Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/46—Phenazines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to substituted benzo[a]phenazine-l l-carboxamides and derivatives thereof. These compounds are cytotoxic agents which have demonstrated topoisomerase I and topoisomerase II inhibition and have the ability to circumvent multidrug resistance mechanisms. They are therefore potential anticancer agents
• topoisomerases are important cellular targets for a number of successful chemotherapeutic agents (Wang, Ann. Rev. Biochem, 65, 635-692, 1996) and are essential enzymes in the regulation of DNA topology which is required if cells are to divide and proliferate (Wang, ⁇ oc cz ⁇ ).
• topoisomerase I principally the camptothecin analogues
• camptothecin analogues More recently, topoisomerases have been shown to be therapeutic targets for antifungal, antibacterial and antiviral drugs (Chen e t a ⁇ , Rev. Pharmacol. Toxicol, 34, 191-218, 1994).
• topoisomerase I and II include intoplicine (Riou e ⁇ a ⁇ , Cancer Res. 53, 5987-5993, 1993), DACA/XR5000 (Finlay et ⁇ Eur. J. Cancer 32A, 708-714, 1996) and TAS-103 (Utsugi et a ⁇ , J. Cancer Res, 88, 992-1002 1997) which are all in clinical evaluation.
• intoplicine Rosou e ⁇ a ⁇
• DACA/XR5000 Frelay et ⁇ Eur. J. Cancer 32A, 708-714, 1996)
• TAS-103 Utsugi et a ⁇ , J. Cancer Res, 88, 992-1002 1997) which are all in clinical evaluation.
• the advantage of joint inhibitors of topoisomerase I and II is their ability to avoid drug resistance and to target two key enzymes that affect the topology of DNA which are active at different points in the cell cycle.
• each of R 1 to R 4 which are the same or different, is selected from hydrogen, halogen, hydroxyl, C C 6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C C 6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO 2 R 10 , CON(R 12 ) 2 , OCON(R i2 ) 2 , SR 10 , SOR 11 , SO 2 R ⁇ , SO 2 N(R 12 ) 2 , N(R 12 ) 2 , NR 10 SO 2 R ⁇ , N(SO 2 R u ) 2 , NR 10 (CH 2 ) n CN, NR 10 COR ⁇ , OCOR 11 or COR 10 ; each of R 5 to R 7 , which are the same or different, is selected from hydrogen, halogen, hydroxy, C r C 6 alkoxy, C r C 6 alkyl, SR 10 and
• Q is C C ⁇ alkylene which is unsubstituted or substituted by (i) C r C 6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not ⁇ to either of the N atoms adjacent to Q in formula (I), (iii) CO 2 R 10 , or (iv) CON(R 12 ) 2 ;
• R 8 and R 9 which are the same or different, are each hydrogen or C 1 -C 6 alkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R 8 and R 9 is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above;
• R 10 is hydrogen, C r
• benzo[a]phenazine carboxamide-11- derivative is of formula (la)
• R 1 to R 9 are as defined above; p is 1 or 2; and
• R 13 is (i) hydrogen (ii) C j -C 6 alkyl which is unsubstituted or substituted by hydroxy, aryl or
• R 12 is as defined above, (iii) CO 2 R 10 , (iv) CON(R 12 ) 2 , or (v) aryl.
• R 1 to R 7 are as defined above for formula (I);
• R 14 is hydrogen or C r C 6 alkyl
• W is a direct bond or a C r C 5 alkylene chain
• a C r C 6 alkyl group may be linear or branched.
• a C r C 6 alkyl group is typically a C r C 4 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group.
• a C r C 6 alkyl group is unsubstituted or substituted, typically by one or more groups selected from hydroxy-C r C 6 alkyl wherein the alkyl moiety is unsubstituted or substituted as specified herein for C r C 6 alkyl, C C 6 alkoxy, phenyl, N(R 12 ) 2 wherein R 12 is as defined above, and hydroxy.
• Examples of hydroxy-C r C 6 -alkyl include, for instance, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.
• C r C 6 alkylene is a C r C 6 alkyl group as defined above which is divalent.
• An aryl group is typically an aromatic C 6 -C 10 carbocyclic group, such as phenyl or naphthyl, which is unsubstituted or substituted by halogen, C r C 6 alkyl, OH, C r C 6 alkoxy, NO 2 , N(R 12 ) 2 , CO 2 R 10 , CN or perhalo C r C 6 alkyl such as CF 3 .
• a halogen is F, Cl, Br or I. Preferably it is F, Cl or Br.
• a Cr- alkoxy group may be linear or branched. It is typically a C r C 4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert- butoxy group.
• a C r C 6 alkoxy group is unsubstituted or substituted, typically by one or more groups selected from N(R 12 ) 2 , CON(R 12 ) 2 , hydroxy, C r C 6 alkoxy, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, CO 2 R 10 , COR 10 , a saturated 5- or 6-membered N-containing heterocyclic group or phenyl, the phenyl group being unsubstituted or substituted by one or more halogen atoms.
• a C 3 -C 10 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Typically it is C 3 -C 6 cycloalkyl.
• a C 2 -C 6 alkenyl group contains one or more unsaturated bonds. It may be, for instance, vinyl, propenyl, butenyl or pentenyl.
• a C 2 -C 6 alkynyl group may be ethynyl, propynyl, butynyl or pentynyl.
• a saturated 5- or 6-membered N-containing heterocyclic ring may be, for example, piperidine, piperazine, morpholine or pyrrolidine.
• a heteroaryloxy group is a group -OHet in which Het is an unsaturated 5- or 6- membered N-containing heterocyclic ring which may include one or more additional O, N or S atoms.
• Examples include furan, thiophene, pyrrole, indole, isoindole, pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, pyridine, quinoline, quinoxaline, isoquinoline, thienopyrazine, pyran, pyrimidine, pyridazine, pyrazine, purine and triazine.
• the aforesaid heterocyclic ring may be unsubstituted or substituted by one or more substituents, for instance one or more substituents selected from OH, halogen, C r C 6 alkyl which is unsubstituted or substituted, for example by halogen (such as CF 3 ), C r C 6 alkoxy, nitro and an amino group N(R 12 ) 2 as defined above.
• R 1 to R 3 in formula (I), (la) or (lb) are each hydrogen and R 4 is other than hydrogen.
• R 4 is C r C 6 alkoxy, hydroxy, C r C 6 alkyl, hydroxy-C ⁇ -C 6 alkyl, nitrile or halogen.
• R 4 in formula (I) is C ⁇ -C 6 alkoxy or hydroxy
• R 7 is hydroxy
• R 1 to R 3 , R 5 and R 6 are each hydrogen.
• R 13 is preferably C C 6 alkyl, more preferably methyl.
• a preferred option for Q is a C 2 - or C 3 - alkylene chain which is substituted ⁇ to the adjacent amide nitrogen atom by C r C 6 alkyl which is unsubstituted or substituted as defined above.
• the substituent on Q is unsubstituted C C 6 alkyl or hydroxy-C 1 -C 6 alkyl such as hydroxymethyl or hydroxyethyl.
• the C 2 - or C 3 - alkylene chain is substituted ⁇ to the adjacent amide nitrogen atom by methyl, ethyl, isopropyl, hydroxymethyl, substituted hydroxymethyl or 1 -hydroxyethyl.
• Compounds of formula (I) may be prepared by a process which comprises: (a) treating an activated derivative of a compound of formula (II):
• R 1 to R 7 are as defined above, with an amine of formula (III): H 2 N ⁇ N(R 8 )(R y ) ( ⁇ i) wherein Q, R 8 and R 9 are as defined above; or (b) treating a compound of formula (IV):
• R 1 to R 7 and R 1 ! are as defined above, with a compound of formula (III) as defined above, either in an organic solvent or neat and at an elevated temperature;
• optical purity of resulting compounds that have an optically active centre for instance the benzo [ajphenazme- 11-carboxamide derivatives of formula (la) and the salts thereof, may be determined by the addition of an NMR shift reagent such as 2,2,2-trifluoro- 1 (9-anthryl) ethanol to NMR samples of the homochiral compounds.
• an NMR shift reagent such as 2,2,2-trifluoro- 1 (9-anthryl) ethanol
• step (a) the carboxylic acid grouping in formula (II) may be activated as the corresponding acid chloride which may be obtained by treating the free carboxylic acid of formula (II) with thionyl chloride.
• the carboxylic acid grouping can be activated by treatment with an appropriate amide-coupling reagent such as 1,1 '- carbonyldiimidazole.
• the reaction between the activated derivative of the compound of formula (II) and the amine of formula (III) is typically conducted in an organic solvent. Suitable solvents include dimethylformamide and dichloromethane.
• the process typically comprises combining the activating agent or coupling agent with the compound of formula (II) in an organic solvent and adding to the resulting reaction mixture the amine of formula (III).
• a compound of formula (II) may be prepared by a process which comprises: (a) treating a 1,2-naphthoquinone of formula (V): wherein R 1 to R 4 are as defined above for formula (I), with a benzoic acid of formula (VI):
• R 5 , R 6 and R 7 are as defined above for formula (I), in an organic solvent, optionally in the presence of an acid.
• the solvent may be, for example, ethanol or acetic acid.
• the regi.oselectivity of the reaction may be controlled.
• the mineral acid is preferably hydrochloric acid, more preferably concentrated hydrochloric acid.
• the salt of the benzoic acid of formula (VI) is typically the acetate salt.
• the 1 ,2-naphthoquinone of formula (V) may be prepared by treating the corresponding
• 1-tetralone of formula (VII) wherein R 1 to R 4 are as defined above for formula (I), with selenium dioxide in accordance with the procedure described in Tetrahedron Letters 1997, 4219-4220.
• the 1-tetralones of formula (VII) are known compounds or may be prepared from known compounds by published methods, for instance as described in the reference examples which follow, adapted where necessary using conventional laboratory techniques to achieve the desired definitions of R 1 to R 4 . Published methods include those described in J. Med. Chem 1997, 40, 3014- 3024; J. Org. Chem. 1984 , 4226; JACS. 1994, 116 pp. 4852-4857 and J. Med. Chem. 1997 p.1049.
• the benzoic acids of formula (VI) are known compounds or may be prepared from known compounds using published methods, adapted where necessary using conventional laboratory techniques to achieve the desired definitions of R 5 to R 7 . Published methods include those described in J. Chem. Soc. Perkin Trans. I, 1984, p2019 and J. Med. Chem 1987, p.843.
• a compound of formula (II) may also be prepared by a process which comprises: (a) treating a 2-halo-3-nitrobenzoic acid of formula (VIII):
• R 1 to R 4 are as defined above, to reductive cyclisation.
• Step (a) is typically conducted in an organic solvent. Suitable examples include butane-2,3-diol and ethylene glycol.
• Step (b) is generally carried out by treatment of the compound of formula (X) with NaBH 4 in sodium methoxide, sodium ethoxide or aqueous NaOH. The process is described in J. Med. Chem. 1987, 30, 843-851.
• a compound of formula (IV) may be prepared by esterification of a corresponding compound of formula (II) under standard reaction conditions, for instance by treatment of the free carboxylic acid compound of formula (II) with an alcohol of formula R 1 ⁇ OH wherein R 1 ' is as defined above.
• Amines of formula (III) are known and commercially available compounds or may be produced from commercially available starting materials using conventional techniques, for instance as described in reference example 2 which follows.
• a compound of formula (I) may be converted into another compound of formula (I) by conventional methods.
• a compound of formula (I) containing an esterified hydroxy group such as -OCOMe may be converted into a compound of formula (I) containing a free hydroxy group by hydrolysis, for instance alkaline hydrolysis.
• a compound of formula (I) contaimng a free hydroxy group may be converted into a compound of formula (I) contaimng an esterified hydroxy group by esterification, for instance by reaction with a suitable carboxylic acid, acid halide or acid anhydride.
• a compound containing a free hydroxy group may also be converted to a compound containing a carbamic acid ester grouping, for instance by treatment with triethylamine and ethyl isocyanate in an aprotic polar solvent, for instance dimethylformamide.
• a compound of formula (I) containing a nitro group may be converted into a compound of formula (I) containing an amino group by reduction, for instance by treatment with indium and a saturated NH 4 C1 solution in an organic solvent.
• a compound containing a C r C 6 alkoxy group may be converted into a compound containing a hydroxy group, for instance by treatment with boron tribromide in a halogenated hydrocarbon solvent, for instance dichloromethane, or with sodium thioethoxide in dimethyl formamide.
• a compound containing a hydroxy group may be converted into a compound containing an optionally substituted C C 6 alkoxy group, for instance by treatment with an appropriate alkylating agent in the presence of a base.
• a compound containing a carboxy group may be converted to a compound containing a hydroxymethyl group by reduction, for instance by treatment with LiAlH 4 in tetrahydrofuran.
• a compound containing a halogen may be converted into a compound containing an alkylsulfanyl or alkoxy group, for instance by treatment with a thioalkoxide or alkoxide salt, respectively, in an organic solvent.
• a compound containing a nitrile group may be converted into a compound containing an N-hydroxycarbamimidoyl group, for instance by treatment with hydroxylamine (optionally in the form of a salt) in the presence of a base such as potassium carbonate.
• a compound substituted by alkylaminomethyl at a benzene ring position may be prepared under Marinich reaction conditions by treating a compound that is substituted by hydroxy ortho to the (unsubstituted) ring position in question with acetic acid followed by treatment with an alkylamine and a solution of formaldehyde in water.
• a compound of formula (I) may be acetylated, for instance on an amine group to form an acetylamino substituent, by treatment with acetyl chloride under suitable conditions.
• Benzo [ajphenazine-l 1-carboxamide derivatives may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods.
• Pharmaceutically acceptable salts of the benzo [a]phenzine-l 1- carboxamide derivatives of formula (I) include salts of inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and salts of organic acids such as acetic acid, oxalic acid, malic acid, methanesulfonic acid, trifluoroacetic acid, benzoic acid, citric acid and tartaric acid.
• the salts include both the above-mentioned salts and the salts of sodium, potassium, calcium and ammonium, which are prepared by treating the compound of formula 1 with or the acid salts with the corresponding metal base or ammonia.
• Multi-drug resistance is a phenomenon whereby cells which are typically sensitive to chemotherapeutic agents develop resistance to those agents and to a wide range of unrelated drugs. MDR represents a major obstacle in the successful clinical therapy of cancer. Cancer cells which exhibit MDR can display a number of diverse cellular alterations including overexpression of P-glycoprotein (P-gp), overexpression of multidrug resistance associated protein (MRP), reduction in levels of topoisomerase II (termed atypical drug resistance) and qualitative changes in expression of topoisomerase I. MDR is a very important clinical problem with many tumors developing resistance to many chemotherapeutic agents including those that specifically target topoisomerase I and/or topoisomerase II.
• P-gp P-glycoprotein
• MRP multidrug resistance associated protein
• topoisomerase II Termed atypical drug resistance
• topoisomerase I and II By simultaneously inhibiting topoisomerase I and II, compounds such as DACA (Finlay e t a j Eur. J. Cancer 32A, 708-714, 1996) have shown no loss of activity when resistance develops to camptothecin or amsacrine due to alteration of either topoisomerase I or II respectively. Qualitatively different cell cycle events have been obtained with inhibitors of topoisomerase I or II. (Kaufman, Biochim. Biophys. Acta 1400, 195-212, 1998). Joint inhibitors of topoisomerases I and II appear to combine the properties of the individual specific inhibitors and act across the cell cycle (Haldane e t ab Cancer Chemother. Pharmacol. 32: 463-470, 1993), resulting in a greater antitumour activity (Riou e f a j, Cancer Res. 53, 5987-5993, 1993).
• MDR due to the overexpression of membrane transporters such as P-glycoprotein (Gottesman et a j, Armu. Rev. Biochem. 62, 385-427, 1993) and MRP (Loe et a ⁇ , Eur. J. Cancer 32A, 945-957, 1996) is known to reduce the clinical efficacy of chemotherapeutic agents such as paclitaxel, etoposide and doxorubicin. Agents that avoid such MDR mechanisms are predicted to show therapeutic benefit in the treatment of cancer.
• Benzo [ajphenazine- 11-carboxamide derivatives of formula I, their pharmaceutically acceptable salts and hydrates and solvates thereof have been found in biological tests to have activity as inhibitors of topoisomerase I and II.
• the present compounds are joint inhibitors of topoisomerase I and topoisomerase II.
• the present compounds may therefore be used as inhibitors of topoisomerase I.
• the present compounds may be used as inhibitors of topoisomerase II.
• they may be used as joint inhibitors of topoisomerase I and topoisomerase II. They have been shown to kill human tumour cells and avoid MDR mechanisms. They therefore have potential in the treatment of cancer.
• types of cancer that the present compounds can be used to treat include leukaemias, lymphomas, sarcomas, carcinomas and adenocarcinomas. Specific examples include breast, colon, brain, lung, ovary, pancreatic, stomach and skin cancer.
• a human or animal patient harbouring a tumour may be treated by a method comprising the administration thereto of one of the present compounds.
• a method of treating human tumours including those which express MDR, for instance the types of MDR referred to above, comprises administering a therapeutically effective amount of one of the present compounds to a patient harbouring a tumour. All types of tumour may thus be treated, both those which express MDR and those which do not.
• the present compound is administered in an amount effective to reduce or eliminate the tumour.
• the present compound is administered orally.
• the present compound is administered by a parenteral route, for instance intravenously. Owing to their activity as inhibitors of topoisomerase I and topoisomerase II the present compounds may also be used as antiviral, antibacterial or antifungal agents.
• the present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously.
• the present compounds may therefore be given by injection or infusion.
• the dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 0.001 to 500 mg/kg, most commonly in the range of 0.01 to 100 mg/kg body weight. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion- over several hours and/or repeated administration.
• a benzo [ajphenazine- 11-carboxamide derivative of formula (I) or a pharmaceutically acceptable salt thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent.
• the compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form.
• An agent for use in the treatment of tumours, including those which express MDR, comprising one of the present compounds is therefore provided.
• the present compounds may be administered in any conventional form, for instance as follows:
• compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• eXcipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricating agents, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulphate.
• inert diluents such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate
• granulating and disintegrating agents for example,
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• Such preparations may be manufactured in a known manner, for example by means of mixing, granulating, tableting, sugar coating or film coating processes.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium • phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium • phosphate or kaolin
• water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides for example polyoxyethylene sorbitan monooleate.
• the said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, such as sucrose or saccharin.
• preservatives for example, ethyl or n-propyl p-hydroxybenzoate
• colouring agents such as sucrose or saccharin.
• Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by this addition of an antioxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurmg phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsion may also contain sweetening and flavouring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.
• a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose.
• Such formulations may also contain a demulcent, a preservative and flavouring and coloring agents;
• This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic paternally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
• Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables;
• 5-Amino-l-tetralone was prepared from ⁇ - tetra lone according to the literature (J. Am. Chem. Soc. 1994, p4852).
• a mixture of 5-amino-l-tetralone (80mg) and concentrated hydrochloric acid (lmL) was cooled to 0° C .
• a solution of sodium nitrite (35mg) in water • (0.5mL) was added dropwise to the stirring solution.
• the cold diazonium solution was then poured rapidly onto a stirring solution of copper (I) chloride (62mg) in concentrated hydrochloric acid (lmL). The reaction mixture was allowed to warm to ambient temperature and then stirred for 1.5 hours.
• Example 1A yielded 5 -chloro- [l,2]naphthoquinone which was coupled with 2,3-diamino- benzoic acid, diacetate salt, as described in Reference Example 1 A to yield the title compound.
• 5 -Methylsulphanyl- 1-tetralone was prepared from 5 -hydroxy- 1-tetralone according to the literature (J. Med. Chem. 1997, pl049). A mixture of 5 -methylsulphanyl- 1-tetralone (221mg) and 3-chloroperbenzoic acid (595mg) was stirred at room temperature for 2 hours. The reaction mixture was then extracted with dichloromethane, washed with water, dried (Na 2 SO 4 ) and the solvent removed n vacuo to yield 5 -methanesulphonyl- 1-tetralone as an off-white solid (210mg)
• 5-Amino- 1-tetralone was prepared from ⁇ - tetra lone according to the literature (J. Am. Chem. Soc. 1994, p4852). To a cold solution of 5 -amino- 1-tetralone (415mg) in water (2mL) and concentrated hydrochloric acid (5mL) was added a solution of sodium nitrite (186mg) in water (1.2mL), maintaining low temperature. After 40 minutes a solution of sodium azide (184mg) in water (1.2mL) was added dropwise. The reaction mixture was allowed to warm to room temperature.
• 7-Nitro- 1-tetralone was prepared according to the literature (J. Am. Chem. Soc, 1994, 116, pp4852-4857). Treatment of 7-nitro- 1-tetralone with selenium dioxide as described in Reference Example 1 A yielded the corresponding 7-nitro- [l,2Jnaphthoquinone, which was coupled with 2,3-diamino-benzoic acid, diacetate salt , as described in Reference Example 1 A to yield the title compound.
• 2-Ammo-6-methoxy-3-nitro-benzoic acid methyl ester was prepared using a procedure analogous to that described in the literature (Kim et al, J.Med. Chem. 1993, p2335). Hydrolysis of the methyl ester was achieved using potassium hydroxide in refluxing ethanol for 2 hours to yield 2-amino-6-methoxy-3-nitro-benzoic acid. Hydrogenation of the nitro group was performed in acetic acid/water over palladium on carbon catalyst on the Parr apparatus at 50psi H 2 to yield 2,3-diamino-6-methoxy-benzoic acid.
• 5-Chloro-3-nitroanthranilic acid was prepared according to the procedure described by Flippin et al (Biorg. Med. Chem. Letts 1996, p477). Hydrogenation of this material in ethyl acetate using palladium on carbon at 50psi H 2 for 2 hours yielded 2,3-diamino-5-chloro- benzoic acid. This was reacted with 5-methoxy-[l,2]naphthoquinone as described in Reference Example 1 A to yield the desired title compound.
• Methyl N-( ⁇ g r/ -butoxycarbonyl)-2-aminobutyrate was prepared as described in the literature( J.Med. Chem. 1989,pl886). Treatment of this compound with diisobutyl. aluminium hydride in toluene at -78° C for 1.5 hours yielded the corresponding aldehyde (prep see H.W. Scheeren et al, J. Org. Chem. 1990, p3998).
• N-(fe r ⁇ -butoxycarbonyl)-DL-phenylalanine methyl ester was prepared from DL- phenylalanine using standard preparative techniques. This was converted into the desired title compound using an analogous procedure to that described in Reference Example 2B.
• reaction mixture was dissolved in ethyl acetate, washed with water, dried (MgSO ), and the solvent removed n vacuo to yield a viscous oil. This was dissolved in dichloromethane, extracted with citric acid, basified with sodium hydroxide, and re-extracted with ethyl acetate. The organic layer was reduced n vacuo to yield the dimethylamino derivative as a white solid (586mg).
• N-[( ⁇ g r ⁇ -Butoxy)carbonylJ-O-( ⁇ er -butyldimethylsilyl)-R-serine methyl ester was prepared according to the literature (H.W. Scheeren et al, J. Org. Chem. 1990, p3998) from D-serine methyl ester hydrochloride . Treatment of this compound with diisobutyl aluminium hydride in toluene at -70°C for 2 hours yielded the correponding aldehyde (H.W. Scheeren et al, J. Org. Chem. 1990, p3998).
• Reductive amination was carried out as described in Reference Example 2G to yield the corresponding dimethylamino derivative, 3-[N-( /er ⁇ -Butoxycarbonyl)aminoJ-4- dimethylamino-butan-1 -ol.
• Deprotection using 4.0M HCl in dioxane as described in Reference Example 2G yielded the desired title compound.
• the free base was obtained by treating a suspension of the hydrochloride salt in toluene (18 mL) with sodium hydroxide (2.4 eq) in water (14 mL) for 30 min. The organic layer was removed, dried over MgSO 4 , filtered and the solvent removed ⁇ n vacuo to yield 2-chloro-N,N,N 1 ,N 1 -tetramethylpropane-l,3-diamine as a yellow liquid.
• Acetyl chloride (4.6mL) was added dropwise to a suspension of 4-methoxy- benzo [ajphenazine- 11-carboxylic acid (II.1 ,see Reference Example 1 A, 4.9g) in methanol (50mL). The mixture was heated to reflux for 4 hours. The volatiles were then removed ⁇ n vacuo t° yield the title compound as a dark solid (quantitative yield).
• NMR, d6-DMSO 8.76(lH,d), 8.41(2H,d), 8.26(lH,d), 8.00(lH,t), 7.90(lH,d), 7.78(lH,t), 7.43(lH,d), 4.08(3H,s), 4.03(3H,s).
• reaction mixture was heated to 100°C for 4 hours.
• the mixture was cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed ⁇ n V acuo to yield the title compounds as a red solid (29mg). Purified after further chemical modification.
• Methyl 2-amino-6-fluoro-3-nitrobenzoate was prepared according to the literature (J.
• Example 1A 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)- amide
• 3 -Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 3 -methoxy-benzo [ajphenazine- 11-carboxylic acid (11.34) and N,N- dimethylethylenediamine;
• 2-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 2 -methoxy-benzo [ajphenazine- 11-carboxylic acid (11.33) and N,N- dimethylethylenediamine;
• 4-Nitro-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from the mixture of 4-nitro-benzo [ajphenazine- 11-carboxylic acid (11.27) and 3-nitro- benzo [ajphenazine- 11-carboxylic acid (11.28), and N,N-dimethylethylenediamine and then purified using flash chromatography;
• 4-Ethoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylammo-ethyl)-amide was prepared from 4-ethoxy-benzo [ajphenazme- 11-carboxylic acid (11.11) and N,N- dimethylethylenediamine;
• 4-Isobutoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-isobutoxy-benzo [ajphenazine- 11-carboxylic acid (11.15) and N,N- dimethylethylenediamine;
• 4-Methylsulfanyl -benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-methylsulfanyl-benzo [ajphenazine- 11-carboxylic acid (11.12) and N,N- dimethylethylenediamine ;
• 4-Bromo-benzo [ajphenazine- 11 -carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-bromo-benzo [ajphenazine- 11-carboxylic acid (II.5) and N,N- dimethylethylenediamine;
• 4-Azido-benzo [ajphenazme- 11 -carboxylic acid(2-dimethylamino-efhyl)-amide was prepared from 4-azido-benzo [ajphenazine- 11-carboxylic acid (II.9) and N,N- dimethylethylenediamine;
• 11 -(2-Dimethylamino-ethylcarbamoyl)-benzo[a]phenazine-4- carboxylic acid methyl ester was prepared from benzo [aJphenazme-4,l l-dicarboxylic acid 4- methyl ester (II.10) and N,N-dimethylethylenediamine;
• 3-Dimethylsulfamoyl-benzo[aJphenazine-l 1-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from the mixture of 4-dimethylsulfamoyl-benzo [ajphenazine- 11 -carboxylic acid (II.23)and 3 -dimethylsulfamoyl-benzo [ajphenazine- 11-carboxylic acid (11.24), and N,N- dimethylethylenediamine.
• Example IB 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-l- methyl-ethyl)-amide A mixture of 4-methoxy-benzo [ajphenazine- 11-carboxylic acid methyl ester (IV.l)
• 4-Methoxy-benzo [ajphenazine- 11 -carboxylic acid (3-amino-2-hydroxy-propyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11 -carboxylic acid methyl ester (IV.l) and 1,3- diamino-2-hydroxypropane (commercially available); 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-propyl)-amide was prepared from
• 4-Dimethylamino-benzo[a]phenazine-l 1-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from the mixture of 4-dimethylamino-benzo [ajphenazine- 11-carboxylic acid methyl ester (IV.3) and 3 -dimethylamino-benzo [ajphenazine- 11 -carboxylic acid methyl ester (IV.4), and N,N-dimethylethylenediamine, followed by flash chromatography purification to remove the minor isomer;
• (2-dimethylamino-ethyl)-amide was prepared from 4,10-dimethoxy-benzo[a]phenazine-l l- carboxylic acid(II.36) and N,N-dimethylethylenediamine;
• 4-Methoxy-benzo [ajphenazine- 11 -carboxylic acid (l-dimethylaminomethyl-propyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and N ⁇ N 1 - dimethyl-butane-l,2-diamine.hydrochloride (III.2) in the presence of triethylamine;
• 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (l-dimethylaminomethyl-2-methyl- propyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and SN ⁇ N ⁇ trimefhyl-butane-l, 2-diamine. Hydrochloride salt (III.3) in the presence of triethylamine;
• 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino- l(R)-methyl-ethyl)- amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and (R) ⁇ Vj -dimethyl-propane-l ⁇ -diamme.Hydrochloride salt (III.6) in the presence of triethylamine;
• 4-Methoxy-benzo [ajphenazine- 11 -carboxylic acid (2-dimethylamino- 1 (S)-hydroxymethy 1- ethyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and (S)-2-Amino-3-dime ylamino-propan-l-ol.Hydrochloride salt (111.7) in the presence of triethylamine
• 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-piperidin-l-yl-ethyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and l-(2- aminoethyl)piperidine (commercially available);
• 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-morpholin-4-yl-ethyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and 4-(2- aminoethyl)morpholine (commercially available);
• 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid (2-diethylamino-ethyl)-amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and N,N- diethylethylenediamine (commercially available);
• 4-Methoxy-benzo [ajphenazine- 11-carboxylic acid ⁇ 2-[bis-(2-hydroxy-ethyl)-aminoJ-ethyl ⁇ - amide was prepared from 4-methoxy-benzo [ajphenazine- 11-carboxylic acid (II.1) and N,N- bis(2-hydroxyethyl)ethylenediamine (commercially available);
• Example 2i 4-Hydroxy-benzo [ajphenazine- 11 -carboxylic acid (2-dimethylamino-ethyl)- amide: hydrobromide salt
• 4-(3-Dimethylamino-propoxy)-benzo[aJphenazine-l 1-carboxylic acid (2-dimethylamino- ethyl)-amide was prepared using 3-dimethylaminopropyl chloride hydrochloride;
• 4-Carbamoylmethoxy-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared using 2-bromoacetamide;
• Example 2vi [1 l-(2-Dimethylamino-ethylcarbamoyl)-benzo[aJphenazin-4-yloxyJ-acetic acid trifluoroacetate salt
• a solution of [ll-(2-dimethylar no-ethylcarbamoyl)-benzo[aJphenazin-4-yloxy]- acetic acid tert-butyl ester (18mg) in dry dichloromethane (lmL) was added trifluoroacetic acid (lmL). After stirring for 4 hours the solvent was removed in vacuo to yield crude product. This was triturated with ether to yield the title compound as a yellow solid (lOmg).
• Example 2vii Benzo[a]phenazine-4,l l-dicarboxylic acid 4-amide l l-[(2-dimethylamine- etl ⁇ yl)-amide]; triflouroacetic acid salt
• Example 2viii 11 -(2-Dimethylamino-ethylcarbamoyl)-benzo[aJphenazine-4-carboxylic acid, trifluoroacetate salt
• Example 2xi 4-Dimethylaminomethyl-3 -hydroxy-benzo [ajphenazine- 11 -carboxylic acid (2-dimethylamino-ethyl)-amide 3 -Hydroxy-benzo [ajphenazine- 11 -carboxylic acid (2-dimethylamino-ethyl)-amide
• Example 2xiii 4-Amino-benzo[aJphenazine-l 1-carboxylic acid (2-dimethylamino-ethyl)- amide
• 4-amino-benzo [ajphenazine- 11-carboxylic acid (2-dimethylamino- ethyl)-amide(69mg) in methanol (lOmL) was added formaldehyde (37%> solution, l.OmL), potassium cyanide(102mg)and 2N HCl (l.OmL).
• formaldehyde 37%> solution, l.OmL
• potassium cyanide(102mg)and 2N HCl l.OmL
• the cytotoxicity of compounds of formula (I) was measured using the H69 parental (H69/P) human small cell lung carcinoma cell line and the drug resistant human small cell lung carcinoma cell line H69/LX4 which overexpresses P-glycoprotein (Pgp).
• the cytotoxicity as measured by the IC 50 (concentration required to give 50%> cell kill) in the H69/LX4 cell line divided by the cytotoxicity in the H69/P cell line gives an indication of the degree to which a compound is affected by Pgp-dependent MDR and is termed the resistance factor (Rf) of the compound.
• H69/P and H69/LX4 cells were pipetted into 96-well tissue culture plates and then allowed to incubate at 37°C for 4 h. A range of concentrations from 0.01 nM to 5 ⁇ M of compounds of formula (I) or the standards TAS-103, Doxorubicin and Topotecan were then added. The plates were incubated for 5-6 days before adding AlamarBlue to each well and returning the plates to the incubator for 5-8 h to allow colour development. The cell numbers in the plates at the end of this period were directly proportional to the absorbance measured at a wavelength of 570 nm (reference wavelength 600 nm).
• the cytotoxicity of the compounds described herein was also measured using the COR-L23 parental (COR-L23/P) human non-small cell lung carcinoma cell line and also the drug resistant human non-small cell lung carcinoma cell line COR-L23/R which overexpresses multidrug resistance associated protein (MRP).
• MRP multidrug resistance associated protein
• the cytotoxicity as measured by the IC 50 (concentration required to give 50%> cell kill) in the L23/R cell line divided by the cytotoxicity in the L23/P cell line gives an indication of the degree to which a compound may be affected by MRP-dependant MDR and is termed the resistance factor (Rf) of the compound.
• L23/P and L23/R cells were pipetted into 96-well tissue culture plates and then allowed to incubate at 37°c for 4 h. A range of concentrations from O.OlnM to 5 ⁇ M of compounds of formula (I) or the standards TAS-103, Doxorubicin and Topotecan were then added. The plates were incubated for 5-6 days before proliferation was assessed using the sulphurhodamine B (SRB) assay as described by Skehan et al, J Natl Cancer Inst 1990, 82, ppl l07-1112.
• SRB sulphurhodamine B
• the cytotoxicity of the compounds described herein was also measured using the Jurkat human leukaemia cell line (JL C ) and also the amsacrine-resistant Jurkat human leukaemia cell line ( Lj) and the doxorubicin-resistant Jurkat human leukaemia cell line (JL D ).
• the cytotoxicity as measured by the IC 0 (concentration- required to give 50%> cell kill) in the JL A or JL D cell line divided by the cytotoxicity in the JL C cell line gives an indication of the degree to which a compound may be affected by atypical drug resistance and is termed the resistance factor (Rf) of the compound.
• the method used has been described previously (Finlay et al, Eur J. Cancer 32A, 708-714, 1996). Compounds were active in the range InM to
• Tablets each weighing 0.15 g and containing 25 mg of a compound of the invention can be manufactured as follows:
• Example 3 The compounds prepared in Example 3 were characterised by proton N.M.R. spectroscopy and mass spectrometry. All proton NMR was performed at 400 MHz.

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