EP0482119A1 - Agents d'intercalation - Google Patents

Agents d'intercalation

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Publication number
EP0482119A1
EP0482119A1 EP90917804A EP90917804A EP0482119A1 EP 0482119 A1 EP0482119 A1 EP 0482119A1 EP 90917804 A EP90917804 A EP 90917804A EP 90917804 A EP90917804 A EP 90917804A EP 0482119 A1 EP0482119 A1 EP 0482119A1
Authority
EP
European Patent Office
Prior art keywords
dione
bis
anthracene
compound
bsu
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90917804A
Other languages
German (de)
English (en)
Inventor
Stephen The Institute Of Cancer Research Neidle
Terence Charles The Institute Of Cancer Jenkins
Mavis The Institute Of Cancer Research Agbandje
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cancer Research Campaign Technology Ltd
Original Assignee
Cancer Research Campaign Technology Ltd
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Filing date
Publication date
Application filed by Cancer Research Campaign Technology Ltd filed Critical Cancer Research Campaign Technology Ltd
Publication of EP0482119A1 publication Critical patent/EP0482119A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes

Definitions

  • the present invention relates to anthraquinone derivatives and to their use as intercalating agents.
  • the present inventors have now developed a series of novel compounds based on anthraquinone which are potential anti-cancer agents.
  • the compounds are capable of binding to DNA, are cytotoxic and non-mutagenic. Accordingly, the present invention provides a compound having the general formula (I) :
  • n 1, 2 or 3 and R 1 and R 2 , which may be the same or different, are -each a hydroxyethyl or hydroxymethyl group; or R 1 and R 2 form, with the nitrogen atom to which they are attached, a cyclic group which is a 2-, or 4-(2-hydroxy- ethyl)-1-piperidino, 1-piperidino, 2-hydroxymethyl-l- piperidino, 4-(2-hydroxyethyl) or 4-methyl-l-piperazino or 4-morpholino group; and pharmaceutically acceptable salts thereof.
  • a further aspect of the invention is a compound of formula (I) or a salt thereof as hereinbefore defined for use in a method of treatment of the human or animal body by surgery or therapy, or of diagnosis practiced on the human or animal body.
  • the present invention provides a compound of formula (I) or a salt thereof as hereinbefore defined for use in the treatment of cancer.
  • the invention also provides the use of a compound of formula (I) or a salt thereof as hereinbefore defined in the manufacture of a medicament for use in the treatment of cancer.
  • n 1, 2 or 3.
  • the first stage of the process to prepare compounds of formula (I) comprises treating 2,6-diaminoanthraquinone with a chloroalkanoyl chloride of formula Cl(CH 2 ) n COCl in which n is 1, 2 or 3. This leads to the formation, in crude form, of a compound of formula (II) as defined above.
  • the reaction is carried out either in neat chloroalkanoyl chloride or in the presence of an organic solvent.
  • n 1 or 2 the reaction is carried out in neat chloroacetyl chloride or neat 3-ch ⁇ oropropanoyl chloride respectively.
  • n 3 the 2,6-diamino- chloride respectively.
  • n 3 the 2,6-diamino ⁇ anthraquinone is typically first suspended in an organic solvent, such as benzene, to which the chloroalkanoyl chloride is then added. The process is carried out with heating, typically under reflux conditions. Heating is generally continued for up to 6 hours.
  • the crude product of formula (II) may be used directly in the second stage of the process without prior purification.
  • the second stage of the process to prepare compounds of formula (I) involves aminolysis of the bis(chloro-alkana ido)anthraquinone intermediate produced in the first stage. This comprises treating a compound of formula (II) as defined above, with the exception of a compound where n - 3, with, in the presence of an organic solvent, an amine of formula HNR 1 R 2 in which R 1 and R 2 are the same or different and are each as defined above in connection with formula (I) .
  • the crude compound (II) is generally first suspended in a solvent, for example an alcohol such as ethanol.
  • a solvent for example an alcohol such as ethanol.
  • the suspension is typically stirred and heated to gentle reflux.
  • the amine of formula HN ⁇ is then added, usually dropwise and usually over a period of 5 to 40 minutes.
  • the reaction mixture is then refluxed for sufficient time for the reaction to reach completion, as evidenced by TLC. This may take anything from 3 to 30 hrs, typically from 5 to 14 hrs.
  • the purified base compound may be converted to a salt.
  • the preferred salt is either the acetate, in which case each of the basic amine functions -NR ⁇ -R 2 in formula (I) is converted to the group -NR 1 R .HOAC; or it is the quaternary methylammonium salt, in which case the amine functions are converted to the group -N + (CH 3 )R 1 R 2 I ⁇ .
  • Other suitable salts include the succinate and the maleate.
  • the base compound (I) is typically suspended in glacial acetic acid, treated with activated charcoal and heated. The resulting solution is filtered and trituration of the filtrate yields the acetate salt as a brightly coloured precipitate.
  • the base compound (I) is typically suspended in acetone, treated with CH 3 I and stirred at room temperature for a day.
  • the compounds of formula (I) and their salts have pharmaceutical utility in that they possess properties making them suitable as anti-cancer agents. They interact with DNA; they are cytotoxic (with the exception of the compound BSU-1022) ; and they are effectively non-mutagenic.
  • the use of biophysical techniques and molecular modelling has shown that interaction with DNA occurs by a mode of binding which is similar to that of certain known anti-cancer agents which may exert their effect by intercalation in the double helix of DNA.
  • the DNA binding properties of some compounds and salts of formula (I) are shown in Table 2 below:
  • Intercalative binding is also shown to be enhanced by the existence of hydrogen bonding which can occur when the side chains of the compounds of formula (I) bear OH substituents.
  • the compounds of formula (I) and the salts thereof are also shown to be capable of unwinding covalently-closed supercoiled plasmid PM2 DNA. Only the diethanolamine- substituted compound BSU-1041 does not cause positive supercoiling of the plasmid DNA, even at high concentrations. The unwinding angles observed are comparable to these determined for known intercalators and lend further support to intercalation being the major mode of binding.
  • the compounds of formula (I) and their salts are all cytotoxic towards L1210 leukaemia and WS tumour cells and Chinese hamster cells as determined in vitro at low concentrations.
  • the known intercalator mitoxantrone also exhibits such differential toxicity.
  • the in vitro studies have shown that biological activity is dependent upon the protonation status of the terminal amine residues in the side-chains of compounds of formula (I). The more basic compounds are the more active.
  • n 2 compounds, BSU-1043 and BSU-1042, to have marginal activity against the L1210 tumour model system.
  • the n 1 compound BSU-1008 (evaluated as the acetate salt BSU-1025) is also slightly active i vivo.
  • the fact that in vivo results obtained hitherto do not correlate well with the in vitro results may be due to several factors such as pharmacokinetics and/or limited drug penetration.
  • Plasma stability studies have shown the compounds to be stable for upwards of 2 hrs during incubation at 37°C and so it is unlikely that the compounds degrade in vivo.
  • the third valuable property of the compounds of formula (I) is that they are non-mutagenic. This is shown using the "Ames test” and persists at levels at which mitoxantrone is mutagenic. Mutagenicity is frequently linked with anti-cancer activity and so these results indicate the clinical use of compounds of formula (I) and their salts as anti-cancer agents.
  • the present invention further provides a method of treating a host suffering from cancer which method comprises administering thereto a pharmaceutically effective amount of a compound of formula (I) .
  • the compounds of the invention can be administered in a variety of dosage form, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories, parenterally, e.g. intramuscularly, or by intravenous injection or infusion.
  • the dosage depends on the age, weight, condition of the patient, type of tumour to be treated, and administration route.
  • a suitable dosage for oral administration to adult humans is from 0.1 to 100 mg per kg body weight per day, preferably from 1 to 10 mg per kg.
  • the invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and, as active principle, a compound of formula (I) .
  • the pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch: lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycol ⁇ ; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycol ⁇
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl
  • starch alginic acid, alginates, or sodium starch glycolate
  • effervescing mixtures dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, ethylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.
  • solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Examples 1 to 18 further illustrate the invention.
  • the compounds were characterised using the following methods. IR spectroscopy was performed on a Perkin Elmer IR model 1310 spectrophotometer using Nujol mulls or pressed KC1 discs; proton magnetic resonance ( 1 H-NMR) spectra were recorded using a BRUKER AC250 250MHz FT-NMR instrument operating at 293 ⁇ 1K; UV-visible spectra were recorded using a Varian Cary 219 spectrophometer, and mass spectra were recorded using a VG7070H mass spectrometer fitted with El(electron- impact) ionisation source (70eV, 390-42OK source temperature) .
  • the fast atom bombardment (FAB) ionisation method was used for the determination of the mass spectra of certain compounds of poor solubility or volatility.
  • FAB fast atom bombardment
  • 2,6-Diaminoanthracene-9,10-dione (30.0 g, 0.126 mol) was refluxed in neat 3-chloropropanoyl chloride (500 g, 3.94 mol) for a period of 5 hrs, after which time the reaction was judged to have reached completion by TLC.
  • the reaction mixture was observed to change colour from the brick red of the dia ine to mustard yellow within 30 mins of reflux.
  • the reaction mixture was cooled in an external ice-water bath and then filtered under vacuum.
  • 2,6-Diaminoanthracene-9,10-dione (30.0 g, 0.126 mol) was suspended in 1000 ml of benzene.
  • 4-Chlorobutyryl chloride 500 ml, 4.46 mol
  • a catalytic amount of pyridine (1 g) were added and the suspension was heated for 4 hrs at 70*C.
  • the solvent was removed to give an essentially quantitative yield of the bis-amide. Yield: 55.8 g (*?99%th) .
  • R f (EtOH) 0.90.
  • a small amount of the crude product was recrystallised from DMF:EtOH (4:1 v/v) for characterisation, m.p. >340°C.
  • 2,6-Bis(2-chloroacetamido)anthracene-9,10-dione (BSU-1001, 10.0 g, 25.6 mmol) was suspended in ethanol (300 ml) with vigorous stirring and heated to gentle reflux. Piperidine (30 ml, 0.30 mol) was added dropwise to the suspension over a period of 15 mins. The reaction mixture was refluxed for a period of 5 hrs, after which time the reaction was shown to have reached completion by TLC. The reaction mixture was observed to change appearance from an initial yellow suspension to a dark brown mixture within 30 mins of reflux. The reaction mixture was cooled in an ice-water bath and then filtered.
  • Diacetate salt (BSU-1032) mp 210-212'C.
  • BSU-1001 2,6-Bis(2-chloroacetamido)anthracene-9,10-dione (BSU-1001, 10.5 g, 26.8 mmol) was suspended in ethanol (300 ml) and the stirred mixture was heated to gentle reflux. Morpholine (25 ml, 0.29 mol) was added dropwise, over a period of 15 mins, to the refluxing solution. The. mixture was refluxed for a period of 7 hrs, at which point the reaction was shown to have reached completion by TLC. During the reaction period, the colour of the reaction mixture was observed to change from mustard yellow to greenish yellow. The solvent and volatile organics were removed under reduced pressure.
  • the yellow solid product was digested in chloroform (100 ml) , treated with activated charcoal and the solution filtered.
  • the clear chloroform filtrate was subsequently passed through a bed of silica gel (10 cm x 3 cm diameter) to give a bright yellow solution.
  • the eluate was evaporated under reduced pressure to give a bright yellow powder which was thoroughly washed with anhydrous diethyl ether (3 x 400 ml). Recrystallisation from ethanol-chloroform (1:1 v/v) gave the title compound as yellow crystals (7.99 g, 64% th) , m.p. 263-264°C.
  • Diacetate salt (BSU-1024) mp 188-189°C. Anal.
  • Methiodide salt (BSU-1007) : mp 240-241.5 ⁇ C dec.
  • Methiodide salt (BSU-1034) : mp 268.5-270 ⁇ C dec.
  • 2,6-Bis(3-chloropropionamido)anthracene-9,10-dione (BSU-1013, 10.0 g, 23.9 mmol) was suspended in ethanol (300ml) and the stirred mixture was heated to gentle reflux. Piperidine (25 ml, 0.25 mol) was added dropwise during 20 mins. Reflux was continued for 5 hrs, after which time the reaction was judged (TLC) to have reached completion. The reaction mixture was observed to change colour from mustard yellow to dark brown during the course of the reaction. The reaction mixture was cooled in an external ice-water bath and the solid product was collected by filtration.
  • Diacetate salt (BSU-1021) mp 244-246 ⁇ C dec.
  • Methiodide salt (BSU-1026) mp 262-264.5°C dec.
  • 2,6-Bis(3-chloropropionamido)anthracene-9 ,10-dione (BSU-1013, 10.0 g, 23.9 mmol) was suspended in ethanol (300 ml) with stirring and heated to gentle reflux. Morpholine (40 ml, 0.46 mol) was added dropwise during 30 mins to the refluxing solution. Reflux was continued for 17 hrs, after which time the reaction was judged to have reached completion by TLC. The colour of the reaction mixture was observed to change from mustard yellow to dark brown during the reaction period. The reaction mixture was cooled in an external ice-water bath and the solid product was collected by filtration.
  • Diacetate salt (BSU-1028) mp 255-257 ⁇ C.
  • Methiodide salt (BSU-1027) : mp 232-233 ⁇ C.
  • 2,6-Bis(3-chloropropanamido)anthracene-9,10-dione (BSU-1013, 10.0 g, 23.9 mmol) was suspended in ethanol (300 ml) and the stirred mixture was heated to reflux. Diethylamine (25 ml, 0.24 mol) was added dropwise during 15 mins to the refluxing solution. The reaction mixture was refluxed for a period of 5 hrs, after which time the reaction was judged to have reached completion by TLC. The colour of the reaction mixture was observed to change from mustard yellow to bright yellow during the course of the reflux. The reaction mixture was cooled using an external ice-water bath and the solid material was collected by filtration.
  • Diacetate salt (BSU-1030) mp 201-203"C dec.
  • Methiodide salt (BSU-1029) mp 242.5-243.5"C.
  • Tetra-acetate salt (BSU-1043) : mp 235-236'C.
  • the base compounds of formula (I) (4-6 mmol) were suspended in glacial acetic acid (30 ml) , treated with activated charcoal ( " 0.5 g) and then heated to 50-60°C using an external water bath. The resulting brightly- coloured solutions were filtered to remove insoluble material (Whatman No. 1 paper) . Trituration with anhydrous diethyl ether afforded bright yellow precipitates. The resulting hygroscopic solids were digested with anhydrous diethyl ether (5 x 100 ml) , filtered and dried in vacuo at room temperature ( ⁇ 0.1 mmHg, 48 hrs) to give the acetate salts as amorphous powders.
  • the elemental analysis of a representative tetra- acetate salt BSU-1025, derived from the free base compound BSU-1008 (i.e BSU-1008. (CH 3 C0 2 H) ) is indicated:
  • the base compounds of formula (I) (2-3 mmol) were suspended in acetone (50-75 ml) with stirring at room temperature. An excess quantity of iodomethane ( " 10 ml) was added to the mixture and stirred for 24 hrs at room temperature. The resulting quaternary methiodide salt products were collected by filtration, thoroughly washed with anhydrous diethyl ether (3 x 100 ml) and dried at 20"C.
  • This Example illustrates the interaction of compounds of formula (I) and their salts with DNA.
  • Calf thymus DNA was complexed with the acetate salts tabulated below, in DNA:drug ratios of 40:1, 20:1 and 10:1 respectively.
  • the increase in melting temperature ( ⁇ Tm) for the DNA was then measured at each ratio.
  • the results tabulated in Table 3 are mean values of T m based on at least three measurements, with esd values of ⁇ (0.1- 0.3) °C.
  • the estimated pKa value for each compound is also shown.
  • This Example further illustrates the interaction of certain compounds of formula (I) and their salts with different DNA's.
  • the Table also lists possible binding site preferences. Values obtained for mitoxantrone are included 15 for comparison.
  • the “critical concentration” is the concentration of drug at which the closed PM-2 almost co-migrates with nicked DNA.
  • the "unwinding angle” ( ⁇ ) is the degree of local unwinding of the DNA helix due to each molecule of drug bound to DNA with values estimated ⁇ 2" .
  • the results are tabulated below in Table 5. Values obtained for ethidium bromide are included for reference.
  • the salts were administered intraperitoneally to test animals once a day on days 3, 5, 6 and 7 for several weeks.
  • the percentage life span (%LS) of the test animals was determined in comparison to a control (100%) to which a saline solution was administered.
  • the percentage increase in life span of the animals was also determined.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule générale (I); où n est égal à 1, à 2 ou à 3; et R1 et R2 représentent chacun, séparément, un groupe éthyle, hydroxyéthyle ou hydroxyméthyle; ou R1 et R2 forment, conjointement avec l'atome d'azote auquel ils sont liés, un groupe cyclique tel qu'un groupe 1-pipéridino, 2- ou 4-(2-hydroxyéthyl)-1-pipéridino, 2-hydroxyméthyl-1-pipéridino, 4-(2-hydroxyéthyl)-pipérazino ou 4-méthyl-1-pipérazino ou 4-morpholino; ou à un sel pharmaceutiquement acceptable d'un tel composé. Ces composés sont utiles comme agents de lutte contre le cancer. Un procédé de préparation de ces composés ainsi que des compositions pharmaceutiques contenant ces composés sont également décrits.
EP90917804A 1989-06-30 1990-06-29 Agents d'intercalation Withdrawn EP0482119A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8915028 1989-06-30
GB898915028A GB8915028D0 (en) 1989-06-30 1989-06-30 Intercalating agents

Publications (1)

Publication Number Publication Date
EP0482119A1 true EP0482119A1 (fr) 1992-04-29

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EP90917804A Withdrawn EP0482119A1 (fr) 1989-06-30 1990-06-29 Agents d'intercalation

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EP (1) EP0482119A1 (fr)
GB (1) GB8915028D0 (fr)
WO (1) WO1991000265A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7846798A (en) * 1996-12-13 1998-07-03 Cancer Research Campaign Technology Limited Further anthraquinones with biological activity
GB9625941D0 (en) * 1996-12-13 1997-01-29 Cancer Res Campaign Tech Anthraquinones with biological activity
US6777564B2 (en) * 2001-12-20 2004-08-17 Industrial Technology Research Institute Anthraquinone compound
TWI422367B (zh) * 2008-11-28 2014-01-11 Nat Defense Medical Ct An onion quinone derivative for inhibiting cancer and a method for producing the same

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3859315A (en) * 1972-10-30 1975-01-07 American Home Prod Disubstituted acetamidoanthraquinones
DE2537878A1 (de) * 1975-08-26 1977-03-10 Hoechst Ag Substituierte 2,6-diamino-anthrachinone und verfahren zu ihrer herstellung
AT351521B (de) * 1976-01-22 1979-07-25 Rudolf Biber Verfahren zur herstellung neuer 2,6-bis- (aminoacylamino)-anthrachinone sowie ihrer saeureadditionssalze
WO1986000892A1 (fr) * 1984-08-01 1986-02-13 Rudolf Biber Nouveaux composes a l'activite immunisante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9100265A1 *

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GB8915028D0 (en) 1989-08-23
WO1991000265A1 (fr) 1991-01-10

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