[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2003048159A1 - Quinoline derivatives - Google Patents

Quinoline derivatives Download PDF

Info

Publication number
WO2003048159A1
WO2003048159A1 PCT/GB2002/005493 GB0205493W WO03048159A1 WO 2003048159 A1 WO2003048159 A1 WO 2003048159A1 GB 0205493 W GB0205493 W GB 0205493W WO 03048159 A1 WO03048159 A1 WO 03048159A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
ethoxy
propoxy
yloxy
Prior art date
Application number
PCT/GB2002/005493
Other languages
French (fr)
Inventor
Laurent Francois Andre Hennequin
Keith Hopkinson Gibson
Kevin Michael Foote
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to AU2002347336A priority Critical patent/AU2002347336A1/en
Publication of WO2003048159A1 publication Critical patent/WO2003048159A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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

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, to 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.
  • 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 kinases 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 ⁇ receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR) and Class HI 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 ⁇ receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI 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 inliibitor 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 disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the non-receptor tyrosine-specific protein kinases that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells, hi particular, it is believed that the compounds of the present invention provide an anti-tumour effect byway 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. Invest.. 1993, 91, 2791-2795 and Missbach et al, Bone, 1999, 24 , 437-49).
  • 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), glomeralonephritis, 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
  • glomeralonephritis for example hepatic cirrhosis and lung fibrosis
  • multiple sclerosis for example herosclerosis and restenosis
  • allergic asthma insulin-dependent diabetes
  • diabetic retinopathy diabetic nopathy
  • 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 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 VEGF 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 VEGF receptor tyrosine kinase.
  • Z is an O
  • S may be the same or different, is hydrogen or (l-6C)alkyl
  • m is O, 1, 2, 3 or 4
  • 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)alkylsul ⁇ honyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl
  • N-(l-6C)alkylsulphamoyl N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ), CO, CH(OR 4 ), CON(R 4 ), N(R 4 )CO, SO 2 N(R 4 ), N(R 4 )SO 2 , OC(R 4 ) 2 , SC(R 4 ) 2 and N(R 4 )C(R 4 ) 2 , wherein R 4 is hydrogen or (l-6C)alkyl, and 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 or heterocyclyl-(l-6C)alkyl, or (R ⁇ m is (l-3C)al
  • X is a direct bond or is selected from CO and N(R )CO, wherein R is hydrogen or (l-6C)alkyl
  • Q 2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl 5 and wherein 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 or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsul ⁇ hinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)
  • X 3 is a direct bond or is selected from O, S, SO, SO 2 , N(R 7 ), CO, CH(OR 7 ), CON(R 7 ), N(R 7 )CO, SO 2 N(R 7 ), N(R 7 )SO 2 , C(R 7 ) 2 O, C(R 7 ) 2 S and N(R 7 )C(R 7 ) 2 , wherein R 7 is hydrogen or (l-6C)alkyl, and Q 3 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 or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl
  • 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; n is O, 1, 2 or 3; and
  • R 3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, 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] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l -6C)alkyl
  • X 6 is a direct bond or is selected from O and N(R 12 ), wherein R 12 is hydrogen or (l-6C)alkyl, and R 11 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 or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
  • X 7 is a direct bond or is selected from O, S, SO, SO 2 , N(R 13 ), CO, CH(OR 13 ), CON(R 13 ), N(R 13 )CO, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or (l-6C)alkyl, and Q 5 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 maybe the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and any heterocyclyl group within Q
  • alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 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 maybe 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 5 ) 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 1 or Q 3 ) 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 5 ) 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 5 ) 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.
  • Suitable values for any of the 'R' groups (R 1 to R 13 ) or for various groups within an R 1 or R 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, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio,
  • N-methylethanesulphonylamino for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido;
  • N-(l-6C)alkyl-(3-6C)alkynoylamino N-methylpropiolamido
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1 -aminoethyl and
  • halogeno-(l-6C)alkyl chloromethyl, 2-chloroethyl, 1-chloroethyl and
  • a suitable value for (R l ) m when it is a (l-3C)alkylenedioxy group is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • an R group forms a group of the formula Q -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 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Q 1 group.
  • adjacent carbon atoms in any (2-6C)alkylene chain within a 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-pyrrolidin- l-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.
  • R 1 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-hydroxy-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-piperidin
  • hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxyethoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (l-6C)alkylsulphonyl-substituted (l-6C)alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
  • 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 , n and R 3 has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter :- (a) Z is O, S, SO, SO 2 , CH 2 or NH;
  • 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,
  • 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 2 is a direct bond or is CO or N(R 6 )CO, wherein R 6 is hydrogen or (l-6C)alkyl, and Q 2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl orheterocyclyl-(l-6C)alkyl, and wherein 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 groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula :
  • 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-[(l)
  • 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 maybe 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;
  • 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-propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propyla
  • 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,
  • X 4 is a direct bond or is selected from O and NH and R 8 is 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula :
  • X 5 is a direct bond or is selected from O, NH and CO and Q 4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-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; and
  • m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and 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, tetrahydro
  • 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-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidin
  • (g) m is 1 and the R 1 group is located at the 6- or 7-position and is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylammo, diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-l -ylethoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
  • n 1 or 2 and the R groups, which may be the same or different, are located at the
  • n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the
  • 3-, 5- and/or 6-positions of the benzofuran-7-yl group are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl,
  • (k) n is 1 and the R 3 group is located at the 5- or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy,
  • X 1 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
  • Q 1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X 1 is a direct bond and
  • 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 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 -Q 4 wherein 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
  • each R 1 group which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula :
  • X 1 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-1 -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, tetrahydrofuran-3-
  • 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, mo ⁇ holino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-mo ⁇ holinoethyl, 3-mo ⁇ holinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylmethyl, 2-piperidin-4
  • X is a direct bond or is selected from O and NH and R is 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,
  • m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which maybe the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol- 1 -ylethoxy, 3 -imidazol- 1 -yl
  • n is 1 or 2 and the R 3 groups, which may be the same or different, are located at the 3-, 4-, 5- and/or 6-positions of the benzofuran-7-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy; and
  • n 1 and the R 3 group is located at the 4-, 5- or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and 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 , n and R has any of the meanings defined hereinbefore provided that :- (A) 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.
  • a particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is O orNH; m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l ,2,4-triazol-l-yl)ethoxy, tefrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3
  • substituents each 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; and n is 0 or 1 and the R group, if present, is located at the 3-, 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl
  • a particular compound of the invention is a quinoline derivative of the Formula I wherein :
  • Z is O or NH; m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and each R 1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyr
  • substituents each 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; and n is 0 or 1 and the R group, if present, is located at the 3-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, e
  • Formula I wherein : Z is O or NH; m is 2 and the first R 1 group is located at the 6-position and is selected from hydroxy, methoxy, ethoxy and propoxy, and the second R 1 group is located at the 7-position and is selected from 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, 2-(2-hydroxyethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy, 2-dimethylaminoethoxy, 3 -dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3 -diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3 -diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)
  • any CH 2 group within the second R 1 group that is attached to two carbon atoms optionally bears a hydroxy group or acetoxy group on said CH 2 group, and wherein any heterocyclyl group within the second R 1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R group, if present, is located at the 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; 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 O orNH; 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-dimethylaminoethoxy, 3-dimethylaminopropoxy,
  • any CH 2 group within the second R 1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH 2 group
  • any heteroaryl group within the second R 1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl
  • any heterocyclyl group within the second R 1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo
  • n is 0 or n is 1 and the R 3 group, if present, is located at the 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo and cyano; 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 O or 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-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is H; 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-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3 -mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-pipe
  • 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-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3 -mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmeth
  • 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 methoxy, ethoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3-mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-tl iazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,
  • 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 methoxy, 3-mo ⁇ holinopropoxy, 3-(l , 1 -dioxotetrahydro-4H-l ,4-thiazin-4-yl)propoxy, 3-(l ,2,3,6-tetrahydropyridin- 1 -yl)propoxy, 4-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)butoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 3-piperazin-l-ylpropoxy, 3 -(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)
  • 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-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-mo ⁇ holinoethoxy, 3 -mo ⁇ holinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3 -(1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-yl
  • 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 3-(4-methylpiperazin-l-yl)propoxy, n is 1 and the R 3 group is a chloro or bromo group located at the 6-position of the benzofuran-7-yl group; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from :-
  • a particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from :-
  • a further particular compound of the invention is, for example, the quinoline derivative of the Formula I being :- 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[4-(4-methylpiperazin-l-yl)butoxy]quinoline, 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 O orNH; m is 1 and the R 1 group is located at the 5 -position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3 -yloxy, tetrahydrothiopyran-4-yloxy,
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tefrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, 1 , 1 -dioxotetraliydrothiopyran-4-yloxy, N-methylazetidin-3 -yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3 -yloxy, pyrrolidin-3 -yloxy, N-methylpyrrolidin-3 -yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3 -yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R 1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-mo ⁇ holinoethoxy, 3-mo ⁇ holinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3 -(4-methylpiperazin- l-yl)propoxy and 3-methylsulphonyl
  • a further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R 1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R 1 is located at the 7-position and is selected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)eth
  • 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 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 tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R 1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy,
  • n 0 or n is 1 and the R 3 group, if present, is a chloro group located at the 6-position of the benzofuran-7-yl 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 tetrahydro ⁇ yran-4-yloxy 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 tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, and the second R 1 group is located at the 7-position and is selected from methoxy and 3-mo ⁇ holinopropoxy; and n is 0; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:-
  • a further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:-
  • 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, m, R 1 , Z, n and R 3 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.
  • L is a displaceable group and m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula in wherein Z is O, S, or N(R ) and n, R and R 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.
  • the reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base.
  • 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, mo ⁇ holine, N-methylmo ⁇ holine 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.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene
  • 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.
  • 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
  • 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
  • reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 0 to 120°C.
  • the quinoline of the Formula II may be reacted with a compound of the Formula in 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, mo ⁇ holine, N-methylmo ⁇ holine 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, mo ⁇ holine, N-methylmo ⁇ hol
  • 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. Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
  • a carboxy protecting group maybe 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 pivaloyloxymethyi); 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
  • 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.
  • lower alkyl groups for example tert-butyl
  • lower alkenyl groups for example allyl
  • lower alkanoyl groups for example acetyl
  • 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 benzy
  • 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.
  • Quinoline starting materials of the Formula ⁇ 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 fiinctional 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-pentafluorophenoxyquinoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as N,N-dimethylformamide.
  • R 1 group is a group of the formula 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
  • 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.
  • 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
  • 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
  • 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, n and R have any ofthe 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.
  • the cleavage reaction may conveniently be carried out by any ofthe many procedures known for such a transformation.
  • the cleavage reaction of a compound ofthe Formula I wherein R 1 is a (l-6C)alkoxy group may be carried out, for example, by treatment ofthe quinoline derivative with an alkali metal (l-6C)alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide.
  • the cleavage reaction may conveniently be carried out, for example, by treatment ofthe quinoline derivative with a boron or aluminium trihalide such as boron tribromide.
  • the cleavage reaction of a compound ofthe Formula I wherein R 1 is a arylmethoxy group may be carried out, for example, by hydrogenation ofthe quinoline derivative in the presence of a suitable metallic catalyst such as palladium or by reaction with an organic or inorganic acid, for example trifluoroacetic acid.
  • a suitable metallic catalyst such as palladium
  • an organic or inorganic acid for example trifluoroacetic acid.
  • Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • Suitable protecting groups for an amino group are, for example, any ofthe protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore.
  • a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis, for example in the presence of trifluoroacetic acid.
  • a suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.
  • an alkyl or substituted alkyl halide for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence
  • a reductive amination reaction may be employed.
  • the conesponding compound containing a N-H group may be reacted with formaldehyde in the presence of a suitable reducing agent.
  • a suitable reducing agent is, for example, a hydride reducing agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydri.de and sodium triacetoxyborohydride.
  • a hydride reducing agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydri.de and sodium triacetoxyborohydride.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example tefrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • a suitable inert solvent or diluent for example tefrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
  • the reaction is performed at a temperature in the range, for example, 10 to 80°C, conveniently at or near ambient temperature, (h)
  • R 1 is an amino-hydroxy-disubstitute
  • 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 protecting groups for a hydroxy group are, for example, any ofthe protecting groups disclosed hereinbefore. Suitable methods for the cleavage of such hydroxy protecting groups are also disclosed hereinbefore, h particular, a suitable protecting group is a lower alkanoyl group such as an acetyl group which may be cleaved under conventional reaction conditions such as under base-catalysed conditions, for example in the presence of ammonia, (j) For the production ofthose compounds ofthe Formula I wherein Z is a SO or SO 2 group, the oxidation of a compound of Formula I wherein Z is a S group.
  • a compound ofthe Formula I wherein an R or R substituent is a halogeno group may be reacted with a metal cyanide to form a compound ofthe Formula I wherein an R 1 or R 3 substituent is a cyano group.
  • the reaction may be carried out in the presence of a suitable catalyst.
  • a suitable metal cyanide is, for example, a heavy metal cyanide such as zinc cyanide.
  • a suitable catalyst is, for example, an organometaUic reagent, for example an organoiron compound such as diphenylphosphinoferrocene.
  • the conversion 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 100°C.
  • a compound ofthe Formula I wherein an R or R substituent is a halogeno group may be reacted with a (2-6C)alkyne to form a compound ofthe Formula I wherein an R or R substituent is a (2-6C)alkynyl group such as an ethynyl group.
  • the reaction may conveniently be carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable catalyst.
  • a suitable catalyst is, for example, an organometaUic reagent, for example an organopalladium compound such as tetrakis(triphenylphosphine)palladiixm(0).
  • the conversion 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 60°C.
  • a compound ofthe Formula I wherein an R 1 or R 3 substituent is a halogeno group may be reacted with an arylboron reagent to form a compound ofthe
  • R or R substituent is an aryl group such as a phenyl group.
  • a suitable arylboron reagent is, for example, an arylboronic acid.
  • the reaction may conveniently be 5 carried out in the presence of a suitable catalyst, for example, an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0).
  • the conversion 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 80°C.
  • the following assays can be used to measure the effects ofthe compounds ofthe present invention as c-Src tyrosine kinase inhibitors, as inhibitors in vitro ofthe proliferation
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa
  • a substrate solution [lOO ⁇ l of a 20 ⁇ g/ml solution ofthe 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
  • Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were transferred 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.
  • 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 transferred 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 kinase (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.
  • 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 liquid in each well was discarded and the wells were washed twice with PBST.
  • Mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology h e. product 05-321; lOO ⁇ l) was diluted by a factor of 1 :6000 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 each well was washed with PBST (x4).
  • Horse radish peroxidase (HRP)-linked sheep anti-mouse lg 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
  • 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) ofthe 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.
  • NTH National Institute of Health
  • 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 O.lmg/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 O.lmg/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 ofthe 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°C in 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. 647 229) was diluted by a factor of 1 : 100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered trade mark), Premier Beverages, Stafford, GB) and an aliquot (lOO ⁇ l) ofthe resultant solution was added to each well.
  • the plates were placed on a plate shaker at ambient temperature for 90 minutes. The wells were washed with PBS (x5) to ensure removal of non-bound antibody conjugate.
  • the plates were blotted dry and tetramethylbenzidine substrate solution (Boehringer Mannheim Catalogue No. 647 229; lOO ⁇ l) was added to each well.
  • This assay determines the ability of a test compoxind to inhibit the migration of adherent mammalian cell lines, for example the human tumour cell line A549.
  • 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) ofthe 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) ofthe cell/agarose mixture was transferred 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 ofthe agarose-containing droplets. Aliquots (90 ⁇ l) of medium which had been cooled to 4°C were transfened 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) ofthe diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% CO 2 : 95% air) incubator for about 48 hours.
  • a migratory inhibitory IC 50 was derived by plotting the mean migration measurement against test compound concentration.
  • This test measures the ability of compounds to inhibit the growth ofthe 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) No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested ofthe 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 ofthe Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
  • compositions ofthe 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 ofthe 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 ofthe total composition.
  • the size ofthe dose for therapeutic or prophylactic pu ⁇ oses of a compound ofthe Formula I will naturally vary according to the nature and severity ofthe conditions, the age and sex ofthe 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.
  • a quinoline derivative ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment ofthe human or animal body by therapy.
  • 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 ofthe non-receptor tyrosine-specific protein 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 quinoline derivatives ofthe present invention are of value as anti- tumour agents, in particular as selective inhibitors ofthe motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • the quinoline derivatives ofthe present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds ofthe present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more ofthe 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 ofthe present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition ofthe 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 ofthe present invention are expected to be useful in the prevention or treatment of solid tumour disease.
  • quinoline derivative ofthe 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 ofthe 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 ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinoline derivative ofthe 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 ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinoline derivative ofthe Fonnula 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 ofthe Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a c-Src kinase inhibitory effect.
  • a method for providing a c-Src kinase inhibitory effect which comprises administering to said animal an effective amo int of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • the anti-invasive treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinoline derivative ofthe invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more ofthe following categories of anti-tumour agents :-
  • anti-invasion agents for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase 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, or, for example, one ofthe prefened antimetabolites disclosed in European Patent Application No.
  • alkylating agents for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitro
  • cytostatic agents such as antioestrogens (for example tamoxifen, 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, letrazole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors ofthe epidermal
  • antiangiogenic agents such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inl ibitors of integrin ⁇ v ⁇ 3 function and angiostatin).
  • Such conjoint treatment may be achieved by way ofthe simultaneous, sequential or separate dosing ofthe individual components ofthe treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other phannaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a quinoline derivative ofthe formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds ofthe 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 :
  • melting points are unconected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products ofthe Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
  • the organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated.
  • the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
  • the material so obtained was dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added.
  • the resultant solid was washed with diethyl ether and dried.
  • the 7-aminobenzofuran used as a starting material was prepared as follows :- Hydrazine hydrate (0.45 ml) was added dropwise to a stined mixture of
  • Diethyl azodicarboxylate (0.25 g) was added dropwise to a suspension of 4-chloro- 3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g; prepared as described in international Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), l-(3-hydroxypropyl)-4-methylpiperazine (0.202 g), triphenylphosphine (0.447 g) and methylene chloride (5 ml) and the mixture was stined at ambient temperature for 2 hours.
  • the resultant mixture was evaporated and the residue was purified by column chromatography on silica using initially increasingly polar mixtures of methylene chloride and ethyl acetate followed by increasingly polar mixtures of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent.
  • the material so obtained was triturated under diethyl ether.
  • the 7-amino-6-chlorobenzofuran used as a starting material was prepared as follows :- Sodium hydride (60% dispersion in mineral oil; 4.6 g) was added to a stined solution of 6-chloroanthranilic acid (18 g) in DMF (100 ml) and the mixture was stined at ambient temperature for 30 minutes. Ethyl iodide (10 ml) was added and the reaction mixture was stined at ambient temperature for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated.
  • the 7-amino-5-fluorobenzofuran used as a starting material was prepared as follows :- Allyl bromide (6 ml) was added to a stined mixture of 4-fluoro-2-nitrophenol (10 g), l,5,7-triazabicyclo[4,4,0]dec-5-ene (11.5 g) and DMF (120 ml) and the reaction mixture was stined at ambient temperature for 20 hours. The reaction mixture was then heated to 50°C for 1.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with a IN aqueous hydrochloric acid solution, water and brine, dried over magnesium sulphate and evaporated.
  • the 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline used as a starting material was prepared as follows :- A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g, prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), potassium tert-butoxide (0.1 g) and DMF (8 ml) was stined at ambient temperature for 15 minutes. l-Bromo-3-choropropane (0.134 g) was added and the reaction mixture was stined at ambient temperature for 16 hours.
  • the resultant mixture was evaporated and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and hexane.
  • reaction mixture was stined at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution.
  • the precipitate was isolated and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent.
  • the reactants were 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (containing some 4-chloro-7-(3-bromopropoxy)-3-cyano-6-methoxyquinoline) and 7-aminobenzofuran and the reaction mixture was heated to 110°C for 3 hours.
  • the l-(2-fluoroethyl)piperazine trifluoroacetate salt used as a starting material was prepared as follows :-
  • Trifluoroacetic acid (20 ml) was added to a mixture of 4-(tert-butoxycarbonyl)- l-(2-fluoroethyl)piperazine (3.7 g), triethylsilane (8 ml) and methylene chloride (100 ml) and the resultant mixture was stined at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was isolated, washed with diethyl ether and dried.
  • the reactants were 4-benzofuran-7-ylamino-7-(4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-acetylpiperazine and the reaction solvent was n-propanol.
  • the reaction mixture was heated to 90°C for 18 hours.
  • the resultant mixture was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution.
  • the organic layer was washed with brine, dried over magnesium sulphate and evaporated.
  • the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
  • the reactants were 4-benzofuran-7-ylamino-7-(4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-methylpiperazine and the reaction solvent was n-propanol.
  • the reaction mixture was heated to 90°C for 18 hours.
  • the resultant mixture was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution.
  • the organic layer was washed with brine, dried over magnesium sulphate and evaporated.
  • the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent.
  • Diisopropyl azodicarboxylate (0.414 g) was added dropwise to a stined suspension of 4-benzofuran-7-ylamino-3-cyano-7-hydroxy-6-methoxyquinoline (0.565 g), 2-(2-methoxyethoxy)ethanol (0.307 g), triphenylphosphine (0.627 g) and methylene chloride (30 ml).
  • the mixture was stined at ambient temperature for 3 hours.
  • the mixture was evaporated and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of ethyl acetate and methanol as eluent.
  • Tris(dibenzylideneacetone)dipalladium (0.037 g) was added to a mixture of 3-cyano-4-(4-iodobenzofuran-7-ylamino)-6,7-dimethoxyquinoline (0.25 g), zinc cyanide (0.064 g), diphenylphosphinofenocene (0.038 g), zinc powder (0.014 g) and DMA (20 ml) and the resultant mixture was stined and heated to 110°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water.
  • the product was eluted off the column with methanol containing triethylamine (1%).
  • the material so obtained was purified further using column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent.
  • Compound X the active ingredient being termed "Compound X"
  • Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • the aerosol formulations (h)-(k) maybe used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns quinoline derivatives of Formula (I) wherein each of Z, m, R1, n and R3 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

Description

OUINOLINE DERIVATIVES
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, to 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. h recent years it has been discovered that a cell may become cancerous by virtue of the transformation 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, 1, 91). Several such 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. Biochem.. 1988, 57, 443; Larsen et al, Ann. Reports in Med. Chem., 1989, Chpt. 13). The first group of tyrosine kinases to be identified arose from such viral oncogenes, for example pp60v"Src tyrosine kinase (otherwise known as v-Src), and the corresponding tyrosine kinases in normal cells, for example pp60c"Src tyrosine kinase (otherwise known as c-Src).
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. Various classes of receptor tyrosine kinases 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, TGFα, Neu and erbB receptors, Class π receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR) and Class HI receptor tyrosine kinases comprising 5 the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF , PDGFβ and colony-stimulating factor 1 (CSF1) receptors.
It is also known that certain 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
10 invasiveness and subsequently metastatic tumour growth (Ullrich et al, Cell 1990, 61, 203- 212, Bolen et al, FASEB J., 1992, 6, 3403-3409, Brickell et al, Critical Reviews in Oncogenesis, 1992, 3, 401-406, Bohlen et al, Oncogene. 1993, 8, 2025-2031, Courtneidge et al, Semin. Cancer Biol. 1994, 5, 239-246, Lauffenburger et al, Cell, 1996, 84, 359-369, Hanks et al, BioEssays, 1996, 19, 137-145, Parsons et al, Current Opinion in Cell Biology,
15 1997, 9, 187-192, Brown et al, Biochimica et Biophvsica Acta, 1996, 1287. 121-149 and Schlaepfer et al, Progress in Biophysics and Molecular Biology, 1999, 71, 435-478). Various classes of non-receptor tyrosine kinases are known including 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.
20 It is known that the 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. However, 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
25 (Cartwright et al, Proc. Natl. Acad. Sci. USA. 1990, 87, 558-562 and Mao et al, Oncogene. 1997, 15, 3083-3090), and breast cancer (Muthuswamy et al, Oncogene, 1995, ϋ, 1801- 1810). The Src family of non-receptor tyrosine kinases has also been located in other common human cancers such as non-small cell lung cancers (NSCLCs) including adenocarcinomas and squamous cell cancer of the lung (Mazurenko et al, European Journal
30 of Cancer. 1992, 28, 372-7), bladder cancer (Fanning et al, Cancer Research. 1992, 52, 1457- 62), oesophageal cancer (Jankowski et al, Gut, 1992, 33, 1033-8), cancer of the prostate, ovarian cancer (Wiener et al, Clin. Cancer Research, 1999, 5, 2164-70) and pancreatic cancer (Lutz et al, Biochem. andBiophys. Res. Comm., 1998, 243, 503-8). As further human tumour tissues are tested for the Src family of non-receptor tyrosine kinases it is expected that its widespread prevalence will be established.
It is further known that the predominant role of 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. In addition c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility. Likewise, important roles are played by the c-Src, c-Yes and c-Fyn non-receptor tyrosine kinases in integrin mediated signalling and in disrupting cadherin-dependent cell-cell junctions (Owens et al, Molecular Biology of the Cell, 2000, ϋ, 51-64 and Klinghoffer et al, EMBO Journal, 1999, 18, 2459-2471). Cellular motility 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. For example, 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).
Accordingly it has been recognised that 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 inliibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth. In particular 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.
We have now found that surprisingly certain quinoline derivatives possess potent anti-tumour activity. Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the non-receptor tyrosine-specific protein kinases that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells, hi particular, it is believed that the compounds of the present invention provide an anti-tumour effect byway 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. It is also known that 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. Invest.. 1993, 91, 2791-2795 and Missbach et al, Bone, 1999, 24 , 437-49). 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), glomeralonephritis, 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. Generally 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 VEGF receptor tyrosine kinase. Furthermore, 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 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 VEGF receptor tyrosine kinase.
It is stated in International Patent Application WO 98/43960 that a range of 3-cyanoquinoline derivatives are useful in the treatment of cancer. Certain of the compounds are stated to be inhibitors of EGF receptor tyrosine kinase, others are stated to be inhibitors of the mitogen-activated protein kinase (MAPK) pathway and others are stated to be inhibitors of growth factors such as vascular endothelial growth factor (VEGF). There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.
It is stated in International Patent Application WO 00/68201 that a range of 3-cyanoquinoline derivatives are also useful in the treatment of cancer. Certain of the compounds are stated to be inhibitors of MEK, a MAPK kinase. There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.
It is disclosed in Journal Medicinal Chemistry, 2001, 44, 822-833 and in Journal Medicinal Chemistry, 2001, 44, 3965-3977 that certain 4-anilino-3-cyanoquinoline derivatives are useful for the inhibition of Src-dependent cell proliferation. There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.
According to one aspect of the invention there is provided a quinoline derivative of the Formula I
wherein Z is an O, S
Figure imgf000006_0001
may be the same or different, is hydrogen or (l-6C)alkyl; m is O, 1, 2, 3 or 4; each R1 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)alkylsulρhonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l -6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino,
N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
Q^X1 - wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-6C)alkyl, and Q1 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 or heterocyclyl-(l-6C)alkyl, or (R^m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X is a direct bond or is selected from CO and N(R )CO, wherein R is hydrogen or (l-6C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl5 and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulρhinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl- (2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R7), CO, CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 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 or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 , 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, 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)alkylsulρhinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl- (l-6C)alkanesulphonylamino, or from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 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 :
-X5- Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 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 R1 optionally bears 1 or 2 oxo or thioxo substituents; n is O, 1, 2 or 3; and
R3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, 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] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l -6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
-X6-Rπ wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or (l-6C)alkyl, and R11 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 or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
-X7-Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R13), CO, CH(OR13), CON(R13), N(R13)CO, SO2N(R13), N(R13)SO2, C(R13)2O, C(R13)2S and N(R13)C(R13)2, wherein R13 is hydrogen or (l-6C)alkyl, and Q5 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 maybe the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceutically-acceptable salt thereof. hi this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However 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 and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di-[(l-6Calkyl]amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl- N-ethylamino.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, 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 maybe 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. Similarly, 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 (Q1 to Q5) 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 (Q1 or Q3) 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 (Q1 or Q3) 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 (Q1 to Q5) 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, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl.
A suitable value for any one of the 'Q' groups (Q1 to Q5) 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-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetral ydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, l,l-dioxotetrahydro-4H-l,4-thiazmyl, piperidinyl or piperazinyl. 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.
In structural Formula I there is a hydrogen atom at the 2-position on the quinoline ring. It is to be understood thereby that the R1 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. It is further to be understood that the R3 group that may be present on the benzofuranyl group within structural Formula I may be located on either the 5- or 6-membered ring portions thereof, for example at the 2-, 3-, 4-, 5- or 6-positions of the benzofuran-7-yl group. It is further to be understood that, when multiple R groups are present, the R groups may be the same or different.
Suitable values for any of the 'R' groups (R1 to R13) or for various groups within an R1 or R 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, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio, ethylthio and propylthio; for (l-6C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (l-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl- N-methylamino and diisopropylamino; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(l-6C)alkylcarbamoyl: N-methylcarbanioyl, 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 and propionyl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; 5 for (2-6C)alkanoylamino: acetamido and propionamido; for N-(l-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido; for N-(l-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl; for N,N-di-[(l-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl; for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino;
10 for N-( 1 -6C)alkyl-( 1 -6C)alkanesulphonylamino : N-methylmethanesulphonylamino and
N-methylethanesulphonylamino; for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido;
15 for N-(l-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; for amino-(l-6C)alkyl: aminomethyl, 2-aminoethyl, 1 -aminoethyl and
3-aminopropyl; for (l-6C)alkylamino-(l-6C)alkyl: methylaminomethyl, ethylaminomethyl,
1 -methylaminoethyl, 2-methylaminoethyl,
20 2-ethylaminoethyl and 3-methylaminopropyl; for di-[(l -6C)alkyl] amino-(l -6C)alkyl: dimethylaminomethyl, diethylaminomethyl,
1-dimethylaminoethyl, 2-dimethylaminoethyl and
3 -dimethylaminopropyl; for halogeno-(l-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl and
25 3-chloropropyl; for hydroxy-(l-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and
3 -hydroxypropyl; for (l-6C)alkoxy-(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl,
2-methoxyethyl, 2-ethoxyethyl and
30 3 -methoxypropyl; for cyano-(l-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and
3-cyanopropyl; for (2-6C)alkanoylamino-(l-6C)alkyl: acetamidomethyl, propionamidomethyl and
2-acetamidoethyl; and for (l-6C)alkoxycarbonylamino-(l-6C)alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and
2-methoxycarbonylaminoethyl. A suitable value for (Rl)m when it is a (l-3C)alkylenedioxy group is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
1 1 1 When, as defined hereinbefore, an R group forms a group of the formula Q -X - and, for example, X1 is a OC(R4)2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R4)2 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Q1 group. Similarly, when, for example a CH group within a R1 substituent bears a group of the formula -X -Q and, for example, X is a C(R )2O linking group, it is the carbon atom, not the oxygen atom, of the C(R7)2O linking group which is attached to the CH3 group and the oxygen atom is linked to the Q group. A similar convention applies to the attacliment of the groups of the formulae Q2-X2- and -X7-Q5.
As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R5) or C≡C. For example, 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.
When, as defined hereinbefore, any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent such as a group of the formula Q2-X2-wherein X2 is, for example, NHCO and Q2 is aheterocyclyl-(l-6C)alkyl group, suitable R1 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-pyrrolidin- l-ylethyl)carbamoylethynyl.
When, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 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 CH2 group and there are suitably 1, 2 or 3 such substituents present on each said CH3 group.
When, as defined hereinbefore, any CH or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent as defined hereinbefore, suitable R1 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-hydroxy-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-moφholinopropylamino, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3 -amino-2-hydroxypropylamino, hydroxy-substituted ( 1 -6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkylamino groups such as 3-dimethylamino-
2-hydroxypropylamino, hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxyethoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (l-6C)alkylsulphonyl-substituted (l-6C)alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
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. Particular 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, R1, n and R3 has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter :- (a) Z is O, S, SO, SO2, CH2 or NH;
(b) Z is O;
(c) Z is NH;
(d) m is 1 or 2, and each R1 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)alkyljamino, 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)alkynoylamino and N-(l-6C)alkyl- (3-6C)alkynoylamino, or from a group of the formula :
Q^ -X1 - wherein X1 is a direct bond or is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloalkyl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is CO or N(R6)CO, wherein R6 is hydrogen or (l-6C)alkyl, and Q2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl orheterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 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-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group of the formula : -X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)all£yl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)aιkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which maybe the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(e) m is 1 or 2, and each R1 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-propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula : c -X1 - wherein X1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH2 and Q1 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)ρroρyl, 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, tetrahydrofιxran-3-yl, 3- or 4-tetrahydropyranyl, 1-, 2- or 3 -pyrrolidinyl, morpholino, l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazm-4-y )ethyl, 3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin- 1 -ylethyl, 3-homopiperidin- 1 -ylpropyl, 2-piperazin- 1 -ylethyl, 3-piperazin-l-ylpropyl, 4-piperazin-l-ylbutyl, 2-homopiperazin-l -ylethyl or 3-homopiperazin- 1 -ylpropyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CONH, NHCO, CH=CH and C≡C, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl or 4-dimethylaminobutyl, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is CO, NHCO or N(Me)CO and Q2 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-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3 -ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-l -ylethyl, 3 -piperazin-1 -ylpropyl or 4-piperazin- 1 -ylbutyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, 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 : -X3-Q3 wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q3 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, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-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, 2-piperazin-l -ylethyl or 3-piperazin- 1 -ylpropyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and NH and R8 is 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, NH and CO and Q4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-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 R1 optionally bears 1 or 2 oxo substituents; and
(f) m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 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, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-l-ylethoxy, 3-imidazol-l-ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-(l ,2,4-triazol- 1 -yl)ethoxy, 3-(l ,2,4-triazol-l -yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, moφholino, piperidino, piperazin-1 -yl, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-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- 4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -(1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin- 1 -ylethoxy, 3-homopiperazin- 1 -ylpropoxy, 2-pyrrolidin- 1 -ylethylarnino, 3-pyrrolidin- 1 -ylpropylamino, 4-pyrrolidin-l-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3 -morpholinopropylamino, 4-morpholinobutylamino, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethylamino, 3-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin- 1 -ylethylamino, 3-homopiperidin- 1 -ylpropylamino, 2-piperazin-l -ylethylamino, 3-piperazin-l-ylpropylamino, 4-piperazin-l-ylbutylamino, 2-homopiperazin- 1 -ylethylamino or 3-homopiperazin- 1 -ylpropylamino, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and when R1 is a vinyl or ethynyl group, the R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from N-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylarninobutyl, dimethylammomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is NHCO or N(Me)CO and Q2 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-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3 -ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1 -ylmethyl, 2-piperazin-l -ylethyl, 3-piperazin-l-ylpropyl or 4-piperazin-l-ylbutyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylammo, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l -ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents.
(g) m is 1 and the R1 group is located at the 6- or 7-position and is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylammo, diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-l -ylethoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
3-pyrrolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin- 1 -ylpropoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy or 3 -homopiperazin-1 -ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylammo, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any phenyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(h) n is 0;
(i) n is 1 or 2 and the R groups, which may be the same or different, are located at the
3-, 5- and/or 6-positions of the benzofuran-7-yl group and are selected from halogeno, trifluoromethyl, cyano, hydroxy, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy; (j) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the
3-, 5- and/or 6-positions of the benzofuran-7-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl,
1-propynyl, 2-propynyl, methoxy and ethoxy;
(k) n is 1 and the R3 group is located at the 5- or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;
(1) m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy,
(l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl-
(2-6C)alkanoylamino, or from a group of the formula :
Ql-Xl- wherein X1 is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X1 is a direct bond and
Q1 is aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino andN-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 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-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is 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 : -X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which maybe the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R optionally bears 1 or 2 oxo substituents;
(m) m is 1 or 2, and each R1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula :
Q^X1- wherein X1 is selected from O, NH, CONH, NHCO and OCH2 and Q1 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-1 -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, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 1-, 2- or 3 -pyrrolidinyl, moφholino, l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1 -yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, moφholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, 2-moφholinoethyl, 3-moφholinopropyl, 4-moφholinobutyl,
2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethyl, 3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,
2-homopiperidin- 1 -ylethyl, 3 -homopiperidin- 1 -ylpropyl, 2-(l ,2,3 ,6-tetrahydropyridin- 1 - yl)ethyl, 3-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)propyl, 4-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)butyl, 2-piperazin- 1 -ylethyl, 3-piperazin- 1 -ylpropyl, 4-piperazin- 1 -ylbutyl, 2-homopiperazin-l -ylethyl or 3 -homopiperazin-1 -ylpropyl, or wherein X1 is a direct bond and Q1 is benzyl, cyclopropylmethyl, 2-imidazol-l -ylethyl, 3 -imidazol-1 -ylpropyl, 2-(l,2,3-triazolyl)ethyl, 3-(l,2,3-triazolyl)propyl, 2-(l,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)proρyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, 1-, 2- or 3-pyrrolidinylmethyl, moφholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, 2-moφholinoethyl, 3-moφholinopropyl, 4-moφholinobutyl,
2-(l , 1 -dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethyl, 3-(l , 1 -dioxotetrahydro-4H-l ,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,
2-homopiperidin- 1 -ylethyl, 3 -homopiperidin- 1 -ylpropyl, 2-piperazin- 1 -ylethyl, 3-piperazin-l-ylpropyl, 4-piperazin- 1 -ylbutyl, 2-homopiperazin-l -ylethyl or 3 -homopiperazin- 1 -ylpropyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CONH, NHCO, CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, 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 :
-X3-Q3 wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, moφholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-l -ylethyl or 3-piperazin- l-ylpropyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which maybe the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent selected from a group of the formula :
-X4-R8 wherein X is a direct bond or is selected from O and NH and R is 2-hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,
3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylammomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula : -X5-Q4 wherein X5 is a direct bond or is selected from O, NH and CO and Q4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, moφholinomethyl, 2-moφholinoethyl, 3-moφholinopropyl, 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 R1 optionally bears 1 or 2 oxo substituents;
(n) m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which maybe the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol- 1 -ylethoxy, 3 -imidazol- 1 -ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 3-(l,2,4-triazol-l-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3 -ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy,
3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 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-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -(1 , 1 -dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)ethoxy, 3 -(1 ,2,3 ,6-tetrahydropyridin- 1 -yl)propoxy, 4-(l,2,3,6-tetrahydropyridin-l-yl)butoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin- 1 -ylethoxy, 3 -homopiperazin- 1 -ylpropoxy, 2-pyrrolidin- 1 -ylethylamino, 3-pyrrolidin- 1 -ylpropylamino, 4-pyrrolidin- 1 -ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-moφholinoethylamino, 3-moφholinopropylamino, 4-moφholinobutylamino, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethylamino, 3 -(1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin- 1 -ylethylamino, 3-homopiperidin-l-ylρropylamino, 2-(l,2,3,6-tetrahydropyridin-l-yl)ethylamino, 3-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)propylarnino, 4-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)butylamino, 2-piperazin- 1 -ylethylamino, 3 -piperazin- 1 -ylpropylamino, 4-piperazin- 1 -ylbutylamino, 2-homopiperazin-l -ylethylamino or 3-homopiperazin-l-ylpropylamino, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, N-methylcarbamoyl, N,N-dimethylcarbarnoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- 1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with methyl, ethyl, propyl, allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminoρropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-fluoroethyl, 3-fluoropropyl, 2-chloroethyl, 3-chloropropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-moφholinoethyl, 3-moφholinoρropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l -ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each 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 R1 optionally bears 1 or 2 oxo substituents; (o) n is 1 or 2 and the R3 groups, which may be the same or different, are selected from halogeno, trifluoromethyl, cyano, hydroxy, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy;
(p) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 4-, 5- and/or 6-positions of the benzofuran-7-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy; and
(q) n is 1 and the R3 group is located at the 4-, 5- or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy.
Further particular 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 , n and R has any of the meanings defined hereinbefore provided that :- (A) R1 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
(B) R1 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.
A particular compound of the invention is a quinoline derivative of the Formula I wherein :
Z is O orNH; m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l ,2,4-triazol-l-yl)ethoxy, tefrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)ethoxy, 3-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)propoxy, 4-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)butoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin-l -ylethoxy and 3-homopiperazin-l-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- 1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with methyl, ethyl, propyl, allyl, prop-2-ynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-fluoroethyl, 3-fluoropropyl,
2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l -ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each 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 R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R group, if present, is located at the 3-, 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.
A particular compound of the invention is a quinoline derivative of the Formula I wherein :
Z is O or NH; m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3 -piperidin-3 -ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin-l -ylethoxy and 3 -homopiperazin-1 -ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- 1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 2-moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l -ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each 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 R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R group, if present, is located at the 3-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; 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 O or NH; m is 2 and the first R1 group is located at the 6-position and is selected from hydroxy, methoxy, ethoxy and propoxy, and the second R1 group is located at the 7-position and is selected from 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, 2-(2-hydroxyethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy, 2-dimethylaminoethoxy, 3 -dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3 -diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3 -diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-allylamino)ethoxy, 3 -(N-allylamino)propoxy, 2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3-(N-methyl-N-prop-2-ynylamino)proρoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3 -yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 2-(4-allylρiperazin-l-yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin- 1 -yl)butoxy, 2-(4-methylsulphonylpiperazin- 1 -yl)ethoxy,
3-(4-methylsulphonylpiperazin-l-yl)propoxy, 4-(4-methylsulphonylpiperazin-l-yl)butoxy,
2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy,
4-(4-acetylpiperazin-l-yl)butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 4-(4-cyanomethylpiperazin-l-yl)butoxy,
2-[2-(4-methylpiperazin- l-yl)ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy,
2-methylsulphonylethoxy and 3-methylsulphonylpropoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group or acetoxy group on said CH2 group, and wherein any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R group, if present, is located at the 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; 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 O orNH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy,
4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3 -diethylaminopropoxy,
4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy,
4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3 -(N-isobutyl-N-methylamino)propoxy,
4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy,
3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy,
3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy,
3 -(N-methyl-N-prop-2-ynylamino)propoxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 4-pyrrolidin-l -ylbutoxy, pyrrolidin-3-yloxy,
N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
3-pyrrolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy,
2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-yhnethoxy,
2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3 -(N-methylpiperidin-3 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3 -(4-hydroxypiperidin- 1 -yl)propoxy, 4-(4-hydroxypiperidin- 1 -yl)butoxy,
2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 4-homopiperidin- 1 -ylbutoxy, 2-(l,2,3,6-tetrahydropyridin-l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)butoxy, 2-piperazin- 1 -ylethoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-piperazin-l -ylbutoxy,
4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 4-(4-prop-2-ynylpiperazin- 1 -yl)butoxy, 2-(4-methylsulphonylpiperazin- 1 -yl)ethoxy, 3 -(4-methylsulphonylpiperazin- 1 -yl)propoxy, 4-(4-methylsulphonylpiperazin- 1 -yl)butoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-[4-(2-fluoroethyl)piperazin- 1 -yl] ethoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 4-[4-(2-fluoroethyl)piperazin-l-yl]butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 4-(4-cyanomethylpiperazin- 1 -yl)butoxy, 2-(2-piperazin- 1 -ylethoxy)ethoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3 -tetrahydropyran-4-ylpropoxy, 2-pyrrol- 1 -ylethoxy, 3 -pyrrol- 1 -ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3 -(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy,
3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo and cyano; 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 O or NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3 -(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3-(N-methyl-N-prop-2-ynylamino)propoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3 -yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3 -yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3 -ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy,
2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiρeridin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-homopiperidin-l-ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 4-homopiperidin- 1 -ylbutoxy, 2-piperazin- 1 -ylethoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-piperazin- 1 -ylbutoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy,
2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 4-(4-methylsulphonylpiperazin- 1 -yl)butoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin-l-yl)butoxy, 2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3 -(4-cyanomethylpiperazin- 1 -yl)propoxy, 4-(4-cyanomethylpiperazin- 1 -yl)butoxy, 2-(2-piperazin- 1 -ylethoxy)ethoxy, 2- [2-(4-methylpiperazin- 1 -yl)ethoxy] ethoxy, 2-chloroethoxy, 3 -chloropropoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3 -tetrahydropyran-4-ylpropoxy, 2-pyrrol- 1 -ylethoxy, 3 -pyrrol- 1 -ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro and bromo; 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 H; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-moφholinoethoxy, 3 -moφholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin- 3 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin- 1 -yι)butoxy, 2-(4-hydroxypiperidin- 1 -yl)ethoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 4-(4-hydroxypiperidin- 1 -yl)butoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin- l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 3-(4-allylpiperazin-l-yl)propoxy, 3 -(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 3-(4-methylsulphonylpiperazin- 1 -yl)propoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 3 -[4-(2-fluoroethyl)piperazin- 1 -yljpropoxy, 2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3-(4-cyanomethylpiperazm- 1 -yl)propoxy, 2-[2-(4-methylpiperazin- 1 -yl)ethoxy] ethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 4-, 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo and iodo; 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 R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-moφholinoethoxy, 3 -moφholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3 -piperidin-3 -ylpropoxy, 3-(N-methylpiperidin- 3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidm-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 3-(4-allylpiperazin-l-yl)propoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 3 -(4-acetylpiperazin- 1 -yl)propoxy, 2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 6-position of the benzofuranyl group and is selected from chloro and bromo; 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 R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-tl iazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin- 1 -yl)butoxy, 2-(4-hydroxypiperidin- 1 -yl)ethoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 3 -(4-allylpiperazin- 1 -yl)propoxy, 3-(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin-l-yl)butoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 3-, 4-, 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo, iodo and cyano; 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 R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from methoxy, 3-moφholinopropoxy, 3-(l , 1 -dioxotetrahydro-4H-l ,4-thiazin-4-yl)propoxy, 3-(l ,2,3,6-tetrahydropyridin- 1 -yl)propoxy, 4-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)butoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 3-piperazin-l-ylpropoxy, 3 -(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 3 -[4-(2-fluoroethyl)piperazin- 1 -yljpropoxy, 3-chloropropoxy, 4-chlorobutoxy and 2-(2-methoxyethoxy)ethoxy; and n is 0 or n is 1 and the R group, if present, is located at the 3-, 4-, 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo, iodo and cyano; 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 R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-moφholinoethoxy, 3 -moφholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)ethoxy, 3 -(1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3 -piperidin-3 -ylpropoxy, 3-(N-methylpiperidin- 3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3 -(4-methylpiperazin- 1 -yl)propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2- [2-(4-methylpiperazin-l-yl)ethoxy] ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from chloro and bromo; 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 R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 3-(4-methylpiperazin-l-yl)propoxy, n is 1 and the R3 group is a chloro or bromo group located at the 6-position of the benzofuran-7-yl group; or a pharmaceutically-acceptable acid-addition salt thereof.
A particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from :-
4-(6-chlorobenzofuran-7-ylamino)-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy] quinoline and 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline, or a pharmaceutically-acceptable acid-addition salt thereof.
A particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from :-
4-(6-chlorobeιizofuran-7-ylammo)-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy] quinoline and
4-benzofLxran-7-ylamino-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline, or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is, for example, the quinoline derivative of the Formula I being :- 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[4-(4-methylpiperazin-l-yl)butoxy]quinoline, 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 O orNH; m is 1 and the R1 group is located at the 5 -position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3 -yloxy, tetrahydrothiopyran-4-yloxy,
1 , 1 -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, 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, N-(2-methoxyethyl)piperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from the group of substituents listed immediately above and the second R1 group is located at the 7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -(1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 2-homopiperidin- 1 -ylethoxy,
3-homopiperidin-l-ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy,
2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy,
3 -(4-cyanomethylpiperazin- 1 -yl)propoxy, 2-[(2S)-2-carbamoylpyrrolidin- 1 -yl] ethoxy,
2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-l-yl]ethoxy, 2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin- 1 -yl] ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy, 3-ρyridylmethoxy, 4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy; and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tefrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, 1 , 1 -dioxotetraliydrothiopyran-4-yloxy, N-methylazetidin-3 -yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3 -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, N-(2-methoxyethyl)piperidin-4-yloxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3 -ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the second R1 is located at the 7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3 -piperidinopropoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin-l -ylpropoxy, 2-piperazin-l -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 3-(4-cyanomethylpiperazin- 1 -yl)propoxy, 2-[(2S)-2-carbamoylpyrrolidin-l-yl]ethoxy, 2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-l- yl]ethoxy, 2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-l-yl]ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3 -methoxypropoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy and 3 -cyanopyrid-4-ylmethoxy; and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof. A further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3 -yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3 -(4-methylpiperazin- l-yl)propoxy and 3-methylsulphonylpropoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinoline derivative of the Formula I wherein : m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R1 is located at the 7-position and is selected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin- 1 -ylpropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3 -(4-methylpiperazin- 1 -yl)propoxy, 3-(4-cyanomethylpiperazin- 1 -yl)propoxy, 3-methylsulphonylpropoxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from chloro and bromo; 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 R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy,
3-pyrrolidin-l-ylpropoxy, 3-piperidinopropoxy, 3-moφholinopropoxy, 3-piperazin-l-ylpropoxy and 3 -(4-methylpiperazin- l-yl)propoxy; n is 0 or n is 1 and the R3 group, if present, is a chloro group located at the 6-position of the benzofuran-7-yl 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 R1 group is located at the 5-position and is selected from tetrahydroρyran-4-yloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, and the second R1 group is located at the 7-position and is selected from methoxy and 3-moφholinopropoxy; and n is 0; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:-
4-(6-chlorobenzoflxran-7-ylamino)-3-cyano-7-methoxy-5-(N-methylpiperidin-
4-yloxy)quinoline,
4-(6-chloroberιzofuran-7-ylamino)-3-cyano-7-(2-pyrrolidin-l-ylethoxy)-
5-tetrahydropyran-4-yloxyquinoline, 4-(6-chlorobeiizofuran-7-ylamino)-3-cyano-7-(3-pyrrolidin-l-ylpropoxy)-
5-tetrahydropyran-4-yloxyquinoline,
4-(6-chlorobenzofuran-7-ylamino)-3 -cyano-7-[3-(4-methylpiperazin- 1 -yl)propoxy] -
5 -tetrahydropyran-4-yloxyquinoline,
4-(6-chloroberιzofuran-7-ylamino)-3-cyano-7-[2-(4-methylpiperazin-l-yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinoline,
4-(6-chlorobei zofuran-7-ylamino)-3-cyano-7-(2-piperidinoethoxy)-5-tetrahydropyran-
4-yloxyquinoline and 4-(6-chlorobenzofuran-7-ylamino)-3-cyano-7-(N-methylpiperidin-4-ylmethoxy)-
5 -tetrahydropyran-4-yloxyquinoline; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:-
4-benzofuran-7-ylammo-3-cyano-5-(N-methylpiperidin-4-yloxy)quinoline, 4-benzofuran-7-ylamino-3-cyano-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinoline and 4-benzoflxran-7-ylamino-3-cyano-7-(3-moφholinopropoxy)-5-tetrahydropyran- 4-yloxyquinoline; or a pharmaceutically-acceptable acid-addition salt thereof.
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, m, R1, Z, n and R3 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.
(a) For the production of those compounds of the Formula I wherein Z is an O, S or N(R2) group, the reaction of a quinoline of the Formula IT
Figure imgf000044_0001
wherein L is a displaceable group and m and R1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula in
Figure imgf000045_0001
wherein Z is O, S, or N(R ) and n, R and R 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. The reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base. 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, moφholine, N-methylmoφholine 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. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 0 to 120°C.
Typically, the quinoline of the Formula II may be reacted with a compound of the Formula in 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.
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. When it is desired to obtain the free base from the salt, 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, moφholine, N-methylmoφholine 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.
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. Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
A carboxy protecting group maybe 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). Examples of 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 pivaloyloxymethyi); 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-lower alkyl groups (for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage.
Examples of 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. Examples of 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.
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.
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, 2nd Edition, by T. Green et al, also published by John Wiley & Son, for general guidance on protecting groups.
Quinoline starting materials of the Formula π may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201. For example, a l,4-dihydroquinolin-4-one of Formula IV
Figure imgf000047_0001
wherein m and R1 have any of the meanings defined hereinbefore except that any fiinctional 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. The 4-chloroquinoline so obtained may be converted, if required, into a
4-pentafluorophenoxyquinoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as N,N-dimethylformamide.
7-Aminobenzofuran starting materials (Formula m, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples. Corresponding
7-hydroxybenzofuran and 7-mercaptobenzofixran starting materials (Formula ffl, when Z is O or S respectively) maybe obtained by conventional procedures.
(b) For the production of those compounds of the Formula I wherein at least one R1 group is a group of the formula
Figure imgf000048_0001
wherein Q1 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 X1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinoline of the Formula V
Figure imgf000048_0002
wherein m, R1, Z, n and R3 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.
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. (c) For the production ofthose compounds ofthe Formula I wherein an R1 group contains a (l-6C)alkoxy or substituted (l-6C)alkoxy group or a (l-6C)alkylamino or substituted (l-6C)alkylamino group, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a quinoline derivative ofthe Formula VI
Figure imgf000049_0001
wherein L is a displaceable group as defined hereinbefore and Z, n and R have any ofthe 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.
The 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.
(d) For the production ofthose compounds ofthe Formula I wherein R1 is an amino-substituted (l-6C)alkoxy group (such as 2-homopiperidin- 1 -ylethoxy or 3-dimethylaminopropoxy), the reaction of a compound ofthe Formula I wherein R1 is a halogeno-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine. The 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.
(e) For the production of those compounds of the Formula I wherein R1 is a hydroxy group, the cleavage of a quinoline derivative ofthe Formula I wherein R1 is a (l-6C)alkoxy or arylmethoxy group.
The cleavage reaction may conveniently be carried out by any ofthe many procedures known for such a transformation. The cleavage reaction of a compound ofthe Formula I wherein R1 is a (l-6C)alkoxy group may be carried out, for example, by treatment ofthe quinoline derivative with an alkali metal (l-6C)alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide. Alternatively the cleavage reaction may conveniently be carried out, for example, by treatment ofthe quinoline derivative with a boron or aluminium trihalide such as boron tribromide. The cleavage reaction of a compound ofthe Formula I wherein R1 is a arylmethoxy group may be carried out, for example, by hydrogenation ofthe quinoline derivative in the presence of a suitable metallic catalyst such as palladium or by reaction with an organic or inorganic acid, for example trifluoroacetic acid. Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
(f) For the production ofthose compounds ofthe Formula I wherein an R1 group contains a primary or secondary amino group, the cleavage ofthe corresponding compound ofthe Formula I wherein the R1 group contains a protected primary or secondary amino group.
Suitable protecting groups for an amino group are, for example, any ofthe protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore. In particular, a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis, for example in the presence of trifluoroacetic acid. (g) For the production of those compounds of the Formula I wherein an R1 group contains a (l-6C)alkoxy or substituted (l-6C)alkoxy group or a (l-6C)alkylamino or substituted (l-6C)alkylamino group, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a quinoline derivative ofthe formula I wherein the R1 group contains a hydroxy group or a primary or secondary amino group as appropriate.
A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (l-6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, conveniently in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.
Conveniently for the production ofthose compounds ofthe Formula I wherein R1 contains a (l-6C)alkylamino or substituted (l-6C)alkylamino group, a reductive amination reaction may be employed. For example, for the production ofthose compounds ofthe Formula I wherein R1 contains a N-methyl group, the conesponding compound containing a N-H group may be reacted with formaldehyde in the presence of a suitable reducing agent. A suitable reducing agent is, for example, a hydride reducing agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydri.de and sodium triacetoxyborohydride. The reaction is conveniently performed in a suitable inert solvent or diluent, for example tefrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is performed at a temperature in the range, for example, 10 to 80°C, conveniently at or near ambient temperature, (h) For the production ofthose compounds ofthe Formula I wherein R1 is an amino-hydroxy-disubstituted (l-6C)alkoxy group (such as 2-hydroxy-3-pyrrolidin-
1-ylpropoxy or 3-[N-allyl-N-methylamino]-2-hydroxypropoxy), the reaction of a compound of the Formula I wherein the R1 group contains an epoxy-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine.
The 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. (i) For the production of those compounds of the Formula I wherein an R1 group contains a hydroxy group, the cleavage ofthe corresponding compound ofthe Formula I wherein the R1 group contains a protected hydroxy group.
Suitable protecting groups for a hydroxy group are, for example, any ofthe protecting groups disclosed hereinbefore. Suitable methods for the cleavage of such hydroxy protecting groups are also disclosed hereinbefore, h particular, a suitable protecting group is a lower alkanoyl group such as an acetyl group which may be cleaved under conventional reaction conditions such as under base-catalysed conditions, for example in the presence of ammonia, (j) For the production ofthose compounds ofthe Formula I wherein Z is a SO or SO2 group, the oxidation of a compound of Formula I wherein Z is a S group.
Conventional oxidation reagents and reaction conditions for such partial or complete oxidation of a sulphur atom are well known to the organic chemist.
(k) The conversion of a compound of the Formula I wherein an R1 or R3 substituent is a halogeno group into a further compound ofthe Formula I wherein the R1 or R3 substituent is, for example, a cyano, ethynyl or phenyl group.
For example, a compound ofthe Formula I wherein an R or R substituent is a halogeno group may be reacted with a metal cyanide to form a compound ofthe Formula I wherein an R1 or R3 substituent is a cyano group. Conveniently, the reaction may be carried out in the presence of a suitable catalyst. A suitable metal cyanide is, for example, a heavy metal cyanide such as zinc cyanide. A suitable catalyst is, for example, an organometaUic reagent, for example an organoiron compound such as diphenylphosphinoferrocene. The conversion 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 100°C. For example, a compound ofthe Formula I wherein an R or R substituent is a halogeno group may be reacted with a (2-6C)alkyne to form a compound ofthe Formula I wherein an R or R substituent is a (2-6C)alkynyl group such as an ethynyl group. The reaction may conveniently be carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable catalyst. For this conversion, a suitable catalyst is, for example, an organometaUic reagent, for example an organopalladium compound such as tetrakis(triphenylphosphine)palladiixm(0). The conversion 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 60°C. For example, a compound ofthe Formula I wherein an R1 or R3 substituent is a halogeno group may be reacted with an arylboron reagent to form a compound ofthe
Formula I wherein an R or R substituent is an aryl group such as a phenyl group. A suitable arylboron reagent is, for example, an arylboronic acid. The reaction may conveniently be 5 carried out in the presence of a suitable catalyst, for example, an organopalladium compound such as tetrakis(triphenylphosphine)palladium(0). The conversion 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 80°C.
When a pharmaceutically-acceptable salt of a quinoline derivative ofthe Formula I is
10 required, 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. Biological Assays
The following assays can be used to measure the effects ofthe compounds ofthe present invention as c-Src tyrosine kinase inhibitors, as inhibitors in vitro ofthe proliferation
15 of c-Src transfected fibroblast cells, as inhibitors in vitro ofthe migration of A549 human lung tumour cells and as inhibitors in vivo ofthe growth in nude mice of xenografts of A549 tissue, (a) In Vitro Enzyme Assay
The ability of test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa
20 assay.
A substrate solution [lOOμl of a 20μg/ml solution ofthe 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
25 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150μl of a 5% solution in PBS) were transferred 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, 300μl/well) before being blotted dry.
30 Each test compound was dissolved in dimethyl sulphoxide and diluted with distilled water to give a series of dilutions (from lOOμM to O.OOlμM). Portions (25μl) of each dilution of test compound were transferred to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25 μl) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40μM) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP. Active human c-Src kinase (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. To start the reactions, aliquots (50μl) of freshly diluted enzyme were added to each well and the plates were incubated at ambient temperature for 20 minutes. The supernatant liquid in each well was discarded and the wells were washed twice with PBST. Mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology h e. product 05-321; lOOμl) was diluted by a factor of 1 :6000 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 each well was washed with PBST (x4). Horse radish peroxidase (HRP)-linked sheep anti-mouse lg antibody (Amersham Catalogue No. NXA 931 ; lOOμl) 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 (lOOμl) ofthe 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. "Blank" (no ATP) and "total" (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibition of enzyme activity, (b) In Vitro c-Src transfected NIH 3T3 fc-src 3T3) Fibroblast Proliferation Assay 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. Using a similar procedure to that described by Shalloway et al, Cell, 1987, 49, 65-73, NTH 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 104 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 O.lmg/ml streptomycin in 0.9% aqueous sodium chloride solution. The plates were incubated overnight at 37°C in a humidified (7.5% CO2 : 95% air) incubator.
Test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots ofthe 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°C in a humidified (7.5% CO2 : 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 (20μl) were added to each well to give a final concentration of lOμM). 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; 50μl) 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 (200μl per well). Anti-BrdU-Peroxidase solution (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1 : 100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered trade mark), Premier Beverages, Stafford, GB) and an aliquot (lOOμl) ofthe resultant solution was added to each well. The plates were placed on a plate shaker at ambient temperature for 90 minutes. The wells were washed with PBS (x5) to ensure removal of non-bound antibody conjugate. The plates were blotted dry and tetramethylbenzidine substrate solution (Boehringer Mannheim Catalogue No. 647 229; lOOμl) was added to each well. The plates were gently agitated on a plate shaker while the colour developed during a 10 to 20 minute period. The absorbance of the wells was measured at 690nm. The extent of inhibition of cellular proliferation at a range of concentrations of each test compound was detennined and an anti-proliferative IC50 value was derived. (c) In Vitro Microdroplet Migration Assay
This assay determines the ability of a test compoxind to inhibit the migration of adherent mammalian cell lines, for example the human tumour cell line A549.
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) ofthe 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 107 cells/ml in the medium and maintained at a temperature of 37°C. A droplet (2μl) ofthe cell/agarose mixture was transferred 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 ofthe agarose-containing droplets. Aliquots (90μl) of medium which had been cooled to 4°C were transfened 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 (lOμl) ofthe diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% CO2 : 95% air) incubator for about 48 hours.
Migration was assessed visually and the distance of migration was measured back to the edge ofthe agar droplet. A migratory inhibitory IC50 was derived by plotting the mean migration measurement against test compound concentration.
(d) In Vivo A549 Xeno graft Growth Assay
This test measures the ability of compounds to inhibit the growth ofthe A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain). A total of about 5 x 106 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. Although the pharmacological properties ofthe compounds ofthe Formula I vary with structural change as expected, in general activity possessed by compounds ofthe Formula I, may be demonstrated at the following concentrations or doses in one or more ofthe above tests (a), (b), (c) and (d):- Test (a):- IC50 in the range, for example, 0.001 - 10 μM;
Test (b):- IC50 in the range, for example, 0.01 - 20 μM;
Test (c):- activity in the range, for example, 0.1-25 μM;
Test (d):- activity in the range, for example, 1-200 mg/kg/day;.
No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested ofthe 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.
According to a further aspect ofthe invention there is provided a pharmaceutical composition which comprises a quinoline derivative ofthe Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
The compositions ofthe 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 ofthe invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, 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 ofthe total composition.
The size ofthe dose for therapeutic or prophylactic puφoses of a compound ofthe Formula I will naturally vary according to the nature and severity ofthe conditions, the age and sex ofthe animal or patient and the route of administration, according to well known principles of medicine.
In using a compound ofthe Formula I for therapeutic or prophylactic puφoses it will generally be administered so that 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. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, 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. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
According to a further aspect ofthe invention there is provided a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment ofthe human or animal body by therapy.
As stated above, it is known that 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. We have found that 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 ofthe non-receptor tyrosine-specific protein 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.
Accordingly the quinoline derivatives ofthe present invention are of value as anti- tumour agents, in particular as selective inhibitors ofthe motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth. Particularly, the quinoline derivatives ofthe present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease. Particularly, the compounds ofthe present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more ofthe 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. Further, the compounds ofthe present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition ofthe 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. Specifically, the compounds ofthe present invention are expected to be useful in the prevention or treatment of solid tumour disease.
Thus according to this aspect ofthe invention there is provided a quinoline derivative ofthe 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.
According to a further feature of this aspect ofthe invention there is provided the use of a quinoline derivative ofthe 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. According to a further feature of this aspect ofthe invention there is provided 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 ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore. According to a further aspect ofthe invention there is provided the use of a quinoline derivative ofthe 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.
According to a further feature of this aspect ofthe invention there is provided 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 ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
According to a further aspect ofthe invention there is provided the use of a quinoline derivative ofthe Fonnula 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.
According to a further feature of this aspect ofthe invention there is provided a method for the prevention or treatment ofthose 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 which comprises administering to said animal an effective amount of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
According to a further aspect ofthe invention there is provided the use of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a c-Src kinase inhibitory effect.
According to a further feature of this aspect ofthe invention there is provided a method for providing a c-Src kinase inhibitory effect which comprises administering to said animal an effective amo int of a quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
The anti-invasive treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinoline derivative ofthe invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more ofthe following categories of anti-tumour agents :-
(i) other anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (ii) 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, or, for example, one ofthe prefened antimetabolites disclosed in European Patent Application No. 562734 such as (2S)-2- {o-fluoro-p- [N- {2,7-dimethyl-4-oxo-3 ,4-dihydroquinazolin-6-ylmethyl)- N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(iii) cytostatic agents such as antioestrogens (for example tamoxifen, 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, letrazole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors ofthe epidermal growth factor family (for example the EGFR tyrosine kinase inhibitors N-(3-chloro-4-fluorophenyl)-7-methoxy- 6-(3-moφholinopropoxy)quinazolin-4-amine (ZD1839), N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (CP 358774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-moφholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors ofthe platelet-derived growth factor family and for example inhibitors ofthe hepatocyte growth factor family; and
(v) antiangiogenic agents such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inl ibitors of integrin αvβ3 function and angiostatin).
Such conjoint treatment may be achieved by way ofthe simultaneous, sequential or separate dosing ofthe individual components ofthe treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other phannaceutically-active agent within its approved dosage range.
According to this aspect ofthe invention there is provided a pharmaceutical product comprising a quinoline derivative ofthe formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
Although the compounds ofthe 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;
(ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) was performed on C18 reverse phase silica, for example on a Dynamax C-18 60 A preparative reversed-phase column;
(iv) yields, where present, are not necessarily the maximum attainable;
(v) in general, the end-products ofthe Formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Jeol JNM EX 400 spectrometer operating at a field strength of 400MHz, Varian Gemini 2000 spectrometer operating at a field strength of 300MHz or a Bruker AM300 spectrometer operating at a field strength of 300MHz]; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
(vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis;
(vii) melting points are unconected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products ofthe Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
(viii) where certain compounds were obtained as an acid-addition salt, for example a mono hydrochloride salt or a dihydrochloride salt, the stoichiometry ofthe salt was based on the number and nature ofthe basic groups in the compound, the exact stoichiometry ofthe salt was generally not determined, for example by means of elemental analysis data;
(ix) the following abbreviations have been used:- DMF N,N-dimethylformamide
DMSO dimethylsulphoxide
THF tetrahydro furan
DMA N,N-dimethylacetamide
Example 1
4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy] quinoline dihydrochloride salt
Sodium hexamethyldisilazane (1M solution in THF; 1.2 ml) was added to a solution of 7-aminobenzofuran (0.16 g) in DMF (10 ml) that had been cooled to 0°C and the mixture was stined for 5 minutes. A solution of 4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin- l-yl)propoxy] quinoline (0.225 g) in DMF (2 ml) was added and the resultant mixture was stined at ambient temperature for 24 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added. The resultant solid was washed with diethyl ether and dried. There was thus obtained the title compound (0.27 g); NMR Spectrum: (DMSOd6 and CD3CO2D) 2.33 (m, 2H), 2.85 (s, 3H), 3.24-3.89 (m, 10H), 4.0 (s, 3H), 4.33 (m, 2H), 6.84 (s, IH), 7.34 (d, IH), 7.42 (t, IH), 7.51 (s, IH), 7.69 (d, IH), 8.01 (s, IH), 8.24 (s, IH), 8.91 (s, IH); Mass Spectrum : M+H+ 472.
The 7-aminobenzofuran used as a starting material was prepared as follows :- Hydrazine hydrate (0.45 ml) was added dropwise to a stined mixture of
7-nifrobenzofuran (J. Med. Chem.. 1988, 31, 1934; 0.5 g), Raney nickel (0.02 g) and methanol (9 ml) that had been warmed to 55°C. The resultant mixture was heated to reflux for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated to give 7-aminobenzofuran (0.4 g) as an oil; NMR Spectrum: (DMSOd6) 5.25 (br s, 2H), 6.55 (d, IH), 6.8 (m, 2H), 6.9 (t, IH), 7.85 (d, IH). The 4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline used as a starting material was prepared as follows :-
A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate (83 g) and ethanol (200 ml) was stined and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The resultant mixture was filtered and the filtrate was evaporated. The residue was purified by distillation at about 60-70°C under about 0.2 mm Hg to give l-(3-hydroxypropyl)-4-methylpiperazine (17 g); NMR Spectrum: (CDC13) 1.72 (m, 2H), 2.3 (s, 3H), 2.2-2.8 (m, 8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, IH).
Diethyl azodicarboxylate (0.25 g) was added dropwise to a suspension of 4-chloro- 3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g; prepared as described in international Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), l-(3-hydroxypropyl)-4-methylpiperazine (0.202 g), triphenylphosphine (0.447 g) and methylene chloride (5 ml) and the mixture was stined at ambient temperature for 2 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using initially increasingly polar mixtures of methylene chloride and ethyl acetate followed by increasingly polar mixtures of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum to give the required starting material (0.15 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.95-2.05 (m, 2H), 2.2 (s, 3H), 2.25-2.5 (m, 10H), 4.05 (s, 3H), 4.3 (m, 2H), 7.45 (s, IH), 7.58 (s, IH), 9.0 (s, IH); Mass Spectrum: M+H+ 375 and 377.
Example 2
Using an analogous procedure to that described in Example 1, the appropriate 4-chloro-3-cyanoquinoline was reacted with the appropriate 7-aminobenzofuran to give the compounds described in Table I. Unless otherwise stated, each product was obtained as a dihydrochlori.de salt.
Table I
Figure imgf000065_0001
Figure imgf000066_0001
Notes
[1] The product gave the following characterising data; NMR Spectrum: (DMSOd6 and
CF3CO2D) 2.35 (m, 2H), 2.86 (s, 3H), 3.31-3.9 (m, 10H), 4.01 (s, 3H), 4.36 (m, 2H), 7.10 (d, IH), 7.51 (d, IH), 7.53 (s, IH), 7.79 (d, IH), 8.03 (d, IH), 8.27 (s, IH), 8.95 (s, IH); Mass
Spectrum: M+H+ 506 and 508.
The 7-amino-6-chlorobenzofuran used as a starting material was prepared as follows :- Sodium hydride (60% dispersion in mineral oil; 4.6 g) was added to a stined solution of 6-chloroanthranilic acid (18 g) in DMF (100 ml) and the mixture was stined at ambient temperature for 30 minutes. Ethyl iodide (10 ml) was added and the reaction mixture was stined at ambient temperature for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 4:1 mixture of petroleum ether (b.p. 60-80°C) and ethyl acetate as eluent. There was thus obtained ethyl 6-chloroanthranilate (15.8 g) as an oil;
NMR Spectrum: (DMSOd6) 1.3 (t, 3H), 4.3 (q, 2H), 5.7 (br s, 2H), 6.6 (d, IH), 6.7 (d, IH),
7.1 (t, IH).
A solution of sodium nitrite (4.5 g) in water (100 ml) was added dropwise during
5 minutes to a stined suspension of ethyl 6-chloroanthranilate (12.7 g) in a mixture of concentrated sulphuric acid (27.9 ml), water (38 ml) and ice (76 g). The reaction mixture was stined at 0°C for an additional 20 minutes and then heated to 120°C for 1 hour. The resultant mixture was poured into a mixture of ice and water and the product was extracted with diethyl ether. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 4:1 mixture of petroleum ether (b.p. 60-80°C) and methylene chloride as eluent. There was thus obtained ethyl 6-chloro-2-hydroxybenzoate (9.8 g); NMR Spectrum: (DMSOd6) 1.3 (t, 3H), 4.3 (q, 2H), 6.9 (d, IH), 6.95 (d, IH), 7.25 (d, IH), 10.45 (br s, IH).
Allyl bromide (5.5 ml) was added to a stirred mixture of ethyl 6-chloro- 2-hydroxybenzoate (9.8 g), l,5,7-triazabicyclo[4,4,0]dec-5-ene (10.4 g) and acetonitrile (250 ml) and the reaction mixture was stined at ambient temperature for 20 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 17:3 mixture of petroleum ether (b.p. 60-80°C) and diethyl ether as eluent. There was thus obtained ethyl 2-allyloxy-6-chlorobenzoate (10.3 g); NMR Spectrum: (DMSOd6) 1.3 (t, 3H), 4.35 (q, 2H), 4.65 (d, 2H), 5.25 (d, IH), 5.4 (d, IH), 6.0 (m, IH), 7.15 (m, 2H), 7.45 (t, IH). The material so obtained was heated to 230°C for 1 hour. The reaction product was cooled to ambient temperature and purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (b.p. 60-80°C) and methylene chloride as eluent. There was thus obtained ethyl 3-allyl-6-chloro-2-hydroxybenzoate (7.3 g); NMR Spectrum: (DMSOd6) 1.3 (t, 3H), 3.3 (m, 2H), 4.35 (q, 2H), 5.05 (m, 2H), 5.95 (m, IH), 6.95 (d, IH), 7.15 (d, IH), 9.7 (br s, IH).
The material so obtained was dissolved in methanol (62 ml) and cooled to -70°C. Ozone was bubbled through the solution for 30 minutes. Dimethyl sulfide (13 ml) was added and the reaction mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. There was thus obtained 2-(4-chloro-3-ethoxycarbonyl- 2-hydroxyphenyl)acetaldehyde which was immediately suspended in 85% phosphoric acid (18 ml) and the mixture was heated to 100°C for 1 hour. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 7:3 mixture of petroleum ether (b.p. 60-80°C) and methylene chloride as eluent. There was thus obtained ethyl 6-chlorobenzofuran-7-carboxylate (5.9 g); NMR Spectrum: (DMSOd6) 1.35 (t, 3H), 4.45 (q, 2H), 7.10 (d, IH), 7.45 (d, IH), 7.85 (d, IH), 8.15 (d, IH).
A mixture ofthe material so obtained, 35% aqueous potassium hydroxide solution (12.7 ml) and methanol (20 ml) was stined and heated to reflux for 1 hour. The methanol was evaporated and the residue was diluted with water and acidified to pHl by the addition of 6N aqueous hydrochloric acid. The resultant precipitate was isolated, washed with water and dried under vacuum over phosphorus pentoxide to give 6-chlorobenzofuran-7-carboxylic acid (4.6 g); NMR Spectrum: (DMSOd6) 7.05 (d, IH), 7.4 (d, IH), 7.75 (d, IH), 8.1 (d, IH). A mixture of a portion (1 g) ofthe material so obtained, diphenylphosphoryl azide (2.2 ml), triethylamine (1.4 ml) and tert-butanol (2.7 ml) was stined and heated to reflux for 18 hours. The mixture was allowed to cool to ambient temperature, poured into water and extracted with ethyl acetate. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on alumina using increasingly polar solvent mixtures starting with mixtures of petroleum ether and methylene chloride and ending with a 4:1 mixture of methylene chloride and ethyl acetate. There was thus obtained a mixture of 7-amino-6-chlorobenzofuran and tert-butyl 6-chlorobenzofuran-7-carbamate. A solution ofthe mixture so obtained in methylene chloride (15 ml) was cooled to 0°C and trifluoroacetic acid (1.2 ml) was added. The resultant mixture was stined for 1 hour. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 3:1 mixture of petroleum ether (b.p. 60-80°C) and methylene chloride as eluent. There was thus obtained 7-amino-6-chlorobenzofuran (0.376 g); NMR Spectrum: (DMSOd6) 5.5 (br s, 2H), 6.85 (m, 2H), 7.1 (d, IH), 7.95 (d, IH); Mass Spectrum: M+H+ 167.
[2] The product gave the following characterising data; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.27 (m, 2H), 2.82 (s, 3H), 3.11-3.79 (m, 10H), 3.99 (s, 3H), 4.3 (m, 2H), 7.41-7.54 (m, 3H), 7.62 (d, IH), 8.09 (s, IH), 8.28 (s, IH), 8.74 (s, IH); Mass Spectrum: M+H* 506 and 508. The 7-amino-3-chlorobenzofuran used as a starting material was prepared as follows :-
7-Nitrobenzofuran (1.2 g) was dissolved in glacial acetic acid (12 ml) and chlorine gas was bubbled through the solution for 30 minutes whilst the temperature ofthe reaction mixture was maintained at about 18°C. The reaction mixture was evaporated and the residue was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 60-80°C) and ethyl acetate as eluent. There was thus obtained a mixture ofthe cis- and trans- isomers of 2,3-dichloro-7-nifro-2,3-dihydrobeιιzofuran (0.77 g); Mass Spectrum: M+H1" 233. After repetition ofthe preceding reaction, cis- and trans- 2,3-dichloro-
7-nitro-2,3-dihydrobenzofuran (0.85 g) was dissolved in ethanol (35 ml) and a 0.8N aqueous potassium hydroxide solution (45.5 ml) was added. The reaction mixture was stined at ambient temperature for 1.25 hours. The mixture was concentrated by evaporation, water was added and the mixture was acidified to pH2 by the addition of 6N aqueous hydrochloric acid. The mixture was extracted with diethyl ether. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. There was thus obtained 3-chloro-7-nifroberizofuran (0.7 g) as a colorless solid; NMR Spectrum: (DMSOd6) 7.65 (t, IH), 8.15 (d, IH), 8.3 (d, IH), 8.65 (s, IH).
The material so obtained was dissolved in methanol (25 ml) was the solution was added dropwise during 5 minutes to a stined mixture of hydrazine hydrate (0.81 ml), Raney nickel (0.16 g) and methanol (30 ml) which had been heated to 60°C. The resultant reaction mixture was then heated to reflux for 5 minutes. The reaction mixture was cooled to ambient temperature and the catalyst was removed by filtration. The filtrate was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 1:1 mixture of petroleum ether (b.p. 60-80°C) and ethyl acetate as eluent. There was thus obtained 7-amino-3-chlorobenzofuran (0.41 g); NMR Spectrum: (DMSOd6) 5.5 (br s, 2H), 6.65 (d, IH), 6.75 (d, IH), 7.05 (t, IH), 8.2 (s, IH). [3] 4-Chloro-3-cyano-6-methoxy-7-(3-moφholinopropoxy)quinoline (International Patent Application WO 00/68201, page 52) was used as a starting material. The reaction mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required product as a free base. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 1.96 (m, 2H), 2.33-2.39 (m, 4H), 2.41-2.5 (m, 2H), 3.55-3.6 (m, 4H), 3.92 (s, 3H), 4.21 (t, 2H), 7.01 (d, IH), 7.24-7.29 (m, 2H), 7.33 (s, IH), 7.57 (m, IH), 7.85 (s, IH), 7.92 (d, IH), 8.37 (s, IH), 9.71 (s, IH); Mass Spectrum: M+H+ 459. [4] 4-Chloro-3-cyano-6,7-dimethoxyquinoline (international Patent Application WO 98/43960) was used as a starting material. The reaction mixture was evaporated and the residue was triturated under methylene chloride. The solid so obtained was washed with methylene chloride and diethyl ether and dried. There was thus obtained the required product as a free base. The product gave the following characterising data; NMR Spectrum:
(DMSOd6) 3.74 (s, 3H), 3.81 (s, 3H), 6.39 (m, IH), 6.64 (m, IH), 6.74 (d, IH), 6.89 (s, IH), 7.7-7.75 (m, 3H); Mass Spectrum: M-H" 362.
The 7-amino-5-fluorobenzofuran used as a starting material was prepared as follows :- Allyl bromide (6 ml) was added to a stined mixture of 4-fluoro-2-nitrophenol (10 g), l,5,7-triazabicyclo[4,4,0]dec-5-ene (11.5 g) and DMF (120 ml) and the reaction mixture was stined at ambient temperature for 20 hours. The reaction mixture was then heated to 50°C for 1.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with a IN aqueous hydrochloric acid solution, water and brine, dried over magnesium sulphate and evaporated. There was thus obtained 4-allyloxy-3-nitro-l-fluorobenzene (9.6 g); NMR Spectrum: (DMSOd6) 4.85 (d, 2H), 5.3 (d, IH), 5.45 (d, IH), 6.05 (m, IH), 7.4 (m, IH), 7.6 (m, IH), 7.9 (m, IH).
A mixture of 4-allyloxy-3 -nitro- 1-fluorobenzene (8 g) and 1,2-dichlorobenzene (14 ml) was heated to 230°C for 32 minutes in a microwave oven (651W for 3 minutes to raise the temperature to 230°C and then 300W for 29 min). The solvent was evaporated and the residue was mixed with methylene chloride (30 ml) and filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (b.p. 60-80°C) and methylene chloride as eluent. There was thus obtained 2-allyl-4-fluoro-6-nitrophenol (3.5 g) as an oil; NMR Spectrum: (DMSOdό) 3.45 (d, 2H), 5.1 (d, 2H), 6.0 (m, IH), 7.5 (m, IH), 7.75 (m, IH), 10.4 (br s, IH). The material so obtained was dissolved in methanol and cooled to -78°C. Ozone was bubbled through the solution for 30 minutes. Dimethyl sulfide (5.4 ml) was added and the reaction mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 1 : 1 mixture of petroleum ether (b.p. 60-80°C) and methylene chloride and then a 9:1 mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 2-(5-fluoro-2-hydroxy- 3-nitrophenyl)acetaldehyde which was immediately suspended in 85% phosphoric acid (18 ml) and the mixture was heated to 100°C for 1 hour. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 1 : 1 mixture of petroleum ether (b.p. 60- 80°C) and methylene chloride as eluent. There was thus obtained 5-fluoro-7-nitrobenzofuran (1.3 g); NMR Spectrum: (DMSOd6) 7.2 (d, IH), 8.05 (m, 2H), 8.35 (d, IH).
Hydrazine hydrate (0.522 ml) was added dropwise to a stirred mixture of 5-fluoro- 7-nitrobenzofuran (0.65 g), Raney nickel (0.03 g) and methanol (12 ml) that had been warmed to 55-60°C. The reaction mixture was then heated to reflux for 45 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of petroleum ether (b.p. 60-80°C) and methylene chloride as eluent. There was thus obtained 7-amino-5-fluorobenzofuran (0.206 g); NMR Spectrum: (DMSOd6) 5.65 (br s, 2H), 6.3 (m, IH), 6.55 (m, IH), 6.8 (d, IH), 7.9 (d, IH).
[5] 7-Amino-4-methoxybenzofuran (J. Med. Chem., 1995, 38, 1942-1954) was used as the appropriate 7-aminobenzofuran. The reaction product was purified by column chromatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained the required product as a free base which contained some of the conesponding 7-(3-bromopropoxy)quinoline. The material so obtained gave the following characterising data; Mass Spectrum: M+H+ 438 and 440.
The 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline used as a starting material was prepared as follows :- A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g, prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), potassium tert-butoxide (0.1 g) and DMF (8 ml) was stined at ambient temperature for 15 minutes. l-Bromo-3-choropropane (0.134 g) was added and the reaction mixture was stined at ambient temperature for 16 hours. The resultant mixture was evaporated and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and hexane. There was thus obtained 4-chloro- 7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (0.131 g containing some 4-chloro- 7-(3-bromopropoxy)-3-cyano-6-methoxyquinoline); NMR Spectrum: (DMSOd6) 2.3 (m, 2H), 3.8 (m, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 7.42 (s, IH), 7.68 (s, IH), 8.95 (s, IH); Mass Spectrum: M+H+ 311. [6] The reaction mixture was stined at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution. The precipitate was isolated and dried. There was thus obtained the required product as a free base which gave the following characterising data; NMR Spectrum: (DMSOd6) 3.93 (s, 3H), 3.95 (s, 6H), 6.84 (d, IH), 6.99 (d, IH), 7.27 (d, IH), 7.31 (s, IH), 7.87 (d, IH), 7.89 (s, IH), 8.3 (s, IH), 9.58 (s, IH); Mass Spectrum: M+H+ 376.
[7] The reaction mixture was stined at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution. The precipitate was isolated and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required product as a free base which gave the following characterising data; NMR Spectrum: (CDC13) 2.09 (m, 2H), 2.45 (m, 4H), 2.54 (t, 2H), 3.54 (s, 3H), 3.71 (m, 4H), 3.95 (s, 3H), 4.24 (t, 2H), 6.64 (d, IH), 6.89 (s, IH), 6.91 (d, IH), 6.94 (s, IH), 7.1 (d, IH), 7.35 (s, IH), 7.48 (d, IH), 8.56 (s, IH); Mass Spectrum: M+H+ 489. [8] The reaction mixture was stined at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution. The precipitate was isolated and dried. There was thus obtained the required product as a free base which gave the following characterising data; NMR Spectrum: (DMSOd6) 1.94 (m, 2H), 2.16 (s, 3H), 2.25-2.5 (m, 8H), 2.45 (t, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.18 (t, 2H), 6.83 (d, IH), 6.98 (d, IH), 7.26 (d, IH), 7.29 (s, IH), 7.85 (m, 2H), 8.3 (s, IH), 9.58 (s, IH); Mass Spectrum: M+H+ 502. [9] The reaction mixture was stined at ambient temperature for 1 hour and then poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with methylene chloride and the organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated and dried. There was thus obtained the required compound as a free base containing 1 equivalent of DMF. The material so obtained gave the following characterising data; NMR Spectrum: (CDC13) 3.62 (s, 3H), 4.04 (s, 3H), 6.72 (d, IH), 6.75 (d, IH), 6.92 (s, IH), 7.02 (s, IH), 7.4 (s, IH), 7.53 (d, IH), 7.65 (d, IH), 8.68 (s, IH); Mass Spectrum: M+H+ 472. Example 3 4-benzofuran-7-ylammo-3-cyano-6,7-dimethoxyquinoIine hydrochloride salt
A mixture of 4-chloro-3-cyano-6,7-dimethoxyquinoline (0.2 g), 7-aminobenzofuran (0.113 g) and n-propanol (15 ml) was stined and heated to 110°C for 3 hours. The yellow precipitate was isolated, washed in turn with n-propanol and diethyl ether and dried under vacuum. There was thus obtained the title compound (0.175 g); NMR Spectrum: (DMSOd6) 4.0 (s, 6H), 7.18 (s, IH), 7.36 (t, IH), 7.44 (d, IH), 7.51 (s, IH), 7.73 (d, IH), 8.0 (s, IH), 8.24 (s, IH), 8.92 (s, IH); Mass Spectrum : M+H* 346.
Example 4
Using an analogous procedure to that described in Example 3, the appropriate 4-chloro-3-cyanoquinoline was reacted with the appropriate 7-aminobenzoflxran to give the compounds described in Table H. Unless otherwise stated, each product was obtained as a hydrochloride salt. Table II
Figure imgf000073_0001
Figure imgf000073_0002
[ 1 ] The reactants were 4-chloro-3 -cyano-7-hydroxy-6-methoxyquinoline and 7-aminobenzofuran. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 4.01 (s, 3H), 7.09 (d, IH), 7.37 (t, IH), 7.44 (d, IH), 7.51 (s, IH), 7.73 (d, IH), 8.01 (s, IH), 8.26 (s, IH), 8.9 (s, IH); Mass Spectrum: M+H* 332. [2] The reactants were 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (containing some 4-chloro-7-(3-bromopropoxy)-3-cyano-6-methoxyquinoline) and 7-aminobenzofuran and the reaction mixture was heated to 110°C for 3 hours. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 2.28-2.42 (m, 2H), 3.67- 3.87 (m, 2H), 4.01 (s, 3H), 4.28^1.35 (m, 2H), 7.08 (d, IH), 7.37 (t, IH), 7.44 (d, IH), 7.54 (s, IH), 7.73 (d, IH), 7.99 (d, IH), 8.23 (s, IH), 8.94 (s, IH); Mass Spectrum : M+H* 407 and 409, 452 and 454.
[3] The reactants were 4-chloro-7-(4-chlorobutoxy)-3-cyano-6-methoxyquinoline (J. Medicinal Chemistry, 2001, 44, 3965-3977) and 7-aminobenzofuran and the reaction mixture was heated to 100°C for 5 hours. The product gave the following characterising data NMR Spectrum: (DMSOd6) 1.95 (m, 4H), 3.75 (m, 2H), 4.0 (s, 3H), 4.23 (m, 2H), 7.08 (d, IH), 7.36 (t, IH), 7.45 (d, IH), 7.56 (s, IH), 7.73 (d, IH), 7.99 (d, IH), 8.30 (s, IH), 8.93 (s, IH), 11.46 (br s, IH); Mass Spectrum: M+H* 422 and 424.
Example 5
7-[3-(4-acetylpiperazin-l-yl)propoxy]-4-benzofuran-7-ylamino-3-cyano- 6-methoxyquinoline
A mixture of 4-benzofuran-7-ylamino-7-(3-chloropropoxy)-3-cyano- 6-methoxyquinoline (0.3 g), 1-acetylpiperazine (0.27 g) and DMF (5 ml) was stined and heated to 90°C for 4 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The resultant residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.205 g); NMR Spectrum: (DMSOd6) 1.92-2.01 (m, 5H), 2.33 (t, 2H), 2.39 (t, 2H), 2.45-2.52 (m, 2H), 3.42 (m, 4H), 3.92 (s, 3H), 4.21 (t, 2H), 7.01 (d, IH), 7.27 (m, 2H), 7.32 (s, IH), 7.58 (m, IH), 7.86 (s, IH), 7.94 (s, IH), 8.38 (s, IH), 9.72 (s, IH); Mass Spectrum: M+H* 500.
Example 6
Using an analogous procedure to that described in Example 5, the appropriate 7-(ω-haloalkoxy)-3-cyanoquinoline was reacted with the appropriate amine or heterocycle to give the compounds described in Table DI. Unless otherwise stated, each compound described in Table m was obtained as a free base.
Table III
Figure imgf000075_0001
Figure imgf000075_0002
Notes
[1] l-(2-Fluoroethyl)piperazine trifluoroacetate salt was used as the heterocycle reactant.
Diisopropylethylamine was added to the reaction mixture as an additional reactant to neutralise the trifluoroacetate salt. The product gave the following characterising data; NMR
Spectrum: (DMSOd6) 1.96 (m, 2H), 2.3-2.7 (m, 12H), 3.93 (s, 3H), 4.2 (t, 2H), 4.42 (t, IH),
4.59 (t, IH), 7.0 (d, IH), 7.25-7.34 (m, 3H), 7.56 (m, IH), 7.84 (m, IH), 7.92 (s, IH), 8.37 (s,
IH), 9.71 (s, IH); Mass Spectrum: M+H* 504.
The l-(2-fluoroethyl)piperazine trifluoroacetate salt used as a starting material was prepared as follows :-
A mixture of l-(tert-butoxycarbonyl)piperazine (5 g), l-bromo-2-fluoroethane
(5.11 g), potassium carbonate (9.26 g) and acetonitrile (60 ml) was stined and heated to 60°C for 4 hours. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was evaporated. The residue was purified by column chomatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 4-(tert-butoxycarbonyl)-l-(2-fluoroethyl)piperazine as a solid (3.7 g); NMR Spectrum: (DMSOd6 and CD3CO2D) 1.37 (s, 9H), 2.34-2.4 (m, 4H), 2.56 (t, IH), 2.67 (t, IH), 3.25-3.34 (m, 4H), 4.42 (t, IH), 4.58 (t, IH).
Trifluoroacetic acid (20 ml) was added to a mixture of 4-(tert-butoxycarbonyl)- l-(2-fluoroethyl)piperazine (3.7 g), triethylsilane (8 ml) and methylene chloride (100 ml) and the resultant mixture was stined at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was isolated, washed with diethyl ether and dried. There was thus obtained l-(2-fluoroethyl)piperazine trifluoroacetic acid salt as a solid (6.0 g); NMR Spectrum: (DMSOd6 and CD3CO2D) 3.0-3.31 (m, 10H), 4.59 (m, IH), 4.75 (m, IH). [2] 1,1 -Dioxotetrahydro-4H-thiazine was used as the heterocycle reactant. The material obtained after chromatographic purification was dissolved in methylene chloride and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was washed with diethyl ether and dried. The product so obtained was the dihydrochloride salt which gave the following characterising data; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.33 (m, 2H), 3.4 (m, 2H), 3.6-3.81 (m, 8H), 4.0 (s, 3H), 4.32 (t, 2H), 7.08 (d, IH), 7.35 (t, IH), 7.44 (d, IH), 7.49 (s, IH), 7.72 (d, IH), 7.96 (d, IH), 8.19 (s, IH), 8.94 (s, IH); Mass Spectrum: M+H* 507.
[3] The reactants were 4-benzofuran-7-ylamino-7-(4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-acetylpiperazine and the reaction solvent was n-propanol. The reaction mixture was heated to 90°C for 18 hours. The resultant mixture was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The product so obtained gave the following characterising data; NMR Spectrum: (CDC13) 1.9 (m, 4H), 2.0 (s, 3H), 2.8-3.2 (m, 5H), 3.45 (m, 2H), 3.55 (m, IH), 3.9-4.0 (m, IH), 4.0 (s, 3H), 4.2 (m, 2H), 4.35 (m, IH), 7.05 (s, IH), 7.3 (t, IH), 7.45 (d, IH), 7.6 (s, IH), 7.7 (d, IH), 8.0 (d, IH), 8.4 (s, IH), 8.9 (s, IH), 11.2 (br s, IH), 11.7 (br s, IH); Mass Spectrum: M+H* 514. [4] The reactants were 4-benzofuran-7-ylamino-7-(4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-methylpiperazine and the reaction solvent was n-propanol. The reaction mixture was heated to 90°C for 18 hours. The resultant mixture was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The product so obtained gave the following characterising data; NMR Spectrum: (CDC13) 1.9 (m, 4H), 2.8 (s, 3H), 3.15-3.8 (m, 10H), 4.0 (s, 3H), 4.2 (m, 2H), 7.05 (s, IH), 7.35 (t, IH), 7.45 (d, IH), 7.6 (s, IH), 7.7 (d, IH), 8.0 (s, IH), 8.35 (s, IH), 8.9 (s, IH), 11.5 (br s, IH), 12.0 (br s, 2H); Mass Spectrum: M+H* 486.
[5] 1,2,3,6-Tetrahydropyridine was used as the heterocycle reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 105°C for 2 hours. The product gave the following characterising data; NMR Spectrum: (CDC13) 2.15 (m, 2H), 2.19 (m, 2H), 2.64 (m, 4H), 3.0 (t, 2H), 3.52 (s, 3H), 4.25 (t, 2H), 5.67 (m, IH), 5.76 (m, IH), 6.84 (d, IH), 6.89 (s, IH), 7.01 (t, IH), 7.2 (t, IH), 7.38 (s, IH), 7.45 (d, IH), 7.6 (d, IH), 8.65 (s, IH); Mass Spectrum: M+H* 455.
[6] 1 ,2,3,6-Tetrahydropyridine was used as the heterocycle reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 105°C for 4 hours. The product gave the following characterising data; NMR Spectrum: (CDC13) 1.73 (m, 2H), 1.94 (m, 2H), 2.17 (m, 2H), 2.47 (m, 2H), 2.56 (t, 2H), 2.96 (m, 2H), 3.52 (s, 3H), 4.17 (t, 2H), 5.65 (m, IH), 5.74 (m, IH), 6.82 (d, IH), 6.95 (s, IH), 7.0 (d, IH), 7.19 (t, IH), 7.26 (s, IH), 7.34 (s, IH), 7.45 (m, IH), 7.57 (d, IH), 8.62 (s, IH); Mass Spectrum: M+H* 469. [7] Piperazine was used as the amine reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 100°C for 3 hours. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 1.96 (m, 2H), 2.32 (m, 4H), 2.44 (t, 2H), 2.7 (m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 4.21 (t, 2H), 6.85 (d, IH), 7.0 (d, IH), 7.27 (d, IH), 7.31 (s, IH), 7.88 (m, 2H), 8.31 (s, IH), 9.6 (br s, IH); Mass Spectrum: M+H* 488. [8] 4-Hydroxypiperidine was used as the amine reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 100°C for 6 hours. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 1.35-1.5 (m, 2H), 1.7-1.80 (m, 2H), 1.97 (m, 2H), 2.09 (m, 2H), 2.49 (m, 2H), 2.76 (m, 2H), 3.47 (m, IH), 3.95 (s, 3H), 3.96 (s, 3H), 4.2 (t, 2H), 4.52 (s, IH), 6.85 (d, IH), 7.0 (s, IH), 7.28 (d, IH), 7.31 (s, IH), 7.88 (m, 2H), 8.32 (s, IH), 9.6 (s, IH); Mass Spectrum: M+H* 503.
Example 7 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[3-(4-prop-2-ynylpiperazin-l- yl)propoxy] quinoline
A mixture of 4-benzofuran-7-ylamino-7-(3-chloroproρoxy)-3-cyano- 6-methoxyquinoline (0.3 g), l-(2-propynyl)piperazine trifluoroacetate salt (International Patent Application WO 98/01164; 0.382 g), diisopropylethylamine (0.541 g) and 2-methoxyethanol (12 ml) was stined and heated to 100°C for 4 hours. The mixture was evaporated and the resultant residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.125 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.98-2.09 (m, 2H), 2.52-2.59 (m, 4H), 2.64-2.76 (m, 6H), 3.11 (m, IH), 3.29 (d, 2H), 3.92 (s, 3H), 4.2 (t, 2H), 7.0 (d, IH), 7.24-7.3 (m, 2H), 7.34 (s, IH), 7.56 (m, IH), 7.86 (s, IH), 7.9 (s, IH), 8.37 (s, IH); Mass Spectrum: M+H* 496.
Example 8
4-benzofuran-7-ylamino-3-cyano-6-methoxy-7-[2-(2-methoxyetlιoxy)etlιoxy]quinolme hydrochloride salt
Diisopropyl azodicarboxylate (0.414 g) was added dropwise to a stined suspension of 4-benzofuran-7-ylamino-3-cyano-7-hydroxy-6-methoxyquinoline (0.565 g), 2-(2-methoxyethoxy)ethanol (0.307 g), triphenylphosphine (0.627 g) and methylene chloride (30 ml). The mixture was stined at ambient temperature for 3 hours. The mixture was evaporated and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of ethyl acetate and methanol as eluent. The material so obtained was dissolved in methylene chloride and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added. The resultant solid was washed with diethyl ether and dried. There was thus obtained the title compound as a solid (0.19 g); NMR Spectrum: (DMSOd6) 3.26 (s, 3H), 3.48 (m, 2H), 3.61 (m, 2H), 3.83 (m, 2H), 3.94 (s, 3H), 4.28 (t, 2H), 7.01 (d, IH), 7.25-7.31 (m, 2H), 7.36 (s, IH), 7.58 (m, IH), 7.86 (s, IH), 7.92 (s, IH), 8.13 (s, IH), 8.39 (s, IH), 9.74 (s, IH); Mass Spectrum: M+H* 434. Example 9 3-cyano-4-(4-cyanobenzofuran-7-ylamino)-6,7-dimethoxyquinoline
Tris(dibenzylideneacetone)dipalladium (0.037 g) was added to a mixture of 3-cyano-4-(4-iodobenzofuran-7-ylamino)-6,7-dimethoxyquinoline (0.25 g), zinc cyanide (0.064 g), diphenylphosphinofenocene (0.038 g), zinc powder (0.014 g) and DMA (20 ml) and the resultant mixture was stined and heated to 110°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic layer was washed with water, dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.123 g); NMR Spectrum: (DMSOd6) 3.93 (s, 3H), 3.99 (s, 3H), 7.2 (d, IH), 7.29 (d, IH), 7.43 (s, IH), 7.76 (s, IH), 7.79 (d, IH), 8.19 (d, IH), 8.62 (s, IH), 10.11 (br s, IH); Mass Spectrum: M+H* 371.
Example 10
4-(benzofuran-7-ylamino)-3-cyano-5-(N-methylpiperidin-4-yloxy)quinoline dihydrochloride salt
A mixture of 4-chloro-3-cyano-5-(N-methylpiperidin-4-yloxy)quinoline (0.15 g), 7-aminobenzofuran (0.073 g) and DMF (5 ml) was stined in an ice-bath. Sodium hexamethyldisilazane (IM solution in THF; 1 ml) was added and the mixture was allowed to warm to ambient temperature over 1 hour. The solvent was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in ethanol (8 ml) and 2 equivalents of IM hydrogen chloride in diethyl ether was added. The mixture was evaporated to give the title compound as a solid (0.131 g); NMR Spectrum: (DMSOd6, warmed to 120°C) 2.27 (m, 2H), 2.43 (m, 2H), 2.65 (s, 3H), 3.21 (m, 4H), 5.07 (m, IH), 7.01 (d, IH), 7.31 (t, IH), 7.4 (m, 2H), 7.65 (m, 2H), 7.81 (t, IH), 7.94 (d, IH), 8.57 (s, IH), 10.27 (br s, IH); Mass Spectrum: M+H* 399.
The 4-chloro-3-cyano-5-( T-methylρiperidin-4-yloxy)quinoline used as a starting material was prepared as follows :-
Dimethyl sulphate (2.38 ml) was added dropwise to a stined mixture of 6-fluoroanthranilic acid (3.9 g), potassium carbonate (7.64 g) and DMF (100 ml) which had been cooled to 0°C. The reaction was allowed to warm to ambient temperature and was stined for 2 hours. The mixture was evaporated and the resulting oil was partitioned between methylene chloride and evaporated. There was thus obtained methyl 6-fluoroanthranilate (4.78 g); NMR Spectrum: (DMSOd6) 3.8 (s, 3H), 6.3 (m, IH), 6.6 (m, 3H), 7.2 (m, IH); Mass Spectrum: M+H* 170.
A mixture ofthe material so obtained and dimethylformamide dimethyl acetal (20 ml) was stined and heated to 115°C for 12 hours. The reaction mixture was allowed to cool to ambient temperature and the excess of dimethylformamide dimethyl acetal was evaporated. Methylene chloride (100 ml) was added to the residual oil and the mixture was filtered. The filtrate was evaporated to provide an orange oil (4.11 g, 71%) which was used without further purification; NMR Spectrum: (DMSOd6) 2.8 (s, 3H), 3.0 (s, 3H), 3.7 (s, 3H), 6.8 (m, 2H), 7.3 (m, IH), 7.8 (s, IH); Mass Spectrum: M+H* 225.
Whilst maintaining a reaction mixture temperature of less than -70°C, a solution in THF (6.5 ml) of a portion (0.8 g) ofthe material so obtained was added dropwise to the mixture obtained when a solution of acetonitrile (0.37 g) in THF (5 ml) was added dropwise to a solution of n-butyllithium (2.5M in hexane; 2.98 ml) in THF (3.5 ml) that had been cooled to -78°C. The resultant reaction mixture was stined at -78°C for 2 hours and at ambient temperature for a further 2 hours. The mixture was cooled to -78°C and acetic acid (3 ml) was added. The reaction mixture was stined vigorously and allowed to warm to ambient temperature over 12 hours. Water (10 ml) was added and the resultant white solid was isolated and dried. There was thus obtained 3-cyano-5-fluoro-4-hydiOxyquinoline (0.43 g); NMR Spectrum: (DMSOd6) 7.1 (m, IH), 7.4 (d, IH), 7.7 (m, IH), 8.6 (s, IH); Mass Spectrum: M+H* 189.
4-Hydroxy-N-methylpiperidine (6.08 g) was added to a stined slurry of sodium hydride (60% dispersion in oil; 4.23 g) in DMA (150 ml) and the mixture was stined at ambient temperature for 10 minutes. 3-Cyano-5-fluoro-4-hydroxyquinoline (6 g) was added in portions and the resultant mixture was stined and heated to 80°C for 6 hours. The solvent was evaporated and the residue was partitioned between water and diethyl ether. The aqueous layer was neutralised by the addition of acetic acid and the resultant mixture was evaporated. Ethanol and toluene were added to the residue and the solution was re-evaporated. This process was repeated using toluene alone. There was thus obtained 3-cyano-4-hydroxy- 5-(N-methylpiperidin-4-yloxy)quinoline as a white solid (8 g). A mixture ofthe material so obtained, phosphoryl chloride (50 ml) and acetonitrile (200 ml) was stined and heated to 95°C for 3 hours. The mixture was allowed to cool to ambient temperature. The solvent was evaporated and the gum so obtained was treated with a mixture of a concentrated aqueous ammonium hydroxide solution and ice. The mixture was 5 allowed to warm to ambient temperature and the solid so obtained was collected, washed with water and dried. There was thus obtained 4-chloro-3-cyano-5-(N-methylpiperidin- 4-yloxy)quinoline (8.07 g); NMR Spectrum: (DMSOd6) 1.9 (m, 2H), 2.06 (m, 2H), 2.27 (s, 3H), 2.36 (m, 2H), 2.71 (m, 2H), 4.72 (m, IH), 7.35 (d, IH), 7.69 (d, IH), 7.88 (t, IH), 8.99 (s, IH); Mass Spectrum: M+H* 302.
10
Example 11
4-(benzofuran-7-ylamino)-3-cyano-7-metlιoxy-5-(N-methylpiperidin-4-yloxy)quinoline dihydrochloride salt
A solution of hydrogen chloride in diethyl ether (IM, 0.36 ml) was added to a mixture
15 of 4-chloro-3-cyano-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinoline (0.12 g),
7-aminobenzofuran (0.053 g) and n-propanol (8 ml) and the resultant mixture was stined and heated to reflux for 6 hours. The mixture was cooled to ambient temperature and the precipitate was isolated and washed with n-propanol. There was thus obtained the title compound as a white solid (0.136 g); NMR Spectrum: (DMSOd6 and CD3CO D; warmed to
20 120°C) 2.21 (m, 2H), 2.38 (m, 2H), 2.7 (s, 3H), 3.23 (m, 4H), 3.99 (s, 3H), 5.11 (m, IH), 7.05 (d, 2H), 7.17 (s, IH), 7.34 (t, IH), 7.43 (d, IH), 7.68 (d, IH), 7.96 (s, IH), 8.7 (s, IH); Mass Spectrum: M+H* 429.
The 4-chloro-3-cyano-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinoline used as a starting material was prepared as follows :-
25 A mixture of 3,5-difluoroaniline (32.25 g), ethyl 2-cyano-3-ethoxyacrylate (42.25 g) and ethanol (200 ml) was heated to reflux for 2 hours. The mixture was allowed to cool to ambient temperature and the precipitate was isolated and washed with a small amount of ethanol. There was thus obtained ethyl 2-cyano-3-(3,5-difluoroanilino)acrylate as white needles (58 g); NMR Spectrum: (DMSOd6) 1.28 (m, 3H), 4.23 (m, 2H), 6.98-7.42 (m, 3H),
30 8.44 (m, IH), 10.8 (m, IH); Mass Spectrum: M+H* 253.
Ethyl 2-cyano-3-(3,5-difluoroanilino)acrylate (12.5 g) was added portionwise over 10 minutes to di(ethylene glycol) dibutyl ether (100 ml) that had been heated to reflux. The resultant mixture was heated to reflux for a further 30 minutes. The mixture was allowed to cool to ambient temperature and the precipitate was collected and washed with ethyl acetate. There was thus obtained 3-cyano-5,7-difluoro-4-hydroxyquinoline as a solid (4.24 g); NMR Spectrum: (DMSOd6) 7.21 (m, IH), 7.3 (m, IH), 8.72 (s, IH), 12.86 (br, IH); Mass Spectrum: M+H* 207.
A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (4.12 g), N-methylpiperidin-4- ol (2.6 g), potassium tert-butoxide (6.72 g) and THF (250 ml) was stined and heated at 60°C for 2 hours. The mixture was acidified to pH6 by the addition of glacial acetic acid and the resultant mixture was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained 3-cyano-7-fluoro-4-hydroxy- 5-(N-methylpiperidm-4-yloxy)quinoline as a foam (3.55 g); NMR Spectrum: (DMSOd6) 1.77 (m, 2H), 1.92 (m, 2H), 2.3 (s, 3H), 2.43 (m, 2H), 2.81 (m, 2H), 4.55 (m, IH), 6.81 (m, 2H), 8.4 (s, IH); Mass Spectrum: M+H* 302. A mixture of a portion (0.6 g) ofthe material so obtained, methanol (0.4 ml), potassium tert-butoxide (IM solution in THF; 10 ml) and DMSO (20 ml) was stined and heated at 70°C for 16 hours. The solution was cooled to ambient temperature and diluted with water (100 ml). The mixture was acidified to pH6 by the addition of dilute aqueous hydrochloric acid and filtered. The filtrate was passed through a cation exchange cartridge (Waters Oasis MCX 6 g) using water (200 ml), a 1 :1 mixture (200 ml) of methanol and water and then methanol (200 ml) as eluent. The product was eluted off the column with methanol containing triethylamine (1%). There was thus obtained 3-cyano-4-hydroxy-7-methoxy-5-(N- methylpiperidin-4-yloxy)quinoline as a white solid (0.46 g); NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 1.83 (m, 2H), 2.12 (m, 2H), 2.15 (s, 3H), 2.64 (m, 2H), 4.31 (m, IH), 6.31 (d, IH), 6.56 (d, IH), 8.16 (s, IH); Mass Spectrum: M+H* 314.
A mixture of a portion (0.313 g) ofthe material so obtained, phosphoryl chloride (1.8 ml) and acetonitrile (10 ml) was stined and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and evaporated. The gum so obtained was treated with a mixture of a concentrated aqueous ammonium hydroxide solution (25 ml) and ice. The mixture was allowed to warm to ambient temperature and the solid so obtained was collected and dried overnight. There was thus obtained 4-chloro-3-cyano-7-methoxy- 5-(N-methylpiperidin-4-yloxy)quinoline as a white solid (0.225 g); NMR Spectrum: (DMSOd6) 1.8 (m, 2H), 1.98 (m, 2H), 2.18 (s, 3H), 2.27 (m, 2H), 2.58 (m, 2H), 3.94 (s, 3H), 4.72 (m, IH), 6.92 (d, IH), 7.09 (d, IH), 8.93 (s, IH); Mass Spectrum: M+H* 332.
Example 12 4-(benzofuran-7-yIamino)-3-cyano-7-(3-morpholinopropoxy)-5-tetrahydropyran-4- yloxyquinoline dihydrochloride salt
A solution of hydrogen chloride in diethyl ether (IM, 0.37 ml) was added to a mixture of 4-chloro-3-cyano-7-(3-moφholinopropoxy)-5-tetrahydropyran-4-yloxyquinoline (0.16 g), 7-aminobenzofuran (0.073 g) and n-propanol (8 ml) and the resultant mixture was stined and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated and washed with n-propanol. There was thus obtained the title compound as a white solid (0.159 g); NMR Spectrum: (DMSOd6; wanned to 120°C) 1.86 (m, 2H), 2.11 (m, 2H), 2.32 (m, 2H), 3.1 (m, 2H), 3.33 (m, 2H), 3.49 (m, 4H), 3.80 (m, 2H), 3.88 (m, 2H), 3.96 (m, 2H), 4.33 (t, 2H), 5.13 (m, IH), 7.09 (d, 2H), 7.15 (d, IH), 7.35 (t, IH), 7.46 (d, IH), 7.72 (d, IH), 8.04 (d, IH), 8.84 (s, IH), 10.84 (s, IH), 11.45 (s, IH); Mass Spectrum: M+H* 529.
The 4-chloro-3-cyano-7-(3-moφholinopropoxy)-5-tetrahydropyran-4-yloxyquinoline used as a starting material was prepared as follows :-
A mixture of 3-cyano-5,7-difluoro-4-hydroxyqumoline (2.06 g), 4-hydroxytetrahydropyran (1.02 g), potassium tert-butoxide (IM solution in THF; 30 ml) and THF (100 ml) was stined and heated to 60°C for 1.5 hours. The mixture was acidified to pH6 by the addition of glacial acetic acid and the resultant mixture was evaporated. Aqueous sodium hydroxide solution (2M, 20 ml) was added to the residue and the mixture was filtered. The filtrate was acidified to pH5 by the addition of glacial acetic acid and the resultant oily precipitate was allowed to stand for 3 days when it had solidified fully. The solid was collected, washed with water and dried. There was thus obtained 3-cyano-7-fluoro- 4-hydroxy-5-tetrahydropyran-4-yloxyquinoline (1.8 g); NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 1.92 (m, 2H), 3.5 (m, 2H), 3.91 (m, 2H), 4.76 (m, IH), 6.81 (m, IH), 6.94 (m, IH), 8.52 (s, IH); Mass Spectrum: M+H* 289. A mixture of a portion (0.864 g) ofthe material so obtained,
4-(3-hydroxypropyl)moφholine (Bull. Soc. Chun. Fr„ 1962, 1117; 0.876 g), potassium tert-butoxide (IM solution in THF; 9 ml) in DMSO (30 ml) was stined and heated to 60°C for 8 hours. The resultant mixture was cooled to ambient temperature and diluted with water (120 ml). The mixture was acidified to pH5 by the addition of glacial acetic acid and passed through a cation exchange cartridge (Waters Oasis MCX 6 g) using water (200 ml), a 1:1 mixture (200 ml) of methanol and water and then methanol (200 ml) as eluent. The product was eluted off the column with methanol containing triethylamine (1%). The material so obtained was purified further using column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 3-cyano- 4-hydroxy-7-(3-moφholinopropoxy)-5-tetrahydropyran-4-yloxyquinoline as a white solid (0.54 g); NMR Spectrum: (DMSOd6; warmed to 120°C) 1.73 (m, 2H), 1.91 (m, 4H), 2.39 (m, 4H), 2.45 (t, 2H), 3.49 (m, 2H), 3.58 (m, 4H), 3.95 (m, 2H), 4.1 (t, 2H), 4.64 (m, IH), 6.46 (d, IH), 6.6 (d, IH), 8.24 (s, IH); Mass Spectrum: M+H* 414.
A mixture of a portion (0.5 g) ofthe material so obtained, phosphoryl chloride (2.5 ml) and acetonitrile (15 ml) was stined and heated to reflux for 4 hours. The mixture was cooled to ambient temperature and evaporated. The gum so obtained was treated with a mixture of a concentrated aqueous ammonium hydroxide solution (25 ml) and ice. The mixture was allowed to warm to ambient temperature and the solid so obtained was collected and dried overnight. There was thus obtained 4-chloro-3-cyano-7-(3-moφholinopropoxy)- 5-tetrahydropyran-4-yloxyquinoline as a white solid (0.48 g); Mass Spectrum: M+H* 432.
Example 13
Pharmaceutical compositions
The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed "Compound X"), for therapeutic or prophylactic use in humans:
(a) Tablet I mg/tablet
Compound X 100
Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0 (b) Tablet U mg/tablet
Compound X 50
Lactose Ph.Eur 223.75
Croscannellose sodium 6.0 Maize starch 15.0
Polyvinylpynolidone (5% w/v paste) 2.25
Magnesium stearate 3.0
(c) Tablet ET mg/tablet Compound X 1.0
Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0
Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0
(d) Capsule mg/capsule
Compound X 10
Lactose Ph.Eur 488.5
Magnesium 1.5
(e) Injection I (50 mg/ml)
Compound X 5.0% w/v
IM Sodium hydroxide solution 15.0% v/v
0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v
Water for injection to 100%
(f) Injection π (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v
0.1M Sodium hydroxide solution 15.0% v/v
Water for injection to 100% (g) Injection m ( 1 mg/ml, buffered to pH6)
Compound X 0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v
Water for injection to 100%
(h) Aerosol I mg/ml
Compound X 10.0 Sorbitan trioleate 13.5
Trichlorofluoromethane 910.0
Dichlorodifluoromethane 490.0
(i) Aerosol H mg/ml Compound X 0.2
Sorbitan trioleate 0.27
Trichlorofluoromethane 70.0
Dichlorodifluoromethane 280.0
Dichlorotefrafluoroethane 1094.0
(j) Aerosol m mg/ml
Compound X 2.5
Sorbitan trioleate 3.38
Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
(k) Aerosol IV mg/ml
Compound X 2.5 Soya lecithin 2.7
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6 (1) Ointment ml
Compound X 40 mg
Ethanol 300 μl
Water 300 μl l-Dodecylazacycloheptan-2-one 50 μl
Propylene glycol to 1 ml
Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)-(k) maybe used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Claims

A quinoline derivative ofthe Formula I
Figure imgf000088_0001
wherein Z is an O, S, SO, SO2, N(R2) or C(R2)2 group, wherein each R2 group, which may be the same or different, is hydrogen or (l-6C)alkyl; m is O, 1, 2, 3 or 4; each R1 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]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino,
N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group ofthe formula : cV-x1- wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl5 (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R^m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group ofthe formula :
Q2-X2- wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (l-6C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)aUcyl- (2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group ofthe formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R7), CO, CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 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 or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, 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]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)aikyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl- (l-6C)alkanesulphonylamino, or from a group ofthe formula : -X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 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 ofthe formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 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 R1 optionally bears 1 or 2 oxo or thioxo substituents; n is 0, 1, 2 or 3; and R3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, 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]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-
(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group ofthe formula :
-X6-Ru wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or (l-6C)alkyl, and R11 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amhιo-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group ofthe formula : -X7-Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R13), CO, CH(OR13), CON(R13), N(R13)CO, SO2N(R13), N(R13)SO2, C(R13)2O, C(R13)2S and N(R13)C(R13)2, wherein R13 is hydrogen or (l-6C)alkyl, and Q5 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 any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceutically-acceptable salt thereof.
2. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(l-6C)alkyl- (2-6C)alkanoylamino, or from a group ofthe formula :
Q^X1 - wherein X1 is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or X1 is a direct bond and Q1 is aryl-(l-6C)alkyl, cycloalkyl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l -6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2 or CH group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyloxy, (2-6C)alkanoylamino and N-(l-6C)alkyl-(2-6C)alkanoylamino, or from a group ofthe formula :
-X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 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-[(l-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group ofthe formula : -X4-R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)all ylamino-(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 ofthe formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 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 R1 optionally bears 1 or 2 oxo substituents.
3. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein R substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring.
4. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : Z is O orNH; m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-l -ylethoxy, 2-(l,2,4-triazol-l-yl)ethoxy, tetrahydrofuran-3 -yloxy, tetrahydropyran-4-yloxy, 2-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy,
3-pynolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3 -yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3 -piperidin-3 -ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin- 1 -ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin-l -ylethoxy and 3-homopiperazin-l-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH=CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pynolidin-2-yl, piperidin-3 -yl, piperidin-4-yl, piperazin- 1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3 -methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, 2-pynolidin- 1 -ylethyl, 3 -pynolidin- 1 -ylpropyl, 2-moφholinoethyl, 3-moφholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l -ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each 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 R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3 group, if present, is located at the 3-, 5- or 6-position ofthe benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.
5. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : Z is O or NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy,
4-diethylaminobutoxy, 2-diisopropylarninoethoxy, 3 -diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy, 3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy, 3 -(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3 -(N-methyl-N-prop-2-ynylamino)propoxy, 2-pynolidin- 1 -ylethoxy, 3-pynolidin-l -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3 -yloxy, N-methylpynolidin-3 -yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy,
3-pynolidin-2-ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro- 4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3 -yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy,
N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3 -piperidin-3 -ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,
3-(N-methylpiperidin-4-yl)propoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 4-(4-hydroxypiperidin- 1 -yl)butoxy. 2-homopiperidin- 1 -ylethoxy, 3-homopiperidin- 1 -ylpropoxy, 4-homopiperidin- 1 -ylbutoxy, 2-(l,2,3,6-tetrahydropyridin-l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)butoxy, 2-piperazin- 1 -ylethoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-piperazin- 1 -ylbutoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy, 2-(4-prop-2-ynylpiperazin- 1 -yl)ethoxy, 3 -(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 4-(4-prop-2-ynylpiperazin- 1 -yl)butoxy, 2-(4-methylsulphonylpiperazin- 1 -yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 4-(4-methylsulphonylpiperazin-l-yl)butoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy,
4-(4-acetylpiperazin- 1 -yl)butoxy, 2- [4-(2-fluoroethyl)piperazin- 1 -yl] ethoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 4-[4-(2-fluoroethyl)piperazin-l-yl]butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 4-(4-cyanomethylpiperazin- 1 -yl)butoxy, 2-(2-piperazin- 1 -ylethoxy)ethoxy, 2- [2-(4-methylpiperazin-l-yl)ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3 -tetrahydropyran-4-ylpropoxy, 2-pynol- 1 -ylethoxy, 3-pynol-l-ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 4-, 5- or 6-position ofthe benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceutically-acceptable acid-addition salt thereof.
6. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : Z is O orNH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy,
3-(N-isopropyl-N-methylamino)propoxy, 4-(N-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-(N-allyl-N-methylamino)ethoxy, 3 -(N-allyl-N-methylamino)propoxy, 2-(N-prop-2-ynylamino)ethoxy, 3-(N-prop-2-ynylamino)propoxy, 2-(N-methyl-N-prop-2-ynylamino)ethoxy, 3 -(N-methyl-N-prop-2-ynylamino)propoxy, 2-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3 -yloxy, N-methylpynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pyrrolidin-2 -ylethoxy, 3-pynolidin-2 -ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 4-moφholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3 -( 1 , 1 -dioxotetrahydro-
4H-l,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3 -yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3 -ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy,
2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3 -piperidin-3 -ylpropoxy, 3 -(N-methylpiperidin-3 -yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(K-methylpiperidin-4-yl)propoxy, 2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 4-homopiperidin- 1 -ylbutoxy, 2-piperazin- 1 -ylethoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3 -piperazin- 1 -ylpropoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-piperazin- 1 -ylbutoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 4-(4-allylpiperazin-l-yl)butoxy, 2-(4-methylsulphonylpiperazin- 1 -yl)ethoxy, 3 -(4-methylsulphonylpiperazin- 1 -yl)propoxy, 4-(4-methylsulphonylpiperazin- 1 -yl)butoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy, 3 -(4-acetylpiperazin- 1 -yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 4-(4-cyanomethylpiperazin- 1 -yl)butoxy, 2-(2-piperazin- 1 -ylethoxy)ethoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3 -tetrahydropyran-4-ylpropoxy, 2-pynol- 1 -ylethoxy, 3 -pynol- 1 -ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position ofthe benzofuran-7-yl group and is selected from fluoro, chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.
7. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : Z is NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, 2-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-(l ,1 -dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-(l,2,3,6-tetrahydropyridin- 1 -yl)butoxy, 2-(4-hydroxypiperidin- 1 -yl)ethoxy, 3 -(4-hydroxypiperidin- 1 -yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 4-(4-methylpiperazin-l-yl)butoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 3 -(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylρiperazin-l-yl)butoxy,
3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 3-, 4-, 5- or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceutically-acceptable acid-addition salt thereof.
8. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : Z is O orNH; m is 1 and the R1 group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3 -yloxy, 1 , 1 -dioxotetrahydrothien-3 -yloxy, tetrahydrothiopyran-4-yloxy, l,l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3 -yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3 -yloxy, pynolidin-3 -yloxy, N-methylpynolidin-3 -yloxy, pynolidin-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, N-(2-methoxyethyl)piperidin-4-yloxy, piperidin-3 -ylmethoxy,
N-methylpiperidin-3 -ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from the group of substituents listed immediately above and the second R1 group is located at the 7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy, 2-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-( 1 , 1 -dioxotetraliydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidm-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 2-homopiperidin- 1 -ylethoxy,
3-homopiperidin-l -ylpropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[(2S)-2-carbamoylpynolidin-l-yl]ethoxy, 2-[(2S)-2-(N-methylcarbamoyl)pynolidin-l-yl]ethoxy, 2-[(2S)-2-(N,N-dimethylcarbamoyl)pynolidin-l-yl]ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3 -methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy; and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl 5 group within a R1 substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a R1 substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 4-, 5- or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, 10 methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.
9. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : m is 2 and the first R1 group is located at the 5-position and is selected from 15 tetrahydropyran-4-yloxy, N-methylpynolidin-3 -yloxy, 4-piperidinyloxy,
N-methylpiperidm-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second R1 is located at the 7-position and is selected from methoxy, benzyloxy, 2-pynolidin- 1 -ylethoxy, 3-pynolidin-l -ylpropoxy, 2-piperidinoethoxy,
3-piperidinopropoxy, 2-moφholinoethoxy, 3-moφholinopropoxy, 2-(4-methylpiperazin- 20 l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy and 3-methylsulphonylpropoxy;
11 is 0 or n is 1 and the R3 group, if present, is located at the 6-position ofthe benzofuran-7-yl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.
25 10. A quinoline derivative ofthe Formula I as claimed in claim 1 wherein : Z is NH; m is 1 and the R1 group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from 30 tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second R1 group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 3-pynolidin-l -ylpropoxy, 3-piperidinopropoxy, 3-moφholinopropoxy, 3 -piperazin-1 -ylpropoxy and 3 -(4-methylpiperazin- l-yl)propoxy; n is 0 or n is 1 and the R group, if present, is a chloro group located at the 6-position ofthe benzofuran-7-yl group; or a pharmaceutically-acceptable acid-addition salt thereof.
11. A process for the preparation of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 which comprises :-
(a) for the production ofthose compounds ofthe Formula I wherein Z is an O, S or N(R2) group, the reaction of a quinoline ofthe Formula E
Figure imgf000100_0001
wherein L is a displaceable group and m and R1 have any ofthe meanings defined in claim 1 except that any functional group is protected if necessary, with a compound ofthe Formula m
Figure imgf000100_0002
wherein Z is O, S, or N(R2) and n, R3 and R2 have any ofthe meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means;
(b) for the production ofthose compounds ofthe Formula I wherein at least one R1 group is a group ofthe formula o x1- wherein Q1 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 X1 is an oxygen atom, the coupling of a quinoline ofthe Formula V
Figure imgf000101_0001
wherein m, R , Z, n and R have any ofthe meanings defined in claim 1 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;
(c) for the production ofthose compounds ofthe Formula I wherein an R1 group contains a (l-6C)alkoxy or substituted (l-6C)alkoxy group or a (l-6C)alkylamino or substituted (l-6C)alkylamino group, the reaction of a quinoline derivative ofthe Formula VI
Figure imgf000101_0002
wherein L is a displaceable group and Z, n and R3 have any ofthe meanings defined in claim 1 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;
(d) for the production ofthose compounds ofthe Formula I wherein R1 is an amino-substituted (l-6C)alkoxy group, the reaction of a compound ofthe Formula I wherein R1 is a halogeno-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine;
(e) for the production ofthose compounds ofthe Formula I wherein R1 is a hydroxy group, the cleavage of a quinoline derivative ofthe Formula I wherein R1 is a (l-6C)alkoxy or arylmethoxy group; (f) for the production ofthose compounds ofthe Formula I wherein an R1 group contains a primary or secondary amino group, the cleavage ofthe conesponding compound of the Formula I wherein the R1 group contains a protected primary or secondary amino group;
(g) for the production ofthose compounds ofthe Formula I wherein an R1 group 5 contains a (l-6C)alkoxy or substituted (l-6C)alkoxy group or a (l-6C)alkylamino or substituted (l-6C)alkylamino group, the alkylation of a quinoline derivative ofthe formula I wherein the R1 group contains a hydroxy group or a primary or secondary amino group as appropriate;
(h) for the production ofthose compounds ofthe Formula I wherein R1 is an
10 amino-hydroxy-disubstituted (l-6C)alkoxy group, the reaction of a compound ofthe Formula I wherein the R1 group contains an epoxy-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine;
(i) for the production ofthose compounds ofthe Formula I wherein an R1 group contains a hydroxy group, the cleavage ofthe conesponding compound ofthe Formula I
15 wherein the R1 group contains a protected hydroxy group;
(j) for the production ofthose compounds ofthe Formula I wherein Z is a SO or SO2 group, the oxidation of a compound of Formula I wherein Z is a S group; or (k) the conversion of a compound of the Formula I wherein an R or R substituent is a halogeno group into a further compound ofthe Formula I wherein the R1 or R3 substituent is a
20 cyano, ethynyl or phenyl group; and when a pharmaceutically-acceptable salt of a quinoline derivative ofthe Formula I is required, it may be obtained by reaction of said quinoline derivative with a suitable acid using a conventional procedure.
25 12. A pharmaceutical composition which comprises a quinoline derivative ofthe
Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier.
13. A quinoline derivative ofthe Formula I, or a pharmaceutically-acceptable salt thereof, 30 according to claim 1 for use in a method of treatment ofthe human or animal body by therapy.
14. The use of a quinoline derivative of the Fonnula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
15. A method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative ofthe Formula I, or a phannaceutically-acceptable salt thereof, according to claim 1.
PCT/GB2002/005493 2001-12-05 2002-12-05 Quinoline derivatives WO2003048159A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002347336A AU2002347336A1 (en) 2001-12-05 2002-12-05 Quinoline derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01403124.9 2001-12-05
EP01403124 2001-12-05

Publications (1)

Publication Number Publication Date
WO2003048159A1 true WO2003048159A1 (en) 2003-06-12

Family

ID=8182999

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/005493 WO2003048159A1 (en) 2001-12-05 2002-12-05 Quinoline derivatives

Country Status (2)

Country Link
AU (1) AU2002347336A1 (en)
WO (1) WO2003048159A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041811A1 (en) * 2002-11-02 2004-05-21 Astrazeneca Ab 3-cyano-quinoline derivatives
US6849625B2 (en) 2000-10-13 2005-02-01 Astrazeneca Ab Quinazoline derivatives with anti-tumour activity
US6939866B2 (en) 2000-10-13 2005-09-06 Astrazeneca Ab Quinazoline derivatives
JP2007501210A (en) * 2003-08-06 2007-01-25 アストラゼネカ アクチボラグ Quinazoline derivatives as angiogenesis inhibitors
US7501516B2 (en) 2001-07-16 2009-03-10 Astrazeneca Ab Quinoline derivatives and their use as tyrosine kinase inhibitors
US7884114B2 (en) 2007-08-15 2011-02-08 Glaxo Group Limited Compounds
JP2011519956A (en) * 2008-05-09 2011-07-14 ハッチソン メディファーマ エンタープライジズ リミテッド Quinazoline derivatives
US8153814B2 (en) 2009-01-12 2012-04-10 Pfizer Limited Sulfonamide derivatives
CN103819343A (en) * 2014-02-17 2014-05-28 青岛农业大学 Preparation method of compound 2-allyl-4-fluoro-6-nitrophenol and agricultural bio-activity thereof
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US9145407B2 (en) 2010-07-09 2015-09-29 Pfizer Limited Sulfonamide compounds
WO2016016894A1 (en) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Media for culturing pluripotent stem cells
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
WO2020152686A1 (en) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Culture media for pluripotent stem cells
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043960A1 (en) * 1997-04-03 1998-10-08 American Cyanamid Company Substituted 3-cyano quinolines
WO2000068201A1 (en) * 1999-05-08 2000-11-16 Astrazeneca Ab Quinoline derivatives as inhibitors of mek enzymes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043960A1 (en) * 1997-04-03 1998-10-08 American Cyanamid Company Substituted 3-cyano quinolines
WO2000068201A1 (en) * 1999-05-08 2000-11-16 Astrazeneca Ab Quinoline derivatives as inhibitors of mek enzymes

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6849625B2 (en) 2000-10-13 2005-02-01 Astrazeneca Ab Quinazoline derivatives with anti-tumour activity
US6939866B2 (en) 2000-10-13 2005-09-06 Astrazeneca Ab Quinazoline derivatives
US7501516B2 (en) 2001-07-16 2009-03-10 Astrazeneca Ab Quinoline derivatives and their use as tyrosine kinase inhibitors
US10266518B2 (en) 2002-07-15 2019-04-23 Symphony Evolution, Inc. Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
US9796704B2 (en) 2002-07-15 2017-10-24 Symphony Evolution, Inc. Substituted quinazolines as receptor-type kinase inhibitors
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
US7173136B2 (en) 2002-11-02 2007-02-06 Astrazeneca Ab 3-Cyano-quinoline derivatives
WO2004041811A1 (en) * 2002-11-02 2004-05-21 Astrazeneca Ab 3-cyano-quinoline derivatives
JP2007501210A (en) * 2003-08-06 2007-01-25 アストラゼネカ アクチボラグ Quinazoline derivatives as angiogenesis inhibitors
JP4890249B2 (en) * 2003-08-06 2012-03-07 アストラゼネカ アクチボラグ Quinazoline derivatives as angiogenesis inhibitors
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use
US7884114B2 (en) 2007-08-15 2011-02-08 Glaxo Group Limited Compounds
JP2011519956A (en) * 2008-05-09 2011-07-14 ハッチソン メディファーマ エンタープライジズ リミテッド Quinazoline derivatives
US8907101B2 (en) 2009-01-12 2014-12-09 Pfizer Limited Sulfonamide derivatives
US8541588B2 (en) 2009-01-12 2013-09-24 Pfizer Limited Sulfonamide derivatives
US8153814B2 (en) 2009-01-12 2012-04-10 Pfizer Limited Sulfonamide derivatives
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US9809549B2 (en) 2009-01-16 2017-11-07 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11091439B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11098015B2 (en) 2009-01-16 2021-08-24 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
US11091440B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N′-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer
US11433064B2 (en) 2009-08-07 2022-09-06 Exelixis, Inc. Methods of using c-Met modulators
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US9145407B2 (en) 2010-07-09 2015-09-29 Pfizer Limited Sulfonamide compounds
CN103819343B (en) * 2014-02-17 2016-03-23 青岛农业大学 The preparation method of the fluoro-6-nitrophenols of compound 2-allyl group-4-and agricultural biological activity
CN103819343A (en) * 2014-02-17 2014-05-28 青岛农业大学 Preparation method of compound 2-allyl-4-fluoro-6-nitrophenol and agricultural bio-activity thereof
WO2016016894A1 (en) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Media for culturing pluripotent stem cells
US11008341B2 (en) 2015-10-05 2021-05-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US10865214B2 (en) 2015-10-05 2020-12-15 The Trustees of Columbia University in they City of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11230558B2 (en) 2015-10-05 2022-01-25 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11261199B2 (en) 2015-10-05 2022-03-01 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
WO2020152686A1 (en) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Culture media for pluripotent stem cells

Also Published As

Publication number Publication date
AU2002347336A1 (en) 2003-06-17

Similar Documents

Publication Publication Date Title
CA2419301C (en) Quinazoline derivatives
EP1292594B1 (en) Quinazoline derivatives for the treatment of tumours
US6849625B2 (en) Quinazoline derivatives with anti-tumour activity
US20070213367A1 (en) Substituted 3-cyanoquinolines as MEK inhibitors
US7501516B2 (en) Quinoline derivatives and their use as tyrosine kinase inhibitors
AU2001278609A1 (en) Quinazoline derivatives
EP1381599B1 (en) Quinazoline derivatives
US20040063733A1 (en) Quinazoline derivatives
US20070191346A1 (en) 3-Cyano-quinoline derivatives
WO2002092578A1 (en) Quinazoline derivatives
US6939866B2 (en) Quinazoline derivatives
WO2002092577A1 (en) Quinazoline derivatives
WO2003048159A1 (en) Quinoline derivatives
WO2003047584A1 (en) Quinoline derivatives
WO2004108704A1 (en) Pyrimidin-4-yl 3-cyanoquinoline derivatives for use in the treatment of tumours
WO2004056812A1 (en) 4- (pyridin-4-ylamino) -quinazoline derivatives as anti-tumor agents
WO2004069250A1 (en) 3-cyano-quinoline derivatives as non-receptor tyrosine kinase inhibitors
WO2004108703A1 (en) Pyrazinyl 3-cyanoquinoline derivatives for use in the treatment of tumours
WO2004108707A1 (en) Pyridazinil quinazoline derivatives for use in the treatment of tumours
WO2004108710A1 (en) 4-pyrimidinyl quinazoline derivatives for use in the treatment of tumours
WO2004069249A1 (en) 3-cyano-quinoline derivatives as non-receptor tyrosine kinase inhibitors
WO2004056801A1 (en) Quinazoline derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP