WO2002030906A1 - Composes antitumoraux - Google Patents

Composes antitumoraux Download PDF

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WO2002030906A1
WO2002030906A1 PCT/AU2001/001265 AU0101265W WO0230906A1 WO 2002030906 A1 WO2002030906 A1 WO 2002030906A1 AU 0101265 W AU0101265 W AU 0101265W WO 0230906 A1 WO0230906 A1 WO 0230906A1
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compound
formula
agents
optionally substituted
conh
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PCT/AU2001/001265
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WO2002030906B1 (fr
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Leslie William Deady
William Alexander Denny
Xianyong Bu
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La Trobe University
Auckland Uniservices Limted
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Priority to AU2001295251A priority Critical patent/AU2001295251A1/en
Publication of WO2002030906A1 publication Critical patent/WO2002030906A1/fr
Publication of WO2002030906B1 publication Critical patent/WO2002030906B1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/08—Aza-anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • 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
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings

Definitions

  • This invention relates to compounds with topoisomerase-inhibitory activity, to pharmaceutical compositions comprising these compounds, and to the use of the compounds in the treatment of cancers .
  • topo II has been viewed as attractive targets for drug development. Because DNA topoisomerases are essential for many aspects of cell multiplication, they are potentially very useful as anti- tumour agents .
  • Compounds which have the ability to intercalate into the DNA double helix represent a major class of' inhibitors of topoisomerases. These agents include synthetic intercalating drugs, such as the aminoacridines, antibiotics such as anthracylines, including doxorubicin, and plant-derived agents such as the ellipticines and camptothecins .
  • topo II inhibitors doxorubicin, mitoxantrone and their analogues as anticancer drugs
  • doxorubicin, mitoxantrone and their analogues as anticancer drugs
  • a great deal of work has been devoted towards other classes of compounds with similar overall topology, eg. polycyclic chromophores bearing a flexible cationic side chain, as topo II inhibitors.
  • the benzoisoquinolinediones amonafide (1) (Asbury et al . , 1998; Leaf et al . , 1997) and the anthrapyrazoles, such as losoxantrone (2) (Diab et al . , 1999; Judson, 1992)
  • phenazine-1- carboxamides eg. 3
  • Rewcastle et al , 1987 have been studied in animal models .
  • the azonafide analogue 7 was on average 40-fold more cytotoxic in a panel of human tumour cell lines than a related tricyclic analogue, the clinical drug amonafide (1) (Sami et al , 1993).
  • Formulae of these compounds are presented in Figure 1.
  • the basic side-chain is linked to the ring system through an alkyl or amino function.
  • topoisomerase inhibitors are bis compounds, such as jis-imidazoacridones and bis- triazenoacridones, and the compounds DMP840 and LU79553 are in Phase II clinical trials.
  • the invention provides a compound of formula II
  • positional numbering refers to the system illustrated above, and one or more W and one or more U are attached to a ring carbon or carbons at any of positions 1-11 or to a ring nitrogen at position 7 if present, and in which:
  • R is hydrogen or a C ] __ alkyl group which is optionally substituted with one or more OH or NH 2 groups,
  • J is H or a Ci-Cg alkyl group optionally substituted with OH, OMe, NH2, NHMe or NMe2 functions,
  • X, Y, V are independently CH or N;
  • Z is CH 2 , CH-C 1 _ 4 alkyl, CO, 0, S, SO, S0 2 , N-C 1 _ 4 alkyl or NH; and
  • U is H, halo, OH, C0 2 H, , nitro, cyano, C _ 6 alkyl, C ] __ haloalkyl, C ⁇ g alkoxy, C ⁇ -s haloalkoxy C ⁇ _6 aminoalkyl or C-__ Q aminoalkoxy in which R ⁇ and R 7 have the same definitions as R 4 and R 5 above; or a pharmaceutically-acceptable salt, N-oxide, hydrate, solvate, pharmaceutically acceptable derivative, pro-drug, tautomer or isomer thereof, with the proviso that W at position 4 cannot be CONH(CH2)2 Me2, CONH (CH2) 2NEt2, CONH (CH2 ) 3NMe2 , CONH(CH2)3NE
  • alkyl used either alone or in a compound word such as “optionally substituted alkyl” or “optionally substituted cycloalkyl” denotes straight chain, branched or mono- or poly- cyclic alkyl, alkyl or cycloalkyl .
  • straight chain and branched alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isbutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2- dimethylpropyl , 1, 1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1- dimethylbutyl, 2 , 2-dimethylbutyl, 3 , 3-dimethylbutyl, 1,2- dimethylbutyl, 1, 3-dimethylbutyl, 1, 2 , 2-trimethylpropyl, 1, 1, 2-trimethylpropyl, heptyl, 5-methylhexyl, 1- methylhexyl, 2 , 2-dimethylpentyl, 3 , 3-dimethylpentyl, 4,4- dimetylpentyl , 1, 2-dimethylpent
  • cyclic alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl and the like.
  • the alkyl may optionally be substituted by any non-deleterious substituent .
  • Me refers to methyl
  • heterocyclic group used either alone or in compound words such as “optionally substituted saturated or unsaturated heterocyclic group” denotes monocyclic or polycyclic heterocyclic groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen.
  • Suitable heterocyclic groups include N- containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4.
  • nitrogen atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3
  • optionally substituted means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino,
  • halo or halogen denotes fluorine, chlorine, bromine, or iodine. Where halogen substitution is present, preferred halogens are chlorine or bromine.
  • X is N; Z is CO, CH 2 , 0 or S; V and Y are CH, N or C-CONH (CH 2 ) 2 N(CH 3 ) 2 ; U is H, Cl, methyl or methoxy; and n is 2.
  • X is N
  • V and Y are CH
  • U is 2 -methyl
  • Z is CO.
  • the compound is N- [2- (dimethylamino) ethyl] -2 -methyl-7-oxo-7H- dibenz [ £, ij ] isoquinoline-11-carboxamide or a pharmaceutically acceptable salt or N-oxide thereof.
  • the present invention also provides a compound of the formula III :
  • one or more W' and U' may be present at any of positions 1-11 of the structure
  • W' has the same definition as W in formula II, or W is H;
  • U', V, X 1 , Y 1 and Z 1 have the same definitions as U, V, X, Y and Z in formula II;
  • L is a linker group of valency x
  • L' is a direct bond or a linker group attached to the ring system at one or two positions; and x is an integer from 2 to 4, or a pharmaceutically-acceptable salt, N-oxide, hydrate, solvate, pharmaceutically acceptable derivative, pro-drug, tautomer or isomer thereof.
  • each bracketed portion of the compound may be different, provided that in each bracketed portion the substituents are individually within the definitions provided.
  • compounds with two or more different units of formula II linked together are to be considered to be within the definition of formula III above .
  • linker group is used herein in its broadest sense to refer to any organic group that links together the adjacent units of the compound together.
  • the linker groups L' in each repeated unit of the compound may be the same or different. Accordingly, the linker may be symmetrical or non-symmetrical.
  • J 1 has the same definition as J in the compound of formula II above, and m has the same definition as n in the compound of formula II above.
  • L may be any suitable linking group that links the bracketed portions of the compound together.
  • L is a nitrogen-containing linker group.
  • R 9 and R 11 are each independently H, CH 3 , or C 2 H 5 , or if p is 1, R 9 and R 11 is preferably -CH 2 CH 2 -
  • L could alternatively be 0, S, an optionally substituted C_.- 2 o alkylene, alkenylene or alkynylene chain, which may optionally be interspersed with one or more aryl or heterocyclic groups (which may also be substituted) and/or one or more 0, S or N atoms; or L may be an optionally substituted saturated or unsaturated aryl or heterocyclic group.
  • alkylene alkenylene and alkynylene are the divalent radical equivalents of the terms “alkyl”, “alkenyl” and “alkynyl”, respectively.
  • the two bonds connecting the alkylene, alkenylene or alkynylene to the adjacent groups may come from the same carbon atom or different carbon atoms in the divalent radical .
  • Preferred optional substituents in the linker group L are selected from halogen; oxy; hydroxy; alkoxy; alkylthio; cyano; azido; acyloxy; alkyl sulphonyl ; aryl and heteroaryl .
  • the compounds of formula III include bis compound forms of the compound of formula II in which W is replaced in each subunit of the bis compound by a linker group.
  • the linker group of the bis compounds preferably has a structure that is based on that of W.
  • the bis form of the compounds within the scope of formula III therefore include compounds having two units of formula II in which the NRCHJ (CH 2 ) n R ⁇ portion of W in each unit of formula II is replaced with a group selected from the following:
  • the linker may alternatively be of the type disclosed in International Patent Application No. WO 96/25400 by The Du Pont Merck Pharmaceutical Company, the entire disclosure of which is incorporated by this cross- reference.
  • the invention provides a pharmaceutical composition comprising a compound of formula II or III as described above, together with a pharmaceutically-acceptable carrier .
  • the invention provides a method of treatment of a neoplastic condition, comprising the step of administering a therapeutically effective dose of a compound of formula II or formula III or a pharmaceutically acceptable derivative thereof, pro-drug thereof, tautomer and/or isomer thereof to a subject in need of such treatment.
  • terapéuticaally-effective amount means an amount of a chemotherapeutic agent to yield a desired therapeutic response, for example, treat or prevent a neoplastic disease.
  • the specific "therapeutically-effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the subject, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the che otherapeutic agent or its derivatives .
  • the compound of the invention may be administered in conjunction with one or more other anti-neoplastic agents, including but not limited to anti-mitotic agents such as taxol, anti-metabolites such as 5-fluorouracil, hormonal regulators such .as tamoxifen, DNA-reactive agents such as cisplatin, or biological agents such as interleukin- 2 (IL-2) or antibodies.
  • the compound of the invention and the second agent may be administered together or sequentially.
  • a second DNA-binding anti-cancer therapeutic agent could be used in conjunction with administration of the compound of formula II or formula III in order to reduce toxicity to the recipient of either or both of the compound of formula II or formula III or the other anticancer agent.
  • the compound formula II or formula III and the other agent may be administered together or sequentially.
  • compounds of the invention may also be administered in the form of tumour- activated prodrugs, in which the active agent is linked to a 'trigger' domain; such compounds may for example be designed to be activated by local hypoxia within a tumour mass.
  • Suitable methods are known the in the art; see for example Denny, 1996; McFadyen et al , 1996.
  • the compound of the invention may also be used in combination with agents which relieve side effects caused by drug treatment such as granulocyte-macrophage-colony stimulating factor (GM-CSF), or anti-emetics.
  • GM-CSF granulocyte-macrophage-colony stimulating factor
  • the compound of the invention is administered in a divided dose schedule, such that there are at least two administrations in total in the schedule. Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour.
  • the divided-dose regimen comprises a second administration of the compound of the invention after an interval from the first administration sufficiently long that the level of active compound in the blood has decreased to approximately from 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of active agent in the blood.
  • one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately from 10-50% of the immediately-preceding maximum
  • the compounds of the invention may be administered by any suitable route, for example orally, buccally, topically or parenterally, for example by intravenous, sub-cutaneous, intramuscular, intra- peritoneal, or intratumoral injection.
  • the dose and route of administration will depend on the condition to be treated, and will be at the discretion of the attending physician or veterinarian. It is contemplated that each administration will supply between 0.1 and 500 mg, preferably 1 to 200, more preferably 1 to 50 mg of active compound .
  • the compounds of the invention are suitably presented in unit dosage form.
  • subject refers to any animal having a disease or condition which requires treatment with an anti-neoplastic agent.
  • the subject is suffering from a cellular proliferative disorder (eg., a neoplastic disorder).
  • a cellular proliferative disorder eg., a neoplastic disorder.
  • Subjects for the purposes of the invention include, but are not limited to, mammals (eg., bovine, canine, equine, feline, porcine) and preferably humans .
  • cell proliferative disorder is meant that a cell or cells demonstrate abnormal growth, typically aberrant growth, leading to a neoplasm, tumor or a cancer.
  • Cell proliferative disorders include, for example, cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, intestinal, exocrine, endocrine, lymphatic, haematopoietic system or head and neck tissue.
  • neoplastic diseases are conditions in which abnormal proliferation of cells results in a mass of tissue called a neoplasm or tumor.
  • Neoplasms have varying degrees of abnormalities in structure and behaviour. Some neoplasms are benign while others are malignant or cancerous.
  • the compounds of the invention are preferably used in the treatment of leukaemias, ly phomas, sarcomas, and brain tumours, and for cancers of the lung, breast, ovary, testes, and colon.
  • the present invention provides for the use of a compound of formula II or III in the manufacture of a medicament for the treatment or prophylaxis of a neoplastic condition.
  • the compound includes one or more U' ' groups and one or more carboxylic acid groups are attached to a ring carbon or carbons or nitrogen when present in the ring structure at positions 1 - 11; and U' ' , V ' , X' ' , Y' ' and Z'' have the same definitions as U, V, X, Y and Z, respectively, in formula II.
  • a method of synthesising a compound of formula II or formula III comprising the step of converting the carboxylic acid of formula IV into the target amide of formula II or formula III.
  • the conversion may involve an intermediate step in which the compound of formula IV is converted into an imidazolide, and reacting the imidazolide intermediate with the appropriate amine to obtain the target amide of formula II or formula III.
  • the reaction involves converting the carboxylic acid of formula IV into an acid halide, and reacting the acid halide with an amine to obtain the target amide of formula II or formula III .
  • the reagent in this second route is preferably thionyl chloride. It will be clearly understood in the above description that in the case of the bis compounds, two units of the carboxylic acid will be reacted with the appropriate diamine to form the target diamide.
  • Figure 1 shows the structures of prior art compounds 1 to 11 referred to herein.
  • Figure 2 shows reaction schemes for the preparation of aminoanthraquinone precursors of the tetracyclic systems.
  • Scheme 2b 4-aminoanthraquinone-l-carboxylic acid
  • Scheme 2c 5- and 8-aminoanthraquinone-l- carboxylic acids
  • Scheme 2d 5- and 8-chloro-l-aminoanthraquinone and an alternative route to 5- and 8-aminoanthraquinone-l- carboxylic acids.
  • Figure 3 shows reaction schemes leading to tetracyclic compounds .
  • Figure 4 shows the structure of the imidazolide intermediate from acid 21a.
  • Figure 5 shows a comparison between the growth of transplanted tumour in the colon 38 in control mice (•) and those receiving a single dose of 24h (65 mg/kg; O) .
  • Figure 6 shows a comparison between the growth of transplanted tumour in the colon 38 in control mice (•) and those receiving multiple doses of 24f (150 mg/kg q4dx3 ; O) .
  • Figure 7 shows a comparison between the growth of transplanted tumour in the colon 38 in control mice (•) and those receiving multiple doses of 24i (65 mg/kg q4dx3 ; ⁇ ) .
  • the description that follows makes use of a number of terms used in pharmaceutical chemistry and cell biology. In order to provide a clear and consistent understanding of the specification and claims, including the scope given such terms, the following definitions are provided.
  • the salts of the compound of Formula II are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic,
  • pharmaceutically acceptable derivative any pharmaceutically acceptable salt, hydrate or any other compound which, upon administration to the subject, is capable of providing (directly or indirectly) a compound of Formula II or an antivirally active metabolite or residue thereof.
  • pro-drug is used herein in its broadest sense to include those compounds which are converted in vivo to compounds of Formula II.
  • tautomer is used herein in its broadest sense to include compounds of Formula II which are capable of existing in a state of quilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound. For example, it will be clearly understood that when U is 2-OH and Y and/or X are N, the invention includes within its scope the keto tautomeric form where V is CO and Y or X is NH.
  • toxic side effects or “side effects” means the deleterious, unwanted effects of chemotherapy on the subject's normal, non-diseased tissues and organs.
  • toxic side effects may include bone marrow suppression (including neutropenia) , cardiac toxicity, hair loss, gastrointestinal toxicity (including nausea and vomiting), neurotoxicity, lung toxicity and asthma.
  • the aldehyde-releasing compound and/or chemotherapeutic agents may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes subcutaneous injections, aerosol, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques.
  • the present invention also provides suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compounds of the present invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations .
  • the 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, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly
  • the compounds and compositions useful in the methods of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together.
  • Administration may be intravenously, intra-arterial, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue .
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution,
  • Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
  • the terms “treating”, “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure of a disease.
  • Treating covers any treatment of, or prevention of a disease in a vertebrate, a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject that may be predisposed to the disease, but has not yet been diagnosed as having it; (b) inhibiting the disease, ie., arresting its development; or (c) relieving or ameliorating the effects, ie., cause regression of the effects of the disease.
  • the invention includes various pharmaceutical compositions useful for treating a disease.
  • the pharmaceutical compositions according to one embodiment of the invention are prepared by one or more compounds according to the invention into a form suitable for administration to a subject using carriers, excipients and additives or auxiliaries .
  • Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers .
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
  • compositions include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co., 1405-1412,1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington:
  • the pharmaceutical compositions are preferably prepared and administered in dose units.
  • Solid dose units are tablets, capsules and suppositories.
  • different daily doses can be used for treatment of a subject. Under certain circumstances, however, higher or lower daily doses may be appropriate.
  • the administration of the daily 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 administration of subdivided doses at specific intervals.
  • the pharmaceutical compositions according to the invention may be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the subject.
  • dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disease.
  • animal models may be used to determine effective dosages for treatment of particular disease.
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or • wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a non- toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol .
  • the acceptable 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.
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • the compounds of the present invention may additionally be combined with other compounds to provide an operative combination.
  • the potassium salt of anthraquinone-1-sulfonic acid was nitrated (Scheme 2d) and, in this case, the 5-nitro (15b) and 8-nitro (15c) isomers were separated by purification of their potassium salts (Ullmann and Kertesz, 1919) .
  • Reaction of 15b with sodium chlorate in concentrated hydrochloric acid replaced the sulfonic group with chlorine (Ullmann and Kertesz, 1919) and then reduction with aqueous sodium sulfide produced the amine 16c (Maki and Nagai, 1930) .
  • Compound 16d. was prepared in the same way from 15c.
  • the product 19d also contained a small amount of the 4-methyl analogue 19h. These were separated at the later carboxamide stage.
  • a carboxylic acid function in the 2-position of both aza and diaza systems was generated by a two-stage oxidation (Scheme 3b).
  • Aldehydes 20a,e,f,g were prepared by selenium dioxide oxidation of the corresponding methyl compounds (I9a,e,f,g). These in turn were efficiently oxidised with sodium chlorite (Lindgren and Nilsson, 1973) (Kraus and Roth, 1980) to the corresponding acids 2ia,e,f,g.
  • the 2,8-diacid 21c was also prepared, from selenium dioxide oxidation of 19 ⁇ . In this case, prolonged reaction gave 21c directly and the intermediate aldehyde was not isolated.
  • the 'deaza' carbocylic system illustrated by 23 , was prepared by a literature route from methyl 2-iodobenzoate and methyl 8-bromo-l-naphthoate (Rule et al , 1934) ( Rule and Smith, 1937) (Scheme 3c) .
  • Electrospray mass spectra were recorded on a VG Bio-Q triple quadruple mass spectrometer, with water/MeOH/AcOH (50:50:1) as the mobile phase. Microanalyses were performed at the Campbell Microanalytical Laboratory, University of Otago, New Zealand.
  • Example 1 Preparation of Anthraquinone precursors according to the Reactions of Figure 2 1 -Methyl -4 -ni troanthraquinone (13b) .
  • Manganese dioxide (Fatiadi, 1976) (3.0 g) was added in portions over 15 min to a stirring mixture of 13b (1.58 g, 5.91 mmol) and concentrated H 2 S ⁇ 4 (15 mL) .
  • the reaction mixture was stirred at room temperature for 15 min then at 60 °C overnight. After being cooled, it was poured on to ice and sodium sulfite (2.0 g) was added to consume unreacted manganese dioxide. The solid which remained was filtered off, washed with water, and then thoroughly extracted with 5% ammonia solution. Some insoluble material was filtered off and the filtrate was acidified with concentrated HCl .
  • Nitrile 16e (1.8 g) in sulfuric acid (40 mL, from concentrated sulfuric acid and water 5:1) was heated on an oil bath at 165 °C for 1.5 h, then cooled and poured onto ice/water. The solid which separated was filtered off, washed with water, then stirred with 4% sodium hydroxide solution and filtered. The filtrate was taken to pH 3-4 with concentrated hydrochloric acid and the solid was filtered off, washed with water and dried to give the acid 14g (1.1 g, 57%) .
  • Example 2 Preparation of 2-Methyl-7-oxo-7H- dibenz [f , ij ] isoquinoline-8-carboxylic acid (19c) .
  • a mixture of 14f (2.67 g, 10.0 mmol), acetone (5.8 g) and 4% NaOH solution (75 L) was refluxed for lh, with stirring, under nitrogen.
  • Example 6 Preparation of 7-oxo-lH- dibenz [ f, ij] isoquinoline-2, 8-dicarboxylic acid (21c) .
  • A. ixture of 19c (2.32 g, 8.0 mmol) and Se ⁇ 2 (4.0 g) in dry dioxane (lOOmL) was heated to reflux, with stirring, for 4 h., then filtered while hot, and the filtrate was evaporated to dryness at reduced pressure. The residue was extracted with 5% NaOH and the extract was acidified with concentrated HCl. The precipitate which formed was collected by filtration, washed with water and dried at 80 °C to give the diacid as a brown solid (2.12 g, 83%) , mp. >316 °C.
  • the amide 24f was obtained as a brick-red solid (63%) , mp 207-208 °C [from benzene/light petroleum (bp 60- 90 °C) ] .
  • the imidazolide was reacted as in the preparation of 24a, but in tetrahydrofuran as solvent and with reflux for 3 days. The solvent was removed and the residue was dissolved in CHC1 2 and treated as for 24a to give the amide 24g as a brick-red solid (67%), mp 174-176 °C [from benzene/light petroleum (bp 60-90 °C) ] .
  • the amide 24c was obtained as a yellow solid (98%) , mp 117-119 °C [from benzene/light petroleum (bp 60-90 °C)] .
  • the amide 24d was obtained as a viscous oil (83%), which gradually solidified at room temperature. Further purification was achieved by column chromatography [alumina, CHCl 3 /benzene (1:1)], followed by recrystallization from CHCl 3 /hexane to give a yellow solid, mp 109-110 °C .
  • the amide 24b was obtained as a yellow solid (82%), mp 141-142 °C [from benzene/light petroleum (bp 60-90 °C)] .
  • the series of tetracyclic carboxamides identified in Table 1 was evaluated for growth inhibitory properties, measured as IC50 values, against murine P388 leukemia cells, Lewis lung carcinoma cells (LLTC), and human Jurkat leukemia cells (JLQ) . together with their amsacrine- and doxorubicin-resistant derivatives (JL/ . and JL ⁇ respectively) , which were obtained and cultured as previously described (Finlay et al , 1990; Finlay et al , 1994) .
  • Growth inhibition assays were performed by culturing cells in microculture plates (150 ⁇ l per well) as follows: P388: 4.5 X 10 3 cells/well; 3 days LLTC: 1 X 10 3 cells/well; 4 days Jurkat lines: 3.75 X 10 3 cells/well; 4 days
  • R 1 (CH 2 ) 2 NMe 2
  • R 2 (CH 2 ) 3 NMe 2
  • R 3 (CH 2 ) 2 N-piperazine
  • R 2 -R do not relate to the corresponding references in formulae II and III
  • Murine P388 leukemia d Murine Lewis lung carcinoma. e Human Jurkat leukemia.
  • the L line is resistant to the DNA intercalator amsacrine and similar agents because of a reduced level of topo II enzyme.
  • the JLjj line is resistant to doxorubicin, primarily by virtue of altered levels of topo II, but probably also via additional mechanisms .
  • topo II inhibitors such as amsacrine, doxorubicin and etoposide have large ratios (10-90 fold)
  • topo I inhibitors such as camptothecin
  • mixed topo I/II inhibitors such as DACA (4) have ratios of only about 2-fold. Values of these ratios of less than about 1.5-2 therefore suggest cytotoxicity by a non-topo II mediated mechanism.
  • tumours were grown subcutaneously from 1 mm fragments implanted in one flank of C57/B1 mice (anaesthetised with pentobarbitone 90 mg/kg) . When tumours reached a diameter of approximately 4 mm (7-8 days) , mice were divided into control and drug treatment groups (5 mice/group) , with similar average tumour volumes in each group. Drugs were administered as solutions of the hydrochloride salts in distilled water, and were injected in a volume of 0.01 mL/g body weight in two equal injections administered 1 h apart.
  • mice treated with the prior art compounds Doxorubicin, Daunorubicin, Amsacrine, Mitoxantrone, DACA, Etoposide or Irinotecan were used as positive controls. The mice were monitored closely, and tumour diameters were measured with callipers three times a week. Tumour volumes were calculated as 0.52xa 2Xb, where a and b are the minor and major tumour axes, and data plotted on a semilogarithmic plot as mean tumour volumes
  • the compounds tested did not show exceptional activity in an in vi tro cell line panel, which included the topoisomerase-II resistant derivatives of the Jurkat leukaemia which indicated that the compounds targetted both topoisomerase I and II enzymes.
  • Colon 38 in subcutaneous Colon 38 tumours in vivo , compound 24h achieved 80-100% cures from various dosing regimes. Colon 38 is relatively refractory to clinical antimetabolites, alkylating agents and topoisomerase-directed agents. While most of the prior art compounds in Table 3 produced growth delays, none induced cures of this tumour.

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Abstract

L'invention concerne un composé de formule (II), dans laquelle la numérotation des positions mentionnée se réfère au système illustré ci-dessus, et au moins un W et au moins un U sont attachés à un anneau de carbone ou à des carbones à n'importe quelle position allant de 1 à 11 ou à un anneau d'azote en position 7 si elle est présente, et dans laquelle W représente C(=Q)NRCHJ(CH2)nR1, où Q représente O ou S, R représente l'hydrogène ou un groupe alkyle C¿1-4? facultativement substitué par au moins un groupe OH ou NH2, J représente l'hydrogène ou un groupe alkyle C1-C6 facultativement substitué par des fonctions OH, OMe, NH2, NHMe ou NMe2, R?1¿ représente C(=NR2)NH2, NHC(=NR3)NH2 ou NR4R5, chaque R2 et R3 représentent indépendamment l'hydrogène ou un groupe alkyle C¿1-4? facultativement substitué par au moins un groupe OH ou NH2, et R?4 et R5¿ représentent indépendamment l'hydrogène ou un groupe alkyle C¿1-4? facultativement substitué par au moins un groupe OH ou NH2 ou bien R?4 et R5¿ avec l'atome d'azote auquel ils sont attachés forment un groupe hétérocyclique insaturé ou saturé substitué facultativement, et n est un nombre entier compris entre 0 et 5, X, Y, V représentent indépendamment CH ou N; Z représente CH¿2?, CH-C1-4 alkyle, CO, O, S, SO, SO2, N-C1-4 alkyle ou NH; et U représente l'hydrogène, halo, OH, CO2H, NR?6R7¿, nitro, cyano, C¿1-6? alkyle, C1-6 haloalkyle, C1-6 alcoxy, C1-6 haloalcoxy, C1-6 aminoalkyle ou C1-6 aminoalcoxy où R?6 et R7¿ ont les mêmes définitions que R4 et R5 susmentionnés ou un sel acceptable pharmaceutiquement, N-oxyde, un hydrate, un solvate, un dérivé acceptable pharmaceutiquement, un promédicament, un tautomère ou isomère correspondant, à condition que W en position 4 ne puisse pas représenter CONH(CH¿2?)2NMe2, CONH(CH2)2NEt2, CONH(CH2)3NMe2, CONH(CH2)3NEt2, CONH(CH2)2Npipéridyle ou CONH(CH2)2Nmorpholinyle, lorsque X et Y représentent N, V représente CH, U représente H et Z représente CO. Cette invention a aussi trait à des composés 'Bis' et à des précurseurs d'acide carboxylique. On utilise ces composés dans le traitement de troubles néoplasiques, tels que le cancer.
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Citations (3)

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