US10385009B2 - Deuterated compounds and uses thereof - Google Patents

Deuterated compounds and uses thereof Download PDF

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US10385009B2
US10385009B2 US14/420,184 US201314420184A US10385009B2 US 10385009 B2 US10385009 B2 US 10385009B2 US 201314420184 A US201314420184 A US 201314420184A US 10385009 B2 US10385009 B2 US 10385009B2
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cells
tumour
bicalutamide
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US20150307441A1 (en
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Stefan Ogrodzinski
Paul Smith
Stephanie McKeown
Laurence Patterson
Rachel Jane Errington
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Oncotherics Ventures Ltd
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Definitions

  • the present invention relates to novel anthraquinone compounds and uses of the same, for example in the treatment of cancer.
  • tumours can have significantly lower median oxygen levels (approximately 1% oxygen; pO2 7.5 mmHg) compared to normal tissues ( ⁇ 5.5% oxygen; 42 mmHg) (summarised from data presented by Brown and Wilson, 2004).
  • oxygenation levels can vary throughout the tumour due to intermittent opening and closing of tumour blood vessels; poor vascularisation, especially in the tumour core, contributes to oxygen levels often being below 0.1% oxygen (1 mm Hg).
  • Hypoxia-selective agents comprise one class of agents that can be used to target tumour cells in very low oxygen environments by virtue of a selective activation to a cytotoxic form under reduced oxygenation, addressing the problems of non-target tissue toxicity, hypoxic cell drug resistance and cancer progression.
  • tumour cells can adapt to low oxygen conditions and change the pharmacodynamic responses to anticancer agents through the induction of active cellular protective mechanisms (Vaupel and Mayer 2007 , Cancer Metastasis Rev 26(2): 225-239). Additionally, it is recognized that tumour cells that survive hypoxic stress often show a more malignant metastatic phenotype (Vaupel P, Metabolic microenvironment of tumor cells: a key factor in malignant progression, Exp Oncol 2010; 32, 125-127); this has significant consequences for the patient. Following treatment with modalities that target predominantly the better-oxygenated cells, the stress-resistant hypoxic cells often repopulate the tumour with cells that have an enhanced potential to spread to distant tissues. The development of more malignant metastatic tumours is often the precursor to a more significant disease-related morbidity and the death of the patient.
  • hypoxia activated prodrug that is non-toxic towards adequately oxygenated cells found in systemic tissues, but becomes activated or converted to a cytotoxic form under reduced oxygenation conditions.
  • N-oxide derivatives of cytotoxic alkylaminoanthraquinones provide anthraquinone pro-drugs that show almost no cytotoxicity.
  • these prodrugs are capable of being converted in vivo under the anaerobic/hypoxic conditions found within neoplastic tissue. Specificity for the tumour is ensured since systemic tissues, except for tumours, almost never experience oxygen levels low enough to facilitate the production of the cytotoxic drug.
  • the anthraquinone N-oxide AQ4N (CAS#136470-65-0) is a prodrug that is selectively bioreduced to AQ4, a potent DNA topoisomerase II inhibitor, in hypoxic tumour cells.
  • Previous publications have taught the fundamental properties and in-vitro/in-vivo characteristics of the prodrug AQ4N (for example, see U.S. Pat. No. 5,132,327).
  • the invention seeks to address the need for improved cancer treatments by providing novel anthraquinone compounds with a combination of preferable pharmacological and hypoxia-sensing properties.
  • the first aspect of the invention provides a compound of Formula I
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of hydrogen, hydroxy, halogeno, amino, C 1-4 alkoxy, C 2-8 alkanoyloxy, —NH-A-NHR, —NH-A-NR′R′′ and —NH-A-N(O)R′R′′ wherein A is an alkylene group with a chain length of at least two carbon atoms (between NH and NHR or N(O)R′R′′), wherein R, R′ and R′′ are each independently selected from C 1-4 alkyl groups and C 2-4 hydroxyalkyl and C 2-4 dihydroxyalkyl groups in which the carbon atom attached to the nitrogen atom does not carry a hydroxy group and no carbon atom is substituted by two hydroxy groups, or wherein R and R′′ together are a C 2-6 alkylene group which with the nitrogen atom to which R′ and R′′ are attached forms a heterocyclic group having 3 to 7 atoms in the group consist
  • the invention provides novel deuterated anthraquinone compounds.
  • deuterated we include that the compound comprises at least one atom of deuterium or heavy hydrogen (i.e. D or 2 H). It will be appreciated by persons skilled in the art that the compound may be partially (i.e. selectively) or fully deuterated (i.e. containing hydrogen present only in the form of deuterium).
  • substituent groups X 1 , X 2 , X 3 and X 4 may be deuterated while the central anthraquinone ring may be free of deuterium.
  • the compound of the invention is selectively deuterated within one or more of substituent groups —NH-A-NHR, —NH-A-NR′R′′ and/or —NH-A-N(O)R′R′′ at positions X 1 , X 2 , X 3 and/or X 4 .
  • substituent groups —NH-A-NHR, —NH-A-NR′R′′ and/or —NH-A-N(O)R′R′′ at positions X 1 , X 2 , X 3 and/or X 4 .
  • substituent groups —NH-A-NHR, —NH-A-NR′R′′ and/or —NH-A-N(O)R′R′′ at positions X 1 , X 2 , X 3 and/or X 4 .
  • A, R, R′ and R′′ may be fully deuterated (i.e. thus containing no 1 H) or may be partially deuterated.
  • the compound is deuterated only within one or more of the terminal groups R, R′ and R′′.
  • R, R′ and/or R′′ may represent:
  • C 1-4 alkyl is intended to include linear or branched alkyl groups comprising between one and four carbons.
  • Preferred alkyl groups which R, R′ and/or R′′ may independently represent include C 1 and C 2 alkyl.
  • lower alkylene is to be construed accordingly.
  • C 2-4 hydroxyalkyl and C 2-4 dihydroxyalkyl are intended to include linear or branched alkyl groups comprising between two and four carbons, to which are attached one or two hydroxy groups, respectively.
  • R, R′ and/or R′′ may independently represent:
  • C 1-4 alkoxy is intended to include linear or branched C 1-4 alkyl groups bound to the core anthraquinone (anthracene-9,10-dione) ring via oxygen.
  • R, R′ and/or R′′ may independently represent:
  • C 2-8 alkanoyloxy is intended to include linear or branched C 2-8 alkanoyl groups bound to the core anthraquinone (anthracene-9,10-dione) ring via oxygen.
  • R, R′ and/or R′′ may independently represent:
  • hydroxy is intended to represent —OH.
  • halogeno is intended to represent any halogen group, such as —Br, —Cl and —F.
  • amino is intended to include primary amine groups, such as —NH 2 .
  • anthraquinone ring of the compounds may be substituted by X 1 , X 2 , X 3 and X 4 at any of ring positions 1, 2, 3, 4, 5, 6, 7 or 8:
  • the compound is substituted at ring positions 1, 4, 5 and 8, in accordance with Formula II:
  • X 1 , X 2 , X 3 and X 4 are each separately selected from the group consisting of hydrogen, hydroxy, —NH-A-NHR, —NH-A-NR′R′′, —NH-A-N(O)R′R′′ and deuterated forms thereof.
  • X 1 , X 2 , X 3 and X 4 are each separately selected from the group consisting of hydroxy, —NH-A-NR′R′′, —NH-A-N(O)R′R′′ and deuterated forms thereof.
  • X 1 and X 2 are both hydroxy and X 3 and X 4 are both —NH-A-N(O)R′R′′ or deuterated forms thereof.
  • X 1 and X 2 are both hydroxy and X 3 and X 4 are both NH-A-NR′R′′ or deuterated forms thereof.
  • A is unbranched.
  • A may be ethylene.
  • R, R′ and R′′ are each independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH(CH 3 )CH 2 OH, —CH 2 CHOHCH 2 OH and deuterated forms thereof.
  • one or two of X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of —NH—(CH 2 ) 2 —N(O)(CH 3 ) 2 , —NH—(CH 2 ) 2 —N(O)(CH 3 )C 2 H 5 , —NH—(CH 2 ) 2 —N(O)(C 2 H 5 ) 2 , —NH—(CH 2 ) 2 —N(O) (CH 2 CH 2 OH) 2 , —NH—(CH 2 ) 2 —N(O)(CH 2 CH 2 CH 2 OH) 2 , —NH—(CH 2 ) 2 —N(O)CH(CH 3 )OH, —NH—(CH 2 ) 2 —N(O)(CH 2 CHOHCH 2 OH) 2 and deuterated forms thereof.
  • one or two of X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of —NH—(CH 2 ) 2 —N(CH 3 ) 2 , —NH—(CH 2 ) 2 —N(CH 3 )C 2 H 5 , —NH—(CH 2 ) 2 —N(C 2 H 5 ) 2 , —NH—(CH 2 ) 2 —N(CH 2 CH 2 OH) 2 , —NH—(CH 2 ) 2 —N(CH 2 CH 2 CH 2 OH) 2 , —NH—(CH 2 ) 2 —NCH(CH 3 )OH, —NH—(CH 2 ) 2 —N(CH 2 CHOHCH 2 OH) 2 and deuterated forms thereof.
  • the compound of the invention comprises one group —NH-A-N(O)R′R′′ and one group —NH-A-NHR, the —NH-A-NHR group being selected from —NH—(CH 2 ) 2 —NHCH 3 , —NH—(CH 2 ) 2 —NHC 2 H 5 , —NH—(CH 2 ) 2 —NHCH 2 CH 2 OH, —NH—(CH 2 ) 2 —NHCH 2 CH 2 CH 2 OH, —NH—(CH 2 ) 2 —NHCH(CH 3 )CH 2 OH, —NH—(CH 2 ) 2 —NHCH 2 CHOHCH 2 OH and deuterated forms thereof.
  • the compound of the invention comprises one group —NH-A-NR′R′′ and one group —NH-A-NHR, the —NH-A-NHR group being selected from —NH—(CH 2 ) 2 —NHCH 3 , —NH—(CH 2 ) 2 —NHC 2 H 5 , —NH—(CH 2 ) 2 —NHCH 2 CH 2 OH, —NH—(CH 2 ) 2 —NHCH 2 CH 2 CH 2 OH, —NH—(CH 2 ) 2 —NHCH(CH 3 )CH 2 OH, —NH—(CH 2 ) 2 —NHCH 2 CHOHCH 2 OH and deuterated forms thereof.
  • both —NH-A-N(O)R′R′′ are —NH—(CH 2 ) 2 N(O)(CH 3 ) 2 or —NH—(CH 2 ) 2 N(O)(CH 2 CH 2 OH) 2 , or deuterated forms thereof and
  • both NH-A-NR′R′′ are —NH—(CH 2 ) 2 N(CH 3 ) 2 or —NH—(CH 2 ) 2 N(CH 2 CH 2 OH) 2 , or deuterated forms thereof.
  • —NH-A-N(O)R′R′′ is —NH—(CH 2 ) 2 N(O)(CH 3 ) 2 or —NH—(CH 2 ) 2 N(O)(CH 2 CH 2 OH) 2 or a deuterated form thereof
  • —NH-A-NHR is NH—(CH 2 ) 2 NHCH 3 or NH(CH 2 ) 2 NHCH 2 CH 2 OH or a deuterated form thereof
  • NH-A-NR′R′′ is —NH—(CH 2 ) 2 N(CH 3 ) 2 or —NH—(CH 2 ) 2 N(CH 2 CH 2 OH) 2 or a deuterated form thereof.
  • the present invention relates to novel anthraquinone compounds and uses of the same, for example in the treatment of cancer.
  • the present invention relates to novel anthraquinone compounds and uses of the same, for example in the treatment of cancer.
  • the compound is of Formula III or IV:
  • Y are each independently selected from the group consisting of hydrogen, hydroxy, halogeno, amino, C 1-4 alkoxy and C 2-8 alkanoxy, or a prodrug thereof.
  • prodrug in this context, is included compounds which may readily be converted in vivo to a compound of Formula III or IV. In one embodiment, the conversion is triggered by the prodrug entering an hypoxic environment, such as a solid tumour.
  • Suitable prodrugs include N-oxide derivatives of the compounds of Formula III or IV.
  • the prodrug is a compound of Formula V or VI:
  • Y are each independently selected from the group consisting of hydrogen, hydroxy, halogeno, amino, C 1-4 alkoxy and C 2-8 alkanoxy.
  • the compound is of Formula VII or VIII:
  • the present invention relates to novel anthraquinone compounds and uses of the same, for example in the treatment of cancer.
  • the present invention relates to novel anthraquinone compounds and uses of the same, for example in the treatment of cancer.
  • the compound is prodrug of Formula IX or X:
  • one or more of the deuterium atoms in one or more of the methyl groups attached to the nitrogen of the terminal amino groups may be replaced by conventional hydrogen (i.e. 1 H), provided that the compound comprises at least one deuterium atom.
  • one, two, three or four of the methyl groups may be —CH 3 , —CH 2 D or —CHD 2 .
  • the methyl groups in the compound are either —CH 3 or —CD 3 .
  • counter-anions include, but are not limited to, halides (e.g. fluoride, chloride and bromide), sulfates (e.g. decylsulfate), nitrates, perchlorates, sulfonates (e.g. methane sulfonate) and trifluoroacetate.
  • halides e.g. fluoride, chloride and bromide
  • sulfates e.g. decylsulfate
  • nitrates e.g. decylsulfate
  • perchlorates e.g. methane sulfonate
  • trifluoroacetate e.g. methane sulfonate
  • Salts which may be mentioned include: acid addition salts, for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids; base addition salts; metal salts formed with bases, for example, the sodium and potassium salts.
  • acid addition salts for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids
  • base addition salts for example, the sodium and potassium salts.
  • the compound is in the form of a halide salt, for example a chloride salt.
  • Compounds of formulae I to X may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
  • a solvent such as methanol, ethanol, water, dimethylformamide, 2-methoxyethanol, acetonitrile, nitrobenzene, N,N,N′N′-tetra-methylenediamine or mixtures thereof.
  • a higher temperature and shorter reaction time may be appropriate, for example with the compounds containing cyclic groups NR′R′′.
  • the leuco derivative is then oxidized to the fully aromatic anthracene-9,10-dione, conveniently using air oxidation or oxidation with hydrogen peroxide, chloranil, sodium perborate or manganese dioxide.
  • leuco compounds are primarily of interest for the preparation of compounds substituted by two —NH-A-NHR′R′′ groups, it is possible to use them to prepare compounds containing more than two such groups.
  • 2,3-dihydro(leuco)-1,4,5,8-tetrahydroxyanthracene-9,10-dione and a large excess of an amine —NH-A-NHR′R′′ an 8-hydroxyanthracene-9,10-dione having three groups —NH-A-NHR′R′′ at the 1, 4 and 5 positions may be prepared.
  • the leuco derivatives themselves are obtainable by heat treatment of the corresponding fully aromatic 1,4-dihydroxyanthracene-9,10-dione, conveniently by heating at above 90° C. for 1 hour or more in a stream of nitrogen and, if necessary, in the presence of a suitable reducing agent such as sodium dithionite or zinc dust.
  • a suitable reducing agent such as sodium dithionite or zinc dust.
  • Various anthracene-9,10-diones, particularly hydroxyanthracene-9,10-diones are commercially available and various syntheses for such compounds are also reported in the literature.
  • One suitable procedure for their preparation involves the reaction of an appropriately substituted phthalic anhydride with hydroquinone in the presence of aluminium chloride and sodium hydroxide at 180° C. for one hour or more.
  • Anthracene-9,10-diones containing one form of substituent group can be modified to provide other forms of substituent group so that, for example, a dione containing an amino group can be treated with sodium hydroxide/dithionite to yield the corresponding hydroxy substituted compound.
  • a KF—NaF-mediated conversion of 3,6-dichlorophthalic anhydride to 3,6-difluorophthalic anhydride as a precursor to making 1,4-difluoro-4,8-dihydroxyanthracene-9,10-dione
  • 1,4-difluoro-4,8-dihydroxyanthracene-9,10-dione see Lee & Denny, 1999 , J. Chem. Soc., Perkin Trans. 1:2755-2758.
  • 1,5-dichloro-4,8-dihydroxyanthracene-9,10-dione may be prepared by selective chlorination of 1,4,5,8-tetrahydroxyanthracene-9,10-dione using a stoichiometric amount of sulphuryl chloride and controlled temperature.
  • This precursor may then be used to prepare an intermediate having groups —NH-A-NR′R′′ at the 1 and 5 positions and hydroxy groups at the 4 and 8 positions, the hydroxy groups conveniently being protected during the reaction with the amine R′′R′N—A—NH 2 .
  • a similar approach is suitable for the preparation of other chlorohydroxyanthracene-9,10-dione intermediates.
  • the compound of the invention contains one or more groups —NH-A-NHR in addition to the one or more groups —N-A-NR′R′′
  • the compound may conveniently be produced by reacting a suitable precursor as discussed above with a mixture of amines RN—A—NH.sub.2 and R′′R′N—A—NH.sub.2, the resultant mixture of products then being separated, for example by chromatography.
  • 2,3-dihydro(leuco)-1,4-dihydroxyanthracene-9,10-dione on reaction with a mixture of 2-(2-hydroxyethylamino)ethylamine and 2-(diethylamino)ethylamine will yield a mixture of 1,4-bis ⁇ [2-(diethylamino)-ethyl]amino ⁇ anthracene-9,10-dione, 1,4-bis ⁇ [2-(2-hydroxyethyl-amino)-ethyl]amino ⁇ -anthracene-9,10-dione and 1-(2-(diethylamino)ethyl]amino)-4- ⁇ [2-(2-hydroxyethylamino)-ethyl]amino ⁇ anthracene-9,10-dione from which the last mentioned compound may be separated, for example by chromatography.
  • chromatography On oxidation, only the tertiary nitrogen atom of the [2-
  • a second aspect of the invention provides a process for making a compound according to the first aspect of the invention comprising reacting an anthracene-9,10-dione with a deuterated alkylenediamine under conditions suitable for the production of an alkylaminoalkylaminoanthraquinone.
  • the process further comprises the step of reacting the alkylaminoalkylaminoanthraquinone with a monoperoxyphthalate to under conditions suitable for the production of an N-oxide derivative of the alkylamino-alkylaminoanthraquinone.
  • the process comprises reacting 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione, 281-005 with deuterated—N,N-dimethylethylene-diamine under conditions suitable for the production of 1,4-bis- ⁇ [2-(deuterated-d6-dimethylamino)ethyl]amino)-5,8-dihydroxyanthracene-9,10-dione.
  • the process comprises the step of reacting the 1,4-bis- ⁇ [2-(deuterated-d6-dimethylamino)ethyl]amino)-5,8-dihydroxyanthracene-9,10-dione with magnesium monoperoxyphthalate under conditions suitable for the production of 1,4-bis- ⁇ [2-(deuterated-d6-dimethylamino-N-oxide)ethyl]amino)-5,8-dihydroxy-anthracene-9,10-dione.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the first aspect of the invention together with pharmaceutically acceptable buffer, diluent, carrier, adjuvant or excipient.
  • pharmaceutically acceptable we include a non-toxic material that does not decrease the therapeutic effectiveness of the compound of the invention.
  • Such pharmaceutically acceptable buffers, carriers or excipients are well-known in the art (see Remington's Pharmaceutical Sciences, 18th edition, A. R Gennaro, Ed., Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000), the disclosures of which are incorporated herein by reference).
  • buffer is intended to mean an aqueous solution containing an acid-base mixture with the purpose of stabilising pH.
  • buffers are Trizma, Bicine, Tricine, MOPS, MOPSO, MOBS, Tris, Hepes, HEPBS, MES, phosphate, carbonate, acetate, citrate, glycolate, lactate, borate, ACES, ADA, tartrate, AMP, AMPD, AMPSO, BES, CABS, cacodylate, CHES, DIPSO, EPPS, ethanolamine, glycine, HEPPSO, imidazole, imidazolelactic acid, PIPES, SSC, SSPE, POPSO, TAPS, TABS, TAPSO and TES.
  • diluent is intended to mean an aqueous or non-aqueous solution with the purpose of diluting the agent in the pharmaceutical preparation.
  • the diluent may be one or more of saline, water, polyethylene glycol, propylene glycol, ethanol or oils (such as safflower oil, corn oil, peanut oil, cottonseed oil or sesame oil).
  • adjuvant is intended to mean any compound added to the formulation to increase the biological effect of the compound of the invention.
  • the adjuvant may be one or more of zinc, copper or silver salts with different anions, for example, but not limited to fluoride, chloride, bromide, iodide, thiocyanate, sulfite, hydroxide, phosphate, carbonate, lactate, glycolate, citrate, borate, tartrate, and acetates of different acyl composition.
  • the adjuvant may also be cationic polymers such as cationic cellulose ethers, cationic cellulose esters, deacetylated hyaluronic acid, chitosan, cationic dendrimers, cationic synthetic polymers such as poly(vinyl imidazole), and cationic polypeptides such as polyhistidine, polylysine, polyarginine, and peptides containing these amino acids.
  • cationic polymers such as cationic cellulose ethers, cationic cellulose esters, deacetylated hyaluronic acid, chitosan, cationic dendrimers, cationic synthetic polymers such as poly(vinyl imidazole), and cationic polypeptides such as polyhistidine, polylysine, polyarginine, and peptides containing these amino acids.
  • the excipient may be one or more of carbohydrates, polymers, lipids and minerals.
  • carbohydrates include lactose, glucose, sucrose, mannitol, and cyclodextrines, which are added to the composition, e.g., for facilitating lyophilisation.
  • polymers are starch, cellulose ethers, cellulose carboxymethylcellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, alginates, carageenans, hyaluronic acid and derivatives thereof, polyacrylic acid, polysulphonate, polyethylenglycol/polyethylene oxide, polyethyleneoxide/polypropylene oxide copolymers, polyvinylalcohol/polyvinylacetate of different degree of hydrolysis, and polyvinylpyrrolidone, all of different molecular weight, which are added to the composition, e.g., for viscosity control, for achieving bioadhesion, or for protecting the lipid from chemical and proteolytic degradation.
  • lipids are fatty acids, phospholipids, mono-, di-, and triglycerides, ceramides, sphingolipids and glycolipids, all of different acyl chain length and saturation, egg lecithin, soy lecithin, hydrogenated egg and soy lecithin, which are added to the composition for reasons similar to those for polymers.
  • minerals are talc, magnesium oxide, zinc oxide and titanium oxide, which are added to the composition to obtain benefits such as reduction of liquid accumulation or advantageous pigment properties.
  • the compounds of the invention may be formulated into any type of pharmaceutical composition known in the art to be suitable for the delivery thereof.
  • the pharmaceutical compositions are administered parenterally, for example, intravenously, intracerebroventricularly, intraarticularly, intraarterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
  • the pharmaceutical compositions may also administered intra-tumourally and/or peri-tumourally.
  • compositions are conveniently used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the pharmaceutical compositions of the invention may be in the form of a liposome, in which the agent is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids, which exist in aggregated forms as micelles, insoluble monolayers and liquid crystals.
  • Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like.
  • Suitable lipids also include the lipids above modified by poly(ethylene glycol) in the polar headgroup for prolonging bloodstream circulation time. Preparation of such liposomal formulations is can be found in for example U.S. Pat. No. 4,235,871, the disclosures of which are incorporated herein by reference.
  • compositions of the invention may also be in the form of biodegradable microspheres.
  • Aliphatic polyesters such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of PLA and PGA (PLGA) or poly(caprolactone) (PCL), and polyanhydrides have been widely used as biodegradable polymers in the production of microspheres. Preparations of such microspheres can be found in U.S. Pat. No. 5,851,451 and in EP 0 213 303, the disclosures of which are incorporated herein by reference.
  • compositions of the invention are provided in the form of polymer gels, where polymers such as starch, cellulose ethers, cellulose carboxymethylcellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, alginates, carageenans, hyaluronic acid and derivatives thereof, polyacrylic acid, polyvinyl imidazole, polysulphonate, polyethylenglycol/polyethylene oxide, polyethyleneoxide/polypropylene oxide copolymers, polyvinylalcohol/polyvinylacetate of different degree of hydrolysis, and polyvinylpyrrolidone are used for thickening of the solution containing the agent.
  • the polymers may also comprise gelatin or collagen.
  • the compounds may simply be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol or oils (such as safflower oil, corn oil, peanut oil, cottonseed oil or sesame oil), tragacanth gum, and/or various buffers.
  • oils such as safflower oil, corn oil, peanut oil, cottonseed oil or sesame oil
  • tragacanth gum and/or various buffers.
  • compositions of the invention may include ions and a defined pH for potentiation of action of the active agent. Additionally, the compositions may be subjected to conventional pharmaceutical operations such as sterilisation and/or may contain conventional adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, buffers, fillers, etc.
  • compositions according to the invention may be administered via any suitable route known to those skilled in the art.
  • routes of administration include parenteral (intravenous, subcutaneous, and intramuscular), topical, ocular, nasal, pulmonar, buccal, oral, parenteral, vaginal and rectal. Also administration from implants is possible.
  • compositions may be administered intranasally or by inhalation (for example, in the form of an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoro-methane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A3 or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA3), carbon dioxide or other suitable gas).
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoro-methane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A3 or 1,1,1,2,3,3,3-heptafluoroprop
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active polypeptide, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • a lubricant e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • compositions will be administered to a patient in a pharmaceutically effective dose.
  • the amount of a compound may vary depending on its specific activity. Suitable dosage amounts may contain a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the required diluent.
  • a therapeutically effective amount of the active component is provided.
  • a therapeutically effective amount can be determined by the ordinary skilled medical or veterinary worker based on patient characteristics, such as age, weight, sex, condition, complications, other diseases, etc., as is well known in the art.
  • the administration of the pharmaceutically effective dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals. Alternatively, the dose may be provided as a continuous infusion over a prolonged period.
  • compositions of the invention may be formulated in unit dosage form, i.e. in the form of discrete portions containing a unit dose or a multiple or sub-unit of a unit dose.
  • a dosage selected in the range from 0.1 to 20 mg/kg per body weight per day, particularly in the range from 0.1 to 5 mg/kg of body weight per day will often be suitable although higher doses than this, for example in the range from 0.1 to 50 mg/kg of body weight per day (or possibly even as high as described in U.S. Pat. No. 4,197,249) may be considered in view of the lower level of toxic side effects obtained with the compounds.
  • This dosage regime may be continued for however many days is appropriate to the patient in question, the daily dosages being divided into several separate administrations if desired.
  • a fourth aspect of the invention provides a compound according to the first aspect of the invention for use in medicine (clinical and/or veterinary).
  • a fifth aspect of the invention provides a compound according to the first aspect of the invention for use as a cytotoxin, or a hypoxia activated prodrug thereof.
  • the compound is for use in vivo as a cytotoxin, or a hypoxia activated prodrug thereof.
  • hypoxic conditions i.e. exhibits greater cytotoxicity under, or following exposure to, hypoxic conditions.
  • N-oxide compounds of the invention such as those of formulae V, VI, IX and X, are relatively non-cytotoxic under normoxic conditions but are readily reduced under hypoxic conditions to generate cytotoxic compounds, such as those of formulae III, IV, VII and VIII.
  • hypooxia may be regarded as an oxygenation level of 4% or lower (or ⁇ 23 mmHg) when measured directly by electrode methods.
  • the level of oxygenation may be lower than 3.0%, 2.5%, 2%, 1.5%, 1% or 0.5 or 0.1%.
  • hypoxia-induced activation of a compound's cytotoxic activity may be determined either in vitro or in vivo.
  • cytotoxicity may be determined in vitro at various oxygenation levels measured by direct electrode methods.
  • the level of oxygenation in a tissue may be measured indirectly, for example using histological sections probed with an enzyme detection assay or by gene expression analysis.
  • oxygenation levels in living tissue may be determined using both the Helzel and OxyLite systems (for example, see Wen et al., 2008 , Radiat. Res. 169:67-75).
  • results of blood flow and perfusion analyses may also infer the existence of hypoxia in a given tissues.
  • the application of agents that modify blood flow or compromise blood vessel formation would also on first principles be expected to reduce oxygenation in affected tissues.
  • the invention provides a compound according to the first aspect of the invention for use in the treatment of cancer in mammals (most notably in humans).
  • the compound may be for use in the treatment of a cancer selected from the group consisting of bladder cancer, breast cancer, bone cancer (primary and secondary, such as osteosarcoma and Ewings sarcoma), brain cancer (including glioblastoma multiforme and astrocytoma), cervical cancer, choriocarcinoma, colon and rectal cancer, endometrial cancer, eye cancer, gallbladder cancer, gastric cancer, gestational tumours, head and neck cancer, kidney (renal cell) cancer, laryngeal cancer, leukaemias (such as ALL, AML, CLL, CML and hairy cell leukaemias), liver cancer, lung cancer, lymphomas (such as Hodkin's lymphoma and non-Hodkin's lymphoma), melanoma, mesothelioma, mouth cancer, myeloma, nasal and sinus cancers, nasopharyngeal cancer, oesophageal cancer, ovarian
  • the compound is for use in the treatment of a solid tumour, such as various forms of sarcoma and carcinoma.
  • the compounds of the invention may be of particular use in the treatment of a tumour that is naturally hypoxic, at least in part (for example, having a median oxygen level of below 3%, e.g. lower than 2.5%, 2%, 1.5%, 1% or 0.5%).
  • a tumour that is naturally hypoxic, at least in part (for example, having a median oxygen level of below 3%, e.g. lower than 2.5%, 2%, 1.5%, 1% or 0.5%).
  • An example of such tumours are pancreatic cancer and prostate cancer, both typically exhibiting low oxygen levels and a propensity for malignant progression.
  • hypoxia-activated cytotoxicity of the prodrug compounds of the invention allows the cytotoxicity to be targeted to the tumour cells, reducing the risk of damage to healthy cells.
  • hypoxia may play a role in facilitating the malignant progression of certain cancers (for example, see Rudolfsson & Bergh, 2009 , Exp. Opin. Ther. Tar. 13:219-225).
  • the compounds of the invention may be able to target cancer cells that are otherwise resistant to treatment, e.g. by radiotherapy or conventional chemotherapeutic agents. Eradication of such resistant cells may, in turn, lead to a reduction in metastasis.
  • the compounds are for use in the treatment or prevention of metastases (which may arise from the aetiology of the cancer or as a consequence of treatment).
  • the compounds of the invention may be used on their own or in combination with other cancer treatments (such as radiotherapeutic modalities, e.g. radioisotopes and external beam radiation, and chemotherapeutic agents; see below).
  • radiotherapeutic modalities e.g. radioisotopes and external beam radiation, and chemotherapeutic agents; see below.
  • the compounds are for use as a monotherapy (i.e. without any other cancer treatments).
  • the cancer patient may also be receiving different types of beneficial medication (such as a painkiller, sedative, antidepressant, antibiotic, etc).
  • the compounds of the invention may alternatively be for use in combination with one or more additional cancer treatments.
  • the compounds may be used in combination with one, two, three, four, five or more additional cancer treatments.
  • the compound is administered to a subject who is receiving one or more additional cancer treatments in the same course of therapy.
  • the term covers not only the concomitant administration of the compound with one or more additional cancer treatments (either as bolus doses or infusions) but also the temporally separate administration of these cancer treatments.
  • the compound may be administered within a treatment schedule/cycle as defined by the patient's oncologist to include one or more additional cancer treatments, administered either before, concomitantly with or after the compound; for example within ten weeks, nine weeks, eight weeks, seven weeks, six weeks, five weeks, four weeks, three weeks, two week, ten days, one week, five days, four days, three days, two days, one day, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 10 minutes or five minutes.
  • Each treatment cycle may be repeated on several occasions, normally up to 6 cycles, but could be more or less than this number depending on the nature of the cancer and its response to treatment.
  • the one or more additional cancer treatments may be chemotherapeutic agents or radiotherapeutic modalities.
  • the one or more additional cancer treatments comprise or consist of one or more chemotherapeutic and/or radiotherapeutic modality.
  • the one or more chemotherapeutic agents and/or radiotherapeutic modalities may be capable of lowering the median oxygen level of the tumour to below 3%, for example below 2.5%, 2%, 1.5%, 1%, 0.5%, 0.4%, 0.3%, 0.2% or below 0.1%.
  • tumour oxygenation levels may be achieved by a number of different means, for example by the disruption of established tumour vasculature, prevention of angiogenesis (new blood vessel formation) and/or vasoconstriction.
  • Suitable cancer treatments may be selected from the group consisting of anti-androgens (steroidal and non-steroidal), vascular disrupting agents, anti-angiogenic agents, anti-VEGFR agents, IL8 inhibitors, NO synthase inhibitors, vasoconstricting agents, vasodilating agents and radiotherapy.
  • anti-androgens steroidal and non-steroidal
  • vascular disrupting agents anti-angiogenic agents
  • anti-VEGFR agents anti-VEGFR agents
  • IL8 inhibitors IL8 inhibitors
  • NO synthase inhibitors NO synthase inhibitors
  • vasoconstricting agents vasodilating agents and radiotherapy.
  • steroidal anti-androgens we include cyproterone acetate.
  • anti-angiogenic agents we include:
  • vascular disrupting agents we include small molecules (such as taxanes, taxol, paclitaxel combretastatins, CA4P, Oxi4503, aurostatins, dolostatins, colchine, azacolchicinol, ZD6126I, MMP-activated colchicines, ICT2588, DMXAA, TZT1027 and AVE8062) and biologicals (such as ADEPT, GDEPT and antibody drug-conjugates that target the tumour vasculature).
  • small molecules such as taxanes, taxol, paclitaxel combretastatins, CA4P, Oxi4503, aurostatins, dolostatins, colchine, azacolchicinol, ZD6126I, MMP-activated colchicines, ICT2588, DMXAA, TZT1027 and AVE8062
  • biologicals such as ADEPT, GDEPT and antibody drug-conjugates that target the tumour va
  • IL8 inhibitors we include repertaxin.
  • NO synthase inhibitors we include N G -methyl-1-arginine hydrochloride (546C88; 1-NMMA), NG-nitro-L-arginine (L-NNA), L-nitroarginine methyl ester (L-NAME), LG-nitro-L-arginine (L-NO-Arg) and 7-Nitro-Indazole (7-NI).
  • vasoconstricting agents we include alpha 1 adrenoceptor agonists (e.g. methoxamine, phenylephrine, oxymetazoline, tetrahydralazine, xylometazoline), alpha 2 adrenoceptor agonists (e.g. clonidine, guanabenz, guanfacine, ⁇ -methyldopa) and vasopressin analogues (e.g. arginine vasopressin and triglycyl lysine vasopressin).
  • alpha 1 adrenoceptor agonists e.g. methoxamine, phenylephrine, oxymetazoline, tetrahydralazine, xylometazoline
  • alpha 2 adrenoceptor agonists e.g. clonidine, guanabenz, guanfacine, ⁇ -methyld
  • vasodilating agents we include alpha-adrenoceptor antagonists (alpha-blockers), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta2-adrenoceptor agonists ( ⁇ 2-agonists), calcium-channel blockers (CCBs), centrally acting sympatholytics, direct acting vasodilators, endothelin receptor antagonists, ganglionic blockers, nitrodilators, phosphodiesterase inhibitors, potassium-channel openers and renin inhibitors.
  • alpha-adrenoceptor antagonists alpha-blockers
  • ACE angiotensin converting enzyme
  • ARBs angiotensin receptor blockers
  • ⁇ 2-agonists beta2-adrenoceptor agonists
  • CBs calcium-channel blockers
  • centrally acting sympatholytics direct acting vasodilators, endothelin receptor antagonists, ganglionic blockers, nitrodilators,
  • radiotherapy modalities we include conventional external beam radiation therapy (2DXRT), stereotactic radiosurgery (SRS), stereotactic body radiation therapy (SBRT) and particle therapy such as proton therapy; brachytherapy such as SAVITM, MammoSiteTM, ConturaTM, ProxcelanTM, TheraSeedTM and I-SeedTM; radioisotope therapy such as metaiodobenzylguanidine (MIBG), iodine-131, hormone-bound lutetium-177 and yttrium-90 (peptide receptor radionuclide therapy).
  • 2DXRT conventional external beam radiation therapy
  • SRS stereotactic radiosurgery
  • SBRT stereotactic body radiation therapy
  • particle therapy such as proton therapy
  • brachytherapy such as SAVITM, MammoSiteTM, ConturaTM, ProxcelanTM, TheraSeedTM and I-SeedTM
  • radioisotope therapy such as metaiodobenzylguanidine (MI
  • the one or more cancer treatments is/are non-steroidal anti-androgens, such as flutamide, nilutamide, bicalutamide, finasteride, dutasteride, bexlosteride, izonsteride, turosteride, epristeride and abiraterone.
  • non-steroidal anti-androgens such as flutamide, nilutamide, bicalutamide, finasteride, dutasteride, bexlosteride, izonsteride, turosteride, epristeride and abiraterone.
  • a compound according to the first aspect of the invention is used in combination with bicalutamide in the treatment of cancer, e.g. the prevention or reduction of metastasis.
  • a compound according to the first aspect of the invention is used in combination with cancer chemotherapeutic agents and/or radiotherapeutic modalities and/or methods to reduce or increase the air being breathed by the patients e.g. carbogen (with or without nicotinamide).
  • a related, sixth aspect of the invention provides the use of a compound of the first aspect of the invention in the preparation of a medicament for treating cancer.
  • a seventh aspect of the invention provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of the first aspect of the invention.
  • the patient is mammalian (e.g. human).
  • An eighth aspect of the invention provides the use of a compound of the first aspect of the invention as a marker of the oxygenation level of cells.
  • a compound of the first aspect of the invention may be used as a cellular hypoxic marker, either in vitro or in vivo.
  • the cells are mammalian (e.g. human).
  • N-oxide forms of the compounds of the invention such as those of formulae V and VI
  • hypoxic cells causes their reduction to the corresponding amine form (such as those of formulae III and IV), which can be readily detected by known means.
  • the presence of the reduced compound can be used to detect hypoxic cells in vitro or in vivo.
  • the innate fluorescence properties retained by the reduced compound(s) and the intracellular persistence of the reduced compound(s) are advantageous for the discrimination, quantification and localisation of cells that have been exposed to, or continue to be exposed to hypoxic conditions.
  • the reduced compound when acting as a cellular marker for hypoxia, maybe detected using method(s) that identify chemical composition or physical properties that include but are not limited to mass spectrometry, infrared spectroscopy, colorimetry, Raman spectroscopy, nuclear magnetic resonance or positron emission tomography.
  • Affinity capture methods would exploit the high affinity binding potential of the reduced compound to DNA or synthetic polynucleotide sequences.
  • Optical properties of the reduced compound(s) may be used to detect compound in biological samples and include but are not limited to flow cytometry and microscopy utilising the innate fluorescent properties of the reduced compound.
  • Secondary methods of detection of reduced compound include but are not limited to a combination with other molecular reporter compounds with the reduced compound participating in resonant energy transfer reactions as either an acceptor or donor.
  • Other secondary methods of detection of reduced compound include but are not limited to methods using antibody based methods for molecular detection.
  • the compounds of the invention are used to identify hypoxic tumour cells in vivo, which may then be visualised in situ or excised surgically.
  • a compound of the first aspect of the invention is used as a cellular hypoxic marker in combination with a non-deuterated form of a compound of the first aspect of the invention.
  • the compounds may be applied to the cells (e.g. administered to a patient) either concomitantly or sequentially (for example, within 24 hours, 12 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 30 minutes, 10 minutes or less).
  • a compound of formulae IX or X is used as a cellular hypoxic marker (in vivo or in vitro) in combination with a compound as disclosed in U.S. Pat. No. 5,132,327 (for example, AQ4N).
  • a related, ninth aspect of the invention provides a kit of parts for use in detecting the oxygenation level of cells comprising a compound according to the first aspect of the invention.
  • the kit further comprises a non-deuterated form of a compound according to the first aspect of the invention (such as a compound as disclosed in U.S. Pat. No. 5,132,327, for example AQ4N).
  • a non-deuterated form of a compound according to the first aspect of the invention such as a compound as disclosed in U.S. Pat. No. 5,132,327, for example AQ4N.
  • the compound(s) is/are provided in a sterile, pyrogen-free form.
  • kits of the invention may further comprise one or more regents, control samples and/or instructions.
  • FIG. 1 The metabolites AQ4 and OCT1001 have similar cell cycle arresting actions, under normal oxygenation conditions, indicating that selective deuteration has not modified intrinsic biological activity.
  • FIG. 2 Similar hypoxia-enhanced cytotoxicity for AQ4N and OCT1002
  • FIG. 3 Exemplification of that the bioactivity of AQ4N and OCT1002 is dependent upon the degree of hypoxia
  • FIG. 4 Hypoxia-dependent growth inhibition by AQ4N and OCT1002 arises from a similar mechanism of cell cycle arrest and is dependent on the degree of hypoxia
  • FIGS. 5 Exemplification of shared bioactivity of AQ4N and OCT1002 under hypoxic conditions for functional p53 (DoHH2) and mutant p53 (SU-DHL-4) human B cell lymphoma cells
  • FIG. 6 Intracellular accumulation of the OCT1001 far-red fluorescent chromophore under hypoxia is responsive to OCT1002 pro-drug dose and oxygenation level
  • FIG. 7 Deuteration does not affect the intrinsic capacity of the metabolite (AQ4 or OCT1001) to accumulate within a cell
  • FIG. 8 Accumulation of converted pro-drug OCT1001 correlates with growth arrest
  • FIGS. 9 (A & B): Demonstration of intracellular fluorescence following exposure to OCT1002 under hypoxic conditions and that prodrug deuteration reduces intracellular accumulation but increases persistence of the metabolite.
  • FIG. 10 Effect of bicalutamide on the oxygenation of 22Rv1 prostate tumours grown as xenografts
  • FIG. 11 Effect of bicalutamide on blood vessels in 22Rv1 tumour xenografts
  • FIG. 12 Effect of bicalutamide only or AQ4N single dose or OCT1002 single dose on 22Rv1 xenografts in mice
  • FIG. 13 Combined effect of AQ4N single dose or OCT1002 single dose on 22Rv1 xenografts in mice treated daily with bicalutamide
  • FIG. 14 Effect of OCT1002 on LNCaP xenografts in mice treated with/without bicalutamide
  • FIG. 15 OCT1002 is reduced in hypoxic LNCaP tumour cells in vivo
  • FIG. 16 OCT1002 reduces the metastatic spread of LNCaP tumours to the lungs
  • the bulk material was purified by flash chromatography (Biotage, 120 g) loading in DCM (through cotton wool plug) eluting with 6 then 10% MeOH (containing 1% NH 3 )/DCM to give 1,4-bis- ⁇ [2-(deuterated-d6-dimethylamino)ethyl]amino)-5,8-dihydroxyanthracene-9,10-dione (2.01 g, 4.73 mmol, 26.7% yield).
  • Example B In Vitro Properties of 1,4-bis- ⁇ [2-(deuterated-d6-dimethylamino-N-oxide)ethyl]amino)-5,8-di-hydroxyanthracene-9,10-dione and Its Active Metabolite
  • Bicalutamide (marketed as Casodex, Cosudex, Calutide, Kalumid) is an oral non-steroidal anti-androgen used in the treatment of prostate cancer including as monotherapy for the treatment of earlier stages of the disease.
  • 22Rv1 is a human prostate carcinoma epithelial cell line (Sramkoski R M, Pretlow T G 2nd, Giaconia J M, Pretlow T P, Schwartz S, Sy M S, Marengo S R, Rhim J S, Zhang D, Jacobberger J W A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999 July-August; 35(7):403-9).
  • the cell line expresses prostate specific antigen (PSA). Growth is weakly stimulated by dihydroxytestosterone and lysates are immunoreactive with androgen receptor antibody by Western blot analysis.
  • PSA prostate specific antigen
  • the first is an earlier effective tumour growth inhibition of OCT1002 on the bicalutamide treated tumours compared to AQ4N;
  • the second indicates a sustained tumour growth inhibition (indicated by a maintained linear response); that reflects a persistence OCT1002 and tumour growth inhibition.

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