WO2004108707A1 - Pyridazinil quinazoline derivatives for use in the treatment of tumours - Google Patents

Pyridazinil quinazoline derivatives for use in the treatment of tumours Download PDF

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Publication number
WO2004108707A1
WO2004108707A1 PCT/GB2004/002365 GB2004002365W WO2004108707A1 WO 2004108707 A1 WO2004108707 A1 WO 2004108707A1 GB 2004002365 W GB2004002365 W GB 2004002365W WO 2004108707 A1 WO2004108707 A1 WO 2004108707A1
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group
alkyl
ethoxy
propoxy
pyrrolidin
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PCT/GB2004/002365
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French (fr)
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Bernard Barlaam
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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 quinazoline 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 quinazoline 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 II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGF1 receptors and insulin-related receptor (IRR) and Class 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 II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGF1 receptors and insulin-related receptor (IRR)
  • tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and
  • Non-receptor tyrosine kinases include the Src family such as the Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
  • Src family of non-receptor tyrosine kinases is highly regulated in normal cells and in the absence of extracellular stimuli such kinases 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
  • 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. and Biophys. Res. Comm., 1998, 243, 503-8).
  • 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. and Biophys. Res. Comm., 1998, 243, 503-8).
  • 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,
  • an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • an inhibitor of such non-receptor tyrosine kinases should be of value as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention provide an anti-tumour effect by way of inhibition of the Src family of non-receptor tyrosine kinases, for example by inhibition of one or more of c-Src, c-Yes and c-Fyn.
  • c-Src non-receptor tyrosine kinase enzyme is involved in the control of osteoclast-driven bone resorption (Soriano et al, Cell, 1991, 64 > 693-702; Boyce et al, J. Clin. Invest.. 1992, 90, 1622-1627; Yoneda et al, J. Clin.
  • An inhibitor of c-Src non-receptor tyrosine kinase is therefore of value in the prevention and treatment of bone diseases such as osteoporosis, Paget's disease, metastatic disease in bone and tumour-induced hypercalcaemia.
  • the compounds of the present invention are also useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example hepatic cirrhosis and lung fibrosis), glomerulonephritis, multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, blood vessel diseases (for example atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
  • inflammatory diseases for example rheumatoid arthritis and inflammatory bowel disease
  • fibrotic diseases for example hepatic cirrhosis and lung fibrosis
  • glomerulonephritis for example hepatic cirrhosis and lung fibrosis
  • multiple sclerosis for example herosclerosis and restenosis
  • allergic asthma insulin-dependent diabetes
  • diabetic retinopathy diabetic nephropathy
  • the compounds of the present invention possess potent inhibitory activity against the Src family of non-receptor tyrosine kinases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory activity against other tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or 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 Idnase.
  • 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 Applications WO 02/092577, WO 02/092578 and
  • WO 02/092579 that a range of quinazoline derivatives are useful in the treatment of cancer.
  • the compounds are stated to possess inhibitory activity against the Src family of non-receptor tyrosine kinases.
  • Certain 4-substituted quinazoline derivatives including certain 4-(2-halo-5-alkoxyanilino)quinazolines.
  • a quinazoline derivative of the Formula I wherein Z is an O, S, SO, SO 2 , N(R 2 ) or C(R 2 )(R 3 ) group wherein each R 2 or R 3 group, which may be the same or different, is hydrogen or (l-8C)alkyl; m is 1, 2 or 3; each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-8C)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)
  • X 2 is a direct bond or is selected from CO and N(R 6 )CO, wherein R 6 is hydrogen or (l-8C)alkyl
  • Q 2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(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 or (l-8C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, oxo, thioxo, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(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-8C)alkyl, and Q 3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl- (l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)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-8C)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-8C)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-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a R 1 substituent optionally bears 1 or 2 oxo or thioxo substituents;
  • R a is halogeno or (l-6C)alkoxy; R is halogeno or (l-6C)alkoxy; and
  • R c is hydrogen, halogeno, (l-8C)alkyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
  • (l-8C)alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclopentylmethyl and 2-cyclopentylethyl.
  • 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.
  • An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy, cyclopentyloxy, cyclopentylmethoxy and 2-cyclobutylethoxy
  • (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino, cyclohexylamino and 2-cyclopropylethylamino
  • di-[(l-6Calkyl] amino includes dimethylamino, diethylamino, N-cyclobutyl-
  • 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 4 ) 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 (3-8C)cycloalkyl or for the (3-8C)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 (3-8C)cycloalkenyl or for the (3-8C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) when it is heteroaryl or for the heteroaryl group within a 'Q' group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, be
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 4 ) when it is heterocyclyl or for the heterocyclyl group within a 'Q' group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxo
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
  • the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
  • Suitable values for any of the 'R' groups (R , R , R and R to R ) or for various groups within an R 1 substituent include:- for halogeno fluoro, chloro, bromo and iodo; for (l-8C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl and 2-cyclopropylethyl; 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)alkynyl
  • N-methylamino and diisopropylamino for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(l-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
  • N,N-di-[(l-6C)alkyl]carbamoyl N,N-dimethylcarbamoyl, N-ethyl-
  • 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; for 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-fluoroethyl, 2-chloroethyl,
  • a suitable value for (R ⁇ m when it is a (l-3C)alkylenedioxy group or for a R 1 substituent when it contains a (l-3C)alkylenedioxy group is, for example, methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • an R 1 group forms a group of the formula Q ⁇ X 1 - and, for example, X 1 is a OC(R 4 ) linking group, it is the carbon atom, not the oxygen atom, of the OC(R 4 ) 2 linking group which is attached to the quinazoline 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- 1 -ylethyl)carbamoylethynyl.
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-8C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-8C)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
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group a substituent as defined hereinbefore, such an optional substituent may be present on a CH 2 or CH 3 group within the hereinbefore defined substituents that may be present on an aryl, heteroaryl or heterocyclyl group within a R 1 substituent.
  • R 1 includes an aryl or heteroaryl group that is substituted by a (l-8C)alkyl group
  • the (l-8C)alkyl group may be optionally substituted on a CH 2 or CH 3 group therein by one of the hereinbefore defined substituents therefor.
  • R 1 includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group
  • the terminal CH 3 group of the (l-6C)alkylamino group may be further substituted by, for example, a (l-6C)alkylsulphonyl group or a (2-6C)alkanoyl group.
  • the R 1 group may be a heteroaryl group such as a thienyl group that is substituted by a N-(2-methylsulphonylethyl)aminomethyl group such that R 1 is, for example, a 5-[N-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group.
  • R 1 includes a heterocyclyl group such as a piperidinyl or piperazinyl group that is substituted on a nitrogen atom thereof by, for example, a (2-6C)alkanoyl group
  • the terminal CH 3 group of the (2-6C)alkanoyl group may be further substituted by, for example, a di-[(l-6C)alkyl] amino group.
  • the R 1 group may be a N-(2-dimethylaminoacetyl)piperidin-4-yl group or a 4-(2-dimethylaminoacetyl)piperazin-l-yl group.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a compound of the Formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid
  • novel compounds of the invention include, for example, quinazoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R 1 , R a , R and R c has any of the meanings defined hereinbefore or in paragraphs (a) to (s) hereinafter :- (a) Z is O, S, SO, SO 2 , CH 2 or NH; (b) Z is O;
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino
  • 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-8C)alkyl
  • Q 2 -X 2 - wherein X is a direct bond or is CO or N(R )CO, wherein R is hydrogen or (l-8C)alkyl, and Q 2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(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, oxo, (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 is hydrogen or (l-8C)alkyl, and Q 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-8C)alkyl, (2-8C)alkenyl, (2- ⁇ C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l)
  • X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l- ⁇ C)alkyl, and R 8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
  • X 5 is a direct bond or is selected from O, N(R 10 ) and CO, wherein R 10 is hydrogen or (l- ⁇ C)alkyl, and Q 4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l- ⁇ C)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
  • X 1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-(l ,2,3-triazolyl)ethyl, 3-(l ,2,3-triazolyl)propyl, 2-(l ,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, tetra
  • Q 2 -X 2 - wherein X 2 is a direct bond or is CO, NHCO or N(Me)CO and Q 2 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-pi ⁇ eridinoethyl
  • X 3 is a direct bond or is selected from O, NH, CONH, NHCO and CH 2 O and Q 3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, ⁇ yrrolidin-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,
  • X 4 is a direct bond or is selected from O and NH and R 8 is 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl,
  • 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,
  • m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m is 2 and the R 1 groups, which may be the same or different, are located at the 5- and 7-positions or at the 6- and 7-positions and each R 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
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-
  • (g) m is 1 and the R 1 group is located at the 7-position or m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and each R 1 is selected from hydroxy, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 4-pyrrolidin-l -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro- 4
  • m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and the R 1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R 1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
  • R a is fluoro, chloro, bromo, methoxy or ethoxy; (1) R a is fluoro, chloro or bromo; (m) R a is chloro or bromo;
  • R is fluoro, chloro, bromo, methoxy or ethoxy; (o) R is methoxy or ethoxy; (p) R is methoxy;
  • R c is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy;
  • R is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy; and
  • R c is hydrogen.
  • quinazoline derivatives of the Formula I or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R 1 , R a , R and R c has any of the meanings defined hereinbefore provided that :-
  • R 1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinazoline ring i.e. the 2- and ⁇ -positions remain unsubstituted; or
  • R 1 substituents may only be located at the 6- and/or 7-positions on the quinazoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
  • the compounds of the present invention possess potent inhibitory activity against the Src family of non-receptor tyrosine kinases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory ativity against other tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase.
  • the receptor tyrosine kinases for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase.
  • certain compounds of the present invention possess substantially better potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, than against EGF receptor tyrosine kinase or 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 EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase.
  • R is halogeno and R is methoxy.
  • a particular compound of the invention is a quinazoline 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 the R 1 groups, which may be the same or different, are located at the 5- and 7-positions or at the 6- and 7-positions and each R 1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopenty
  • 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
  • R a is fluoro, chloro, bromo, methoxy or ethoxy
  • R is fluoro, chloro, bromo, methoxy or ethoxy
  • R° is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the
  • Z is NH; m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and the R 1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R 1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pyrrolidin- 1 -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,
  • R a is chloro or bromo
  • R is methoxy or ethoxy
  • R c is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline 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-l-ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 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, 2-piperidin-3 -ylethoxy, 2-(N
  • R is chloro or bromo
  • R is methoxy
  • R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline 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- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpipe
  • R is methoxy
  • R c is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Formula I wherein : Z is NH; m is 2 and the R 1 groups, which may be the same or different, are located at the 5- and
  • the R 1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R 1 group at the 7-position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, 2-pyrrolidin-2-ylethoxy , 3 -pyrrolidin-2-ylylbutoxy
  • R a is fluoro, chloro, bromo, methoxy or ethoxy
  • R is fluoro, chloro, bromo, methoxy or ethoxy
  • R c is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Formula I wherein :
  • Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, l,l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, 1 , l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-piperid
  • N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from the group of substituents listed immediately above and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l -ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3
  • R a is fluoro, chloro or bromo
  • R is methoxy or ethoxy
  • R c is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Formula I wherein :
  • Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from propoxy, isopropoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy,
  • R is methoxy
  • R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Formula I wherein :
  • Z is NH; m is 1 and the R 1 group is located at the 5-position and is selected from propoxy, isopropoxy, tetrahydro ⁇ yran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from the group of substituents listed immediately above, and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl] ethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3 -morpholinopropoxy , 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,
  • R a is chloro
  • R is methoxy
  • R c is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the
  • Z is NH; m is 2 and the first R 1 group is located at the 5-position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl
  • R is methoxy
  • R c is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a quinazoline 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 quinazoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, Z, m, R 1 , R a , R and R c 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(R 2 ) group, the reaction of a
  • 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 HI
  • Z is O, S, or N(R 2 ) and R 2 , R a , R and R c have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • a suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0jundec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydr
  • the quinazoline 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 quinazoline derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L wherein L has the meaning defined hereinbefore.
  • the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0jundec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diaza
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxyme hyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl) ; tri (lower alkyl
  • 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.
  • groups such as 2-nitrobenzyloxycarbonyl
  • hydrogenation for groups such as benzyl
  • photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • the reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2 nd Edition, by T. Green et al., also published by John Wiley & Son, for general guidance on protecting groups.
  • Quinazoline starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 01/94341 and WO 02/16352.
  • a l,4-dihydroquinolin-4-one of Formula IV may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 01/94341 and WO 02/16352.
  • a l,4-dihydroquinolin-4-one of Formula IV may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 01/94341 and WO 02/16352.
  • m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.
  • the 4-chloroquinazoline so obtained may be converted, if required, into a 4-pentafluorophenoxyquinazoline 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.
  • 4-Aminopyridazine starting materials (Formula HI, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples.
  • Corresponding 4-hydroxy- and 4-mercaptopyridazine starting materials (Formula HI, when Z is O or S respectively) may be obtained by conventional procedures.
  • R 1 group is a halogeno-(l-6C)alkoxy group or a group of the formula c ⁇ x 1 - wherein Q 1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group or an optionally substituted alkyl group and X 1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinazoline of the Formula V
  • m, R 1 , Z, R a , R and R c have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means.
  • a suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to l ⁇ 0°C, preferably in the range 60 to 120°C.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • a pharmaceutically-acceptable salt of a quinazoline derivative of the Formula I for example an acid-addition salt, it may be obtained by, for example, reaction of said quinazoline derivative with a suitable acid using a conventional procedure.
  • the following assays can be used to measure the effects of the compounds of the present invention as c-Src tyrosine Idnase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue.
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src Idnase was assessed using a conventional Elisa assay.
  • a substrate solution [lOO ⁇ l of a 20 ⁇ g/ml solution of the polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azidej was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were 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.
  • PBS Bovine Serum Albumin
  • 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 ( ⁇ OmM) containing adenosine-5'-tri ⁇ hosphate (ATP; 40 ⁇ M) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
  • ⁇ OmM aqueous magnesium chloride solution
  • ATP adenosine-5'-tri ⁇ hosphate
  • 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.
  • HRP horse radish peroxidase
  • Ig antibody (Amersham Catalogue No. NXA 931; lOO ⁇ l) was diluted by a factor of 1:500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).
  • a PCSB capsule (Sigma Catalogue No. P4922) was dissolved in distilled water
  • phosphate-citrate pH5 buffer 50mM containing 0.03% sodium perborate.
  • An aliquot (50ml) of this buffer was mixed with a 50mg tablet of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; Boehringer Catalogue No. 1204 521). Aliquots (lOO ⁇ l) of the resultant solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0.
  • This assay determined the ability of a test compound to inhibit the proliferation of National Institute of Health (NTH) mouse 3T3 fibroblast cells that had been stably-transfected with an activating mutant (Y530F) of human c-Src.
  • 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 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
  • test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots of the stock solution were diluted with the DMEM medium described above and added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which test compound was not added were included on each plate. The plates were incubated overnight at 37°C in a humidified (7.5% CO 2 : 95% air) incubator. BrdU labelling reagent (Boehringer Mannheim Catalogue No.
  • This assay determines the ability of a test compound 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) of the agar solution was added to RPMI medium (10 ml) immediately prior to its use.
  • A549 cells (Accession No. ATCC CCLl ⁇ 5) were suspended at a concentration of 2 x 10 7 cells/ml in the medium and maintained at a temperature of 37°C.
  • a droplet (2 ⁇ l) of the cell/agarose mixture was 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 of the agarose-containing droplets. Aliquots (90 ⁇ l) of medium which had been cooled to 4°C were transferred into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (lO ⁇ l) of the diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% CO 2 : 95% air) incubator for about 4 ⁇ 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 of the A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain).
  • a total of about 5 x 10 6 A549 cells in matrigel (Beckton Dickinson Catalogue No. 40234) were injected subcutaneously into the left flank of each test mouse and the resultant tumours were allowed to grow for about 14 days. Tumour size was measured twice weekly using callipers and a theoretical volume was calculated. Animals were selected to provide control and treatment groups of approximately equal average tumour volume.
  • Test compounds were prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth was assessed.
  • Test (d) - activity in the range, for example, 1-200 mg/kg/day.
  • the quinazoline compound disclosed within Example 2 possesses the following activity :- Test (a), IC 50 approximately 0.04 ⁇ M.
  • Test (d) No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.
  • compositions of the invention which comprises a quinazoline derivative of the Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
  • the compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository
  • 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 9 ⁇ percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a compound of the Formula I for therapeutic or prophylactic purposes 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.
  • 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 preferred, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • a quinazoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the 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 quinazoline derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the non-receptor tyrosine-specific protein 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 quinazoline derivatives of the present invention are of value as anti-tumour agents, in particular as selective inhibitors of the motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • the quinazoline derivatives of the present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more of the multiple non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of the enzyme c-Src, i.e. the compounds may be used to produce a c-Src enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention are expected to be useful in the prevention or treatment of solid tumour disease.
  • a quinazoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
  • a 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 quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinazoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • a method for 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 which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the quinazoline derivative of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of uroldnase 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
  • 6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZDl ⁇ 39), N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32 ⁇ 56 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin v ⁇ 3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immuno therapy approaches including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore and an additional anti -tumour agent as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of c-Src. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
  • the 4-amino-3-chloiO-6-methoxypyridazine that was used as a starting material was prepared as follows :-
  • the solid was purified by column chromatography using a Waters Symmetry column (C18 reversed-phase, 5 microns, 20 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 5% methanol and 1% acetic acid) and acetonitrile as eluent.

Abstract

The invention concerns quinazoline derivatives of Formula (I) wherein Z is an O, S, SO, SO2, N(R2) or C(R2)(R3) group wherein each R2 or R3 group is hydrogen or (1-8C)alkyl, m is 1, 2 or 3, each R1 group has any of the meanings defined in the description, Ra is halogeno or (1-6C)alkoxy, Rb is halogeno or (1-6C)alkoxy, and Rc is hydrogen, halogeno, (1-8C)alkyl or (1-6C)alkoxy, or a pharmaceutically-acceptable salt thereof; 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

OUINAZOLINE DERIVATIVES
The invention concerns certain novel quinazoline 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 quinazoline 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. In 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 pρ60v~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, TGF , Neu and erbB receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGF1 receptors and insulin-related receptor (IRR) and Class HI receptor tyrosine kinases comprising 5 the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGFα, 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 is highly regulated in normal cells and in the absence of extracellular stimuli such kinases 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, 11, 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 of Cancer, 1992, 28,
30 372-7), 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. and Biophys. 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, IT, 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 inhibitor 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 quinazoline 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. In particular, it is believed that the compounds of the present invention provide an anti-tumour effect by way of inhibition of the Src family of non-receptor tyrosine kinases, for example by inhibition of one or more of c-Src, c-Yes and c-Fyn. 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), glomerulonephritis, multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, blood vessel diseases (for example atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
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 Idnase. 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 Applications WO 02/092577, WO 02/092578 and
WO 02/092579 that a range of quinazoline derivatives are useful in the treatment of cancer. The compounds are stated to possess inhibitory activity against the Src family of non-receptor tyrosine kinases. There is the disclosure therein of certain 4-substituted quinazoline derivatives including certain 4-(2-halo-5-alkoxyanilino)quinazolines. There is no disclosure therein of any 4-(pyridazinylamino)quinazoline derivatives.
According to one aspect of the invention there is provided a quinazoline derivative of the Formula I
Figure imgf000006_0001
wherein Z is an O, S, SO, SO2, N(R2) or C(R2)(R3) group wherein each R2 or R3 group, which may be the same or different, is hydrogen or (l-8C)alkyl; m is 1, 2 or 3; 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-8C)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 : CAX1 - 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(R )SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-8C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl- (l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)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-8C)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 X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (l-8C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(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 or (l-8C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, oxo, thioxo, (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)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di- [( 1 -6C)alkyl] sulphamoyl, ( 1 -6C)alkanesulphonylamino and N-( 1 -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-8C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl- (l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)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 R1 substituent 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-8C)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, N-(l-6C)alkylsulphamoyl,
N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino, N-(l-6C)alkyl- (l-6C)alkanesulphonylamino and (l-3C)alkylenedioxy, 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-8C)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-8C)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-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo or thioxo substituents;
Ra is halogeno or (l-6C)alkoxy; R is halogeno or (l-6C)alkoxy; and
Rc is hydrogen, halogeno, (l-8C)alkyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
In this specification the generic term "(l-8C)alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-8C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and also (3-6C)cycloalkyl-(l-2C)alkyl groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclopentylmethyl and 2-cyclopentylethyl. 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, cyclopentyloxy, cyclopentylmethoxy and 2-cyclobutylethoxy, (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino, cyclohexylamino and 2-cyclopropylethylamino, and di-[(l-6Calkyl] amino includes dimethylamino, diethylamino, N-cyclobutyl-
N-methylamino, N-cyclohexyl-N-ethylamino and N-cyclopentylmethyl-N-methylamino. 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 may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. 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 Q4) 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 (3-8C)cycloalkyl or for the (3-8C)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 (3-8C)cycloalkenyl or for the (3-8C)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 Q4) 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 Q4) 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, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, l,l-dioxotetrahydro-4H-l,4-thiazinyl, 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, (3-8C)cycloalkyl-(l-6C)alkyl, (3-8C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
In structural Formula I, it is to be understood that there is a hydrogen atom at the 2-position on the quinazoline 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 quinazoline ring i.e. that the 2-position remains unsubstituted. f π C 1 i n Suitable values for any of the 'R' groups (R , R , R and R to R ) or for various groups within an R1 substituent include:- for halogeno fluoro, chloro, bromo and iodo; for (l-8C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl and 2-cyclopropylethyl; 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-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl ;
5 for N,N-di-[(l-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-
N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl and isobutyryl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; 10 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; for N-(l-6C)alkyl-(l-6C)alkanesulphonylamino: N-methylmethanesulphonylamino and
15 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; for N-(l-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido;
20 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,
2-ethylaminoethyl and 3-methylaminoρroρyl; 25 for di-[(l-6C)alkyl]amino-(l-6C)alkyl: dimethylaminomethyl, diethylaminomethyl,
1-dimethylaminoethyl, 2-dimethylaminoethyl and
3 -dimethyl aminopropyl ; for halogeno-(l-6C)alkyl: chloromethyl, 2-fluoroethyl, 2-chloroethyl,
1-chloroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
30 3-fluoropropyl, 3-chloropropyl, 3,3-difluoropropyl and 3,3,3-trifluoropropyl; 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 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 (R^m when it is a (l-3C)alkylenedioxy group or for a R1 substituent when it contains a (l-3C)alkylenedioxy group is, for example, methylenedioxy, ethylidenedioxy, isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
When, as defined hereinbefore, an R1 group forms a group of the formula Q^X1- and, for example, X1 is a OC(R4) linking group, it is the carbon atom, not the oxygen atom, of the OC(R4)2 linking group which is attached to the quinazoline ring and the oxygen atom is attached to the Q1 group. Similarly, when, for example a CH3 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 attachment of the group of the formula Q -X"-.
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 a heterocyclyl-(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- 1 -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-8C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-8C)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-morpholinopropylamino, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkylamino groups such as 2-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-mo holinopropylaminomethyl.
It is to be understood that when, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent as defined hereinbefore, such an optional substituent may be present on a CH2 or CH3 group within the hereinbefore defined substituents that may be present on an aryl, heteroaryl or heterocyclyl group within a R1 substituent. For example, if R1 includes an aryl or heteroaryl group that is substituted by a (l-8C)alkyl group, the (l-8C)alkyl group may be optionally substituted on a CH2 or CH3 group therein by one of the hereinbefore defined substituents therefor. For example, if R1 includes a heteroaryl group that is substituted by, for example, a (l-6C)alkylamino-(l-6C)alkyl group, the terminal CH3 group of the (l-6C)alkylamino group may be further substituted by, for example, a (l-6C)alkylsulphonyl group or a (2-6C)alkanoyl group. For example, the R1 group may be a heteroaryl group such as a thienyl group that is substituted by a N-(2-methylsulphonylethyl)aminomethyl group such that R1 is, for example, a 5-[N-(2-methylsulphonylethyl)aminomethyl]thien-2-yl group. Further, for example, if R1 includes a heterocyclyl group such as a piperidinyl or piperazinyl group that is substituted on a nitrogen atom thereof by, for example, a (2-6C)alkanoyl group, the terminal CH3 group of the (2-6C)alkanoyl group may be further substituted by, for example, a di-[(l-6C)alkyl] amino group. For example, the R1 group may be a N-(2-dimethylaminoacetyl)piperidin-4-yl group or a 4-(2-dimethylaminoacetyl)piperazin-l-yl group.
A suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R1, Ra, R and Rc has any of the meanings defined hereinbefore or in paragraphs (a) to (s) 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-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)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-8C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-8C)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-8C)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 X is a direct bond or is CO or N(R )CO, wherein R is hydrogen or (l-8C)alkyl, and Q2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(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, oxo, (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 R is hydrogen or (l-8C)alkyl, and Q 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-8C)alkyl, (2-8C)alkenyl, (2-δC)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl and (l-3C)alkylenedioxy, 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-δC)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, 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-δC)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-δC)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 :
Q^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)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, 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-moφholinopropyl, 4-morpholinobutyl, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethyl, 3-(l , 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-( 1 ,2,3 ,6-tetrahydropyridin- l-yl)ethyl, 3-(l,2,3,6-tetrahydropyridin-l-yl)propyl, 4-(l,2,3,6-tetrahydropyridin-l-yl)butyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl, 4-piperazin-l-ylbutyl, 2-homopiperazin- 1-ylethyl or 3-homopiperazin-l-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 CH = 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-piρeridinoethyl, 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, oxo, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl- N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula :
-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, ρyrrolidin-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, acetyl, propionyl, isobutyryl, methylenedioxy, ethylidendioxy and isopropylidenedioxy, 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-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl,
3,3,3-trifluoropropyl, 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;
(f) m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and the R1 groups, which may be the same or different, are located at the 5- and 7-positions or at the 6- and 7-positions and each R 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- 1 -ylethoxy,
3 -imidazol-1 -ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-( 1 ,2,4-triazol- 1 -yl)ethoxy, 3 -( 1 ,2,4-triazol- 1 -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, morpholino, 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-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)ethoxy 3-( 1 ,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- 1 -ylethoxy, 3 -homopiperazin- 1 -ylpropoxy, 2-pyrrolidin- 1 -ylethylamino, 3-pyrrolidin-l-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-( 1 , 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- 1 -ylethylamino , 3 -piperazin- 1 -ylpropylamino,
4-piperazin-l-ylbutylamino, 2-homopiperazin-l -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-methylaminobutyl, dimethylaminomethyl, 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, oxo, 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, methoxy, ethoxy, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylenedioxy, ethylidendioxy and isopropylidenedioxy, 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, ethylsulphonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminoρropyl, 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 δ 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;
(g) m is 1 and the R1 group is located at the 7-position or m is 2 and the R1 groups, which may be the same or different, are located at the 6- and 7-positions and each R1 is selected from hydroxy, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 4-pyrrolidin-l -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro- 4H- 1 ,4-thiazin-4-yl)ethoxy, 3-(l , l-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-l -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 3-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)propoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin- 1 -ylpropoxy, 2-homopiperazin- 1 -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, 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, arnino, methyl, ethyl, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (h) m is 1 and the R1 group is located at the 5-position or m is 2 and the R1 groups, which may be the same or different, are located at the 5- and 7-positions and each R1 is selected from hydroxy, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin-l -ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l , l-dioxotetrahydro-4H-l ,4-thiazin-4-yl)ethoxy, 3-(l ,l-dioxotetrahydro-4H-l ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-l -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy,
3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy, 3 -homopiperazin-1 -ylpropoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, 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 CH 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(i) m is 2 and the R1 groups, which may be the same or different, are located at the 6- and 7-positions and the R1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 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-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 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, 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, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy and 3 -homopiperazin-1 -ylpropoxy, 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (j) m is 2 and the R1 groups, which may be the same or different, are located at the 5- and 7-positions and the R1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R1 group at the 7-position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3 -morpholinopropoxy, 4-morpholinobutoxy, 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, 4-piperidinobutoxy, 2-piperidin-3 -ylethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-l -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 3-(l ,2,3,6-tetrahydropyridin- l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy and 3-homopiperazin-l -ylpropoxy, and wherein any CH 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(k) Ra is fluoro, chloro, bromo, methoxy or ethoxy; (1) Ra is fluoro, chloro or bromo; (m) Ra is chloro or bromo;
(n) R is fluoro, chloro, bromo, methoxy or ethoxy; (o) R is methoxy or ethoxy; (p) R is methoxy;
(q) Rc is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy; (r) R is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy; and (s) Rc is hydrogen. Further particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R1, Ra, R and Rc 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 quinazoline ring i.e. the 2- and δ-positions remain unsubstituted; or
(B) R1 substituents may only be located at the 6- and/or 7-positions on the quinazoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
As stated hereinbefore, 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 ativity 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 EGF receptor tyrosine kinase or 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 EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase.
According to this aspect of the invention, there are provided quinazoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R1 and Rc has any of the meanings defined hereinbefore and :- a b
R is halogeno and R is methoxy.
A particular compound of the invention is a quinazoline 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 the R1 groups, which may be the same or different, are located at the 5- and 7-positions or at the 6- and 7-positions and each 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- 1 -ylethoxy, 3-imidazol- 1 -ylpropoxy, 2-( 1 ,2,3-triazol- 1 -yl)ethoxy, 3-( 1 ,2,3-triazol- 1 -yl)propoxy, 2-(l,2,4-triazol-l-yι)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, morpholino, 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-( 1 ,2,3 ,6-tetrahydropyridin- 1 -yl)ethoxy 3-(l ,2,3 ,6-tetrahydropyridin- 1 -yl)propoxy, 4-( 1 ,2,3 ,6-tetrahydropyridin- l-yl)butoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin- 1 -ylethoxy, 3 -homopiperazin- 1 -ylpropoxy, 2-pyrrolidin- 1 -ylethylamino , 3-pyrrolidin-l-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,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethylamino, 3-(l,l-dioxotetrahydro- 4H-l,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-ylethyl amino , 2-homopiperidin- 1 -ylethylamino ,
3 -homopiperidin- 1 -ylpropylamino, 2-piperazin- 1 -ylethylamino, 3-piperazin- 1 -ylpropylamino, 4-piperazin-l-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 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-methylaminobutyl, dimethylaminomethyl, 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- 1 -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 CH or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, oxo, 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, methoxy, ethoxy, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylenedioxy, ethylidendioxy and isopropylidenedioxy, 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, ethylsulphonyl, acetyl, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 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 δ 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;
Ra is fluoro, chloro, bromo, methoxy or ethoxy;
R is fluoro, chloro, bromo, methoxy or ethoxy; and
R° is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof. A further particular compound of the invention is a quinazoline derivative of the
Formula I wherein :
Z is NH; m is 2 and the R1 groups, which may be the same or different, are located at the 6- and 7-positions and the R1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 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-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 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, 4-piρeridinobutoxy, 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-l -ylpropoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy and 3-homopiperazin-l-ylpropoxy, 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
Ra is chloro or bromo;
R is methoxy or ethoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinazoline 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-l-ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 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, 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- 1 -yl)propoxy, 2-(4-hydroxypiperidin- 1 -yl)ethoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 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- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 2-(4-prop-2-ynylpiperazin- 1 -yl)ethoxy , 3 -(4-prop-2-ynylpiperazin- 1 -yl)propoxy , 2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-isobutyrylpiperazin- 1 -yl)ethoxy, 3-(4-isobutyrylpiperazin- 1 -yl)propoxy, 4-(4-isobutyrylpiperazin-l-yl)butoxy, 2-[4-(2-fluoroethyl)piperazin-l-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethoxy, 3- [4-(2,2,2-trifluoroethyl)piperazin- 1 -yljpropoxy, 2-(4-cyanomethylpiperazin- 1 -yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; and
R is chloro or bromo;
R is methoxy; and
R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinazoline 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- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy, 2-(4-isobutyrylpiperazin- 1 -yl)ethoxy, 3-(4-isobutyrylpiperazin- 1 -yl)propoxy, 2- [4-(2,2,2-trifluoroethyl)piperazin- 1 -yljethoxy and 3- [4-(2,2,2-trifluoroethyl)piperazin- 1 -yljpropoxy; and Ra is chloro;
R is methoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinazoline derivative of the Formula I wherein : Z is NH; m is 2 and the R1 groups, which may be the same or different, are located at the 5- and
7-positions and the R1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R1 group at the 7-position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, 2-pyrrolidin-2-ylethoxy , 3 -pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 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, 4-piperidinobutoxy, 2-piperidin-3 -ylethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 3-( 1 ,2,3 ,6-tetrahydropyridin- l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy and 3 -homopiperazin-1 -ylpropoxy, 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
Ra is fluoro, chloro, bromo, methoxy or ethoxy; R is fluoro, chloro, bromo, methoxy or ethoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinazoline 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 ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, l,l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, 1 , l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 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 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l -ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 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-ρiperidinopropoxy, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3-ρiperidin-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- 1 -yl)propoxy, 2-(4-hydroxypiperidin- 1 -yl)ethoxy, 3-(4-hydroxypiperidin- 1 -yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy,
2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- l-yl)butoxy, 2-(4-allylpiperazin-l-yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-methylsulphonylpiperazin- 1 -yl)ethoxy, 3-(4-methylsulphonylpiperazin- 1 -yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-isobutyrylpiperazin- 1 -yl)ethoxy, 3-(4-isobutyrylpiperazin- 1 -yl)propoxy, 4-(4-isobutyrylpiperazin-l-yl)butoxy, 2-[4-(2-fluoroethyl)piperazin-l-yl]ethoxy,
3-[4-(2-fluoroethyl)piperazin-l-yljpropoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethoxy, 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxyjethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy;
Ra is fluoro, chloro or bromo;
R is methoxy or ethoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinazoline 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 propoxy, isopropoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy,
N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin- 3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin- 4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 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 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 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 , 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-( 1,2,3, 6-tetrahydropyridin-l-yl)ethoxy, 3-(l,2,3,6-tetrahydropyridin- l-yl)propoxy, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- 1 -yl)butoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-isobutyrylpiperazin- 1 -yl)ethoxy, 3-(4-isobutyrylpiperazin- 1 -yl)propoxy, 4-(4-isobutyrylpiperazin- 1 -yl)butoxy, 2- [4-(2-fluoroethyl)piperazin- 1 -yljethoxy, 3-[4-(2-fluoroethyl)piperazin-l-yl]propoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yljethoxy, 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3 -(4-cyanomethylpiperazin- 1 -yl)propoxy, 2- [2-(4-methylpiperazin- 1 -yl)ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; Ra is chloro or bromo;
R is methoxy; and
R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular compound of the invention is a quinazoline 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 propoxy, isopropoxy, tetrahydroρyran-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 the group of substituents listed immediately above, and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl] ethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3 -morpholinopropoxy , 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, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1-ylbutoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy,
2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin- 1 -yl)propoxy, 2-(4-prop-2-ynylpiperazin- 1 -yl)ethoxy, 3-(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 2-(4-acetylpiperazin- 1 -yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 2-(4-isobutyrylpiperazin-l-yl)ethoxy, 3-(4-isobutyrylpiperazin-l-yl)propoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yljethoxy and 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]propoxy; and
Ra is chloro;
R is methoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof. A further particular compound of the invention is a quinazoline derivative of the
Formula I wherein :
Z is NH; m is 2 and the first R1 group is located at the 5-position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 2-(4-isobutyrylpiperazin-l-yl)ethoxy, 3-(4-isobutyrylpiperazin-l-yl)propoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethoxy and 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yljpropoxy; and Ra is chloro;
R is methoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
Particular compounds of the invention are, for example, the quinazoline derivatives of the Formula I that are disclosed within the Examples hereinafter.
A quinazoline 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 quinazoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, Z, m, R1, Ra, R and Rc 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
Figure imgf000036_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 HI
Figure imgf000036_0002
wherein Z is O, S, or N(R2) and R2, Ra, R and Rc 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, morpholine, N-methylmorpholine or diazabicyclo[5.4.0jundec-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 quinazoline 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 quinazoline 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, morpholine, N-methylmorpholine or diazabicyclo[5.4.0jundec-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 may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). 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, propionyloxyme hyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl) ; tri (lower alkyl)silyl-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.
Quinazoline starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 01/94341 and WO 02/16352. For example, a l,4-dihydroquinolin-4-one of Formula IV
Figure imgf000039_0001
wherein m and R1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means. The 4-chloroquinazoline so obtained may be converted, if required, into a 4-pentafluorophenoxyquinazoline 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.
4-Aminopyridazine starting materials (Formula HI, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples. Corresponding 4-hydroxy- and 4-mercaptopyridazine starting materials (Formula HI, when Z is O or S respectively) may be obtained by conventional procedures. (b) For the production of those compounds of the Formula I wherein at least one R1 group is a halogeno-(l-6C)alkoxy group or a group of the formula cΛx1- 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 quinazoline of the Formula V
Figure imgf000040_0001
wherein m, R1, Z, Ra, R and Rc 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 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 reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a quinazoline derivative of the Formula VI
Figure imgf000041_0001
wherein L is a displaceable group as defined hereinbefore and Z, Ra, R and Rc have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or arnine 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 of those compounds of the Formula I wherein R1 is an amino-substituted (l-6C)alkoxy group (such as a 2-(4-methylpiperazin-l-yl)ethoxy or
3-dimethylaminopropoxy group), the reaction of a compound of the Formula I wherein R1 is a halogeno-substituted (l-6C)alkoxy group with a nitrogen-containing heterocyclyl compound or an appropriate arnine.
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 lδ0°C, preferably in the range 60 to 120°C.
(e) For the production of those compounds of the Formula I wherein R is an amino-hydroxy-disubstituted (l-6C)alkoxy group (such as 2-hydroxy-3-pyrrolidin- 1-ylρropoxy 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 arnine.
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. (f) For the production of those compounds of the 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.
When a pharmaceutically-acceptable salt of a quinazoline derivative of the Formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said quinazoline derivative with a suitable acid using a conventional procedure.
Many of the intermediates defined herein are novel and these are provided as a further feature of the invention. For example, many compounds of the Formula HI
Figure imgf000042_0001
wherein Z is O, S, or N(R ) and R , R , R and R have any of the meanings defined hereinbefore are novel compounds. For example, although 4-aminopyridazine starting materials (Formula HI, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples, compounds such as 4-amino-3-chloro- 6-methoxypyridazine is a novel compound which is provided as a further feature of the invention. Biological Assays
The following assays can be used to measure the effects of the compounds of the present invention as c-Src tyrosine Idnase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue. (a) In Vitro Enzyme Assay
The ability of test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src Idnase was assessed using a conventional Elisa assay.
A substrate solution [lOOμl of a 20μg/ml solution of the polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azidej was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 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.
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 (25μl) of an aqueous magnesium chloride solution (δOmM) containing adenosine-5'-triρhosphate (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 Inc. 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
Ig 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) of the resultant solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0. "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 NTH 3T3 (c-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, 19δ7, 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 of the stock solution were diluted with the DMEM medium described above and added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which test compound was not added were included on each plate. The plates were incubated overnight at 37°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) of the 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 determined and an anti-proliferative IC50 value was derived.
(c) In Vitro Microdroplet Migration Assay
This assay determines the ability of a test compound 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) of the agar solution was added to RPMI medium (10 ml) immediately prior to its use. A549 cells (Accession No. ATCC CCLlδ5) 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) of the 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 of the agarose-containing droplets. Aliquots (90μl) of medium which had been cooled to 4°C were transferred into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (lOμl) of the 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 4δ hours.
Migration was assessed visually and the distance of migration was measured back to the edge of the agar droplet. A migratory inhibitory IC50 was derived by plotting the mean migration measurement against test compound concentration.
(d) In Vivo A549 Xenograft Growth Assay
This test measures the ability of compounds to inhibit the growth of the A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain). A total of about 5 x 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 of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d):-
Test (a):- ICs0 in the range, for example, 0.001 - 10 μM; Test (b):- IC50 in the range, for example, 0.1 - 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.
In general, particular compounds of the Formula I such as those provided hereinafter as Examples possess activity at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d):-
Test (a):- ICso in the range, for example, 0.001 - 0.5 μM;
Test (b):- IC50 in the range, for example, 0.1 - 5 μM;
Test (c):- activity in the range, for example, 0.1-5 μM;
Test (d):- activity in the range, for example, 1-200 mg/kg/day. For example, the quinazoline compound disclosed within Example 2 possesses the following activity :- Test (a), IC50 approximately 0.04μM.
No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. 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 9δ percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a compound of the Formula I for therapeutic or prophylactic purposes 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 preferred, 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 of the invention there is provided a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the 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 quinazoline derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the non-receptor tyrosine-specific protein 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 quinazoline derivatives of the present invention are of value as anti-tumour agents, in particular as selective inhibitors of the motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth. Particularly, the quinazoline derivatives of the present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease. Particularly, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more of the multiple non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells. Further, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of the enzyme c-Src, i.e. the compounds may be used to produce a c-Src enzyme inhibitory effect in a warm-blooded animal in need of such treatment. Specifically, the compounds of the present invention are expected to be useful in the prevention or treatment of solid tumour disease.
Thus according to this aspect of the invention there is provided a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
According to a further feature of this aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
According to a further feature of this aspect of the 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 quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man. According to a further feature of this aspect of the 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 quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
According to a further feature of this aspect of the invention there is provided a method for 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 which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a c-Src kinase inhibitory effect.
The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinazoline derivative of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) other anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of uroldnase 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; 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, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™] and the anti-erbBl antibody cetuximab [C225]), farnesyl transf erase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-
6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZDlδ39), N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32δ56 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin vβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immuno therapy approaches, including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
According to this aspect of the invention there is provided a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore and an additional anti -tumour agent as defined hereinbefore for the conjoint treatment of cancer.
Although the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of c-Src. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
The invention will now be illustrated in the following Examples in which, generally :
(i) operations were carried out at ambient temperature, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as argon unless otherwise stated;
(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 Clδ reverse phase silica, for example on a Waters C-lδ 5 microns preparative reversed-phase column; (iv) yields, where present, are not necessarily the maximum attainable; (v) in general, the end-products of the 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 uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the 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 of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the 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 THE tetrahydrofuran Example 1
4-(3-chloro-6-methoxypyridazin-4-ylarnino)-5-isopropoxy-
7-(2-morpholinoethoxy)quinazoϊine
Sodium hexamethyldisilazane (1M solution in THF; 0.57 ml) was added dropwise to a mixture of 4-amino-3-chloro-6-methoxypyridazine (0.045 g), 4-chloro-5-isopropoxy- 7-(2-morpholinoethoxy)quinazoline (0.1 g) and THF (1.5 ml) that had been cooled to 0°C. The resultant mixture was stirred at 0°C for 15 minutes, allowed to warm to ambient temperature and stirred at ambient temperature for 2 hours. Acetic acid (0.05 ml) was added and the resultant mixture was evaporated. The mixture was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water, 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 title compound as a solid (0.09 g); NMR Spectrum: (CDC13) 1.58 (s, 3H), 1.59 (s, 3H), 2.6 (m, 4H), 2.87 (m, 2H), 3.76 (m, 4H), 4.14 (s, 3H), 4.25 (m, 2H), 4.91 (m, 1H), 6.67 (s, 1H), 6.89 (s, 1H), 8.7 (m, 2H); Mass Spectrum: M+H+ 475 and 477.
The 4-chloro-5-isopropoxy-7-(2-morpholinoethoxy)quinazoline that was used as a starting material was prepared as follows :-
Sodium hydride (60% dispersion in mineral oil; 1 g) was added portionwise to a solution of isopropanol (1.25 g) in DMF (20 ml) that had been cooled to 5°C. The resultant mixture was allowed to warm to ambient temperature and was stirred for 15 minutes. The mixture was recooled to 5°C and 5,7-difluoro-3,4-dihydroquinazolin-4-one (International Patent Application WO 01/94341; 2 g) was added portionwise. The mixture was stirred at ambient temperature for 30 minutes. The mixture was poured into water (200 ml) and, with vigorous stirring, glacial acetic acid was added to acidify the mixture to pH4. The resultant solid was isolated, washed with water and with diethyl ether and dried under vacuum. There was thus obtained 7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one (1.75 g); NMR Spectrum: (DMSOd6) 1.31 (s, 6H), 4.73 (m, 1H), 6.δ9 (m, 1H), 6.95 (m, 1H), 7.96 (s, 1H); Mass Spectrum: M+H+ 223. A mixture of 7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one (1 g),
2-morpholinoethanol (0.71 g), potassium tert-butoxide (3 g) and THF (40 ml) was stirred and heated to reflux for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography on a Waters Symmetry column (C18 reversed-phase, 5 microns, 20 mm diameter, 100 mm length; Waters Inc., Milford, MA01757, USA) using decreasingly polar mixtures of water (containing 5% methanol and 1% acetic acid) and acetonitrile as eluent. The material so obtained was stirred under a 7M methanolic ammonia solution (20 ml) for 5 minutes. The mixture was evaporated and the residue was stirred under methylene chloride. The mixture was filtered and the filtrate was evaporated. There was thus obtained 5-isopropoxy- 7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-one (0.876 g); Mass Spectrum: M+FT" 334.
A mixture of the material so obtained, triphenylphosphine (1.72 g), carbon tetrachloride (0.δ9 ml) and 1,2-dichloroethane (50 ml) was stirred and heated to 70°C for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 7M methanolic ammonia solution as eluent. There was thus obtained 4-chloro-5-isopropoxy- 7-(2-morpholinoethoxy)quinazoline as an oil which crystallised on standing (O.δ g); NMR Spectrum: (CDC13) 1.48 (s, 3H), 1.49 (s, 3H), 2.59 (m, 4H), 2.87 (t, 2H), 3.76 (m, 4H), 4.26 (d, 2H), 4.72 (m, 1H), 6.62 (s, 1H), 6.91 (s, 1H), 8.79 (s, 1H); Mass Spectrum: M+H+ 352 and 354.
The 4-amino-3-chloiO-6-methoxypyridazine that was used as a starting material was prepared as follows :-
Using a cold water bath to prevent the temperature of the reaction mixture from rising above 40 to 45°C, potassium dichromate (43 g) was added portionwise over 30 minutes to a mechanically stirred mixture of 3,6-dichloro-4-methylpyridazine (T. Kuraishi, Pharm. Bull. (Tokyo), 1957, 5, 587; 20 g) and concentrated sulphuric acid (125 ml). The resultant mixture was stirred at ambient temperature for 2 hours. The mixture was poured onto a mixture of ice and water and extracted with diethyl ether (3 x 500 ml). The organic layer was separated and evaporated. The residue was partitioned between diethyl ether and a 5% aqueous sodium bicarbonate solution. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 200 ml). The organic solution was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained 3,6-dichloropyridazine-4-carboxylic acid (containing some 6-chloro-3-hydroxypyridazine- 4-carboxylic acid) as a white solid (18.4 g); NMR Spectrum: (DMSOd6) 8.32 (s, 1H);
13C NMR Spectrum: (DMSOd6) 130.δ, 134.9, 152.δ, 157, 163.δ; Mass Spectrum: M+H 193. A mixture of a portion (10 g) of the material so obtained, concentrated sulphuric acid (10 drops) and anhydrous ethanol (50 ml) was heated to reflux for 24 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was dissolved in phosphoryl chloride (70 ml) and the solution was heated to 70°C for 2 hours. The resultant mixture was cooled to ambient temperature, poured onto a mixture of ice and water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate soluiton, 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 40-60°C) and ethyl acetate as eluent. There was thus obtained ethyl 3,6-dichloropyridazine- 4-carboxylate as an oil (5.7 g); NMR Spectrum: (CDC13) 1.45 (t, 3H), 4.49 (q, 2H), 7.δ7 (s, IIP; Mass Spectrum: M+H+ 221.
Sodium methoxide (0.735 g) was added portionwise over 15 minutes to a stirred mixture of ethyl 3,6-dichloropyridazine-4-carboxylate (3 g) and methanol (40 ml) and the resultant mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic solution was dried over magnesium sulphate and evaporated. A mixture of the solid so obtained and a cooled 30% aqueous ammonium hydroxide solution (18 ml) was stirred at 0°C for 24 hours. The solid so obtained was isolated, washed with a small volume of water and dried under vacuum in the presence of phosphorus pentoxide. The solid was purified by column chromatography using a Waters Symmetry column (C18 reversed-phase, 5 microns, 20 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 5% methanol and 1% acetic acid) and acetonitrile as eluent. There were so obtained in turn :- 3-chloro-6-methoxypyridazine-4-carboxamide (0.342 g); NMR Spectrum: (DMSOd6) 4.05 (s, 3H), 7.43 (s, 1H), 8.03 (br s, 1H), 8.2 (br s, 1H); Mass Spectrum: M+H* 188; 3,6-dichloropyridazine-4-carboxamide (0.164 g); NMR Spectrum: (DMSOd6) 8.19 (br s, 1H), 8.22 (s, 1H), 8.27 (br s, 1H); Mass Spectrum: M+H+ 192; and
6-chloro-3-methoxypyridazine-4-carboxamide (0.634 g): NMR Spectrum: (DMSOd6) 4.1 (s, 3H), 7.93 (s, 1H), 8.0 (br s, 1H), 8.04 (br s, 1H); Mass Spectrum: M+ϊ 188.
Bromine (0.091 ml) was added dropwise to an ice-cooled 2N aqueous sodium hydroxide solution (3.5 ml) and the mixture was stirred for 2 minutes. 3-Chloro- 6-methoxypyridazine-4-carboxamide (0.332 g) was added and the mixture was stirred at ambient temperature for 2 hours and then heated to 70°C for 2 hours. The mixture was cooled to ambient temperature and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 10:3 mixture of methylene chloride and ethyl acetate as eluent. There were thus obtained in turn 4-amino-5-bromo-3-chloro-6-methoxypyridazine (0.075 g); NMR Spectrum: (CDC13) 4.14 (s, 3H), 5.07 (br s, 2H); 13C NMR Spectrum: (CDCI3) 56.1, 96.2, 139.1, 142.6, 161.7; Mass Spectrum: M+H " 238; and the required 4-amino-3-chloro-6-methoxypyridazine (0.045 g); NMR Spectrum: (CDCI3) 4.04 (s, 3H), 4.66 (br s, 2H), 6.17 (s, IH); 13C NMR Spectrum: (CDCI3) 55, 97.3, 141.1, 144.1, 160; Mass Spectrum: M+H1" 160.
Example 2
4-(6-chloro-3-methoxypyridazin-4-ylamino)-5-isopropoxy- 7-(3-morpholinopropoxy)quinazoline
Using an analogous procedure to that described in Example 1, 4-amino-6-chloro- 3-methoxypyridazine (0.066 g) was reacted with 4-chloro-5-isopropoxy- 7-(3-morpholinopropoxy)quinazoline (0.152 g) to give the title compound as a solid in 70% yield; NMR Spectrum: (CDCI3) 1.59 (s, 3H), 1.6 (s, 3H), 2.04 (m, 2H), 2.49 (m, 4H), 2.55 (m, 2H), 3.73 (m, 4H), 4.18 (m, 2H), 4.26 (s, 3H), 4.90 (m, IH), 6.6 (s, IH), 6.9 (s, IH), 8.76 (s, IH), 9.12 (s, IH); Mass Spectrum: M+H+ 489 and 491.
The 4-chloro-5-isopropoxy-7-(3-morpholinopropoxy)quinazoline that was used as a starting material was prepared using analogous procedures to those described in the portion of Example 1 that is concerned with the preparation of starting materials. Thus :- Using sodium tert-pentoxide in place of potassium tert-butoxide, 7-fluoro-
5-isopropoxy-3,4-dihydroquinazolin-4-one was reacted with 3-morpholinopropanol (Bull. Soc. Chim. Fr., 1962, 1117) to give 5-isopropoxy-7-(3-morpholinopropoxy)- 3,4-dihydroquinazolin-4-one in 23% yield; NMR Spectrum: (CDC13) 1.46 (s, 3H), 1.47 (s, 3H), 2.03 (m, 2H), 2.51 (m, 4H), 2.56 (m, 2H), 3.74 (m, 4H), 4.13 (m, 2H), 4.63 (m, IH), 6.49 (s, IH), 6.74 (s, IH), 7.95 (s, IH); Mass Spectrum: M+H 348.
The material so obtained was reacted with carbon tetrachloride and triphenylphosphine to give 4-chloro-5-isopropoxy-7-(3-morpholinopropoxy)quinazoline in 59% yield; NMR Spectrum: (CDC13) 1.48 (s, 3H), 1.5 (s, 3H), 2.04 (m, 2H), 2.48 (m, 4H), 2.55 (t, 2H), 3.73 (m, 4H), 4.19 (t, 2H), 4.72 (m, IH), 6.58 (s, IH), 6.92 (s, IH), 8.78 (s, IH). The 4-amino-6-chloro-3-methoxypyridazine that was used as a starting material was prepared as follows :-
Bromine (0.464 g) was added dropwise to an ice-cooled 2N aqueous sodium hydroxide solution (5.8 ml) and the mixture was stirred for 2 minutes. 6-Chloro- 3-methoxypyridazine-4-carboxamide (0.544 g) was added and the mixture was stirred at ambient temperature for 1 hour and then heated to 70°C for 4 hours. The mixture was cooled to ambient temperature and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 10:3 mixture of methylene chloride and ethyl acetate as eluent. There were thus obtained in turn 4-amino-5-bromo-6-chloro-3-methoxypyridazine (0.16 g); Mass Spectrum: M+H+ 238; and the required 4-amino-6-chloro-3-methoxypyridazine (0.068 g); NMR Spectrum: (DMSOd6) 3.98 (s, 3H), 6.54 (s, IH), 6.62 (br s, 2H); 13C NMR Spectrum: (DMSOd6) 55, 106.1, 140.1, 150.5, 155.4; Mass Spectrum: M+lT" 160.

Claims

A quinazoline derivative of the Formula I
Figure imgf000058_0001
wherein Z is an O, S, SO, SO2, N(R2) or C(R2)(R3) group wherein each R2 or R3 group, which may be the same or different, is hydrogen or (l-8C)alkyl; m is 1, 2 or 3; 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-8C)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)alkynoylarnino,
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-8C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl- (l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R1)™ 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-8C)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 CH = or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyljcarbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyljamino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (l-8C)alkyl, and Q is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -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 or (l-8C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, oxo, thioxo, (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)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-8C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl- (l-6C)alkyl, (3-8C)cycloalkenyl, (3-8C)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 R1 substituent 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-8C)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- [( 1 -6C)alkyl] amino, ( 1 -6C)alkoxycarbonyl, N-( 1 -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- [( 1 -6C)alkyl] sulphamoyl, ( 1 -6C)alkanesulphonylamino, N-( 1 -6C)alkyl- (l-6C)alkanesulphonylamino and (l-3C)alkylenedioxy, 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-8C)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-8C)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-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a R1 substituent optionally bears 1 or 2 oxo or thioxo substituents;
Ra is halogeno or (l-6C)alkoxy; R is halogeno or (l-6C)alkoxy; and
Rc is hydrogen, halogeno, (l-8C)alkyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
2. A quinazoline derivative of the Formula I according to claim 1 wherein :- each of Z, m, R1 and Rc has any of the meanings defined in claim 1, Ra is halogeno and R is methoxy.
3. A quinazoline derivative of the Formula I according to claim 1 wherein :- Z is NH; m is 2 and the R1 groups, which may be the same or different, are located at the 6- and
7-positions and the R1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 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-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 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, 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, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy and 3 -homopiperazin-1 -ylpropoxy, and wherein any CH2 or CH 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3 -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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
Ra is chloro or bromo; R is methoxy or ethoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
4. A quinazoline derivative of the Formula I according to 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 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 2-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]ethoxy, 3 - [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl] propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-allylpiperazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 2-(4-isobutyrylpiperazin-l-yl)ethoxy, 3-(4-isobutyrylpiperazin-l-yl)propoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethoxy and 3- [4-(2,2,2-trifluoroethyl)piperazin- 1 -yljpropoxy; and Ra is chloro;
R is methoxy; and Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
5. A quinazoline derivative of the Formula I according to claim 1 wherein :- Z is NH; m is 2 and the R1 groups, which may be the same or different, are located at the 5- and 7-positions and the R1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R1 group at the 7-position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -ylbutoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 2-piperidin-3 -ylethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin- 1 -ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 3-(l,2,3,6-tetrahydropyridin- l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin-l -ylethoxy and 3 -homopiperazin-1 -ylpropoxy, 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, oxo, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy, and wherein any 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, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pyrrolidin-2-yl, pyrrolidin-3-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, propionyl, isobutyryl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or cyanomethyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
Ra is fluoro, chloro, bromo, methoxy or ethoxy;
R is fluoro, chloro, bromo, methoxy or ethoxy; and
R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
6. A quinazoline derivative of the Formula I according to claim 1 wherein :- Z is NH; m is 1 and the R1 group is located at the 5-position and is selected from propoxy, isopropoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3 -yloxy,
N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin- 3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin- 4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 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 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 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, 2-(4-hydroxypiperidin-l-yl)ethoxy, 3-(4-hydroxypiperidin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 4-(4-methylpiperazin- l-yl)butoxy, 2-(4-allylpiperazin-l-yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin- 1 -yl)ethoxy, 3-(4-prop-2-ynylpiperazin- 1 -yl)propoxy, 2-(4-methylsulphonylpiperazin-l-yl)ethoxy, 3-(4-methylsulphonylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 4-(4-acetylpiperazin- 1 -yl)butoxy, 2-(4-isobutyrylpiperazin- 1 -yl)ethoxy, 3-(4-isobutyrylpiperazin- 1 -yl)propoxy, 4-(4-isobutyrylpiperazin-l-yl)butoxy, 2-[4-(2-fluoroethyl)piperazin-l-yljethoxy, 3- [4-(2-fluoroethyl)piperazin- 1 -yljpropoxy, 2- [4-(2,2,2-trifluoroethyl)piperazin- 1 -yljethoxy, 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[2-(4-methylpiperazin-l-yl)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; Ra is chloro or bromo;
R is methoxy; and Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
7. A quinazoline derivative of the Formula I according to claim 1 wherein :- Z is NH; m is 2 and the first R1 group is located at the 5-position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second R1 group is located at the 7-position and is selected from 2-pyrrolidin-l -ylethoxy, 3-pyrrolidin-l -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljethoxy,
3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-allylpiρerazin- 1 -yl)ethoxy, 3-(4-allylpiperazin-l-yl)propoxy, 2-(4-prop-2-ynylpiperazin-l-yl)ethoxy, 3-(4-prop-2-ynylpiperazin-l-yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, 2-(4-isobutyrylpiperazin-l-yl)ethoxy, 3-(4-isobutyrylpiperazin-l-yl)propoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethoxy and 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]propoxy; and
Ra is chloro;
R is methoxy; and
Rc is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
8. A process for the preparation of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 which comprises :-
(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
Figure imgf000065_0001
wherein L is a displaceable group and m and R1 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the Formula HI
Figure imgf000065_0002
wherein Z is O, S, or N(R ) and R , R , R and R have any of the 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 of those compounds of the Formula I wherein at least one R1 group is a halogeno-(l-6C)alkoxy group or a group of the formula 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 quinazoline of the Formula V
Figure imgf000066_0001
wherein m, R1, Z, Ra, R and Rc have any of the 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 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 reaction of a quinazoline derivative of the Formula VI
Figure imgf000066_0002
wherein L is a displaceable group and Z, Ra, R and Rc have any of the 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 of those compounds of the Formula I wherein R1 is an amino-substituted (l-6C)alkoxy group, the reaction of a compound of the Formula I wherein R1 is a halogeno-substituted (l-6C)alkoxy group with a nitrogen-containing heterocyclyl compound or an appropriate amine;
(e) for the production of those compounds of the Formula I wherein R1 is an amino-hydroxy-disubstituted (l-6C)alkoxy group, 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; or
(f) for the production of those compounds of the Formula I wherein Z is a SO or SO2 group, the oxidation of a compound of Formula I wherein Z is a S group; and when a pharmaceutically-acceptable salt of a quinazoline derivative of the Formula I is required, it may be obtained by reaction of said quinazoline derivative with a suitable acid using a conventional procedure.
9. A pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier.
10. The use of a quinazoline derivative of the Formula 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.
PCT/GB2004/002365 2003-06-05 2004-06-03 Pyridazinil quinazoline derivatives for use in the treatment of tumours WO2004108707A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012501313A (en) * 2008-09-02 2012-01-19 ノバルティス アーゲー Heterocyclic PIM kinase inhibitor
JP2014534975A (en) * 2011-11-14 2014-12-25 スンシネ ルアケ プハルマ カンパニー リミテッド Aminoquinazoline derivatives and their salts and methods of use

Citations (2)

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Publication number Priority date Publication date Assignee Title
US5721237A (en) * 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
WO2001021597A1 (en) * 1999-09-21 2001-03-29 Astrazeneca Ab Therapeutic quinazoline derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721237A (en) * 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
WO2001021597A1 (en) * 1999-09-21 2001-03-29 Astrazeneca Ab Therapeutic quinazoline derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012501313A (en) * 2008-09-02 2012-01-19 ノバルティス アーゲー Heterocyclic PIM kinase inhibitor
US8759338B2 (en) 2008-09-02 2014-06-24 Novartis Ag Heterocyclic kinase inhibitors
JP2014534975A (en) * 2011-11-14 2014-12-25 スンシネ ルアケ プハルマ カンパニー リミテッド Aminoquinazoline derivatives and their salts and methods of use

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