WO2004069249A1 - Derives de la 3-cyano-quinoleine, en tant qu'inhibiteurs de tyrosine kinase non recepteurs - Google Patents

Derives de la 3-cyano-quinoleine, en tant qu'inhibiteurs de tyrosine kinase non recepteurs Download PDF

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WO2004069249A1
WO2004069249A1 PCT/GB2004/000367 GB2004000367W WO2004069249A1 WO 2004069249 A1 WO2004069249 A1 WO 2004069249A1 GB 2004000367 W GB2004000367 W GB 2004000367W WO 2004069249 A1 WO2004069249 A1 WO 2004069249A1
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group
alkyl
ethoxy
formula
propoxy
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Bernard Barlaam
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention concerns certain novel quinoline derivatives, or pharmaceutically- acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body.
  • the invention also concerns processes for the manufacture of said quinoline derivatives, pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial.
  • Alternative approaches to anti-tumour agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action.
  • a cell may become cancerous by virtue of the transfonnation of a portion of its DNA into an oncogene i.e. a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis, 1986, I, 91).
  • oncogenes give rise to the production of peptides which are receptors for growth factors. Activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al, Ann. Rev.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
  • EGF epidermal growth factor
  • Various classes of receptor tyrosine ldnases are known (Wilks, Advances in Cancer Research. 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases.
  • the classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF ⁇ , Neu and erbB receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGF1 receptors and insulin-related receptor (IRR) and Class IH receptor tyrosine kinases comprising 5 the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF ⁇ , PDGF ⁇ and colony-stimulating factor 1 (CSF1) receptors.
  • EGF EGF family of receptor tyrosine kinases
  • TGF ⁇ TGF ⁇
  • Neu and erbB receptors Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGF1 receptors and insulin-related receptor (IRR)
  • tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and
  • Non-receptor tyrosine kinases include the Src family such as the Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
  • Src family of non-receptor tyrosine kinases are highly regulated in normal cells and in the absence of extracellular stimuli are maintained in an inactive conformation.
  • some Src family members for example c-Src tyrosine kinase, are frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer
  • NSCLCs non-small cell lung cancers
  • c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility.
  • colon tumour progression from localised to disseminated, invasive metastatic disease has been correlated with c-Src non-receptor tyrosine kinase activity (Brunton et al, Oncogene, 1997, 14 . 283-293, Fincham et al, EMBO J, 1998, 17, 81-92 and Verbeek et al, Exp. Cell Research, 1999, 248, 531-537).
  • an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • an inhibitor of such non-receptor tyrosine kinases should be of value as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention provide an anti-tumour effect by way of inhibition of the Src family of non-receptor tyrosine kinases, for example by inhibition of one or more of c-Src, c-Yes and c-Fyn.
  • c-Src non-receptor tyrosine kinase enzyme is involved in the control of osteoclast-driven bone resorption (Soriano et al, Cell, 1991, 64, 693-702; Boyce et al, J. Clin. Invest., 1992, 90, 1622-1627; Yoneda et al, J. Clin.
  • An inhibitor of c-Src non-receptor tyrosine kinase is therefore of value in the prevention and treatment of bone diseases such as osteoporosis, Paget's disease, metastatic disease in bone and tumour-induced hypercalcaemia.
  • the compounds of the present invention are also useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example hepatic cirrhosis and lung fibrosis), glomerulonephritis, multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, blood vessel diseases (for example atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
  • inflammatory diseases for example rheumatoid arthritis and inflammatory bowel disease
  • fibrotic diseases for example hepatic cirrhosis and lung fibrosis
  • glomerulonephritis for example hepatic cirrhosis and lung fibrosis
  • multiple sclerosis for example herosclerosis and restenosis
  • allergic asthma insulin-dependent diabetes
  • diabetic retinopathy diabetic nephropathy
  • the compounds of the present invention possess potent inhibitory activity against the Src family of non-receptor tyrosine kinases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory activity against other tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or NEGF receptor tyrosine kinase.
  • the receptor tyrosine kinases for example EGF receptor tyrosine kinase and/or NEGF receptor tyrosine kinase.
  • certain compounds of the present invention possess substantially better potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, than against VEGF receptor tyrosine Idnase.
  • Such compounds possess sufficient potency against the Src family of non-receptor tyrosine Idnases, for example c-Src and or c-Yes, that they may be used in an amount sufficient to inhibit, for example, c-Src and/or c-Yes whilst demonstrating little activity against NEGF receptor tyrosine kinase.
  • Z is an O, S, SO, SO 2 , N(R 2 ) or C(R 2 )(R 3 ) group wherein each R 2 or R 3 group, which may be the same or different, is hydrogen or (l-6C)alkyl; m is 1, 2 or 3; each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]a
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ), CO, CH(OR 4 ),
  • R 4 is hydrogen or (l-6C)alkyl
  • Q 1 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl o heterocyclyl-(l-6C)alkyl, or (R ⁇ m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent are optionally separated by the insertion into the chain of
  • X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l-6C)alkyl, and R 8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula :
  • X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl
  • Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo or thioxo substituents;
  • R a is hydrogen or halogeno
  • R b is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; R c is (l-6C)alkoxy;
  • R d is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; or
  • R e and R d together form a (l-3C)alkylenedioxy group; or a pharmaceutically-acceptable salt thereof.
  • alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-6C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight- chain version only
  • references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only
  • references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only.
  • (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy
  • (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino
  • di-[(l-6Calkyl] amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q ) when it is aryl or for the aryl group within a 'Q' group is, for example, phenyl or naphthyl, preferably phenyl.
  • a suitable value for any one of the 'Q' groups (Q or Q ) when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one of the 'Q' groups (Q 1 or Q 3 ) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) when it is heteroaryl or for the heteroaryl group within a 'Q' group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, be
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) when it is heterocyclyl or for the heterocyclyl group within a 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxo
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
  • the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
  • R 1 substituents may only be located at the 5-, 6-, 7- or 8-positions on the quinoline ring i.e. that the 2-position remains unsubstituted.
  • Suitable values for any of the 'R' groups (R a , R , R c , R d and R 1 to R 10 ) or for various groups within an R 1 substituent include :- for halogeno fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, is
  • N-(l-6C)alkylcarbamoyl N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for N,N-di-[(l-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl and isobutyryl; 20 for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; for N-(l-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido; for N-(l-6C)al
  • N-methylethanesulphonylamino for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; 30 for (3-6C)alkynoylamino: propiolamido; for N-(l-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and
  • halogeno-(l-6C)alkyl chloromethyl, 2-fluoroethyl, 2-chloroethyl,
  • a suitable value for (R ⁇ m when it is a (l-3C)alkylenedioxy group or for a R 1 substituent when it contains a (l-3C)alkylenedioxy group is, for example, methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • a suitable value is, for example, a methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy group, particularly a methylenedioxy group.
  • an R 1 group forms a group of the formula Q l -X ⁇ - and, for example, X 1 is a OC(R 4 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 4 ) 2 linldng group which is attached to the quinoline ring and the oxygen atom is attached to the Q 1 group.
  • R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 5 ) or C ⁇ C.
  • a group such as O, CON(R 5 ) or C ⁇ C.
  • insertion of a C ⁇ C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • suitable R 1 substituents so formed include, for example, N-[heterocyclyl- (l-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-l-ylethyl)carbamoylvinyl or N-[heterocyclyl-(l-6C)alkyl]carbamoylethynyl groups such as N-(2-pyn-olidin- 1 -ylethyl)carbamoylethynyl.
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CH 2 group and there are suitably 1, 2 or 3 such substituents present on each said CH 3 group.
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group a substituent as defined hereinbefore
  • suitable R substituents so formed include, for example, hydroxy-substituted heterocyclyl- (l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-
  • 3-morpholinopropoxy hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydiOxy-3-methylaminopropoxy, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl- (l-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy- 3-morpholinopropylamino, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkylamino groups such as 2-
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group a substituent as defined hereinbefore, such an optional substituent may be present on a CH 2 or CH 3 group within the hereinbefore defined substituents that may be present on an aryl, heteroaryl or heterocyclyl group within a R 1 substituent.
  • R 1 includes an aryl or heteroaryl group that is substituted by a (l-6C)alkyl group
  • the (l-6C)alkyl group may be optionally substituted on a CH 2 or CH 3 group therein by one of the hereinbefore defined substituents therefor.
  • R 1 includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group
  • the terminal CH 3 group of the (l-6C)alkylamino group may be further substituted by, for example, a (l-6C)alkylsulphonyl group or a (2-6C)alkanoyl group.
  • the R 1 group may be a heteroaryl group such as a thienyl group that is substituted by a N-(2-methylsulphonylethyl)aminomethyl group such that R 1 is, for example, a 5-[N-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group.
  • R 1 includes a heterocyclyl group such as a piperidinyl or piperazinyl group that is substituted on a nitrogen atom thereof by, for example, a (2-6C)alkanoyl group
  • the terminal CH 3 group of the (2-6C)alkanoyl group may be further substituted by, for example, a di-[(l-6C)alkyl] amino group.
  • the R 1 group may be a N-(2-dimethylaminoacetyl)pi ⁇ eridin-4-yl group or a 4-(2-dimethylaminoacetyl)piperazin-l-yl group.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a compound of the Formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid
  • novel compounds of the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R 1 , R a , R b , R c and R d has any of the meanings defined hereinbefore or in paragraphs (a) to (v) hereinafter :-
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkenoylamino, (3-6C)alkenoy
  • X 1 is a direct bond or is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-6C)alkyl
  • X 3 is a direct bond or is selected from O, N(R 6 ), CON(R 7 ), N(R 7 )CO and C(R 7 ) 2 O, wherein R 7 is hydrogen or (l-6C)alkyl
  • Q 3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R 1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(
  • X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l-6C)alkyl, and R 8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
  • X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l-6C)alkyl, and Q 4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents; (e) m is 1 or 2, and each R 1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2-prop
  • X 1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1 -imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-(l,2,3-triazolyl)ethyl, 3-(l,2,3-triazolyl)propyl, 2-(l,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, te
  • Q 2 -X 2 - wherein X 2 is a direct bond or is CO, NHCO or N(Me)CO and Q 2 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pynOlidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl,
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, oxo, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl- N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula :
  • X 3 is a direct bond or is selected from O, NH, CONH, NHCO and CH 2 O and Q 3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pynolidin- 2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl,
  • X 4 is a direct bond or is selected from O and NH and R 8 is 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypro ⁇ yl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonyla
  • X 5 is a direct bond or is selected from O, NH and CO and Q 4 is pynolidin-1-ylmethyl, 2-pyn-olidin-l-ylethyl, 3-pynOlidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents;
  • m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and the R 1 groups, which may be the same or different, are located at the 5- and 7-positions or at the 6- and 7-positions and each R !
  • Q 2 -X 2 - wherein X 2 is a direct bond or is NHCO or N(Me)CO and Q 2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-mor ⁇ holinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl
  • (g) m is 1 and the R 1 group is located at the 7-position or m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and each R 1 is selected from hydroxy, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, 2-pyrrolidin-l-ylethoxy, 3 -pyrrolidin- 1-ylpropoxy, 4-pyrrolidin-l-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy , 2-pyrrolidin-2-ylethoxy, 3 -pyrrolidin-2-ylpropoxy , 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro-
  • m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and the R 1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R 1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin- 1 -ylethoxy, 3-pynolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
  • R a is hydrogen; (m) R a is fluoro, chloro or bromo;
  • R a is chloro or bromo
  • R b is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy;
  • R b is hydrogen, chloro or bromo
  • R b is hydrogen;
  • R c is methoxy or ethoxy;
  • R d is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy;
  • R d is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy;
  • novel compounds of the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R 1 , R a , R b , R c and R d has any of the meanings defined hereinbefore provided that :-
  • R 1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring i.e. the 2- and 8-positions remain unsubstituted; or
  • R 1 substituents may only be located at the 6- and/or 7-positions on the quinoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
  • the compounds of the present invention possess potent inhibitory activity against the Src family of non-receptor tyrosine Idnases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory ativity against other tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase.
  • the receptor tyrosine kinases for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase.
  • certain compounds of the present invention possess substantially better potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, than against EGF receptor tyrosine kinase or NEGF receptor tyrosine kinase.
  • Such compounds possess sufficient potency against the Src family of non-receptor tyrosine kinases, for example c-Src and or c-Yes, that they may be used in an amount sufficient to inhibit, for example, c-Src and/or c-Yes whilst demonstrating little activity against EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase.
  • quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof wherein, unless otherwise stated, each of Z, m, R , R and R has any of the meanings defined hereinbefore and R is halogeno and R c is (l-4C)alkoxy.
  • quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof wherein, unless otherwise stated, each of Z, m, R 1 and R has any of the meanings defined hereinbefore, R a is halogeno c d and R andR together form a (l-3C)alkylenedioxy group.
  • quinoline derivatives of the Formula I or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m and R 1 has any of the meanings defined hereinbefore and :- R a is chloro or bromo, R is hydrogen, R° is methoxy and R is hydrogen.
  • R a is chloro or bromo
  • R is hydrogen and R c and R together form a methylenedioxy group.
  • a particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is O or ⁇ H; m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and the R 1 groups, which may be the same or different, are located at the 5- and 7-positions or at the 6- and 7-positions and each R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy
  • R a is hydrogen, fluoro, chloro or bromo
  • R b is hydrogen, chloro or bromo;
  • R c is methoxy or ethoxy;
  • R d is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and the R 1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R 1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pynolidin- 1-ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pynolidin-l-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
  • R is hydrogen, chloro or bromo
  • R c is methoxy or ethoxy
  • R is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin- 1-ylethoxy, 3 -pyrrolidin- 1-ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l , l-dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-y
  • R a is chloro or bromo
  • R is hydrogen
  • R c is methoxy or ethoxy
  • R d is hydrogen; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin- 1-ylethoxy, 3 -pyrrolidin- 1-ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 2-(4-allylpiperazin-l-yl)ethoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 2-(4-prop-2-ynylpiperazin- 1 -
  • R a is chloro
  • R b is hydrogen
  • R c is methoxy
  • R d is hydrogen; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R 1 group is a 6-methoxy group and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin- 1-ylethoxy, 3 -pyrrolidin- 1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)
  • R c is methoxy
  • R d is hydrogen; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the
  • Z is NH; m is 2 and the R 1 groups, which may be the same or different, are located at the 5- and 7-positions and the R 1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3 -ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R 1 group at the 7- ⁇ osition is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrroli
  • R a is hydrogen, chloro or bromo
  • R b is hydrogen, chloro or bromo
  • R c is methoxy or ethoxy
  • R d is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy
  • R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, l,l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, l,l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3 -yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3 -yloxy, pyrrolidin-2-ylmethoxy
  • R b is hydrogen, chloro or bromo
  • R c is methoxy or ethoxy
  • R d is hydrogen, chloro, bromo or methoxy; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from propoxy, isopropoxy, tetrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin- 3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin- 4-yloxy, piperidin-3 -ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cycl
  • R b is hydrogen
  • R c is methoxy or ethoxy
  • R d is hydrogen, chloro or methoxy; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from propoxy, isopropoxy, tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from the group of substituents listed immediately above, and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin- 1-ylethoxy, 3 -pyrrolidin- 1-ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxy ⁇ yrrolidin-l-yl]ethoxy,
  • R a is chloro or bromo
  • R b is hydrogen
  • R c is methoxy or ethoxy
  • R d is hydrogen; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH; m is 2 and the first R 1 group is located at the 5-position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin- 1-ylethoxy, 3 -pyrrolidin- 1-ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljethoxy,
  • R c is methoxy; and R d is hydrogen; or R c and R d together form a methylenedioxy group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • Particular compounds of the invention are, for example, the quinoline derivatives of the Formula I that are disclosed within Examples 1 and 2 hereinafter. Further particular compounds of the invention are, for example, the quinoline derivatives of the Formula I that are disclosed within Examples 6 and 7 hereinafter.
  • a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof may be prepared by any process known to be applicable to the preparation of chemically- related compounds. Such processes, when used to prepare a quinoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, Z, m, R 1 , R a , R b , R c and R d have any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • Z is O, S, or N(R 2 ) and R 2 , R a , R b , R c and R d have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydr
  • the quinoline of the Formula II may be reacted with a compound of the Formula m in the presence of an aprotic solvent such as N,N-dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 70°C.
  • an aprotic solvent such as N,N-dimethylformamide
  • a base for example potassium carbonate or sodium hexamethyldisilazane
  • the quinoline derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore.
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diaza
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-(
  • Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage.
  • hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
  • amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl) ; lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
  • aryl-lower alkyl groups for example
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • groups such as 2-nitrobenzyloxycarbonyl
  • hydrogenation for groups such as benzyl
  • photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • the reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2 nd Edition, by T. Green et al, also published by John Wiley & Son, for general guidance on protecting groups.
  • Quinoline starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201.
  • a l,4-dihydroquinolin-4-one of Formula IV may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201.
  • m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
  • the 4-chloroquinoline so obtained may be converted, if required, into a
  • 4-Aminopyridine starting materials (Formula HI, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples.
  • R 1 group is a halogeno-(l-6C)alkoxy group or a group of the formula c ⁇ x 1 - wherein Q 1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group or an optionally substituted alkyl group and X 1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinoline of the Formula V
  • m, R 1 , Z, R a , R b , R c and R d have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means.
  • a suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • L is a displaceable group as defined hereinbefore and Z, R , R b , R c and R d have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or amine as appropriate whereafter any protecting group that is present is removed by conventional means.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 180°C, preferably in the range 60 to 120°C.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • Suitable acylating agents are well known to the man skilled in the art.
  • a compound of the Formula I wherein a R 1 group contains a piperidinyl or piperazinyl group having an unsubstituted NH group may be reacted under conventional conditions with an optionally substituted carboxylic acid or a reactive derivative thereof.
  • a suitable reactive derivative of an optionally substituted carboxylic acid is, for example, a carboxylic acid halide; a carboxylic acid amide; a mixed anhydride, for example an anhydride formed by the reaction of the carboxylic acid and a chloroformate such as isobutyl chloroformate; the product of the reaction of the carboxylic acid with a carbodiimide such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide; the product of the reaction of the carboxylic acid with a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine; or the product of the reaction of the carboxylic acid with a uronium salt such as 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • a pharmaceutically-acceptable salt of a quinoline derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said quinoline derivative with a suitable acid using a conventional procedure.
  • the following assays can be used to measure the effects of the compounds of the present invention as c-Src tyrosine kinase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue, (a) In Vitro Enzyme Assay
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa assay.
  • a substrate solution [lOO ⁇ l of a 20 ⁇ g/ml solution of the polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azide] was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were transfened into each substrate-coated assay well and incubated for 1 hour at ambient temperature to block non specific binding. The assay plate wells were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and with Hepes pH7.4 buffer (50mM, 300 ⁇ l/well) before being blotted dry.
  • PBS Bovine Serum Album
  • test compound was dissolved in dimethyl sulphoxide and diluted with distilled water to give a series of dilutions (from lOO ⁇ M to O.OOl ⁇ M). Portions (25 ⁇ l) of each dilution of test compound were transfened to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25 ⁇ l) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40 ⁇ M) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
  • aqueous magnesium chloride solution 80mM
  • ATP adenosine-5'-triphosphate
  • Active human c-Src Idnase (recombinant enzyme expressed in Sf9 insect cells; obtained from Upstate Biotechnology Inc. product 14-117) was diluted immediately prior to use by a factor of 1:10,000 with an enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
  • enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
  • enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
  • aliquots (50 ⁇ l) of freshly diluted enzyme were added to each well and the plates were incubated at ambient temperature for 20 minutes. The supernatant
  • HRP horse radish peroxidase
  • sheep anti-mouse Ig antibody (Amersham Catalogue No. NXA 931; lOO ⁇ l) was diluted by a factor of 1:500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).
  • HRP horse radish peroxidase
  • sheep anti-mouse Ig antibody (Amersham Catalogue No. NXA 931; lOO ⁇ l) was diluted by a factor of 1:500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).
  • a PCSB capsule (Sigma Catalogue No. P4922) was dissolved in distilled water (100ml) to provide phosphate-citrate pH5 buffer (50mM) containing 0.03% sodium perborate. An aliquot (50ml) of this buffer was mixed with a 50mg tablet of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; Boehringer Catalogue No. 1204 521). Aliquots (lOO ⁇ l) of the resultant solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0.
  • This assay determined the ability of a test compound to inhibit the proliferation of National Institute of Health (NTH) mouse 3T3 fibroblast cells that had been stably-transfected with an activating mutant (Y530F) of human c-Src.
  • NIH 3T3 cells were transfected with an activating mutant (Y530F) of human c-Src.
  • the resultant c-Src 3T3 cells were typically seeded at 1.5 x 10 4 cells per well into 96-well tissue- culture-treated clear assay plates (Costar) each containing an assay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma) plus 0.5% foetal calf serum (FCS), 2mM glutamine, 100 units/ml penicillin and 0.1 mg/ml streptomycin in 0.9% aqueous sodium chloride solution.
  • DMEM Dulbecco's modified Eagle's medium
  • FCS foetal calf serum
  • 2mM glutamine 100 units/ml penicillin and 0.1 mg/ml streptomycin in 0.9% aqueous sodium chloride solution.
  • the plates were incubated overnight at 37°C in a humidified (7.5% CO 2 : 95% air) incubator.
  • Test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots of the stock solution were diluted with the DMEM medium described above and added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which test compound was not added were included on each plate. The plates were incubated overnight at 37°Cin a humidified (7.5% CO 2 : 95% air) incubator. BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1:100 in DMEM medium containing 0.5% FCS and aliquots (20 ⁇ l) were added to each well to give a final concentration of lO ⁇ M).
  • the plates were incubated at 37°C for 2 hours. The medium was decanted. A denaturating solution (FixDenat solution, Boehringer Mannheim Catalogue No. 647 229; 50 ⁇ l) was added to each well and the plates were placed on a plate shaker at ambient temperature for 45 minutes. The supernatant was decanted and the wells were washed with PBS (200 ⁇ l per well). Anti-BrdU-Peroxidase solution (Boehringer Mannheim Catalogue No.
  • RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose (Difco Catalogue No. 0142-01) was warmed to 37°C in a water bath.
  • a stock 2% aqueous agar solution was autoclaved and stored at 42°C.
  • An aliquot (1.5 ml) of the agar solution was added to RPMI medium (10 ml) immediately prior to its use.
  • A549 cells (Accession No. ATCC CCL185) were suspended at a concentration of 2 x 10 7 cells/ml in the medium and maintained at a temperature of 37°C.
  • a droplet (2 ⁇ l) of the cell/agarose mixture was transfened by pipette into the centre of each well of a number of 96-well, flat bottomed non-tissue-culture-treated microtitre plate (Bibby Sterilin Catalogue No. 642000). The plates were placed briefly on ice to speed the gelling of the agarose-containing droplets. Aliquots (90 ⁇ l) of medium which had been cooled to 4°C were transferred into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (lO ⁇ l) of the diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets.
  • This test measures the ability of compounds to inhibit the growth of the A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain).
  • a total of about 5 x 10 6 A549 cells in matrigel (Beckton Dickinson Catalogue No. 40234) were injected subcutaneously into the left flank of each test mouse and the resultant tumours were allowed to grow for about 14 days. Tumour size was measured twice weekly using callipers and a theoretical volume was calculated. Animals were selected to provide control and treatment groups of approximately equal average tumour volume.
  • Test compounds were prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth was assessed.
  • Test (d) - activity in the range, for example, 1-200 mg/kg/day;.
  • each of the quinoline compounds disclosed within Example 2 and as Compound 4 within Example 7 possesses the following activity :- Test (a), IC 50 approximately O.Ol ⁇ M; Test (b), IC 50 approximately 0.2 ⁇ M; and Test (c) activity at approximately 0.7 ⁇ M.
  • Test (d) No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.
  • a pharmaceutical composition which comprises a quinoline derivative of the Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • the compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however prefened, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • c-Src non-receptor tyrosine kinase the predominant role of c-Src non-receptor tyrosine kinase is to regulate cell motility which is necessarily required for a localised tumour to progress through the stages of dissemination into the blood stream, invasion of other tissues and initiation of metastatic tumour growth.
  • the quinoline derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the non-receptor tyrosine-specific protein ldnases such as c-Src kinase that are involved in the quinoline signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • the derivatives of the present invention are of value as anti-tumour agents, in particular as selective inhibitors of the motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • the quinoline derivatives of the present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more of the multiple non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of the enzyme c-Src, i.e. the compounds may be used to produce a c-Src enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of solid tumour disease.
  • quinoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
  • a quinoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
  • a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • a quinoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a c-Src Idnase inhibitory effect.
  • the anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinoline derivative of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • anti-invasion agents for example metalloproteinase inhibitors like marimastat and inhibitors of uroldnase plasminogen activator receptor function
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactin
  • alkylating agents for
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride;
  • inhibitors of growth factor function for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cet
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace abenant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytoldnes such as interleuldn 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytoldne-transfected dendritic cells, approaches using cytoldne-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytoldnes such as interleuldn 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • approaches to decrease T-cell anergy approaches using transfected immune cells such as cytoldne-transfected dendritic cells
  • approaches using cytoldne-transfected tumour cell lines and approaches using anti-idiotypic antibodies may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ
  • a pharmaceutical product comprising a quinoline derivative of the formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of c-Src. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the invention will now be illustrated in the following Examples in which, generally : (i) operations were carried out at ambient temperature, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as argon unless otherwise stated;
  • the resultant concentrate and DMF washings were combined and injected directly on to a Waters Symmetry column (C18 reversed-phase, 5 microns, 19 mm diameter, 100 mm length) and eluted with decreasingly polar mixtures of water (containing 5% methanol and 1% acetic acid) and acetonitrile.
  • the material so obtained was mixed with methylene chloride (20 ml) that contained 5% methanol. Potassium carbonate (0.5 g) was added and the mixture was stirred at ambient temperature for 10 minutes. The solids were filtered off and the filtrate was evaporated. The resultant residue was triturated under diethyl ether.
  • Fuming sulphuric acid (18 ml, containing 18-24% free SO 3 ) was added to fuming nitric acid (33 ml) that had been cooled to 0°C. Whilst maintaining cooling to 0°C, a solution of 5-chloro-2-methoxypyridine N-oxide (7.4 g) in concentrated sulphuric acid (12 ml) was added dropwise. The resultant mixture was stined at ambient temperature for 1 hour and then heated to 80°C for 5 hours. After cooling, the mixture was poured onto ice/water. Solid sodium carbonate was added to basify the solution to pH 9. The mixture was extracted with methylene chloride and the organic extract was dried over magnesium sulphate and evaporated.
  • Raney nickel (Raney 2800 nickel, slurry in water; approximately 14 g) was added to a stined mixture of 5-chloro-2-methoxy-4-nitropyridine (0.8 g) and 5-chloro-2-methoxy- 4-nitropyridine N-oxide (1.05 g), ethyl acetate (5 ml) and methanol (50 ml) that had been cooled to 0°C. After 10 minutes, an excess of Raney nickel (approximately another 14 g) was added for completion of the reaction. The resultant mixture was filtered and the filtrate was evaporated.
  • the 4-amino-5-chloro-2,3-methylenedioxypyridine used as a starting material was prepared as follows :- Bromochloromethane (20 ml) was added to a mixture 5 ⁇ chloro-2,3-dihydroxypyridine
  • the material so obtained was dissolved in methylene chloride (35 ml) and the solution was cooled to 0°C. Trifluoroacetic acid (15 ml) was added and the mixture was stined at 0°C for 3 hours. The mixture was allowed to warm to ambient temperature and was stined for 16 hours. The solvent was evaporated and the residue was diluted with ice water and neutralised to ⁇ H7 by the addition of 2N aqueous sodium hydroxide solution whilst keeping the mixture temperature at 0°C. The resultant mixture was extracted with methylene chloride and the extract dried over magnesium sulphate and evaporated.
  • the 4-amino-2,3-methylenedioxypyridine used as a starting material was prepared as follows :-
  • Dibromomethane (31.5 ml) was added to a mixture 2,3-dihydroxypyridine (33 g), potassium carbonate (62 g) and NMP (200 ml) and the mixture was stined and heated to 90°C for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between diethyl ether (5 x 100 ml) and water (200 ml). The organic extracts were combined and concentrated under vacuum to a volume of about 20 ml. Petroleum ether (b.p 40-60°C; 300 ml) was added and the solution was washed with brine. The organic layer was separated and evaporated.
  • 6-methoxyquinoline Sodium hexamethyldisilazane (1M solution in THF; 3.6 ml) was added dropwise to a mixture of 4-amino-5-chloro-2,3-methylenedioxypyridine (0.35 g), 4-chloro- 7-(2-chloroethoxy)-3-cyano-6-methoxyquinoline (J. Med. Chem., 2001, 44, 3965-3977; 0.5 g) and DMF (8 ml) that had been cooled to 0°C. The mixture was stirred at 0°C for 5 minutes and at ambient temperature for 30 minutes. Acetic acid (0.12 ml) was added and the resultant mixture was evaporated.
  • the reaction mixture was cooled to ambient temperature and filtered and the filtrate was injected directly on to a Hypersil column (C18 reversed-phase, 5 microns, 20 mm diameter, 100 mm length) of a preparative HPLC -MS system and eluted with decreasingly polar mixtures of water [containing ammonium formate (2 g per litre)] and acetonitrile.
  • the material so obtained was triturated under diethyl ether.
  • the l-prop-2-ynylpiperazine used as a starting material was prepared as follows :- Propargyl bromide (80% solution in toluene; 40 ml) was added dropwise during

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Abstract

L'invention concerne des dérivés de la quinoléine de formule (I), dans laquelle Z désigne O, S, SO, SO2, N(R2) ou un groupe C(R2)(R3) où chaque groupe R2 ou R3 désigne l'hydrogène ou un (1-6C) alkyle, m est égal à 1, 2 ou 3, chaque groupe R1 est choisi à partir des groupes ci-après : halogéno, (1-6C) alkyle, (1-6C) alcoxy et l'un quelconque des autres groupes spécifiés dans la description, Ra désigne l'hydrogène ou un halogéno, Rb désigne l'hydrogène, un halogéno, un (1-6C) alkyle ou (1-6C) alcoxy, Rc désigne un (1-6C) alcoxy et Rd désigne l'hydrogène, un halogéno, un (1-6C) alkyle ou (1-6C) alcoxy, ou Rc et Rd forment ensemble un groupe (1-3C) alkylènedioxy, ou des sels pharmaceutiquement acceptables de ces composés. L'invention concerne en outre des procédés de préparation de ces composés, des compositions pharmaceutiques les renfermant, ainsi que leur utilisation dans la fabrication d'un médicament destiné à être utilisé comme agent anti-invasif dans le confinement et/ou le traitement de maladies à tumeurs solides.
PCT/GB2004/000367 2003-02-03 2004-01-30 Derives de la 3-cyano-quinoleine, en tant qu'inhibiteurs de tyrosine kinase non recepteurs WO2004069249A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2699546C2 (ru) * 2012-04-13 2019-09-06 Эпизайм, Инк. Комбинированная терапия для лечения рака

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WO1998043960A1 (fr) * 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
WO2000068201A1 (fr) * 1999-05-08 2000-11-16 Astrazeneca Ab Derives quinoline inhibiteurs d'enzymes mek
WO2003008409A1 (fr) * 2001-07-16 2003-01-30 Astrazeneca Ab Derives quinoline et utilisation en tant qu'inhibiteurs de tyrosine kinase

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Publication number Priority date Publication date Assignee Title
WO1998043960A1 (fr) * 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
WO2000068201A1 (fr) * 1999-05-08 2000-11-16 Astrazeneca Ab Derives quinoline inhibiteurs d'enzymes mek
WO2003008409A1 (fr) * 2001-07-16 2003-01-30 Astrazeneca Ab Derives quinoline et utilisation en tant qu'inhibiteurs de tyrosine kinase

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Title
BOSCHELLI D H ET AL: "OPTIMIZATION OF 4-PHENYLAMINO-3-QUINOLINECARBONITRILES AS POTENT INHIBITORS OF SRC KINASE ACTIVITY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, no. 23, 8 November 2001 (2001-11-08), pages 3965 - 3977, XP001105608, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2699546C2 (ru) * 2012-04-13 2019-09-06 Эпизайм, Инк. Комбинированная терапия для лечения рака

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