WO2004081000A1 - Dérivés quinazoliniques - Google Patents

Dérivés quinazoliniques Download PDF

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Publication number
WO2004081000A1
WO2004081000A1 PCT/GB2004/000942 GB2004000942W WO2004081000A1 WO 2004081000 A1 WO2004081000 A1 WO 2004081000A1 GB 2004000942 W GB2004000942 W GB 2004000942W WO 2004081000 A1 WO2004081000 A1 WO 2004081000A1
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group
alkyl
formula
ethoxy
pyrrolidin
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PCT/GB2004/000942
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English (en)
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Bernard Barlaam
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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 ldnases 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 QRR) and Class DI receptor tyrosine ldnases 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 QRR
  • tyrosine kinases belong to the class of non-receptor tyrosine ldnases 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
  • NSCLCs non-small cell lung cancers
  • adenocarcinomas adenocarcinomas
  • c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility.
  • colon tumour progression from localised to disseminated, invasive metastatic disease has been correlated with c-Src non-receptor tyrosine kinase activity (Brunton et al, Oncogene, 1997, 14, 283-293, Fincham et al, EMBO J, 1998, 17, 81-92 and Verbeek et al, Exp. Cell Research, 1999, 248, 531-537).
  • an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • an inhibitor of such non-receptor tyrosine ldnases 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 ldnases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory activity against other tyrosine ldnase enzymes such as the receptor tyrosine ldnases, for example EGF receptor tyrosine ldnase and/or VEGF receptor tyrosine ldnase.
  • the receptor tyrosine ldnases for example EGF receptor tyrosine ldnase and/or VEGF receptor tyrosine ldnase.
  • certain compounds of the present invention possess substantially better potency against the Src family of non-receptor tyrosine ldnases, for example c-Src and/or c- Yes, than against VEGF receptor tyrosine kinase.
  • Such compounds possess sufficient potency against the Src family of non-receptor tyrosine ldnases, 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 ldnase.
  • VEGF receptor tyrosine ldnase inhibitory activity it is advantageous to minimise VEGF receptor tyrosine ldnase inhibitory activity as some compounds having that activity have been found to act as potassium channel blockers, for example in a human ether- a-go-go-related-gene (hERG)-encoded potassium channel assay. Such activity may give rise to electrocardiogram (ECG) changes in vivo.
  • ECG electrocardiogram
  • the anti-cancer treatment defined hereinafter 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. It is well known that nearly all drugs are metabolised to some degree in the human, generally to a less lipid soluble compound which is more easily excreted by the kidney.
  • Cytochrome P450 is a family of isoenzymes found in hepatic microsomes. Six specific P450 isoenzymes are responsible for the metabolism of most of the commonly used drugs, namely P450 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Combination chemotherapy can be problematic if one or more of the component drugs of the combination are metabolised by Cytochtome P450 3A4 (hereinafter CYP 3A4).
  • Such a component may be a substrate for CYP 3A4 or it may be an inducer or an inhibitor of that isoenzyme.
  • Such effects can affect the pharmacokinetics of the other component of the combination therapy.
  • certain compounds of the present invention have the advantageous property of being less liable to metabolism by such P450 isoenzymes, particularly by CYP 3 A4. Accordingly, it is possible to administer such compounds in combination anti-cancer therapy with greater safety.
  • certain compounds of the present invention are doubly advantageous in that they possess little activity against VEGF receptor tyrosine kinase and they show little or no tendency to be metabolised by P450 isoenzymes such as CYP 3A4.
  • 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 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,
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ), CO, CH(OR 4 ),
  • R 4 is hydrogen or (l-8C)alkyl
  • Q 1 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 R 1 substituent are optionally separated by the insertion into the chain of
  • 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
  • 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 substituent on R 1 optionally bears 1 or 2 oxo or thioxo substituents;
  • R a is hydrogen or halogeno
  • R is hydrogen, halogeno, (l-8C)alkyl or (l-6C)alkoxy;
  • R c is hydrogen, halogeno, (l-8C)alkyl or (l-6C)alkoxy; and
  • R d is (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.
  • (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- N-methylamino, N-cyclohexyl-N-ethylamino and N-cyclopentylmethyl-N-methylamino.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 1 to Q 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 , 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)alkynyloxy: ethy
  • 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-methylethanesulphonylamino for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido;
  • N-(l-6C)alkyl-(3-6C)alkynoylamino N-methylpropiolamido
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl and
  • an R 1 group forms a group of the formula Q ⁇ X 1 - and, for example, X 1 is a OC(R 4 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 4 ) 2 linking group which is attached to the quinazoline ring and the oxygen atom is attached to the Q 1 group.
  • R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 5 ) or C ⁇ C.
  • a group such as O, CON(R 5 ) or C ⁇ C.
  • insertion of a C ⁇ C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • suitable R 1 substituents so formed include, for example, N-[heterocyclyl- (l-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-l-ylethyl)carbamoyl vinyl or N-[heterocyclyl-(l-6C)alkyljcarbamoylethynyl groups such as N-(2-pyrrolidin- l-ylethyl)carbamoylethynyl.
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno or (l-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-piperid
  • 2-methylsulphonylethoxy and heterocyclyl-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
  • any CH 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 , R c and R has any of the meanings defined hereinbefore or in paragraphs (a) to (v) hereinafter :-
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-8C)alkyl, (2-8C)alkenyl,
  • X 1 is a direct bond or is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-8C)alkyl
  • X 2 is a direct bond or is CO or N(R 6 )CO, wherein R 6 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, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulphonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkylcarbamo
  • 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, 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-8C)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-8C)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 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,
  • 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, pyn"olidin-l-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-py ⁇ olidin-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-piperidinoethy
  • any CH or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, oxo, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl- N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula : -X 3 -Q 3 wherein X 3 is a direct bond or is selected from O, NH, C
  • 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 fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetyl, propionyl, isobutyryl, methylenedioxy, ethylid
  • X 5 is a direct bond or is selected from O, NH and CO and Q 4 is pyrrolidin-1 -ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl, 3-pi ⁇ eridinopropyl, piperazin-1 -ylmethyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo substituents; (f) m is 1 and the R 1 group is located at the 5-, 6- or 7-position or m
  • Q 2 -X 2 - wherein X 2 is a direct bond or is NHCO or N(Me)CO and Q 2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1 -ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperid
  • (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- 4H
  • m is 1 and the R 1 group is located at the 5-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 and each R 1 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, py ⁇ olidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholino
  • 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 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 R 1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl, methoxy, methylenedioxy, e
  • (j) m is 2 and the R 1 groups, which may be the same or different, are located at the 5- and 7-positions and the R 1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3 -ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R 1 group at the 7-position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2- ⁇ yrrolidin- 1 -ylethoxy, 3-pyrrolidin- 1 -ylpropoxy, 4-pyrrolidin- 1 -
  • R is hydrogen;
  • R c is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy;
  • R c is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy;
  • R is hydrogen;
  • u is methoxy or ethoxy; and
  • R is methoxy.
  • 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 , R c and R has any of the meanings defined hereinbefore provided that :- (A) R 1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinazoline ring i.e. the 2- and 8-positions remain unsubstituted; or
  • R 1 substituents may only be located at the 6- and/or 7-positions on the 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 ldnase enzymes such as the receptor tyrosine ldnases, for example EGF receptor tyrosine kinase and or VEGF receptor tyrosine ldnase.
  • the receptor tyrosine ldnases for example EGF receptor tyrosine kinase and or VEGF receptor tyrosine ldnase.
  • 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 ldnase.
  • Such compounds possess sufficient potency against the Src family of non-receptor tyrosine ldnases, 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 ldnase or VEGF receptor tyrosine kinase.
  • quinazoline derivatives of the Formula I or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, R 1 , R and R c has any of the meanings defined hereinbefore and R a is halogeno and R is methoxy.
  • quinazoline derivatives of the Formula I or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m and R 1 has any of the meanings defined hereinbefore and :- R is chloro or bromo, R is hydrogen, R c is hydrogen 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, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy,
  • 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 hydrogen, fluoro, chloro or bromo
  • R b is hydrogen, chloro or bromo
  • R c is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy
  • R d is methoxy or ethoxy; 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 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,
  • R a is hydrogen, chloro or bromo
  • R b is hydrogen, chloro or bromo
  • R c is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy; and R d is methoxy or ethoxy; 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-l-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,
  • 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 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypyrrolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 2-(4-allylpiperazin-l-yl)ethoxy, 3-(4-allylpiperazin-
  • R a is chloro; R is hydrogen;
  • R is hydrogen
  • R is methoxy; 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-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy,
  • R a is chloro
  • R is hydrogen; R c is hydrogen;
  • R is methoxy; 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 7-positions and the R 1 group at the 5-position is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R 1 group at the 7-position is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pyrrolidin- 1 -ylethoxy, 3
  • R is hydrogen, chloro or bromo
  • R b is hydrogen, chloro or bromo
  • R c is hydrogen, fluoro, chloro, bromo, methoxy or ethoxy; and R d is methoxy or ethoxy; 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-1 -ylpropoxy, 2- [ (3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1-yl] ethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4
  • 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 c is hydrogen, chloro or methoxy
  • R d is methoxy; 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, tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R 1 group is located at the 5-position and is selected from the group of substituents listed immediately above, and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin-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-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl
  • R c is hydrogen
  • R d is methoxy; 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 group is located at the 5-position and is selected from isopropoxy and tetrahydropyran-4-yloxy, and the second R 1 group is located at the 7-position and is selected from 2-pyrrolidin- 1 -ylethoxy, 3 -pyrrolidin- 1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypyrrolidin- 1 -yljethoxy, 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- 1
  • R b is hydrogen
  • R c is hydrogen
  • R d is methoxy; 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-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy, 3-(4-methylpiperazin- 1 -yl)propoxy, 2-(4-prop-2-ynylpiperazin- 1 -yl)ethoxy, 3-(4-prop-2-ynylpiperazin- l-yl)propoxy, 2-(4-acetylpiperazin- l-yl)ethoxy and 3-(4-acetylpiperazin-l-yl)propoxy; and
  • R is chloro; R is hydrogen; R is hydrogen; and
  • R is methoxy; 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 Examples 3, 4, 5 and 9 hereinafter and within Examples 11 and 16 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, R 1 , R a , R , R c and R have any of the meanings defined hereinbefore.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • L is a displaceable group and m and R 1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula HI
  • 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[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
  • an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as
  • a suitable inert solvent or diluent for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as
  • reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 0 to 120°C.
  • the quinazoline of the Formula II may be reacted with a compound of the Formula m in the presence of an aprotic solvent such as N,N-dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 70°C.
  • 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[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
  • a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydro
  • 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).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and
  • 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
  • (2-6C)alkenyl groups for example allyl.
  • 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.
  • 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.
  • 3-Aminopyridine starting materials (Formula HI, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples.
  • Corresponding 3-hydroxy- and 3-mercaptopyridine starting materials (Formula m, 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 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
  • a suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine.
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
  • L is a displaceable group as defined hereinbefore and Z
  • R a , R , R c and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or amine as appropriate whereafter any protecting group that is present is removed by conventional means.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • a suitable reactive derivative of an optionally substituted carboxylic acid is, for example, a carboxylic acid halide; a carboxylic acid amide; a mixed anhydride, for example an anhydride formed by the reaction of the carboxylic acid and a chloroformate such as isobutyl chloroformate; the product of the reaction of the carboxylic acid with a carbodiimide such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide; the product of the reaction of the carboxylic acid with a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine; or the product of the reaction of the carboxylic acid with a uronium salt such as 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium
  • reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.
  • a pharmaceutically-acceptable salt of a quinazoline derivative of the Formula I 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.
  • Biological Assays The following assays can be used to measure the effects of the compounds of the present invention as c-Src tyrosine ldnase 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, and for inhibition in vitro of the hERG-encoded potassium channel.. (a) In Vitro Enzyme Assay
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src ldnase was assessed using a conventional Elisa assay.
  • a substrate solution [lOO ⁇ l of a 20 ⁇ g/ml solution of the polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azide] was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were 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 0.00 l ⁇ M). Portions (25 ⁇ l) of each dilution of test compound were transferred to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25 ⁇ l) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40 ⁇ M) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
  • aqueous magnesium chloride solution 80mM
  • ATP adenosine-5'-triphosphate
  • Active human c-Src kinase (recombinant enzyme expressed in Sf9 insect cells; obtained from Upstate Biotechnology Inc. product 14-117) was diluted immediately prior to use by a factor of 1:10,000 with an enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
  • enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA.
  • HRP horse radish peroxidase
  • sheep anti-mouse Ig antibody (Amersham Catalogue No. NXA 931; lOO ⁇ l) was diluted by a factor of 1:500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).
  • HRP horse radish peroxidase
  • sheep anti-mouse Ig antibody (Amersham Catalogue No. NXA 931; lOO ⁇ l) was diluted by a factor of 1:500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).
  • 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
  • This assay determined the ability of a test compound to inhibit the proliferation of National Institute of Health (NIH) mouse 3T3 fibroblast cells that had been stably-transfected with an activating mutant (Y530F) of human c-Src.
  • NASH National Institute of Health
  • 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
  • 2mM glutamine 100 units/ml penicillin and O.lmg/ml streptomycin in 0.9% aqueous sodium chloride solution.
  • the plates were incubated overnight at 37°C in a humidified (7.5% CO 2 : 95% air) incubator.
  • Test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots 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 : 95% air) incubator.
  • BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1:100 in DMEM medium containing 0.5% FCS and aliquots (20 ⁇ l) were added to each well to give a final concentration of lO ⁇ M). The plates were incubated at 37°C for 2 hours. The medium was decanted. A denaturating solution (FixDenat solution, Boehringer Mannheim Catalogue No. 647 229; 50 ⁇ l) was added to each well and the plates were placed on a plate shaker at ambient temperature for 45 minutes. The supernatant was decanted and the wells were washed with PBS (200 ⁇ l per well).
  • Anti-BrdU-Peroxidase solution (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1:100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered trade mark), Premier Beverages, Stafford, GB) and an aliquot (lOO ⁇ l) 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; lOO ⁇ l) was added to each well.
  • 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 CCL185) were suspended at a concentration of 2 x 10 7 cells/ml in the medium and maintained at a temperature of 37°C.
  • a droplet (2 ⁇ l) of the cell/agarose mixture was 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 : 95% air) incubator for about 48 hours.
  • a migratory inhibitory IC 50 was derived by plotting the mean migration measurement against test compound concentration.
  • hERG-encoded Potassium Channel Assay determines the ability of a test compound to inhibit the tail current flowing through the hERG-encoded potassium channel.
  • Human embryonic kidney (HEK) cells expressing the hERG-encoded channel were grown in Eagle's Minimum Essential Medium (EMEM; Sigma- Aldrich catalogue number M2279), supplemented with 10% Foetal Calf Serum (Labtech International; product number 4-101-500), 10% Ml serum-free supplement (Egg Technologies; product number 70916) and 0.4 mg/ml Geneticin G418 (Sigma- Aldrich; catalogue number G7034).
  • the cells were detached from the tissue culture flasks with Accutase (TCS Biologicals) using standard tissue culture methods. They were then put onto glass coverslips resting in wells of a 12 well plate and covered with 2 ml of the growing media.
  • TCS Biologicals Accutase
  • a glass coverslip containing the cells was placed at the bottom of a Perspex chamber containing bath solution (see below) at ambient temperature ( ⁇ 20°C). This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately after placing the coverslip in the chamber, bath solution was perfused into the chamber from a gravity-fed reservoir for 2 minutes at a rate of ⁇ 2 ml/minute. After this time, perfusion was stopped.
  • a patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus) using a P-97 micropipette puller (Sutter Instrument Co.) was filled with pipette solution (see hereinafter).
  • the pipette was connected to the headstage of the patch clamp amplifier (Axopatch 200B, Axon Instruments) via a silver/silver chloride wire.
  • the headstage ground was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded in 3% agar made up with 0.85% sodium chloride.
  • the cell was recorded in the whole cell configuration of the patch clamp technique. Following “break-in", which was done at a holding potential of -80m V (set by the amplifier), and appropriate adjustment of series resistance and capacitance controls, electrophysiology software (Clampex, Axon Instruments) was used to set a holding potential (-80m V) and to deliver a voltage protocol. This protocol was applied every 15 seconds and consisted of a 1 s step to +40mV followed by a 1 s step to -50mV. The current response to each imposed voltage protocol was low pass filtered by the amplifier at 1kHz. The filtered signal was then acquired, on line, by digitising this analogue signal from the amplifier with an analogue to digital converter.
  • the digitised signal was then captured on a computer running Clampex software (Axon Instruments). During the holding potential and the step to + 40mV the current was sampled at 1kHz. The sampling rate was then set to 5kHz for the remainder of the voltage protocol.
  • the compositions, pH and osmolarity of the bath and pipette solution are tabulated below.
  • the amplitude of the hERG-encoded potassium channel tail current following the step from +40mV to -50mV was recorded on-line by Clampex software (Axon Instruments). Following stabilisation of the tail current amplitude, bath solution containing the vehicle for the test substance was applied to the cell. Providing the vehicle application had no significant effect on tail current amplitude, a cumulative concentration effect curve to the compound was then constructed.
  • test compound potency was determined by fitting the percentage inhibition values making up the concentration-effect to a four parameter Hill equation using a standard data-fitting package. If the level of inhibition seen at the highest test concentration did not exceed 50%, no potency value was produced and a percentage inhibition value at that concentration was quoted.
  • Cytochrome P450 isoenzyme assays may be conducted by conventional means. 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 (d) No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.
  • a pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/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.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however 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 ldnase 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.
  • 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 :-
  • anti-invasion agents for example metalloproteinase inhibitors like marimastat and inhibitors of uroldnase plasminogen activator receptor function
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5 -fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, d
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
  • inhibitors of growth factor function for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cet
  • 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 BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytoldnes such as 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.
  • cytoldnes 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 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 here
  • 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-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline used as a starting material was prepared as follows :- 1,2-Dichloroethane (400 ml) was added to a stirred mixture of 7-hydroxy-6-methoxy-
  • N-Chlorosuccinimide (1.07 g) was added portionwise over 10 minutes to an ice-cooled solution of 2-amino-6-methoxypyridine (Rec. Trav. Chim. Pays-Bas, 1946, 65, 65; 1 g) in chloroform (30 ml). The mixture was stirred at 0°C for 1 hour and at ambient temperature for a further hour. The mixture was diluted with methylene chloride, washed with water and dried over magnesium sulphate. The solvents were evaporated and the residue was purified by column chromatography on silica gel using a 5:1 mixture of petroleum ether (b.p. 40-60°C) and ethyl actetate as eluent.
  • Ammonium formate 45 g was added portionwise over 1.25 hours to a stirred mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (International Patent Application WO 02/16352, Example 1 thereof; 20 g), 10% palladium-on-carbon catalyst (3.3 g) and DMF (530 ml) and the reaction mixture was stirred for an additional 30 minutes. The catalyst was removed by filtration and the solvent was evaporated.
  • Di-tert-butyl azodicarboxylate (2.3 g) was added portionwise over a few minutes to a stirred mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (1.65 g), 3-chloropropanol (0.7 ml), triphenylphosphine (2.6 g) and methylene chloride (100 ml) and the reaction mixture was stirred at ambient temperature for 2 hours.
  • the mixture was concentrated to a volume of about 30 ml by evaporation and the residue was purified by column chromatography on silica using increasingly polar mixtures of petroleum ether (b.p 40-60°C) and ethyl acetate as eluent.
  • the organic layer was dried over magnesium sulphate, concentrated by evaporation and injected directly on to a Waters Symmetry column (C18 reversed-phase, 5 microns, 19 mm diameter, 100 mm length; Waters Inc., Milford, MA01757, USA) and eluted with decreasingly polar mixtures of water (containing 5% methanol and 1% acetic acid) and acetonitrile.
  • the material so obtained was triturated under diethyl ether.
  • the l-prop-2-ynylpiperazine used as a starting material was prepared as follows :- Propargyl bromide (80% solution in toluene; 40 ml) was added dropwise during
  • Acetic anhydride (1.51 ml) was added dropwise to a stirred mixture of 7-(2-piperazin-l-ylethoxy)-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5 g) and water (20 ml) and the resultant mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum.
  • Trifluoroacetic acid (5 ml) was added to a solution of 4-(3-chloro-6-methoxypyridin- 2-ylamino)-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline (1.24 g) in methylene chloride (20 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated. The residue was dissolved in methylene chloride (20 ml) and a 7M methanolic ammonia solution (4 ml) was added. The mixture was filtered and the filtrate was evaporated. The solid so obtained was washed with diethyl ether and dried under vacuum.
  • the 4-chloro-7-(2-chloroethoxy)-5-tetrahydropyran-4-yloxyquinazoline used as a starting material was prepared as follows :- A mixture of 7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (International Patent Application WO 01/94341, Example 15, Note [10] thereof; 12.16 g) triphenylphosphine (21 g), carbon tetrachloride (11.6 ml) and 1,2-dichloroethane (500 ml) was heated at 70°C for 2 hours. The mixture was cooled to ambient temperature and the solvents were evaporated under vacuum.
  • Di-tert-butyl azodicarboxylate (2.35 g) was added portionwise over a 5-minute period to a stirred, ice-cooled mixture of 4-chloro-7-hydiOxy-5-tetrahydiOpyran-4-yloxyquinazoline (2.1 g), 2-chloroethanol (0.55 ml), triphenylphosphine (2.88 g) and methylene chloride (25 ml).
  • the mixture was allowed to warm to ambient temperature and was stirred for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 5:2 mixture of petroleum ether (b.p.
  • the 4-chloro-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline used as a starting material was prepared as follows :- Using an analogous procedure to that described in the second paragraph of the portion of Example 12 that is concerned with the preparation of starting materials, 4-chloro- 7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline was reacted with 3-chloropropanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine.
  • Example 14 7-(3-chloropropoxy)-4-(3-chloro-6-methoxypyridin-2-ylamino)-5-isopropoxyquinazoline
  • the reaction mixture was cooled to ambient temperature and filtered and the filtrate was injected directly on to a Hypersil column (C18 reversed-phase, 5 microns, 20 mm diameter, 100 mm length) of a preparative HPLC-MS system and eluted with decreasingly polar mixtures of water [containing ammonium formate (2 g per litre)] and acetonitrile.
  • the material so obtained was triturated under diethyl ether.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés quinazoliniques représentés par la formule I, dans laquelle Z représente un groupe O, S, SO, SO2, N(R2) ou C(R2)(R3), dans lequel chaque groupe R2 ou R3 représente hydrogène ou (1-8C)alkyle, m représente 1, 2 ou 3, chaque groupe R1 est choisi parmi halogène, (1-8C)alkyle, (1-6C)alcoxy et toutes autres significations données dans le descriptif, Ra représente hydrogène ou halogène, Rb hydrogène ou halogène, (1-6C)alkyle ou (1-6C)alcoxy, Rc hydrogène, halogène, (1-8C)alkyle ou (1-6C)alcoxy, et Rd (1-6C)alcoxy ou des sels pharmaceutiquement acceptables de ceux-ci ; l'invention concerne également leurs procédés de préparation, des compositions pharmaceutiques les contenant et leur utilisation dans la fabrication d'un médicament utilisé comme anti-invasif permettant d'endiguer et/ou de traiter une maladie à tumeur solide.
PCT/GB2004/000942 2003-03-10 2004-03-05 Dérivés quinazoliniques WO2004081000A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03290581 2003-03-10
EP03290581.2 2003-03-10

Publications (1)

Publication Number Publication Date
WO2004081000A1 true WO2004081000A1 (fr) 2004-09-23

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PCT/GB2004/000942 WO2004081000A1 (fr) 2003-03-10 2004-03-05 Dérivés quinazoliniques

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WO (1) WO2004081000A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012501313A (ja) * 2008-09-02 2012-01-19 ノバルティス アーゲー ヘテロ環ｐｉｍキナーゼ阻害剤
CN110746398A (zh) * 2019-10-18 2020-02-04 刘沛友 4-杂环取代喹唑啉类衍生物及其制备方法和用途
US11661426B2 (en) 2017-06-15 2023-05-30 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase

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WO2002092579A1 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Derives de 4-anilinoquinazoline
WO2002092577A1 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Derives quinazoliniques
WO2002092578A1 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Derives de quinazoline

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WO2002092579A1 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Derives de 4-anilinoquinazoline
WO2002092577A1 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Derives quinazoliniques
WO2002092578A1 (fr) * 2001-05-14 2002-11-21 Astrazeneca Ab Derives de quinazoline

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Title
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REWCASTLE, GORDON W. ET AL: "Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor.", JOURNAL OF MEDICINAL CHEMISTRY , 38(18), 3482-7 CODEN: JMCMAR; ISSN: 0022-2623, 1995, XP002285421 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012501313A (ja) * 2008-09-02 2012-01-19 ノバルティス アーゲー ヘテロ環ｐｉｍキナーゼ阻害剤
US8759338B2 (en) 2008-09-02 2014-06-24 Novartis Ag Heterocyclic kinase inhibitors
US11661426B2 (en) 2017-06-15 2023-05-30 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase
CN110746398A (zh) * 2019-10-18 2020-02-04 刘沛友 4-杂环取代喹唑啉类衍生物及其制备方法和用途

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