwrrolef 3.2-b 1 carb.rol—2-csgboxvllc acid (0.030 g, 32%) m.p. 21S-217°C (dacomp.) (Foundt C, 74.44; H, б.00; N, 9.14; cigHig*2®2 r*9uirBB c» 74.49; H, 5.92; N, 9.14); 6^( {2Hg)-DM80) 12.98 (IB, br, a, COOB), 8.14 (IB, d, J7.6, 9-H), 8.04 (IB, a, 10-H), 7.48-7.38 (2H, m, 6-H, 7-H), 7.18-708 (1H, m, 8-H), 4.01 (3H, a, 5-CH3), 3.97 (3H, a, 1-CH3), 3.12 (3H, a, 4-CH ) and 2.84 (3H, a, 3-CH,); m/a (%) 306(100,M*), 279(25), -1 232(38), 197(34), 181(80) and 149(25); »ma<>(KBr Diac)/cm 1935 and 1659. h) 3.4-Dlmthvlpvrrolof3.2-b 1 cagb»gol«-2-carboxvllc aeld 3 Tha athyl aatar (500mg, 1.6mmol) in water (15 em ) and methanol 3 (35 cm ) waa haatad to raflux and aufficiant methanol to achieve diaaolutlon waa addad. caaaium carbonata (5.32g; 16mmol) waa addad and tha mixtura was haatad to raflux undar nitrogan for 18h. Aftar cooling, solvent waa removed in vacuo to leave approximately 20 cm3 of solution which waa brought to pH3 by the addition of 0.1K hydrochloric acid whereupon the title compound precipitated out. Filtration, waahing with water and drying under vacuum yielded analytically pure product (437mg; 96%) which waa apectroacopically identical to that obtained in Example 5a. WO 94/02483 - 43 PCT/GB93/01512 imtolt 6 PrrgQlQfa.?-*>'g«gfa»«al»»a-fl»rtM«vello Acid Mtm - general procedure The pyrrolo [ 3,2-b) oarbasola-2-aarboxylic aeld (1.0 nnol) and H, H'-carbony1 dliaidaaole (1.1 naol) were diaaolved in freahly diatillad tetrahydrofuran undar a nitrogen ataoaphere. Tha raaulting auapanaion waa atirrad at rooai temperature for at laaat ona hour, and complete eonvaraion of tha aeid to tha ialdasolida intermediate waa varlfiad by TLC. Tha aleohol or phanol (1.5-2.0 nnol, i.a. an axeaaa) waa addad in ona portion; and tha raaulting nixtura was haatad to raflux until TLC ahowed ooaplata conauaption of tha ialdasolida intaraadiata. Tha product waa obtainad by coluan ohroaatography on alllea, followad by raeryatalllaation. a) Phenyl 3.4-<Hmathv1nvggnlof3.2-h 1 eagha«ol—2-oarbo«vlaf waa obtainad froa tha raaction of tha ialdasolida intaraadiata with phanol. Chroaatography (aluting with 10% acatona/90% patrol) followad by raeryatalllaation front acetone-petrol gave orange eryatala (0.230 g, 65%) a.p. >230°C (decoosp.) (Foundt C,78.17; H, 5.09; M, 7.77. raquirea C, 77.95; H, 5.12; M, 7.90%); 5( [2Bfi]-OMSO) 11.55 (1H, a, 1-HH), 10.64 (IB, a, 5-HH), 8.10 (1H, d, J 7.5, 9-H), 7.94 (1H, a, 10-H), 7.30-7.58 (7B, a, PhB, 6-H, 7-H), 7.09 (IB, ddd, J 7.5, 5.5, 2, 8-H) and 2.97 and 2.95 (2 x SB, 2 x a, 3-CHj and 4-CH3); a/s(%) 355(40,H*); v _ (KBr DieO/ca"1 3396, 1701 and 1180. BIX b> f f 2-I?1athYlinln0)«thYli 1 3.4-dlmathvlpvrrolo f 3.2-b 1 carba«ole -2-eariboatvlaf waa obtained froa the reaction of the ialdasolida interaediate with (2-diaethylanino)ethanol. Chroaatography (elutlng with 10% aethenol/90% DCM) gave a yallow aolid (0.350 g, 99%). WO 94/02483 44 PCT/GB93/015* * Raeryatalllaation of a portion from DCM gava yallow crystals with a.p. 174.0-175.7°C (daeoop.) (Foundt C, 70.46; H, 6.48; N, 11.76. C21H23II302.0.18CB2C12 raquiraa C, 70.29; H, 6.45; N, 11.55%)i iH((2B6)-DMSO) 11.It (IB, a, 1-NH), 10.60 (IB, a, 5-MB), 8.07 (IB, d, J 8, 9-H), 7.89 (IB, a, 10-H), 7.30-7.43 (2H, a, C-B, 7-H), 7.09 (IB, ddd, J 8, 6, 2.5, 8-H), 4.41 (2B, t, J 6, OCH2), 2.91 (6H, a, 3-CH3 and 4-CH3), 2.69 (2H, t, J 6.0, MCH2) and 2.27 (6H, a, N(CB3)2); a/a(%) 380(46,(M+l)+), 261(68) and 133(100); V (KBr DisO/cnf1 3377, 1661 and 1238. imjc C) f Ia-Dlwthvlnilnolphanvl 1 3.4-dlmsthvlpygrolof 3.2-b1 orbaaol—2- carbgyylatt was obtainad froa tha 0.95 nnol seals raaction of tha imidaso-lida intaraadiata with (3-dinathylamino)phanol. Chroaatography (aluting with 10% athyl aeatata/90% toluana) followad by raeryatalllaation froa athyl aeatata gava yallow cryatals (0.272 g, 72%) a.p. 240-242°C (daeeap.) (Foundt C, 75.37; B, 5.71; N, 10.36. C2sH23N302 raquiraa C, 75.55; B, 5.83; N, 10.57%; 5H ((2B6l-DMSO) 11.49 (IB, s# 1-MB), 10.64 (IB, s, 5-NH), 8.08 (IB, d, J 8, 9-H), 7.91 (IB, S, 10-H), 7.34-7.48 (2B, a, 6-H, 7-B), 7.27 (IB, t, J 8, 5'-B), 7.10 (IB, ddd, J 8, 6, 2, 8-H), 6.56-6.70 (SB, a, 2'-B, 4'-B, 6'-H), 2.96 (3H, s) and 2.94 (9H,a) (3-CB3,4-CH3, M(CH3»2); a/* (%) 398(38, M*l)+, 261(25), 232(21) and 217(100); (^(XBr Disc)/cm"1 3350, 1674, 1610 and 1232. d) (3-Pvrldvl) 3.4-d imathvlnvrrolo f 3.2-b 1 carbstol—2-csrboxvlaf waa obtainad froa tha raaction of tha ialdasolida intaraadiata with S^hydroaypyrIdlna. Chroaatography (aluting with 504 athyl aeatata/50% patrol) followad by raeryatalllaation froa aeatona gava yallow eryatala (' .230 g, 65%) with a.p. >270°c (daeoap.) (Poundt C, 73.88; B, 4.76; N, 11.50. C22B17N302.0.2H20 raquiraai C, 73.61; H, 4.89; N, 11.71%); 6R ((2H6)-DMSO) 11.59 WO 94/02483 - 48 - PCT/GB93/01S12 (1H, s, 1-NH), 10.68 (1H, a, 5-HH), 8.63 (1H, d, J 2, 2'-H), e.88 (1H, dd, J 4, 1, I'-H), 8.10 (1H, d, J 8, 9-H), 7.90 (1H, s, 10-H), 7.86 (1H, ddd, J 8, 3, 1, B'-H), 7.88{1H, dd, J 8, 8, 4'-H), 7.32-7.48 (2H, a, 6-H, 7-H), 7.09(1H, ddd, J 8, 6, 2, 8-H) and 2.97 and 2*94 (2 x 3H, 2 x a, 3-CH, and 4-CH,); m/s (%) * —1 386(18, (M+l) ). Disc)/cm 3377, 1718 and 1173. (1-Cirh8l8gYlBhtnYl) a i4-d tmtthvlpvfrol° 13. 2-b I oagbasol—a- sagbgyvlif waa obtainad from tha raaetion of tha ialdasolida intaraadiata with 3-hydroxybansaaida. Raorystalliaation free athanol gava a yallow powdar, and an iapura residue. Tha lattar aatarial was furthar purified by ooluan chroaatography on ailioa (alutad with 5%) methanol/98% DCM than 10% methanol/90% DCM) followad by raorystalliaation froa athanol. (0.262 g, 66%) a.p. >2S0°C (daeoop.) (Pounds C, 71.72; H, 4.81; N, 10.26. raquiraa C, 71.88; H, 4.88; N, 10.48%); 5R (( HgJ-DMBO 11.56 (1H, s, 1-HH), 10.63 (1H, a, 5-NH), 7.90-8.12 (SH, a, 9-H, 10-H, 3*-H, 5'-H, aside N-H), 7.33-7.49 (SH, a, 6-H, 7-H, 2'-H, 6'-H, aaida N-H), 7.09 (1H, ddd, J 8.5, 6, 1.5, 8-H) and 2.95 and 2.93 (2 x 3H, 2 x a, 3-CH3 and 4-CH3); a/s (%) 398(10, {M+l)*), 279(100); r (KBr Diac)/ca-1 3423, 1717, 1695 and 1171. f) f Pvglflvl-4-wthvl) 3.4-tiiarthvlPvrrQlPf 3.2-bl carto«Pl8-2- fiAEtasuolAfc* waa obtainad froa tha raaetion of tha ialdasolida intaraadiata with 4-pyridylearbinol. Chreastography (aluting with athyl aoatata/patrol, gradient 60%, 80%, 100% athyl aeatata, than methanol/ethyl acetate, gradient 10%, 20%) followed by raeryatalllaation froa tatrahydrofuran gava orange eryatala (0.168 g, 46%) with a.p. >240°C(decoap.) (Pounds C, 72.16} H, 5.12; N, 10.73. C23H19N302.0.7H20 raquires C, 72.31; H, 5.38; M, 11.00%); 5B([2H6)-OMSO 11.31 (1H, s, 1-NH), 10.62(1H, a, 5-NH), WO 94/02483 - 46 - PCT/GB93/01S*'' 8.62 (2B, dd, J 4.8, 0.8, 2'-H, 6'-H), 8.08 (IB, d, J 7.8, 9-H), 7.89 (IB, a, 10-H), 7.83(2B, d, J 8.8, 3'-H, I'-H), 7.32-7.43 (2H, a, 6-H, 7-H), 7.07 (IB, ddd, J 8, 8, 1, 8-H), 8.48 (2H, ■, ArCHg) and 2.94 and 2.92 (2.x 38, 2 x 3-CBj and 4-CH^)j m/s (%) 369(27, (8*1)*), 327(70) and 298(100)} ^(Jdt Diaci/ea"1 3400, 1709 and 1232. 9) n iB-n'^ryTmnmrairrMt 1*-'"ri^hYlTrm'n,"r'l'3-K,w'-K*"0~0- o.rbowl.f waa obtainad froa tha 1.8 aaol aeala raaetion of tha iaidaiolida intermediate with (l,3-dibansyloxy-2-propanol). Chromatography (aluting with 20% athyl aeatata/80% toluana than 40% athyl aeatata/60% toluana) followad by raoryatalliaation from athyl aeatata-athar-patrol gava yallow eryatala (0.776 g, 97%) m.p. 124.8-126°C (dacomp.) (rounds C, 76.38} H, 6.07} N, 8.12. C34H32N2°4 rfl?u*'r*s C, 76.67} H, 6.06} N, 8.26%} 0R( [ Hg)-DMS°) 11.18 (IB, a, 1-NH), 10.60 (IB, a, 5-NH), 8.06 (IB, 4, J 7.8, 9-B), 7.88 (IB, a, 10-H), 7.22-7.42 (12B, m, 2 x PhHj, 8-H, 7-H), 7.07 (1H, ddd, J 8, 6.8,1.8, 8-H), 8.44 (1H, quintal:, J 8, l'-B), 4.60 and 4.83 (2 x 2H, 2 x dd, J 12, 2 x PhCBjO), 3.77 (4H, d, J 8.8, OCBfCB^) and 2.91 and 2.89 (2 x 3H, 2 x a, 3-CBj and 4-C8^)} m/s(%) 832(80,8*), 260(68) and 91(100)1 F (Or Diae)/ea~1 3388, 1681 and 1234. h) r 4-Mthvl«ttlt>hlnvlah«nvl 1 3.4-H«—»h~i ^yrrolo f 3 ■ 2-b 1 parbaanl—2-B8rtQIYl»t> waa obtainad from tha raaetion of the ialdasolida intaraadiata with 4 asthylaulphinylphanol. Chroaatography (aluting with athyl' aeatata/patrol, gradiant 90%, 98%, 98%, 100V athyl aeatata, than 10% aathanol/athyl aeatata) followad by raeryatalllaation froa tatrahydrofuran gava a yallow powder (0.261 g, 63%) a.p. >230°C (daeeap.) (Founds C, 68.40} H, 4.81} N, 6.44. C24H20N2038.0.3H20 raquiraa C, 68.32} H, 4.92} N, WO 94/02483 - 47 PCT/GB93/01512 6.64%; 6h((2H€)-DMSO) 11.59 (IB, a, 1-NH), 10.68 (IB, S, 5-HH), 8.10 (IB, d, J 8, 9-H), 7.93 (1H, a, 10-H), 7.82(2H, d, J 9.5, 3'-H, B'-H), 7.19 <2H, d, J 9.5, 2'-H, 6'-H), 7.33-7.48 <2H, a, 6-H, 7-H), 7.09 (1H, ddd, J 8, 6, 2.8, 8-H), 2.99 and 2.98 (2 x 3H, 2 it a, 3-CHj and 4-CB}) and 2.82 (3H, a, CHjftO); m/t (%) 417(2,M+l*), 261(100) and 233(78); v (Mr Dieo/ea"1 3427, ux 3288, 1717 and 1200. 1) HttttlVl 3.4-tllMfhYlrywfalof 3»2-bl a»gh*»al—3-flarbowvlaf was obtainad froa tha raaetion of the iaidaaolida intaraadiata with aathanol. Chroaatography (aluting with 30% athyl aeatata/patrol), followad by reeryatalliaation froa athyl aeatata gava a yallow powder (0k88g, 64%) with a.p. 211-213°C (daosap.) (Pounds C,74.06, H, 5.49, N,9.42, r#*uirMI C, 73.98; H, 5.52; H, 9.58%); dR((2H6)-DH80) 11.25 (1H, a, 1-NH), 10.62 (1H, a, 5-NH), 8.08 (1H, d, J 8, 9-H), 7.89 (IB, a, 10-H), 7.33-7.58 (2H, a, 6-H, 7-H), 7.09 (1H, ddd, J 8, 6, 1, 8-H), 3.92 (3H, a, OCH^), 2.92 and 2.91 (2 x 3H, 2 x a, 3-CH3 and 4-CBj); a/s (%) 292(68, M*), 260(100), 232(39); (KBr diaO/ea'1 3342, 1684 and 1236. j) f f 2-Hethvliulphonvl lethvn3.4-di«ethvlpvrrolo13.2-b 1 c*rb«»ol«-2- attwffUtt Naa obtainad froa tha raaetion of tha iaidaaolida intaraadiata with (2-aathylaulphonyl) athanol. Chroauitography (gradient elution with ethyl aeatata/petrol, 30% - 100%) followed by raeryatalllaation froa aeatona gava fine yellow eryatala (0.222 g, 88%) with a.p. 258—287°C (deeoap.) (Pounds C, 62.23; H, 8.25; N, 7.08. C20H20n2°4* r#*uir** c' 62*4®» 5.24; N, 7.-29%); iH(2H6)-DH»° 11.19 (1H, B, 1-NH), 10.60 (1H, S, 5-NH), 8.09 (IB, d, J 7.5, 9-H), 7.89 (IB, a, 10-H), 7.32-7.45 (2B, a, 6-H, 7-B), 7.09 (IB, ddd, J 7.5, 5.5, 3, 8-H), 4.69 (2H, t, J 5.5, 0CH2), 3.69 (2B, t, J 5.5 , 802CH2), 3.12 (3H, a, S02CB2), 2.93 (6H, a. WO 94/02483 48 - PCT/GB93/015'*> 3-CHj and 4-CH_); a/a («) 384 (17, M+), 260(13), 89(100); p (KBr dlae)/eB 3387, 1661, 1234. k) Tarfc-butvl a. hvlnvrrolor 3-3-blaarba«ola-2-oarbo«vlata Tha pyrrolof3,2-b)oarbaaola-2-oarboxylie aoid (0.86 aaol) and triphanylphoaphina (0.91 aaol, 1.08 aq.) wara diaaolvad in fraahly diatillad tatrahydrofuran undar a nitrogan atmoaphara. Tartlarv-butanol (2.12 aaol, 2.B aq.) waa addad by ayringa, and finally diathyl asodiearboxylata (0.95 wool, 1.1 aq.) waa addad dropwiaa ovar 10 ninutaa. Tha raaulting auapanaion waa atirrad at rooai taaqparatura for two hour a, by whieh tiaa TLC ahowad complata consumption of tha atarting acid. Tha titla compound waa obtainad froa tha oruda raaetion nixtura in aavaral atagaai ooluan chroaatography on ailica, aluting with 20% athar/80% patrol than 50% athar/50% patrol; column chromatography on ailioa (aluting with 28% athar/75% patrol than 40% athar/60% patrol); and finally, raorystalliaa- tion froa DCM gava yallow powdar (0.030 g, 10%) a.p. 187-189°C (daeoop.) (roundi C, 73.24; H, 6.53; M, 7.93. Cj HjjMjOj.O.ISCHjClj raquiraa C, 73.18; H, 6.47; N, 8.07%); &a(( H6)-DMSO) 10.95 (1H, a, 1-NH), 10.57 (IB, a, 5-NH), 8.05 (1H, d, J 8, 9-H), 7.88 (IB, a, 10-H), 7.29-7.43 (2H, a, 6-H, 7-B), 7.05 (1H, ddd, J 8, 6, 1, 8-H), 2.89 and 2.87 (2 x SB, 2 x a, 3-CB3 and 4-CB3) and 1.59 (9B, a, C(CB3)3); a/a (%) 355(62, M+l*), 278(90), 233(38), 126(32), 91(78) and 57(100); (^(XBr Diae)/ea"13337, 1664 and 1240. FKITOII 7 Pvrrolol3.2-b 1e«rba«ola-2-carbiMcvllc Acid Amldas t t a) 3„4-Dia*thvl-2-i 1-ialdaKol vcarbonvl 1 cvrrolo f 3.2-b 1 carb««ol« 3,4—Dimathylpyrrolo[3,2-b)carbaaola-2-oarboxylie aeid (0.280 g, I.0 aaaol) and &,&'-carbonyldilaldaaola (0.164 g, 1.0 nol) wara disaolvad in frashly diatillad tatrahydrofuran (5 ca^) undar a WO 94/02483 49 PCT/GB93/01512 nitrogen ataoaphere. Tha raaulting auapanaion waa atirrad at rooa taaparature for two hours, and oomplata conversion of tha aeid to tha iaidaaolida waa verified by TLC. The THF waa removed and tha reaidua raerystalliaad froa ethyl acetate to give tha product aa a yellow aolid (0.125 g, 38%) a.p. 252°C (deeoap.) (rounds C, 73.17; B, 4.87; H, 16.80, , jo u 4 requireet C, 73.IB; B, 4.91; N, 17.06%); &H((B6)-DM80) 11.B3 (IB# a, 1-NH), 10.20 (IB, a, 5-NB), 6.30 (IB, a, 8.12 (IB, d, J8, 9-H), 7.94 (IB, a, 10-H), 7.79 (IB, a, 5'-B), 7.33-7.47 (2B, a, 6-H, 7-B), 7.19 (IB, a, 3'-H), 7.09 (IB, ddd, J8, 6, 2, 8-H), 2.9S (3B, a, 3-CH3), 2.73 (3H, a, 4-C»3); a/s (%) 261 (40); f^fKBr Disc)/cm"1 3427, 1699 and 1242. b) a. nvrrolol 3.2-b 1 e»rb.«aU. 2-carboxamlda 3,4-Diaathylpyrrolo[3,2-b)earbasole-2-oarboxylie acid (0.278 g, 1.0 aaol) waa diaaolvad in diaathoxyathana (10 ca3) to give a yellow aolution. To thia were addad diiaopropylethylamina (0.260 g, 2.0 aaol), ethylaaine hydrochloride (0.24B g, 3.0 nnol) and the tetrafluorborata aalt of 0-bensotriasolyl-H,H,]i', H'- tetraaathyluroniua (TBTO) (0.482 g, 1.5 naol) to give a white auapenaion in the yellow aolution. The reaction aixture waa atirrad at room taoperature for 24 h by whieh time TLC ahowad no reaalnlng aeid. The aolvent waa removed in vacuo to give a yellow-brown aolid. This was subjected to column chroaatography on ailica aluting firatly with DCM and than with 10% ltOAc/90% DCM to give the ethylaaide product aa a yellow aolid (0.240 g, 79%). To raaova a trace impurity, a portion waa reeryetalliaed froa diehlororethane/petrol to give the compound analytically pure aa a yellow powder with a.p. 235°C (dacomp.) (Foundi C, 73.21; B, 6.10; N, 13.33. C19H19H30.0.1C2B4C12 requireet C, 73.15; B, 6.20; N, 13.32%); dR((2B6)-DM80) 10.72 (IB, a, 1-NH), 10.57 (1H, a, 5-NH), 8.09 (1H, d, J8, 9-H), 7.93 (1H, t, J5, aaide N-B), 7.83 (1H, a, 10-H), 7.27-7.41 (2B, a, 6-H, 7-B), 7.06 (IB, d, J8, 8-H), 3.35 (2B, q, J 7.5, CBjCH^, WO 94/02483 - SO - PCI7GB93/015'" 2.89 and 2.71 (2 x 3H, 2 x a, 3-CH3 and 4-CHj), 1.18 (3H, t, <7 7.S, CH2qa3)l m/s (%) 305 (65,M+), 260 (100); (KBr Disc)/cm-1 3314, 1603 and 1545. c) * a-n<^^vipvrpfliaf3.a.hlb»fh»«olo-2-e*pbp»>ibld« 3,4-Dimethylpyrrolo(3,2-fe)earbasole-2-carboxylic aeid (0.556 g, 2.Pimm 1) waa diaaolvad in dimethoxyethana (20ol) to giva a yallow aolution. To this wara addad diisopropylathylamine (0.520 g, 4.0 nmol), aunonium hydrochlorida (0.321 g, 6.0mmol) and tha tatrafluorborata aalt of 0-bensotriasolyl-H,]i,ir,H'' -tetramethyluronium (TBTD) (0.963 g, 3.0nmol) to giva a whlta suspenaion in tha yallow aolution. Tha raaction mixtura waa atirrad at room tamparatura for 24 hours, by which time TLC ahowad no ramaining acid. Tha aolvant was removed In vacuo to give a yellow-brown eolid. Thie waa aubjected to column chromatography on ailiea (aluting with athyl acetate/DCM, gradient 10%-30%) to give the amida product ae a yallow solid (0.350 g, 63%). To remove a trace impurity, a portion waa recryatalliaed from ethyl acetate/petrol and than purified by preparative BPLC (column aise 25 cm x 2.12 cm i.d., packed with Cfl Zorbax, gradient elutions 5% acatonitrile/95% water to 95% acatonitrile/watery defected at 340 na) to give a yellow powder with m.p. 240°C (decomp.) d_((2H,J-DMSO) 10.82 (IB, e, 1-NH), n © 10.54 (IB, a, 5-NB), 8.08 (IB, d, J 7.5, 9-H), 7.84 (1H, a, 10-H), 7.29-7.43 (4B, m, 6-B, 7-B, NHj), 7.07 (IB, ddd, J 8, 5.5, 2, 8-H), 2.89 and 2.85 (2 x 3B, 2 x a, 3-CH3 and 4-CH3); m/s (%) 277 (62, K+), 260 (100), 232 (44)) ^ (KBr diacj/eaf1 3317, 1628, 1595) (rounds M+, 277.1205, C17H15N30 requires 277.1215). f * d) Phenyl 3.4-dimathvlpvrrelof3.2-fr)Clrt«gl»-2-Ctrt0X«Bldl 3,4-Diaethylpyrrolo(3,2-)2)carbasole-2-carboxylic acid (0.278 g, 1.0 mmol) was diaaolvad in dimethoxyethana (10ml) to give a WO 94/02483 - 51 - PCT/GB93/01512 yallow aolution. To thia wara addad diisopropylethylamina (0.130 g, l.Ommol), anilina (0.190 g, 2.0mnal) and tha tatrafluorborata aalt of O-bansotriaaolyl-KrHtfi' »H'#-tatra-aathyluronlua (TEXU) (0.4*2 g, l.Baaol) to giva a whlta auapanaion in tha yallow aolution. Tha raaetion mixtura was ■tirred at room tamparatura for 42 houra, toy whieh tiaa TLC ahowed no rasuining aeid. Tha solvent waa removed Aa Mtluo to giva a yallow aolid, whieh waa diaaolvad in athyl aeatata and the reaulting aolution waahed with water. Tha organic layer waa dried over MglO^, concentrated, and aubjected to column chromatography on ailica, aluting with KtOAc/patrol (gradient elution 5%-100%<) followed toy recryatalliaation from acetone to giva the phenylamide product aa a yallow powder (0.10 g, 30%) with m.p. 260°C (decamp.) (round> c, 77.79; H, 5.26; N, 11.64. C23U19N3° r*Quirast c» 78.16; H, 5.42; N, 11.89%); $H(t2H6J- DM80) 11.10 (IB, a, 1-NH), 10.59 (1H, ■, 5-NH), 9.96 (1H, a, amide N-H), 8.10 (1H, d, J 7.5, 9-H), 7.89 (IB, a, 10-H), 7.79 (2H, d, J 9, 2'-H, 6'-H), 7.29-7.45 (4H, m,6-H, 7-B, 3'-B, 5'-H), 7.00-7.14 (2R, m, 8-H, 4'-H), 2.93 and 2.88 (2 x 3H, 2 x a, 3-CH.); m/s (%) 353 (46, M+), 260 (100); V (KBr diaej/cm"1 j mix 3310, 1614, 1595 and 1317. a) 3.4-Dlmathvl—2—I hvdraglnocarbonvl \ pvrrolo f 3.2-1 carhagola Bthyl 3,4-dimethylpyrrolo(3,2-b)carbaxole-2-carboxylate (500 mg) and 95% hydrasine (5 cm3) were stirred and heated at 120°C for 6h in a Reedi-Vial. The mixture was allowed to stand overnight, cooled in ice and filtered. The resulting yellow solid was waahed carefully with water and dried. Yield of titla compound 350mg>' (73%), no eharp m.p. but decompoeaa at 285°C. (round: c, 69;19; B, 5.57; N, 19.38. Calc. for C^H^N^O. O.lHjO requires C, 69.42; H, 5.55; M, 19.05%); fil'H.)-DMSO) 10.80 (IB, s, n o exchangeable, MB), 10.55 (IB, s, exchangeable, NH), 9.20 (IB, a, exchangeable, NH), 8.06 (IB, d, J7.5 9-H), 7.81 (1H, s, 10-H), WO 94/02483 52 PCT/GB93/015*'* 7.42-7.28 <2H, a, 6-H and 7-B) 7.12-7.01 (1H, m, 8-H, 4.5 (2H, br, m, exchangeable, NHg), and 2.4 and 2.3 (2 x m, 4-CK^ and 3-CH3), m/s 293 <H+1)+, VAB)). amu a 2-Aeatvl-3.4-djjaathvlovgrolo f 3.2-b1 c*rbatol. 8tn l 2,4-Diacaty1-3,5-dlnathylpyrrola waa praparad from aeatylaoatona and hydroxylanine-O-aulphonic acid according to tha procadura of Y.Tamura, 8. Kato and M.Xkeda (Cham 6 Xnd., 1971, 767). 8tW 2 2-Xcatoxvnethvl-3.5-dlae*tvl-4-«*fchvlnvrgola To a atirrad mixture of 2,4-diacaty 1-3,5-diawthylpyrrola (1.0 3 g), dichloromathane (35 ca ) and potaaaiun carbonate (7.73 g) at 0-5°C waa addad a aolution of aulphuryl chloride (0.79 g) in dichloromathane (IS en3). The tenperature of tha nixtura waa maintained at 0.5°C during tha addition toy external cooling and than the nixtura waa atirrad at thia temperature until adjudged complete by t.l.c. (ea 2h). Tha mixture waa than filtered and evaporated to give crude 2-chlorcoethyl-3,5-diaeetyl-4-methyl-pyrrole. This material waa diaaolvad in acetic aeid (10 em3), aodium aeatata (1.83g) added, and then nore acetic aeid (10 em3) added. The adxture waa atirrad overnight at room temperature, evaporated jjQ XABlfi, and the reeidue atirrad with ice-cold water for 2h. A eolid waa collected by filtration and the filtrate extracted twiee with ethyl aeatata. The 'extracta were dried (Mg804), evaporated and the reaidue combined with the aolid above, to give the crude product. Chromatography on ailiea elating with ethyl aeetate-hexene (Isl) gave 0.075 g. of pure product an an off-white aolid n.p. 112.5-114.5°C* m/z 238 WO 94/02483 - 53 - PCT/GB93/01512 (M++l, FAB), 6b, CDC13) 2.16 (3H, a, OCOCH3), 2.50 (3H, a, CHj), 2.53 (3H, a, CH3)# 2.62 (3H, a, CH3), 5.38 (2H, a, OCHj). ttlLi To a solution of 2-aeatoxymathyl-3,S-diaeatyl-4-mathylpyrrola (0.200 g) and indola (0.098 g) in dichloroathana (90 en3) waa addad Montmorillonita K10 clay (0.30 g). Tha mixtura waa atirrad and haatad at raflux for 80 h. Aftar cooling tha clay waa removed by filtration and tha filtrata concantratad to ea 20 3 em vacuo. Tha crude product waa ramovad by filtration and than chromatographad on' ailica. Elution with chloroform- mathanol (60il) yialdad 0.08 g of tha titla compound aa a yallow aolid m.p. 258-260°C, m/a (II) 276 (M+) 6_( (2H,]-DHS0) 2.58 n © (3H, a, COCHj), 2.88 (3H, a, CHj), 2.92 (3H, a, CH3), 7.05 (1H, m, 8-H) , 7.38 (2H, m, 6-H, 7-H), 7.85 (1H, a, 10-H), 8.08(1H, J, 8 Ha, 9-H), 10.6 (1H, a, HH), 11.17 (1H, a, NH). (Poundi C, 77.0; H, 5.74; N, 9.76; C18R16N2°' 0,14 BtOAc raquiraa C, 77.2; H, 5.98; N, 9.70*.) 9 Ethvl 1.5-dlhvdroindenof 2.1-f1lndole-2-cagboxvlef st«p 1 Ethvl 2-»gido-3-fluofn-2-vlacrvlat« Sodium (1.7aq) waa addad to abaolute ethanol atirrad undar nitrogen at room tamparatura. Whan diaaolution waa complete tha raaction waa cooled to -10°C and fluorana-2-earboxaldahyda (laq) and athyl aaidoaeatata (3aq) diaaolvad together in tha minimum of tatrahydrofuran ware addad dropwiaa. Tha mixtura waa atirrad at -10°C for 20h and than quanchad by tha addition of WO 94/02483 - 54 - PCT/GB93/015* "* water and dichloromathane. Th* combined organic extract! wara driad (Mgso^) and evaporated in vacuo. riaah chroaatography yialdad tha pura product (37%) v (CHC1,)/cm-1 2120 and 1765. imw j 8tw 2 Ethyl 2-asido-3-fluoren-2-ylacrylate auapandad in dry toluana waa haatad at raflux for Ih, and tha raaulting aolution waa than avaporatad to drynaaa ia vacuo. Tha raaulting .mixtura of athyl l,5-dihydroindino(2,1-X) indole-2-carboxylate and athyl l,10-dihydroindino[l,2-s]-indole-2-carboxylate waa cryatalliaad from athanol, thua ramoving moat of tha [1,2 a) iaomar and laaving tha titla compound (oontaminatad with approximately 30% of tha [ 1,2-s] iaomar) in tha mothar Iiquora whieh wara avaporatad to drynaaa. 6^ (CDCl^) 9.11 (1H, a, br, 1-NH), 7.82-7.76 (3H, m), 7.56-7.52 (1H, m), 7.37 (H, dd, J 1 and 7), 7.34-7.28 (1H, a), 7.25 (1H, dd. J 1 and 2), 4.45 (2B, q, OCB2CH3), 3.97 (2H, a, CB2) and 1.46 (3H, t, OCHgCBj). Exampla 10 Effact of compounda of tha invantion in datranaformation ("flattening") aaaay using HT1080acc2 and HT10801c call linaa. Call Linaa and Culture Condltlona Transformed and revertant HT1080 sub-linaa, HT1080acc2'and HTlOSOlc wara obtainad from tha Inatituta of Cancer Raaearch, Cheater Beatty Laboratoriee, rulham Road, London. They were maintained routinely in Dulbeoco'a Modified Eagle'a Medium (DMSM) aupplemented with 10% foetal calf aerum (PCS) and 1% penicillin/streptomycin solution containing 10,000 unite per ml. All reagenta were obtainad from Gibco Ltd. WO 94/02483 - 85 - PCT/GB93/01512 • o Calls war* ineubatad in tiaaua culture grada plaatic vaaaals at 37 c in 5 pareant CO^ in air. ftgiiv for BBBMMlfl artlTttY Aaaaya for call prolifaration/cytotoxlty wara carriad out in tiaaua uultura grada 96 wall microtitra plataa (Coatar). Calla in log growth 3 wara addad to tha plataa at a eoneantration of 1x10 calla par wall on day 0 and aarially dilutad compounda wara than addad on day 1. Plataa wara than ineubatad at 37°C in 5% CO^ in air for a furthar 4 daya. For quantitation of call growth, tha mathylana blua biomaaa staining mathod waa uaad, tha taat baing raad on a Multiaean plata raadar at wavalangth of 620na. Tha morphology of tha calla waa chackad microacopically undar phaaa-contraat imnadiataly bafora tha fixation and ataining with mathylana blua, and by ordinary light microaoopy tharaaftar. XC50 valuaa for aotiva compounda wara obtainad uaing tha computar prograana, 081 and doaa-raaponaa alopaa wara alao plottad. Whan compounda wara taatad for activity in a colony forming aasay tha mathoda uaad wara idantical to thoaa daacribad aarliar axcapt that aarially dilutad compound waa addad to tha a loppy agar whan tha taat waa aat up, and raplaniahad at tha aama eoneantration on day 7. Tha taat raaulta wara raad on day 14. rfultl comoaratlva growth and morphology of HT10B0aee2 and HTlOBOlc Growth ratas in taxaa of call numbar wara aimilar for both Una a to day 4 but tharaaftar HT1080aec2 calla continuad to divida to raach saturation danaitiaa approxiaataly 2 to 3 timaa highar than HTlOBOlc by day 5. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 94/02483 - 56 - PC17GB93/01? Phenotypic differences batwaan tha 2 linaa wara clearly avidant. HTlOBOlc calls diaplayad a orach flatter morphology than tha transformed calls and only a fsw mitotic calls wara seen in confluent araas of tha cultural. HT1080soc2 calls however continuad to divide with nuaarous mitotio calla visible aftar confluanca. « * Grown undar anchorage independent conditions in soft agar, HT10B0soc2 produced aavaral large colonias whereas HT10801c calls failsd to produce any coloniaa greater than 0.1am in diameter. at Mlicttd gflBwandB A number of compounds of the invention were evaluated againat the cell linea. The compounda of tha invention exhibited low toxicity with IC50 values in tha range SO-lOOpM. Below the resulta of tha "flattening" aaaay for compounds of call invantion ara shown*- The compounds ara effective at achieving "flattening" ie de-transfonset ion, at levels aignifieantly below their toxicity level. r The aaam compounds were also tested in assaya using MCF7 human breaat cancer cells, A431 epidermoid carcinoma celle and A285 melanoma calla. in all caaas tha compounds war* affective in the range 1-5/iM. compound Example 3 8cc2 flattening fuml 0.04 0.04 0.04 0.8 0.B 25 25 Bxample 4(a) Example 4(b) Example 4(f) Example 4(e) Example 4(h) Example 4(g) 254207 WHAT WE CLAIM IS: 1. A compound of the formula (I) R 6 W- R 5 R (I) and salts and physiologically functional derivatives thereof, wherein A is X is 0,S,S0,S02,CHa, CO or NR7, wherein R7 is H, C^k, alkyl, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, aryl containing up to 10 carbon atoms, alkenyl, Ci.10 acyl, ai:%ynyl, or sulphonyl, optionally substituted by Cx.10 alkyl, aryl containing up to 10 carbon atoms or aralkyl containing 1 to 4 carbon atoms o 2 - 58 - 254207 in the alkyl portion and up to 10 carbon atoms in the aryl portion; Y is 0, S, SO, S02» CH2, CO or NR7; R1 is COR8, COOR®, CHO, CH2OH, CH2OR9, CONH2 f CONHNR^R11, CONHR10, CONR10Rn, COO (CH2)nNR10Rn wherein R8 is H, C^^ alkyl, aryl containing up to 10 carbon atoms, and optionally substituted by C^k, alkyl, C^^ alkoxy, halo, sulphinyl, amino (optionally substituted by one or tv.'o Ci.io alkyl groups) , haloalkyl, sulphonyl or cyano or aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, R9 is C^o acyl optionally substituted by C^^ alkyl, C^io alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C^q alkyl groups) , haloalkyl, sulphonyl or cyano, R10 and R11 are independently hydrogen, Cj.^ alkyl or aryl containing up to 10 carbon atoms and n is 1 to 4; R2 is H, COOR8, Ci.jQ alkyl, aryl containing up to 10 carbon atoms and optionally substituted by C^q alkyl, ci-io alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C^o alkyl groups) , haloalkyl, sulphinyl or cyano or CH2CH2C02R12 wherein 12 R is C^iQ alkyl or aryl containing up to 10 carbon atoms; R3 and R4 are independently H, hydroxy, C^^ alkyl, haloalkyl, C^^ alkoxy, halo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl substituted by C1.10 MZ. f,-. rr 1 3 FEB 1997 254207 59 alkyl, C^o alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C^,, alkyl groups) , haloalkyl, sulphonyl or cyano, carboxyl or COaR13; R5 is H, Ci.io alkyl, optionally substituted by alkyl, Ci.jo alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C^q alkyl groups) , haloalkyl, sulphonyl or cyano, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, nitro, amino, halo, cyano, CHO or COOR8; Rs is H, Cj.!,, alkyl, aryl containing up to 10 carbon atoms, aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, nitro, halogen, CHO or COR13 wherein R13 is Cx_ 10 alkyl or aryl containing up to 10 carbon atoms with the proviso that (i) when R2, R3, R4, R5 and R6 are all H and A is i wherein Y is NH and X is 0 or S, then R1 is not C02H or C02Et ; (ii) when R2, R3, R4, R5 and R6 are all H and A is - 60 - 254207 wherein Y is NH, and X is 0 or S then Rl is not CHO; (iii) Y is not O when X is 0; (iv) when Ra to Rs are all H, A is or \= \, wherein X is S and Y is NH, then R1 is not CHO; (v) when R2 to R6 are all H, and A is \L, V \o, 25420 wherein X and Y are both NH, then R1 is not C02H or C02Et; (vi) when Ra to R6 are all H, and A is 2 wherein X is CH2 or CO and Y is NH, then R1 is not C02H or C02Et and ; (vii) when R2 to R6 are all H, and A is wherein X is S or O and Y is NH, then R1 is not C02 or C02Et. 2. A compound according to Claim 1 in which t .... i 1 3 FEB 1997 i 25420 X is 0, S or NR7, wherein R7 is H, Cj,.10 alkyl, sulphonyl or toluene sulphonyl; Y is NR7; R1 is COR8, COOR8, CHjOR9, CONHa, CONHNR10 Ru, CONHR10, CONR10 Ru, COO (CHa) „ NR10 R11 wherein R8 is H, Cx.10 alkyl, aryl containing up to 10 carbon atoms, and optionally substituted by C^o alkyl, C1.10 alkoxy, halo, sulphinyl, amino (optionally substituted by one or two Ci^o alkyl groups), haloalkyl, sulphonyl or cyano or aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion, R9 is Cx.10 acyl optionally substituted by C alkyl, C^o alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C^io alkyl groups), haloalkyl, sulphonyl or cyano, R10 and R11 are independently hydrogen, Cx.10 alkyl or aryl containing up to 10 carbon atoms and n is 1 to 4; R2 is COua8, Cx.10 alkyl or CH2CH2C02R12 wherein R12 is Cx_ 10 alkyl or aryl containing up to 10 carbon atoms; R3 and R4 are independently H, hydroxy, Cx. 10 alkyl, Cx.10 alkoxy, halo, cyano, alkyl substituted by ci-io alkyl, Cj.!,, alkoxy, halo, sulphinyl, amino (optionally substituted by one or two C)_.10 alkyl groups), haloalkyl,sulphonyl or cyano or carboxyl; R5 is H or Ci.jo alkyl; 254207 - 63 - R® is H, Cx.io alkyl or aryl containing up to 10 carbon atoms; together with salts and physiologically functional derivatives thereof. A compound according to Claim 1 or 2 in which X is S or NH; Y is NH; A is \2 R1 is COOR* wherein R* is C^,, alkyl, or aralkyl containing 1 to 4 carbon atoms in the alkyl portion and up to 10 carbon atoms in the aryl portion; Ra is H or Ci^o alkyl; R3 is H, Ci^o alkoxy, or halo; R4 is H, Cx.10 alkoxy or halo; R5 is Ci.m alkyl; Rs is hydrogen; and salts and physiologically functional derivatives thereof. 254207 - 64 - A compound selected from 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 -1rimethylpyrrolo[3,2-fa]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£]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-: -carboxylate; benzyl 3,4,6-trimethylpyrrolo[3,2-b]carbazole-2- carboxylate; f c ; n';1 65 254 ethyl 3,4, 6-trimethylpyrrolo [3,2, ia] 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-mcthoxy-3,4-dimethylpyrrolo[3,2-h]carbazole-2-carboxylate; 3,4,6-trimethylpyrrolo[3,2-b]carbazole-2-carboxylic acid; and benzyl 8-methoxy-3,4-dimethylpyrrolo[3,2-b]carbazole-2-carboxylate; and salts and physiologically functional derivatives thereof. Ethyl 3,4-dimethylpyrrolo!3,2-b]carbazole-2-carboxylate; and salts and physiologically functional derivatives thereof. A pharmaceutical formulation which comprises a compound of formula (I) according to any one of Claims to 5 together with a pharmaeeutieally acceptable carrier thereof. 1 3 FEB ffl? 25 420 7 7. A compound of formula (I) according to any one of Claims 1 to 5 for use in medicine. 8. use of a compound of formula (I) as claimed in any one of Claims 1 to 5 but including the disclaimed compound of disclaimer (iv) to (vii) or a pharmaeeutieally acceptable salt or physiologically functional derivative thereof in the manufacture of a medicament for the treatment of tumours. 9. A process for preparing compounds of general formula (I) as described in Claim 1 which process comprises: (a) catalysed ring closure of compounds of formula (IV) in the presence of a strong acid 6 R 3 R 5 (IV) wherein X, Y, R1, Ra, R3, R4, R5, and R6 are as defined in Claim 1; or (b) conversion of one compound of formula (I) into another compound of formula (I). - 67 - 10. Compounds of the formula (IV): 25420 v 7 r ^ 1 -r r R3 (IV) wherein X, Y, R1, R2, R3, R4, R5 and R* are as defined in Claim 1 . DATED THIS DAY OF A. J^PARK.& SON ' PER agents for th^ iramts </div>