WO1995021171A1 - Tricyclic derivatives and their use as anti-cancer agents - Google Patents
Tricyclic derivatives and their use as anti-cancer agents Download PDFInfo
- Publication number
- WO1995021171A1 WO1995021171A1 PCT/GB1995/000203 GB9500203W WO9521171A1 WO 1995021171 A1 WO1995021171 A1 WO 1995021171A1 GB 9500203 W GB9500203 W GB 9500203W WO 9521171 A1 WO9521171 A1 WO 9521171A1
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- Prior art keywords
- alkyl
- compound
- aryl
- coor
- indole
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- 0 *C1=C(*)c2c(*)c(CC=C3)c3c(*)c2*1 Chemical compound *C1=C(*)c2c(*)c(CC=C3)c3c(*)c2*1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to heterocyclic compounds which have been found to have anti-tumour activity. More specifically, the invention concerns benzo[1,2-b:4,5-b']dipyrroles, benzo[1,2-b:5,4-b' dipyrroles, cyclopent[f]indoles, benzo[1,2-b:4,5-b']difurans, benzo[1,2-b:5,4-b']difurans, 2H-indeno[5,6-b]furans, benzo[1,2-b:4,5-b']dithiophenes, benzo[1,2-b:5,4-b']dithiophenes, cyclopent[f]indenes and 5H-furo[2,3-f]indoles methods for their preparation, pharmaceutical formulations containing them and their use as anti-tumour agents.
- anti-tumour agents which have differing degrees of efficacy.
- Standard clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cis-platinum, vincristine and vinblastine.
- these presently available anti-tumour agents are known to have various disadvantages, such as toxicity to healthy cells and resistance to certain tumour types.
- novel compounds which exhibit anti-tumour cell activity including a group of novel compounds which exhibit anti-tumour cell activity with low toxicity against normal cell lines.
- the present invention provides a compound of the general formula (1)
- X is O, S, SO, SO 2 , CH 2 , CO or NR 7 , wherein R 7 is H, alkyl, aralkyl, aryl, alkenyl, acyl, alkynyl, sulphonyl, substituted sulphonyl, or COOMe;
- Y is O, S, SO, SO 2 , CH 2 , CO or NR 7 ;
- R 1 is COR 8 , CHO, CH 2 OH, CH 2 OR 8 , CONH 2 , COOR 8 , CONHR 8 , CONR 8 R 9 , CSOR 8 , CSSR 8 , COSR 8 , CSNHR 8 , CSNR 8 R 9 , CNHOR 8 wherein R 8 and R 9 are independently hydrogen, alkoxyalkyl, heterocycloalkyl, heteroaralkyl, or C 1-10 optionally substituted hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain; or R 8 and R 9 are a sugar group.
- R 2 is H, halo, cyano, COOR 8 , alkyl, aryl, alkenyl, alkynyl, alkoxy, (wherein alkyl, aryl, alkenyl, alkynyl and alkoxy can be substituted) or CH 2 CH 2 CO 2 R 12 wherein R 12 is alkyl or aryl;
- R 3 is H, alkyl, halogen, cyano, amino, COOR 8 , CONHR 8 , COR 8 , CH 2 OH, CH 2 OR 8 , CONH 2 , CONR 8 R 9 , CSOR 8 , CSSR 8 , COSR 8 , CSNHR 8 , CSNR 8 R 9 or CNHOR 8 ;
- R 4 is H, halogen, cyano, amino, alkyl, COOR 8 , CONHR 8 , COR 8 , CH 2 OH, CH 2 OR 8 , CONH 2 , CONR 8 R 9 , CSOR 8 , CSSR 8 , COSR 8 , CSNHR 8 , CSNR 8 R 9 or CNHOR 8 ;
- R 5 is H, hydroxy, aryloxy, aralkyloxy, alkyl, substituted alkyl, aralkyl, nitro, amino, halo, cyano COOR 8 or CHO;
- R 6 is H, aryl, alkyl, aralkyl, nitro, halogen, CHO or COR 13 wherein R 13 is alkyl or aryl; wherein R 8 is not H when R 2 is H and R 3 is not H or Me when A is
- Alkyl groups present in general formula (I) may be straight or branched chain alkyl groups, and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, t-butyl and the like.
- Acyl groups may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable acyl groups include ethanoyl and propanoyl groups.
- Alkoxy may be straight or branched and may contain 1-10 carbon atoms and suitably 1-6 carbon atoms. Examples of suitable alkoxy groups include methoxy, ethoxy and the like.
- Aryl includes both carbocyclic aryl groups and heterocyclic aryl groups normally containing a maximum of 10 ring atoms.
- Carbocyclic aryl groups include, eg phenyl and naphthyl and contain at least one aromatic ring.
- Heterocyclic aryl groups include eg thienyl, furyl, pyridyl, indole and guinoline rings.
- An aralkyl group may contain from 1 to 4 atoms in the alkyl portion and the aryl portion may be a carbocyclic or heterocyclic aryl group.
- Cycloalkyl includes both cycloalkyl groups and heterocyclo alkyl groups normally containing between 3 and 6 ring atoms.
- Heterocycloalkyl groups include e.g. raorpholino, thiomorpholino, piperidino, imidazolino, pyrrolidino, pyrazolidino, piperazino, tetrahydrofuranyl, tetrahydropyranyl.
- R 8 and R 9 are independently optionally substituted C 1-10 hydrocarbyl which may optionally contain one or two oxygen atoms in the chain this includes optionally substituted alkyl, hydroxyalkyl, alkenyl, alkynyl, carbamoylalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, aralkyl, aryloxyalkyl.
- Substituents which may be present on the C 1-10 hydrocarbyl group which may optionally contain one or two oxygen atoms in the chain include hydroxy, azido, alkenyl, halo, nitro (NO 2 ), amino, (optionally substituted by one or 2 alkyl groups), cyano, carboxylate, alkyl ester, aralkyl esters or aryl esters, (wherein the alkyl ester, aralkyl ester and aryl ester can be substituted) alkyl, aryl, aralkyl, aryloxy, arylalkoxy, substituted arylalkoxy, sulphinyl, sulphonyl, thio, alkylthio, alkoxy, hydroxyalkyl, halo alkyl, phosphate, phosphonate, silyl, silyloxy, (wherein silyl and silyloxy may be substituted by one or more C 1-6 alkyl or aryl
- R 8 is a sugar this group may be present in a protected or unprotected form.
- Preferred sugar-protecting groups include isopropylidene, benzylidene acetate, benzoyl, paranitrobenzyl, paranitrobenzoyl, benzyl, substituted silyl and tetrahydropyranyl.
- R 8 is a sugar such as a tetrose, pentose, hexose (including furanose and pyranose) or heptose
- preferred sugars include glucose, fructose, mannose, ribose, arabinose.
- Substituents which may be present on the sulphonyl and sulphinyl include alkyl, aryl and aralkyl.
- Halogen represents fluoro, chloro, bromo or iodo.
- X preferably represents NH, A is preferably
- Y preferably represents NH.
- R 1 is preferably COOR 8 , with R 8 preferably being alkyl or aralkyl.
- R 2 is preferably H, alkyl, or COOR 8 wherein R 8 is preferably alkyl
- R 3 is preferably alkyl
- R 1 is preferably alkyl or COOR 8 .
- R 5 is preferably hydrogen and
- R 6 is preferably hydrogen or methyl and salts and physiologically functional derivatives thereof.
- One group of preferred compounds according to the present invention includes: Ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2-carboxylate;
- a second group of preferred compounds according to the invention include:
- the present invention also provides a process for preparing compounds of general formula (I), which process comprises the catalysed reaction of a compound of formula (II) with a compound of formula (III) in an inert solvent at a temperature between room temperature and the reflux temperature of the solvent, wherein X, Y, R 1 , R 2 , R 3 R 4 , R 5 and R 6 are as defined herein except that R 3 and R 4 may not be hydrogen when X is NH, and L is a leaving group:-
- Preferred catalysts are Montmorillonite K 10 clay or p-toluenesulphonic acid.
- Preferred solvents are 1,2-dichloroethane or toluene. Examples of suitable leaving groups include -OCOCH 3 , OEt, -N + Me 3 and halo.
- the appropriate aromatic polyheterocycle can be reacted with a formylating agent, such as that generated by the reaction between SnCl, and Cl 2 CHOCH 3 or equivalent reagents.
- a formylating agent such as that generated by the reaction between SnCl, and Cl 2 CHOCH 3 or equivalent reagents.
- Suitable functional groups include CHBr 2 , CH 3 , COR 14 wherein R 14 is a primary or secondary C 1-6 alkyl group, COOH or a derivative thereof such as an ester, amide, acid chloride or CN; or
- the compounds of the present invention are useful for the treatment of tumours. They may be employed in treating various forms of cancer of mammals including carcinomas, for instance of the stomach, pancreas, breast, uterus and colon; adenocarcinomas, for instance of the lung and colon; sarcomas, for instance fibrosarcoma; leukaemias, for instance lymphocytic leukaemia and lymphomas, for instance myeloid lymphoma.
- the invention thus further provides a method for the treatment of tumours in animals, including mammals, especially humans, which comprises the administration of a clinically useful amount of compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative in a pharmaceutically useful form, once or several times a day or in any other appropriate schedule, orally, rectally, parenterally, or applied topically.
- a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for use in therapy for example as an antitumour agent.
- the amount of compound of formula (I) required to be effective against the aforementioned tumours will, of course, vary and is ultimately at the discretion of the medical or veterinary practitioner.
- the factors to be considered include the condition being treated, the route of administration, and nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered.
- a suitable effective anti-tumour dose is in the range of about 0.01 to about 100 mg/kg body weight, eg 0.1 to about 100 mg/kg body weight, preferably 1-30 mg/kg body weight.
- the total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day or by intravenous infusion for selected duration.
- the dose range would be about 8 to 900 mg per day, and a typical dose could be about 50 mg per day. If discrete multiple doses are indicated treatment might typically be 15 mg of a compound of formula (I) given up to 4 times per day.
- Formulations of the present invention for medical use, comprise a compound of formula (I) or a salt thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
- the carrier(s) should be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the present invention therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof together with a pharmaceutically acceptable carrier thereof.
- a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier thereof.
- Formulations according to the present invention include those suitable for oral, topical, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration.
- Preferred formulations are those suitable for oral or parenteral administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into desired formulations.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a solution or suspension in an aqueous or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active compound with any suitable carrier.
- a syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients.
- a sugar for example sucrose
- accessory ingredients(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredients, such as a polyhydric alcohol for example glycerol or sorbitol.
- Formulations for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter.
- Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
- Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.
- Useful formulations also comprise concentrated solutions or solids containing the compound of formula (I) which upon dilution with an appropriate solvent give a solution for parenteral administration as above.
- the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or physiologically functional derivative thereof for the manufacture of a medicament for the treatment of tumours.
- IR spectra were recorded on a Perkin-Elmer 257 grating spectrophotometer or a Bruker FS66 spectrophotometer.
- Example 2 The general procedure of Example 1 was followed using ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrolo-2 carboxylate (0.692g, 2.59mmol), 3-methoxycarbonyl-2-methylpyrrole (0.360g, 2.59mmol), 1,2-dichloroethane (25 cm 3 ) and Montmorillonite clay (2g). Chromatographic separation using (0-20%) ethyl acetate in dichloromethane gave ethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2-carboxylate as a pale yellow solid (0.0124g, 1.8%) m.p.
- Toluene-p-sulfonic acid (100 mg) was added to the solution of the 3-acetyl-5-ethoxycarbonyl-2-(1'-methoxy-carbonylpyrrol-2'-ylmethyl)-4-methlypyrrole (0.435 g, 1.31 mmol) in benzene (50 cm 3 ), the reaction mixture was heated under reflux for 5h (using Dean-Stark apparatus).
- Assays for cell proliferation/cytotoxity were carried out in tissue culture grade 96 well microtitre plates (Costar). Cells in log growth were added to the plates at a concentration of 1 ⁇ 10 3 cells per well on day 0 and serially diluted compounds were then added on day 1. Plates were then incubated at 37°C in 5% CO 2 in air for a further 4 days.
- the methylene blue biomass staining method was used, the test being read on a Multiscan plate reader at wavelength of 620nm.
- the morphology of the cells was checked microscopically under phase-contrast immediately before the fixation and staining with methylene blue, and by ordinary light microscopy thereafter.
- IC50 values for active compounds were obtained using the computer programme, GS1 and dose-response slopes were also plotted.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/875,667 US6201129B1 (en) | 1995-02-01 | 1995-02-01 | Tricyclic derivatives and their use as anti-cancer agents |
EP95907087A EP0807113A1 (en) | 1994-02-02 | 1995-02-01 | Tricyclic derivatives and their use as anti-cancer agents |
JP7520450A JPH11501004A (en) | 1995-02-01 | 1995-02-01 | Tricyclic derivatives and their use as anticancer agents |
AU15422/95A AU701025B2 (en) | 1995-02-01 | 1995-02-01 | Heterocyclic compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9401994A GB9401994D0 (en) | 1994-02-02 | 1994-02-02 | Heterocyclic compounds |
Publications (1)
Publication Number | Publication Date |
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WO1995021171A1 true WO1995021171A1 (en) | 1995-08-10 |
Family
ID=10749741
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1995/000203 WO1995021171A1 (en) | 1994-02-02 | 1995-02-01 | Tricyclic derivatives and their use as anti-cancer agents |
Country Status (3)
Country | Link |
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EP (1) | EP0807113A1 (en) |
GB (1) | GB9401994D0 (en) |
WO (1) | WO1995021171A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999045926A1 (en) * | 1998-02-27 | 1999-09-16 | University College Cardiff Consultants Limited | Condensed heterocyclic compounds as anti-inflammatory and immunomodulatory agents |
US7196089B2 (en) | 2003-01-29 | 2007-03-27 | Asterand Uk Limited | EP4 receptor antagonists |
US7417068B2 (en) | 2003-10-16 | 2008-08-26 | Asterand Uk Limited | EP4 receptor antagonists |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1902050A1 (en) * | 1969-01-16 | 1970-08-13 | Farbenfabriken Bayer Ag, 5090 Leverkusen | Benzo- (mono-, bis- and tris-) thiophenes |
US5248692A (en) * | 1990-06-11 | 1993-09-28 | Kyowa Hakko Kogyo Co., Ltd. | DC-89 derivatives as anti-tumor agents |
-
1994
- 1994-02-02 GB GB9401994A patent/GB9401994D0/en active Pending
-
1995
- 1995-02-01 EP EP95907087A patent/EP0807113A1/en not_active Withdrawn
- 1995-02-01 WO PCT/GB1995/000203 patent/WO1995021171A1/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1902050A1 (en) * | 1969-01-16 | 1970-08-13 | Farbenfabriken Bayer Ag, 5090 Leverkusen | Benzo- (mono-, bis- and tris-) thiophenes |
US5248692A (en) * | 1990-06-11 | 1993-09-28 | Kyowa Hakko Kogyo Co., Ltd. | DC-89 derivatives as anti-tumor agents |
Non-Patent Citations (14)
Title |
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ACTA POL. PHARM., vol. 36, no. 6, pages 651 - 655 * |
BERNATEK: "Bromination and subsequent Ozonisation of Ethyl 2,6-Dimethylbenzo[1.2-b,4.5-b']difuran-3,7-dicarboxylate", ACTA CHEM. SCAND., vol. 15, no. 2, pages 429 - 430 * |
BULL. SOC. CHIM. BELG., vol. 100, no. 1, pages 1-4 * |
CHEMICAL ABSTRACTS, vol. 102, no. 1, 7 January 1985, Columbus, Ohio, US; abstract no. 6243c, page 567; * |
CHEMICAL ABSTRACTS, vol. 114, no. 19, 13 May 1991, Columbus, Ohio, US; abstract no. 185077u, page 747; * |
CHEMICAL ABSTRACTS, vol. 93, no. 21, 24 November 1980, Columbus, Ohio, US; abstract no. 204496w, page 675; * |
GRINEV ET AL.: "Synthesis of furio[2,3-f]- and furo[3,2-e]indole derivatives", CHEM. HETEROCYCL. COMPD., vol. 13, pages 621 - 624 * |
GUIOTTO ET AL.: "Bis-basic derivatives of planar heterocyclic compounds", IL FARMACO - ED. SC., vol. 34, no. 9, pages 774 - 783 * |
HISHMAT; EL-EBRASHI; SHALASH; ISMAIL: "Synthesis of Difuran Derivatives and their Biological Activity", ARZNEIM. FORSCH./DRUG RES., vol. 29, no. 8, pages 1081 - 1083 * |
KADZHRISHVILI ET AL.: "Electrophilic substitution in the 1H,5H-pyrrolo[2,3-f]indole and 3H,6H-pyrrolo[3,2-e]indole series", CHEM. HETEROCYCL. COMPD., vol. 19, pages 871 - 876 * |
KHIM. GETEROTSIKL. SOEDIN, vol. 9, pages 1219-122 * |
KUCKLAENDER: "Beobachtungen zum Mechanismus der Nenitzescu-Reaktion", TETRAHEDRON, vol. 29, pages 921 - 927 * |
RENE ET AL.: "Analogues difurobenzéniques et furochroméniques du psoralène et du pseudopsoralène", EUR. J. MED. CHEM - CHIM. THER., vol. 12, no. 1, pages 31 - 34 * |
SAMSONIYA; LOMTATIDZE; DOLIDZE; SUVOROV: "Synthesis and biocidal properties of some 1H,6H-pyrrolo[2,3-e]indole and 1H,7H-pyrrolo[3,2f]indole derivatives", PHARM. CHEM. J., vol. 18, no. 12, pages 819 - 823 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999045926A1 (en) * | 1998-02-27 | 1999-09-16 | University College Cardiff Consultants Limited | Condensed heterocyclic compounds as anti-inflammatory and immunomodulatory agents |
US7196089B2 (en) | 2003-01-29 | 2007-03-27 | Asterand Uk Limited | EP4 receptor antagonists |
US7507754B2 (en) | 2003-01-29 | 2009-03-24 | Asterand Uk Limited | EP4 receptor antagonists |
US7528157B2 (en) | 2003-01-29 | 2009-05-05 | Asterand Uk Limited | EP4 receptor antagonists |
US7858644B2 (en) | 2003-01-29 | 2010-12-28 | Asterand Uk Limited | EP4 receptor antagonists |
US7417068B2 (en) | 2003-10-16 | 2008-08-26 | Asterand Uk Limited | EP4 receptor antagonists |
US7569602B2 (en) | 2003-10-16 | 2009-08-04 | Asterand Uk Limited | Furan derivatives as EP4 receptor antagonists |
Also Published As
Publication number | Publication date |
---|---|
GB9401994D0 (en) | 1994-03-30 |
EP0807113A1 (en) | 1997-11-19 |
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