WO2004056801A1 - Quinazoline derivatives - Google Patents

Quinazoline derivatives Download PDF

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Publication number
WO2004056801A1
WO2004056801A1 PCT/GB2003/005540 GB0305540W WO2004056801A1 WO 2004056801 A1 WO2004056801 A1 WO 2004056801A1 GB 0305540 W GB0305540 W GB 0305540W WO 2004056801 A1 WO2004056801 A1 WO 2004056801A1
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group
alkyl
formula
ethoxy
pynolidin
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PCT/GB2003/005540
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French (fr)
Inventor
Bernard Barlaam
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2003290279A priority Critical patent/AU2003290279A1/en
Publication of WO2004056801A1 publication Critical patent/WO2004056801A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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 cunent 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 ldnases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases.
  • the classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF ⁇ , Neu and erbB receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGF1 receptors and insulin-related receptor (IRR) and Class HI receptor tyrosine kinases comprising
  • PDGF platelet-derived growth factor
  • CSF1 colony-stimulating factor 1
  • 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 ldnases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
  • Src family of non-receptor tyrosine kinases are highly regulated in normal cells and in the absence of extracellular stimuli are maintained in an inactive conformation.
  • some Src family members for example c-Src tyrosine kinase, are frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer
  • NSCLCs non-small cell lung cancers
  • c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility.
  • colon tumour progression from localised to disseminated, invasive metastatic disease has been conelated with c-Src non-receptor tyrosine kinase activity (Brunton et al, Oncogene, 1997, 14, 283-293, Fincham et al, EMBO J, 1998, 17, 81-92 and Verbeek et al, Exp. Cell Research, 1999, 248, 531-537).
  • an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • an inhibitor of such non-receptor tyrosine kinases should be of value as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
  • the compounds of the present invention provide an anti-tumour effect by way of inhibition of the Src family of non-receptor tyrosine kinases, for example by inhibition of one or more of c-Src, c-Yes and c-Fyn.
  • c-Src non-receptor tyrosine kinase enzyme is involved in the control of osteoclast-driven bone resorption (Soriano et al, Cell, 1991, 64, 693-702; Boyce et al, J. Clin. Invest., 1992, 90, 1622-1627; Yoneda et al, J. Clin.
  • An inhibitor of c-Src non-receptor tyrosine kinase is therefore of value in the prevention and treatment of bone diseases such as osteoporosis, Paget's disease, metastatic disease in bone and tumour-induced hypercalcaemia.
  • the compounds of the present invention are also useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example hepatic cinhosis 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 cinhosis and lung fibrosis
  • glomerulonephritis for example hepatic cinhosis and lung fibrosis
  • multiple sclerosis for example hepatic cinhosis and lung fibrosis
  • psoriasis hypersensitivity reactions of the skin
  • 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. 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.
  • Z is an O, S, SO, SO 2 , N(R ) or C(R )(R ) group wherein each R or R group, which may be the same or different, is hydrogen or (l-6C)alkyl; m is 1, 2 or 3; each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C
  • X 2 is a direct bond or is selected from CO and N(R )CO, wherein R 6 is hydrogen or (l-6C)alkyl, and 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-6C)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 ),
  • R is hydrogen or halogeno
  • R is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; R is (l-6C)alkoxy; and R is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
  • (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy
  • (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino
  • di-[(l-6Calkyl] amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl- N-ethylamino.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques refened to hereinafter.
  • Suitable values for the generic radicals refened 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 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 such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopynolidinyl, 2-thioxopynolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopynolidinyl, 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.
  • 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-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthi
  • 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;
  • 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.
  • 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.
  • 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- ⁇ C)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
  • each R 1 group which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoyla
  • X 1 is a direct bond or is selected from O, N(R 4 ), CON(R 4 ), N(R 4 )CO and OC(R 4 ) 2 wherein R 4 is hydrogen or (l-6C)alkyl
  • X 3 is a direct bond or is selected from O, N(R 6 ), CON(R 7 ), N(R 7 )CO and C(R 7 ) 2 O, wherein R is hydrogen or (l-6C)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-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsul ⁇ honyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(
  • X 4 is a direct bond or is selected from O and N(R 9 ), wherein R 9 is hydrogen or (l-6C)alkyl, and R 8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
  • X 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 pynolidin-1-ylmethyl, 2-pynolidin-l-ylethyl, 3-pynolidin-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
  • (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-pynolidin-l-ylethoxy, 3 -pynolidin-1 -ylpropoxy, 4-pynolidin-l -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-dioxot
  • m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and the R 1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R 1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pynolidin-l -ylethoxy, 3-pynolidin-l-ylpropoxy, 4-pynolidin-l -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy,
  • R a is hydrogen, fluoro, chloro or bromo; (1) R is chloro or bromo; (m) R is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy; (n) R is hydrogen, chloro or bromo; (o) R c is methoxy or ethoxy; (p) R is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy; and (q) R is hydrogen.
  • 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 , R , R c and R 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 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.
  • 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 and R 1 has any of the meanings defined hereinbefore and :- R is chloro or bromo, R is hydrogen, R Q is methoxy or ethoxy and R is hydrogen.
  • 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- ⁇ osition 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, benzy
  • 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, pynolidin-1-ylmethyl, 2-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, 4-pynolidin-l-ylbutyl, pynolidin-2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pynolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperidinoeth
  • R is hydrogen, chloro or bromo
  • R is methoxy or ethoxy
  • Z is NH; m is 2 and the R 1 groups, which may be the same or different, are located at the 6- and 7-positions and the R 1 group at the 6-position is selected from hydroxy, methoxy, ethoxy and propoxy, and the R 1 group at the 7-position is selected from methoxy, ethoxy, propoxy, 2-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-( 1 , 1 -di
  • R is hydrogen, chloro or bromo
  • R is hydrogen, chloro or bromo
  • 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-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy,
  • R is hydrogen, chloro or bromo
  • R is hydrogen, chloro or bromo; R is 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 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-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-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-
  • R is hydrogen, chloro or bromo
  • R is 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 :
  • R is hydrogen
  • 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
  • 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, pynolidin-3-yloxy, pynolidin-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-pynolidin- 1 -ylethoxy, 3-pynolidin- 1 -ylpropoxy, 4-pynolidin
  • R is hydrogen, chloro or bromo; R is hydrogen, chloro or bromo;
  • R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Fonnula I wherein :
  • 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-pynolidin- 1 -ylethoxy, 3-pynolidin-l-yl ⁇ ropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l , l-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, pynolidin-3-yloxy,
  • R° is 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 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-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy, 2- [ (3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy , 3- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yljpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l,l-dioxotetrahydro-4H-l,4-thi
  • R is chloro or bromo
  • R is hydrogen or chloro; R° is methoxy or ethoxy; and
  • 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-pynolidin- 1 -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-[(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-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
  • R is chloro
  • R is methoxy; and R is hydrogen; or a pharmaceutically-acceptable acid-addition salt thereof.
  • 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-pynolidin- 1 -ylethoxy, 3-pynolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -y 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 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 Example 3, and Examples 4(2) and 4(3) hereinafter and within Example 2, and Examples 14(11) and 14(17) 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 , R , R 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 IJJ
  • Z is O, S, or N(R 2 ) and R 2 , R a , R , R° and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
  • 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-methylpynolidin-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 tetra
  • 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 di
  • 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.
  • 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.
  • 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.
  • 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 in, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples. Conesponding 3-hydroxy- and 3-mercaptopyridine 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 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
  • m, R 1 , 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 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
  • 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 canied 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)-
  • a suitable amino- substituted carboxylic acid is N,N-dimethylglycine and a suitable reactive derivative thereof is
  • 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 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 kinase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue, (a) In Vitro Enzyme Assay The ability of test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa assay.
  • a substrate solution [lOO ⁇ l of a 20 ⁇ g/ml solution of the polyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azide] was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were transfened into each substrate-coated assay well and incubated for 1 hour at ambient temperature to block non specific binding. The assay plate wells were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and with Hepes pH7.4 buffer (50mM, 300 ⁇ l/well) before being blotted dry.
  • PBS Bovine Serum Album
  • test compound was dissolved in dimethyl sulphoxide and diluted with distilled water to give a series of dilutions (from lOO ⁇ M to O.OOl ⁇ M). Portions (25 ⁇ l) of each dilution of test compound were transfened to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25 ⁇ l) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40 ⁇ M) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
  • aqueous magnesium chloride solution 80mM
  • ATP adenosine-5'-triphosphate
  • Active human c-Src 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 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; Boehringer Catalogue
  • NIH 3T3 cells were transfected with an activating mutant (Y530F) of human c-Src.
  • the resultant c-Src 3T3 cells were typically seeded at 1.5 x 10 4 cells per well into 96-well tissue- culture-treated clear assay plates (Costar) each containing an assay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma) plus 0.5% foetal calf serum (FCS), 2mM glutamine, 100 units/ml penicillin and 0. 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 0. 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 2 : 95% air) incubator.
  • BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1:100 in DMEM medium containing 0.5% FCS and aliquots (20 ⁇ l) were added to each well to give a final concentration of lO ⁇ M). The plates were incubated at 37°C for 2 hours. The medium was decanted. A denaturating solution (FixDenat solution, Boehringer Mannheim Catalogue No. 647 229; 50 ⁇ l) was added to each well and the plates were placed on a plate shaker at ambient temperature for 45 minutes. The supernatant was decanted and the wells were washed with PBS (200 ⁇ l per well).
  • Anti-BrdU-Peroxidase solution (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1:100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered trade mark), Premier Beverages, Stafford, GB) and an aliquot (lOO ⁇ l) 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.
  • RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose (Difco Catalogue No. 0142-01) was warmed to 37°C in a water bath.
  • a stock 2% aqueous agar solution was autoclaved and stored at 42°C.
  • An aliquot (1.5 ml) of the agar solution was added to RPMI medium (10 ml) immediately prior to its use.
  • A549 cells (Accession No. ATCC CCL185) were suspended at a concentration of 2 x 10 7 cells/ml in the medium and maintained at a temperature of 37°C.
  • a droplet (2 ⁇ l) of the cell/agarose mixture was transfened by pipette into the centre of each well of a number of 96-well, flat bottomed non-tissue-culture-treated microtitre plate (Bibby Sterilin Catalogue No. 642000). The plates were placed briefly on ice to speed the gelling of the agarose-containing droplets. Aliquots (90 ⁇ l) of medium which had been cooled to 4°C were transfened into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above.
  • 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 Dicldnson 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 weeldy 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.
  • 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 (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.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however prefened, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • 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 ldnase the predominant role of c-Src non-receptor tyrosine ldnase 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 ldnases 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 phannaceutically-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.
  • 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, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol
  • 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;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serme/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, ZD1839), N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- N-(3-chlor
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace abenant genes such as abenant p53 or abenant 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
  • immunotherapy 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, interleuldn 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
  • 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.
  • the invention will now be illustrated in the following Examples in which, generally :
  • HPLC high pressure liquid chromatography
  • MS mass spectrometry
  • melting points are unconected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products 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; (ix) 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; (x) the following abbreviations have been used:-
  • the 3-amino-2-chloro-5-methoxypyridine used as a starting material above and 3-amino-2,6-dichloro-5-methoxypyridine used as a starting material in Example 4 hereinafter were prepared as follows :- A solution of hydrogen peroxide (30% aqueous solution; 4.6 ml) in water (5 ml) was added dropwise (approximately 0.05 ml/minute) to a solution of 3-amino-5-methoxypyridine (Y. Tamura et al, J. Org.
  • 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 stined mixture of 7-hydroxy-6-methoxy- 3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (International Patent Application WO 02/16352, Example 2, Note [4] thereof; 85 g), potassium carbonate (77 g) and DMF (400 ml) and the reaction mixture was heated to 70°C for 16 hours. The reaction mixture was cooled to ambient temperature and filtered.
  • the filtrate was evaporated and the solid so obtained was washed with water and dried over phosphorus pentoxide at 50°C.
  • the material so obtained was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent.
  • the 7- [2-(4-acetylpiperazin- 1 -yl)ethoxy] -4-chloro-5-tetrahydropyran- 4-yloxyquinazoline used as a starting material was prepared as follows :- Sodium hydride (60% dispersion in mineral oil; 0.6 g) was added portionwise to a solution of 4-hydroxytetrahydropyran (0.78 g) in DMF (10 ml) that had been cooled to 5°C. The mixture was allowed to warm to ambient temperature and was stined for 15 minutes.
  • Acetic anhydride (1.51 ml) was added dropwise to a stined 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 stined 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.
  • the material so obtained was reacted with an excess of acetic anhydride but using methylene chloride rather than water as the reaction solvent.
  • the reaction mixture was stined at ambient temperature for 15 minutes.
  • the mixture was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution.
  • the organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated.
  • the residue was triturated under a mixture of acetonitrile and diethyl ether.
  • Ammonium formate 45 g was added portionwise over 1.25 hours to a stined 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 stined 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 stined 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 stined 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 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.
  • Example 14 Using an analogous procedure to that described in Example 13, the appropriate chloroalkoxy substituted quinazoline was reacted with the appropriate heterocycle to give the compounds described in Table H. Unless otherwise stated, each compound described in Table H was obtained as a free base and, generally, the products were obtained in a yield in the range of 15% to 70%. Table II
  • 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 25 10 minutes to a stined mixture of 1 -tert-butoxycarbonylpiperazine (50 g), potassium carbonate (74.2 g) and acetonitrile (2 litres) that had been cooled to 0°C. The mixture was stined for 1.5 hours and allowed to warm to ambient temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There 30 was thus obtained tert-butyl 4-prop-2-ynylpiperazine-l -carboxylate as an oil (45.5 g); NMR

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 (1-6C)alkyl, m is 1, 2 or 3, each R1 group is selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy and any of the other meanings defined in the description, Ra is hydrogen or halogeno, Rb is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy, Rc is (1-6C)alkoxy, and Rd is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy, or pharmaceutically-acceptable salts 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 cunent 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 ceils (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. Biαchem., 1988, 57, 443; Larsen et al, Ann. Reports in Med. Chem., 1989, Chpt. 13). The first group of tyrosine kinases to be identified arose from such viral oncogenes, for example pp60v"Src tyrosine kinase (otherwise known as v-Src), and the conesponding 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 ldnases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases. The classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGFα, 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, Cunent 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 ldnases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
20 It is known that the Src family of non-receptor tyrosine kinases are highly regulated in normal cells and in the absence of extracellular stimuli are maintained in an inactive conformation. However, some Src family members, for example c-Src tyrosine kinase, are frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer
25 (Cartwright et al, Proc. Natl. Acad. Sci. USA, 1990, 87, 558-562 and Mao et al, Oncogene. 1997, 15, 3083-3090), and breast cancer (Muthuswamy et al, Oncogene, 1995, U, 1801- 1810). The Src family of non-receptor tyrosine kinases has also been located in other common human cancers such as non-small cell lung cancers (NSCLCs) including adenocarcinomas and squamous cell cancer of the lung (Mazurenko et al, European Journal
30 of Cancer, 1992, 28, 372-7), bladder cancer (Fanning et al, Cancer Research, 1992, 52, 1457- 62), oesophageal cancer (JankowsM 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 Biophvs. Res. Comm., 1998, 243, 503-8). As further human tumour tissues are tested for the Src family of non-receptor tyrosine kinases it is expected that its widespread prevalence will be established.
It is further known that the predominant role of c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin. In addition c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility. Likewise, important roles are played by the c-Src, c-Yes and c-Fyn non-receptor tyrosine kinases in integrin mediated signalling and in disrupting cadherin-dependent cell-cell junctions (Owens et al, Molecular Biology of the Cell, 2000, ϋ, 51-64 and Klinghoffer et al, EMBO Journal, 1999, 18, 2459-2471). Cellular motility is necessarily required for a localised tumour to progress through the stages of dissemination into the blood stream, invasion of other tissues and initiation of metastatic tumour growth. For example, colon tumour progression from localised to disseminated, invasive metastatic disease has been conelated 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 cinhosis 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. 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-(3-pyridylamino)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(R ) or C(R )(R ) group wherein each R or R group, which may be the same or different, is hydrogen or (l-6C)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-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula :
Q^X1 - wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R^m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, ( 1 -6C)alkoxycarbonyl, N-(l -6C)alkylcarbamoyl, N,N-di- [( 1 -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(R )CO, wherein R6 is hydrogen or (l-6C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, 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)S02, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl,
N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)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-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
R is hydrogen or halogeno;
R is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; R is (l-6C)alkoxy; and R is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (l-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di-[(l-6Calkyl] amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl- N-ethylamino.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms 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 refened to hereinafter.
Suitable values for the generic radicals refened 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 (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a 'Q' group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a
1 'λ suitable value for any one of the 'Q' groups (Q or Q ) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a 'Q' group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. A suitable value for any one of the 'Q' groups (Q1 to 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, pynolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pynolidinyl, 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-oxopynolidinyl, 2-thioxopynolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopynolidinyl, 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 conesponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
It is to be understood that there is a hydrogen atom at the 2-position on the quinazoline ring in structural Formula I. Thereby 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.
Suitable values for any of the 'R' groups (R , 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-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (l-6C)alkylthio: methylthio, ethylthio and propylthio; for (l-6C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (l-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl] amino: dimethylamino, diethylamino, N-ethyl-
N-methylamino and diisopropylamino; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(l-6C)alkylcarbamoyl: N-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-methylaminopropyl; 25 for di-[(l-6C)alkyl]amino-(l-6C)alkyl: dimethylaminomethyl, diethylaminomethyl,
1-dimethylaminoethyl, 2-dimethylaminoethyl and
3-dimethylaminopropyl; for halogeno-(l-6C)alkyl: chloromethyl, 2-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 ( 1 -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 adj acent 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)2 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 -X3-Q3 and, for example, X3 is a C(R7)2O linking group, it is the carbon atom, not the oxygen atom, of the C(R7)20 linking group which is attached to the CH3 group and the oxygen atom is linked to the Q3 group. A similar convention applies to the attachment of the group of the formula Q2-X2-.
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-pynolidin-l-ylethyl)carbamoyl vinyl or N-[heterocyclyl-(l-6C)alkyl]carbamoylethynyl groups such as N-(2-pynolidin- 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-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CH2 group and there are suitably 1, 2 or 3 such substituents present on each said CH3 group. When, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent as defined hereinbefore, suitable R substituents so formed include, for example, hydroxy-substituted heterocyclyl- (l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy- 3-morpholinopropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-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 -morpholinopropylaminomethyl.
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-δC)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 , Rc and R has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter :- (a) Z is O, S, SO, SO2, CH2 or NH;
(b) Z is O;
(c) Z is NH;
(d) m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylamino, di-[(l-6C)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-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, cycloal yl- (l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is CO or N(R6)CO, wherein R6 is hydrogen or (l-6C)alkyl, and Q 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-6C)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-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylsulρhonyl, 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-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, and from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(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 -pynolidinyl, 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-pynolidinylmethyl, morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or 4-homopiperidinylmethyl, 2-pynolidin-l-ylethyl, 3-pynolidin-2-ylpropyl, pynolidin-2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pynolidin-l-ylpropyl, 4-pynolidin-l-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethyl, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin- 4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin-l-ylethyl, 3-homopiperidin-l-ylpropyl, 2-(l,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 CH2= or HC≡ position a substituent selected from carbamoyl,
N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl or 4-dimethylaminobutyl, or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is CO, NHCO or N(Me)CO and Q2 is pyridyl, pyridylmethyl, 2-pyridylethyl, pynolidin-1-yl, pynolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pynolidin-1-ylmethyl, 2-pynolidin-l-ylethyl, 3-ρynolidin-l-ylpropyl, 4-pynolidin-l-ylbutyl, pynolidin-2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pynolidin-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-ρiρeridin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl, 3-piperazin-l-ylpropyl or 4-ρiperazin-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 CH20 and Q3 is pyridyl, pyridylmethyl, pynolidin-1-yl, pynolidin-2-yl, morpholino, piperidino, piperidin-3-yl, ρiperidin-4-yl, piperazin-1-yl, 2-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, pynolidin- 2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pynolidin-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- l-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 pynolidin-1-ylmethyl, 2-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,
3-ρiperidinopropyl, 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-l-ylethoxy,
3-imidazol-l-ylpropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 3-(l,2,4-triazol-l-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pynolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pynolidin-l-ylethoxy, 3 -pynolidin- 1 -ylpropoxy , 4-pyrrolidin- 1 -ylbutoxy , pynolidin-3 -yloxy , pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3 -pynolidin-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, 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-l-ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-( 1,2,3, 6-tetrahydropyridin- 1 -yl)butoxy , 2-piperazin- 1 -ylethoxy , 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-homopiperazin-l-ylethoxy, 3 -homopiperazin-1 -ylpropoxy, 2-pynolidin-l-ylethylamino, 3-ρynolidin-l-ylpropylamino, 4-pynolidin-l-ylbutylamino, pynolidin-3-ylamino, pynolidin-2-ylmethylamino, 2-pynolidin-2-ylethylamino, 3-pynolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)ethylamino, 3-(l,l-dioxotetrahydro- 4H- 1 ,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-ρiperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin-l -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 X is a direct bond or is NHCO or N(Me)CO and Q is imidazolylmethyl,
2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pynolidin-1-ylmethyl, 2-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, 4-pynolidin-l-ylbutyl, pynolidin-2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pynolidin-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-aminoρropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl,
3-dimethylaminopropyl, 2-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-piperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which 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-pynolidin-l-ylethoxy, 3 -pynolidin-1 -ylpropoxy, 4-pynolidin-l -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(l,l-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-l-ylethoxy, 3-homopiperidin-l-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, amino, methyl, ethyl, methoxy, methylenedioxy, ethylidendioxy and isopropylidenedioxy, and a pynolidin-2-yl, pynolidin-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-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin-l -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-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-l-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 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 pynolidin-2-yl, pynolidin-3-yl, piperidin-3-yl, ρiperidin-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-pynolidin-l -ylethoxy, 3-pynolidin-l-ylpropoxy, 4-pynolidin-l -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy,
3-ρynolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydiO-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-l -ylpropoxy, 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin-l-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 pyιτolidin-2-yl, pynolidin-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, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 3-piperidinyloxy, 4-piperidinyloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the R1 group at the 7-ρosition is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-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-l-ylpropoxy, 3-(l,2,3,6-tetrahydropyridin- l-yl)propoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin-l-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 pynolidin-2-yl, pynolidin-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 hydrogen, fluoro, chloro or bromo; (1) R is chloro or bromo; (m) R is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy; (n) R is hydrogen, chloro or bromo; (o) Rc is methoxy or ethoxy; (p) R is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy; and (q) R 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, R , R , Rc and R has any of the meanings defined hereinbefore provided that :-
(A) R1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinazoline ring i.e. the 2- and 8-positions remain unsubstituted; or
(B) R1 substituents may only be located at the 6- and/or 7-positions on the quinazoline ring i.e. the 2-, 5- and 8-positions remain unsubstituted.
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 and R1 has any of the meanings defined hereinbefore and :- R is chloro or bromo, R is hydrogen, RQ is methoxy or ethoxy and R is hydrogen. Further particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein :- Z is O or NH; m is 2 and each R1 substituent has any of the meanings defined hereinbefore provided that the R1 substituents are located at the 6- and 7-positions on the quinazoline ring; Ra is chloro or bromo; R is hydrogen; Rc is methoxy or ethoxy; and R is hydrogen.
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-ρosition 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-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, 2-(l,2,4-triazol-l-yl)ethoxy, 3-(l,2,4-triazol-l-yl)propoxy, pyrid-2-ylmethoxy, ρyrid-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, ρynolidin-1-yl, morpholino, piperidino, piperazin- 1-yl, 2-pynolidin- 1 -ylethoxy, 3-pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3-yloxy, ρynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-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, 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-l -ylethoxy, 3-homopiperidin-l-ylpropoxy, 2-(l,2,3,6-tetrahydropyridin- l-yl)ethoxy 3-(l,2,3,6-tetrahydropyridin-l-yl)propoxy, 4-( 1,2,3, 6-tetrahydropyridin- l-yl)butoxy, 2-piperazin- 1 -ylethoxy, 3-piperazin-l-ylpropoxy, 4-piperazin-l -ylbutoxy, 2-homopiperazin- 1 -ylethoxy, 3 -homopiperazin- 1 -ylpropoxy, 2-pynolidin- 1 -ylethylamino , 3-pynolidin-l-ylpropylamino, 4-pynolidin- 1-ylbutylamino, pynolidin-3-ylamino, pynolidin-2-ylmethylamino, 2-pynolidin-2-ylethylamino, 3-pynolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethylamino, 3-( 1 , 1 -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-piρeridin-4-ylethylamino , 2-homopiperidin- 1 -ylethylamino ,
3 -homopiperidin- 1 -ylpropylamino, 2-piperazin- 1 -ylethylamino , 3 -piperazin- 1 -ylpropylamino , 4-ρiperazin- 1-ylbutylamino, 2-homopiperazin- 1 -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 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, pynolidin-1-ylmethyl, 2-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, 4-pynolidin-l-ylbutyl, pynolidin-2-ylmethyl, 2-pynolidin-2-ylethyl, 3-pynolidin-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 pynolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- 1-yl or homopiperazin- 1-yl group within a R1 substituent is optionally N-substituted with allyl, 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-pynolidin-l-ylethyl, 3-pynolidin-l-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-l-ylethyl or 3-ρiperazin-l-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; R is hydrogen, fluoro, chloro or bromo;
R is hydrogen, chloro or bromo;
R is 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-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy, 3-pynolidin-2-ylpropoxy, 2-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)proρoxy, 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- 1 -yl)propoxy, 2-piperazin- 1 -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin- 1 -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 pynolidin-2-yl, pynolidin-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;
R is hydrogen, chloro or bromo;
R is hydrogen, chloro or bromo;
R is 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 first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy,
2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy ,
3- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl]propoxy, 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-piρerazin- 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-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- 1 -yl)ethoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy, 4-(4-acetylpiperazin- l-yl)butoxy, 2-(4-isobutyrylpiperazin-l-yl)ethoxy, 3-(4-isobutyrylpiperazin-l-yl)propoxy, 4-(4-isobutyrylpiperazin- 1 -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-tiifluoroethyl)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; and
R is hydrogen, chloro or bromo;
R is hydrogen, chloro or bromo; R is 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 first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-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 -yl)propoxy, 2-(4-prop-2-ynylpiperazin- 1 -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 hydrogen, chloro or bromo;
R is hydrogen, chloro or bromo;
R is 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 first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-pynolidin- 1 -ylethoxy, 3-pynolidin-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- 1 -yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy and 3-(4-acetylpiperazin-l-yl)propoxy; and R is chloro;
R is hydrogen;
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 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, pynolidin-3-yloxy, pynolidin-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-pynolidin- 1 -ylethoxy, 3-pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, 2-ρyιτolidin-2-ylethoxy, 3-pynolidin-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-l-ylpropoxy, 3-(l ,2,3,6-tetrahydropyridin- l-yl)propoxy, 2-piperazin-l -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin- 1 -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 pynolidin-2-yl, pynolidin-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;
R is hydrogen, chloro or bromo; R is hydrogen, chloro or bromo;
Rc is 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 Fonnula 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, 1 , l-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, l,l-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pynolidin-3-yloxy, N-methylpyrroridin-3-yloxy, pynolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin-4-yloxy, N-(2-methoxyethyl)piperidin-4-yloxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from the group of substituents listed immediately above and the second R1 group is located at the 7-position and is selected from 2-pynolidin- 1 -ylethoxy, 3-pynolidin-l-ylρropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-l-yl]propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 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, 2-piperidin-3 -ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, 3 -piperi din-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-l-yl)ethoxy, 3-(4-methylpiperazin-l-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-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-yl]ethoxy,
3 - [4-(2-fluoroethyl)piperazin- 1 -yljpropoxy, 2- [4-(2,2,2-trifluoroethyl)piperazin- 1 -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)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 3-ρyridylmethoxy and 2-cyanopyrid-4-ylmethoxy; Ra is hydrogen, chloro or bromo; R is hydrogen, chloro or bromo; Rc is 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 1 and the R1 group is located at the 5-position and is selected from propoxy, isopropoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, pynolidin-3-yloxy,
N-methylpynolidin-3-yloxy, pynolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin- 3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin- 4-yloxy, 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-pynolidin- 1 -ylethoxy, 3-pynolidin-l -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -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-tetrahydiOpyridin-l-yl)ethoxy, 3-( 1,2,3, 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- 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-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-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-l-yl]propoxy, 2-(4-cyanomethylpiperazin-l-yl)ethoxy, 3-(4-cyanomethylpiperazin-l-yl)propoxy, 2-[2-(4-methylpiρerazin-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;
R is hydrogen, chloro or bromo; R is hydrogen, chloro or bromo;
R° is 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 1 and the R1 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 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-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy, 2- [ (3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy , 3- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 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-piperazin-l -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1 -ylbutoxy, 2-(4-methylpiperazin- 1 -yl)ethoxy , 3 - (4-methylpiperazin- 1 -yl)propoxy , 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-acetylpiperazin- 1 -yl)ethoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy, 2-(4-isobutyrylpiperazin- 1 -yl)ethoxy,
3-(4-isobutyrylpiperazin-l-yl)proρoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]ethoxy and 3-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]propoxy; and
R is chloro or bromo;
R is hydrogen or chloro; R° is 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 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-pynolidin- 1 -ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-[(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-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-yl]propoxy; and
R is chloro;
R is hydrogen or chloro;
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 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-pynolidin- 1 -ylethoxy, 3-pynolidin-l-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(4-methylpiperazin- 1 -y 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
Ra is chloro; R is hydrogen or chloro;
R is methoxy; and
R 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 Example 3, and Examples 4(2) and 4(3) hereinafter and within Example 2, and Examples 14(11) and 14(17) 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, R , R , R 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.
(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 quinazoline of the Formula If
Figure imgf000037_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 IJJ
Figure imgf000037_0002
wherein Z is O, S, or N(R2) and R2, Ra, R , R° and R have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
The reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base. A suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.
A suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpynolidin-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 LI may be reacted with a compound of the Formula HI 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[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
A carboxy protecting group 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, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and
1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri (lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-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 refened 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 imgf000040_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. 3-Aminopyridine starting materials (Formula in, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples. Conesponding 3-hydroxy- and 3-mercaptopyridine 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
Figure imgf000041_0001
wherein Q1 is an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl- (l-6C)alkyl, heteroaryl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group or an optionally substituted alkyl group and X1 is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinazoline of the Formula V
Figure imgf000041_0002
wherein m, R1, Z, Ra, R , Rc and R 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 imgf000042_0001
wherein L is a displaceable group as defined hereinbefore and Z, Ra, R , Rc 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.
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 amine.
The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 180°C, preferably in the range 60 to 120°C. (e) For the production of those compounds of the Formula I wherein R1 is an amino-hydroxy-disubstituted (l-6C)alkoxy group (such as 2-hydroxy-3-pynolidin- 1-ylpropoxy or 3-[N-allyl-N-methylamino]-2-hydroxypropoxy), the reaction of a compound of the Formula I wherein the R1 group contains an epoxy-substituted (l-6C)alkoxy group with a heterocyclyl compound or an appropriate amine.
The reaction is conveniently canied 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. (g) For the production of those compounds of the Formula I wherein an R1 group contains an N-acylated heterocyclic group, the acylation, conveniently in the presence of a suitable base as defined hereinbefore, of a quinazoline derivative of the Formula I wherein the R1 group contains a heterocyclic group having an unsubstituted NH group.
Suitable acylating agents are well known to the man skilled in the art. For example, a compound of the Formula I wherein a R1 group contains a piperidinyl or piperazinyl group having an unsubstituted NH group may be reacted under conventional conditions with an optionally substituted carboxylic acid or a reactive derivative thereof.
A suitable reactive derivative of an optionally substituted carboxylic acid is, for example, a carboxylic acid halide; a carboxylic acid amide; a mixed anhydride, for example an anhydride formed by the reaction of the carboxylic acid and a chloroformate such as isobutyl chloroformate; the product of the reaction of the carboxylic acid with a carbodiimide such as dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide; the product of the reaction of the carboxylic acid with a mixture of an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine; or the product of the reaction of the carboxylic acid with a uronium salt such as 2-(7-azabenzotriazol-l-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate(V). For example, a suitable amino- substituted carboxylic acid is N,N-dimethylglycine and a suitable reactive derivative thereof is
2-dimethylaminoacetyl chloride.
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. 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 kinase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue, (a) In Vitro Enzyme Assay The ability of test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa 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 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; 150μl of a 5% solution in PBS) were transfened into each substrate-coated assay well and incubated for 1 hour at ambient temperature to block non specific binding. The assay plate wells were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and with Hepes pH7.4 buffer (50mM, 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 transfened to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25μl) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40μM) was added to all test wells except the "blank" control wells which contained magnesium chloride without ATP.
Active human c-Src kinase (recombinant enzyme expressed in Sf9 insect cells; obtained from Upstate Biotechnology Inc. product 14-117) was diluted immediately prior to use by a factor of 1:10,000 with an enzyme diluent which comprised lOOmM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA. To start the reactions, aliquots (50μl) of freshly diluted enzyme were added to each well and the plates were incubated at ambient temperature for 20 minutes. The supernatant liquid in each well was discarded and the wells were washed twice with PBST. Mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology 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 NIH 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 (NLH) mouse 3T3 fibroblast cells that had been stably-transfected with an activating mutant (Y530F) of human c-Src. Using a similar procedure to that described by Shalloway et al, Cell, 1987, 49, 65-73,
NIH 3T3 cells were transfected with an activating mutant (Y530F) of human c-Src. The resultant c-Src 3T3 cells were typically seeded at 1.5 x 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 0. 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 CCL185) were suspended at a concentration of 2 x 107 cells/ml in the medium and maintained at a temperature of 37°C. A droplet (2μl) of the cell/agarose mixture was transfened by pipette into the centre of each well of a number of 96-well, flat bottomed non-tissue-culture-treated microtitre plate (Bibby Sterilin Catalogue No. 642000). The plates were placed briefly on ice to speed the gelling of the agarose-containing droplets. Aliquots (90μl) of medium which had been cooled to 4°C were transfened into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (lOμl) of the diluted test compounds were transfened to the wells, again talcing care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% CO2 : 95% air) incubator for about 48 hours. Migration was assessed visually and the distance of migration was measured back to the edge 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 Dicldnson 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 weeldy 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):- IC50 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):- IC50 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;.
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 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.
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 prefened, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
According to a further aspect 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 ldnase 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 ldnases 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 phannaceutically-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 Idnases 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 5α-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 transferase inhibitors, tyrosine kinase inhibitors and serme/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, ZD1839), 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 (Cl 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) anti angiogenic 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 97/32856 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 abenant genes such as abenant p53 or abenant 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) immunotherapy 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, interleuldn 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 cytoldne-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 canied 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;
(iv) high pressure liquid chromatography (HPLC) was performed using a combined liquid chromatography (LC) mass spectrometry (MS) instrument, namely a
Waters 2790 / ZMD Micromass system equipped with a Waters Symmetry column (C18 reverse phase silica, 3 microns, 4.6 mm diameter, 50 mm length), that utilised UN detection at 254 nM; when retention times (RT) were measured the elution flow rate was 2.5 ml/minute and a linear solvent gradient from a 95 : 4.76 : 0.24 mixture of water, methanol and formic acid to a 40 : 55 : 4.76 : 0.24 mixture of water, acetonitrile, methanol and formic acid was applied over 3 minutes followed by a linear solvent gradient applied over 1 minute to a 95 : 4.76 : 0.24 mixture of acetonitrile, methanol and formic acid; (v) yields, where present, are not necessarily the maximum attainable; (vi) 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;
(vii) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis;
(viii) melting points are unconected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products 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; (ix) 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; (x) the following abbreviations have been used:-
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide THF tetrahydrofuran
DMA N,N-dimethylacetamide Example 1 7-(2-chloroethoxy)-4-(2-chloro-5-methoxypyridin-3-yIamino)-6-methoxyquinazoline
A mixture of 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (0.064 g), 3-amino-2-chloro-5-methoxypyridine (0.041 g) and isopropanol (0.5 ml) was stined and heated to 80°C for 30 minutes. The resultant mixture was allowed to cool to ambient temperature. Diethyl ether was added and the solid was isolated. The solid was stined under a mixture of methylene chloride (4.5 ml) and 7M methanolic ammonia solution (0.5 ml). The mixture was filtered and the filtrate was evaporated. There was thus obtained the title compound (0.082 g); NMR Spectrum: (CDC13) 3.95 (s, 3H), 3.96 (t, 2H), 4.08 (s, 3H), 4.46 (t, 2H), 7.08 (s, IH), 7.30 (s, IH), 7.82 (m, 2H), 8.76 (s, IH), 9.01 (s, IH); Mass Spectrum: M+lT" 395 and 397.
The 3-amino-2-chloro-5-methoxypyridine used as a starting material above and 3-amino-2,6-dichloro-5-methoxypyridine used as a starting material in Example 4 hereinafter were prepared as follows :- A solution of hydrogen peroxide (30% aqueous solution; 4.6 ml) in water (5 ml) was added dropwise (approximately 0.05 ml/minute) to a solution of 3-amino-5-methoxypyridine (Y. Tamura et al, J. Org. Chem., 1981, 46, 3564; 3.8 g) in 12N aqueous hydrochloric acid (60 ml) that was heated to 70°C and the resultant mixture was stined and heated to 70°C for 30 minutes. The mixture was cooled to ambient temperature and the precipitate was isolated. The solid so obtained was 3-amino-2,6-dichloro-5-methoxypyridine (0.165 g). The filtrate was cooled to 0°C and the acidity of the solution was reduced to pH4 by the addition of ION aqueous potassium hydroxide solution. The resultant solution was extracted with methylene chloride and the organic layer was 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 diethyl ether as eluent. There was thus obtained 3-amino- 2-chloro-5-methoxypyridine as a white solid (1.3 g); NMR Spectrum: (CDC13) 3.81 (s, 3H), 4.08 (m, 2H), 6.6 (s, IH), 7.51 (s, IH); Mass Spectrum: M+H* 159. On further elution using a 2: 1 mixture of petroleum ether (b.p. 40-60°C) and diethyl ether, there was obtained as a solid a second portion (0.342 g) of 3-amino-2,6-dichloro-5-methoxypyridine; NMR Spectrum: (CDC13) 3.86 (s, 3H), 4.12 (m, 2H), 6.65 (s, IH); Mass Spectrum: M+H1" 193.
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 stined mixture of 7-hydroxy-6-methoxy- 3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (International Patent Application WO 02/16352, Example 2, Note [4] thereof; 85 g), potassium carbonate (77 g) and DMF (400 ml) and the reaction mixture was heated to 70°C for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the solid so obtained was washed with water and dried over phosphorus pentoxide at 50°C. The material so obtained was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 7-(2-chloroethoxy)-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one as a white solid (65.6 g); NMR Spectrum: (CDC13) 1.2 (s, 9H), 3.9 (t, 2H), 4.0 (s, 3H), 4.4 (t, 2H), 5.95 (s, 2H), 7.1 (s, IH), 7.7 (s, IH), 8.2 (s, IH); Mass Spectrum: M+H+ 369 and 371.
A mixture of the material so obtained and a saturated solution of ammonia gas in methanol (1.6 litres) was stined at ambient temperature for 2 days. The solvent was concentrated by evaporation to about one-fourth of the original volume and the precipitate was collected by filtration and washed with diethyl ether. There was thus obtained
7-(2-chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one as a white solid (44 g); NMR Spectrum: (DMSOd6) 3.9 (s, 3H), 4.05 (t, 2H), 4.4 (t, 2H), 7.15 (s, IH), 7.45 (s, IH), 8.0 (s, IH); Mass Spectrum: M+H1" 255 and 257.
A mixture of a portion (5 g) of the material so obtained, thionyl chloride (28 ml) and DMF (0.7 ml) was stined and heated to 80°C for 1.5 hours. The excess of thionyl chloride was evaporated and toluene was added and evaporated. The residual solid was suspended in a mixture of ice and water and basified to pH7.5 by the addition of 2N aqueous sodium hydroxide solution followed by a saturated aqueous sodium bicarbonate solution. The resultant solid was collected by filtration, washed with water and diethyl ether and dried over over phosphorus pentoxide under vacuum. The material so obtained was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and acetonitrile as eluent. There was thus obtained 4-chloro-7-(2-chloroethoxy)- 6-methoxyquinazoline (3.06 g; NMR Spectrum: (CDC13) 3.95 (t, 2H), 4.1 (s, 3H), 4.5 (t, 2H), 7.35 (s, IH), 7.45 (s, IH), 8.9 (s, IH); Mass Spectrum: M+H+ 273 and 275. Example 2
7-[2-(4-acetyIpiperazin-l-yI)ethoxy]-4-(2-chloro-5-methoxypyridin-3-ylamino)-
6-methoxyquinazoline
A mixture of 7-(2-chloroethoxy)-4-(2-chloro-5-methoxypyridin-3-ylamino)- 6-methoxyquinazoline (0.082 g), 1-acetylpiperazine (0.053 g), potassium iodide (0.069 g) and DMA (1 ml) was stined and heated to 95°C for 4 hours. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was injected directly on to a Waters Symmetry column (C18 reversed-phase, 5 microns, 19 mm diameter, 100 mm length) and eluted with decreasingly polar mixtures of water (containing 5% methanol and 1% acetic acid) and acetonitrile. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.059 g); NMR Spectrum: (CDC13) 2.1 (s, 3H), 2.64 (m, 4H), 2.98 (t, 2H), 3.52 (m, 2H), 3.67 (m, 2H), 3.95 (s, 3H), 4.06 (s, 3H), 4.34 (t, 2H), 7.05 (s, IH), 7.31 (s, IH), 7.8 (br s, IH), 7.82 (s, IH), 8.75 (s, IH), 9.01 (s, IH); Mass Spectrum: M+H" 487 and 489.
Example 3
7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-(2-chloro-5-methoxypyridin-3-ylamino)-
5-tetrahydropyran-4-yIoxyquinazoline
A mixture of 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-chloro-5-tetrahydropyran- 4-yloxyquinazoline (0.11 g), 3-amino-2-chloro-5-methoxypyridine (0.042 g) and isopropanol (1 ml) was stined and heated to 80°C for 1 hour. The resultant mixture was allowed to cool to ambient temperature. Diethyl ether was added and the solid was isolated. The solid was stined under a mixture of methylene chloride (9 ml) and a 7M methanolic ammonia solution (1 ml). The mixture was filtered and the filtrate was evaporated. The residue so obtained was purified by column chromatography on silica using a 25: 1 mixture of methylene chloride and methanol as eluent. The solid so obtained was triturated under diethyl ether. There was thus obtained the title compound (0.057 g); NMR Spectrum: (CDC13) 2.09 (m, 2H), 2.1 (s, 3H), 2.23 (m, 2H), 2.59 (m, 4H), 2.9 (m, 2H), 3.7-3.5 (m, 6H), 3.92 (s, 3H), 4.09 (m, 2H), 4.25 (m, 2H), 4.76 (m, IH), 6.62 (s, IH), 6.87 (s, IH), 7.84 (s, IH), 8.6 (s, IH), 8.74 (s, IH); Mass Spectrum: M+H* 557 & 559.
The 7- [2-(4-acetylpiperazin- 1 -yl)ethoxy] -4-chloro-5-tetrahydropyran- 4-yloxyquinazoline used as a starting material was prepared as follows :- Sodium hydride (60% dispersion in mineral oil; 0.6 g) was added portionwise to a solution of 4-hydroxytetrahydropyran (0.78 g) in DMF (10 ml) that had been cooled to 5°C. The mixture was allowed to warm to ambient temperature and was stined for 15 minutes. 5,7-Difluoro-3,4-dihydroquinazolin-4-one (International Patent Application WO 01/94341; 0.9 g) was added and the mixture was stined at ambient temperature for 30 minutes. The mixture was poured into water (100 ml) and, with vigorous stirring, glacial acetic acid was added to acidify the mixture to pH5. The resultant solid was isolated, washed with water and with diethyl ether and dried under vacuum. There was thus obtained 7-fluoro- 5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1.1 g); NMR Spectrum: (DMSOd6) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.5-3.6 (m, 2H), 3.85-3.95 (m, 2H), 4.8 (m, IH), 6.9 (m, IH), 7.05 (m, IH), 8.0 (s, IH); Mass Spectrum: M+H" 265.
After repetition of the prior reaction, a mixture of 7-fluoro-5-tetrahydropyran- 4-yloxy-3,4-dihydroquinazolin-4-one (5.3 g), 2-piperazin- 1-ylethanol (3.9 g), potassium tert-butoxide (6.7 g) and THF (200 ml) was stined and heated to reflux for 3 hours. A second portion (6.7 g) of potassium tert-butoxide was added and the mixture was heated to reflux for a further 12 hours. The mixture was cooled to ambient temperature and filtered. The filtrate 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. The material so obtained was triturated under diethyl ether. There was thus obtained 7-(2-piperazin-l-ylethoxy)-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5.2 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.75 (m, 2H), 2.03 (m, 2H), 3.2-4.0 (m, 14H), 4.59 (m, 2H), 4.92 (m, IH), 6.88 (s, IH), 6.9 (s, IH), 9.28 (s, IH); Mass Spectrum: M+H" 375.
Acetic anhydride (1.51 ml) was added dropwise to a stined 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 stined 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. There was thus obtained 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4-yloxy- 3,4-dihydroquinazolin-4-one (5.5 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.75 (m, 2H), 2.03 (m, 2H), 2.08 (s, 3H), 3.0-4.2 (m, 13H), 4.56 (m, 3H), 4.94 (m, IH), 6.84 (s, IH), 6.9 (s, IH), 9.21 (s, IH); Mass Spectrum: M+H" 417.
A mixture of a portion (0.416 g) of the material so obtained, triphenylphosphine (0.655 g), carbon tetrachloride (0.34 ml) and 1,2-dichloroethane (20 ml) was stined and heated to 70°C for 1.5 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 (a solvent gradient having from 1% to 3% methanolic ammonia solution) as eluent. There was thus obtained 7-[2-(4-acetylpiperazin-l-yl)ethoxy]- 4-chloro-5-tetrahydropyran-4-yloxyquinazoline as a solid (0.35 g); NMR Spectrum: (CDC13) 2.0 (m, 2H), 2.1 (s, 3H), 2.12 (m, 2H), 2.58 (m, 4H), 2.9 (m, 2H), 3.51 (m, 2H), 3.68 (m, 4H), 4.05 (m, 2H), 4.25 (m, 2H), 4.75 (m, IH), 6.62 (s, IH), 6.94 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H+ 435 and 437.
Example 4
Using an analogous procedure to that described in Example 3, the appropriate 4-chloroquinazoline was reacted with the appropriate 3-aminopyridine to give the compounds described in Table I. Unless otherwise stated, each compound described in Table I was obtained as a free base. Table I
Figure imgf000059_0001
Notes [1] The product was obtained in 26% yield and gave the following characterising data; NMR Spectrum: (CDC13) 2.08 (m, 2H), 2.1 (s, 3H), 2.23 (m, 2H), 2.57 (m, 4H), 2.9 (m, 2H), 3.68-3.51 (m, 6H), 4.0 (s, 3H), 4.1 (m, 2H), 4.25 (m, 2H), 4.76 (m, IH), 6.64 (s, IH), 6.88 (s,
IH), 8.6 (s, IH), 8.91 (s, IH), 9.93 (s, IH); Mass Spectrum: M+H* 591 and 593.
[2] The product was obtained in 54% yield and gave the following characterising data;
NMR Spectrum: (CDC13) 1.57 (s, 3H), 1.59 (s, 3H), 2.1 (s, 3H), 2.59 (m, 4H), 2.89 (t, 2H, J= 5.5 Hz), 3.52 (m, 2H), 3.67 (m, 2H), 3.92 (s, 3H), 4.25 (t, 2H, J= 5.5 Hz), 4.89 (m, IH), 6.6 (s,
IH), 6.85 (s, IH), 7.82 (s, IH), 8.6 (s, IH), 8.81 (s, IH); Mass Spectrum: M+H1" 515 and 517. Using analogous procedures to those described in the portion of Example 3 that is concerned with the preparation of starting materials, the 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-
4-chloro-5-isopropoxyquinazoline that is required as a starting material was prepared. Thus :- 5,7-Difluoro-3,4-dihydroquinazolin-4-one was reacted with isopropanol to give
7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one in 73% yield; NMR Spectrum:
(DMSOd6) 1.31 (s, 6H), 4.73 (m, IH), 6.89 (m, IH), 6.95 (m, IH), 7.96 (s, IH); Mass
Spectrum: M+H1" 223.
The material so obtained was reacted with 2-piperazin- 1-ylethanol to give 5-isopropoxy-7-(2-piperazin-l-ylethoxy)-3,4-dihydroquinazolin-4-one in 63% yield; NMR
Spectrum: (CDC13) 1.45 (s, 3H), 1.46 (s, 3H), 2.4-3.0 (m, 10H), 4.2 (t, 2H), 4.62 (m, IH), 6.51
(s, IH), 6.72 (s, IH), 7.9 (s, IH).
The material so obtained was reacted with an excess of acetic anhydride but using methylene chloride rather than water as the reaction solvent. The reaction mixture was stined at ambient temperature for 15 minutes. The mixture was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of acetonitrile and diethyl ether. There was thus obtained
7-[2-(4-acetylpiperazin-l-yl)ethoxy]-5-isopropoxy-3,4-dihydroquinazolin-4-one in 70% yield; NMR Spectrum: (CDC13) 1.46 (s, 3H), 1.47 (s, 3H), 2.1 (s, 3H), 2.58 (m, 4H), 2.87 (t, 2H),
3.5 (m, 2H), 3.66 (m, 2H), 4.21 (t, 2H), 4.63 (m, IH), 6.51 (s, IH), 6.72 (s, IH), 7.9 (s, IH),
9.9 (br s, IH); Mass Spectrum: M+H* 375.
The material so obtained was reacted with carbon tetrachloride and triphenylphosphine to give 7-[2-(4-acetylpiperazin-l-yl)ethoxy]-4-chloro-5-isopropoxyquinazoline in 68% yield which was used without further purification.
[3] The product was obtained in 51% yield and gave the following characterising data;
NMR Spectrum: (CDC13) 1.57 (s, 3H), 1.59 (s, 3H), 2.1 (s, 3H), 2.59 (m, 4H), 2.89 (t, 2H,
J= 5.5 Hz), 3.52 (m, 2H), 3.67 (m, 2H), 3.92 (s, 3H), 4.25 (t, 2H, J= 5.5 Hz), 4.89 (m, IH), 6.6 (s, IH), 6.85 (s, IH), 7.82 (s, IH), 8.6 (s, IH), 8.81 (s, IH); Mass Spectrum: M+H" 549 and 551.
Example 5 4-(2-chloro-5-methoxypyridin-3-ylamino)-7-hydroxy-5-tetrahydropyran- 4-yloxyquinazoIine
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; 0.966 g), phosphoryl chloride (0.353 ml), N,N-diisopropyl-N-ethylamine (1.43 ml) and methylene chloride (20 ml) was stined and heated to 80°C for 2.5 hours. The resultant mixture was cooled and the solvents were evaporated under vacuum. A mixture of the material so obtained, 3-amino-2-chloro-5-methoxypyridine (0.527 g) and isopropanol (10 ml) was stined and heated to 80°C for 1 hour. The resultant mixture was allowed to cool to ambient temperature and evaporated under vacuum. The residue was dissolved in 7M methanolic ammonia solution (10 ml) and the mixture was stined at ambient temperature for 1 hour. The solvents were evaporated under vacuum and the residue was triturated under a 1:1 mixture of diethyl ether and isopropanol. The resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (0.99 g); NMR Spectrum: (CDC13) 2.09 (m, 2H), 2.2 (m, 2H), 3.48 (m, 2H), 3.93 (s, 3H), 4.06 (m, 2H), 4.69 (m, IH), 6.61 (s, IH), 6.98 (s, IH), 7.81 (s, IH), 8.42 (s, IH), 8.72 (s, IH); Mass Spectrum: M+H1" 403 & 405.
Example 6
4-(2-chloro-5-methoxypyridin-3-ylamino)-7-(3-chloropropoxy)-5-tetrahydropyran-
4-yloxyquinazoIine A mixture of 4-(2-chloro-5-methoxypyridin-3-ylamino)-7-hydroxy-5-tetrahydropyran-
4-yloxyquinazoline (0.5 g), l-bromo-3-chloropropane (0.135 ml), caesium carbonate (1.21 g) and DMF (5 ml) was stined and heated to 60°C for 80 minutes. The mixture was cooled to ambient temperature and the solvents were evaporated. The residue was purified by column chromatography on silica using a 20: 1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.405 g); NMR Spectrum: (CDC13) 2.1 ( , 2H), 2.23 (m, 2H), 2.31 (m, 2H), 3.58 (m, 2H), 3.78 (t, 2H), 3.93 (s, 3H), 4.1 (m, 2H), 4.27 (t, 2H), 4.77 (m, IH), 6.6 (s, IH), 6.9 (s, IH), 7.84 (s, IH), 8.61 (s, IH), 8.75 (s, IH); Mass Spectrum: M+H* 479 and 481. Example 7
4-(2-chIoro-5-methoxypyridin-3-ylamino)-7-(2-chloroethoxy)-5-tetrahydropyran-
4-yloxyquinazoline
A mixture of 4-(2-chloro-5-methoxypyridin-3-ylamino)-7-hydroxy-5-tetrahydropyran- 4-yloxyquinazoline (0.5 g), 1,2-dichloroethane (6 ml), potassium carbonate (0.257 g) and DMF (3 ml) was stined and heated to 80°C for 80 minutes. The mixture was cooled to ambient temperature and the solvents were evaporated. The residue was purified by column chromatography on silica using a 25:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.386 g); NMR Spectrum: (CDC1 ) 2.1 (m, 2H), 2.23 (m, 2H), 3.58 (m, 2H), 3.9 (t, 2H), 3.93 (s, 3H), 4.1 (m, 2H), 4.38 (t, 2H), 4.77 (m, IH), 6.66 (s, IH), 6.85 (s, IH), 7.84 (s, IH), 8.61 (s, IH), 8.74 (s, IH); Mass Spectrum: M+H* 465 and 467.
Example 8 7-(3-chloropropoxy)-4-(2-chloro-5-methoxypyridin-3-ylamino)-6-methoxyquinazoline
Using an analogous procedure to that described in Example 1, 4-chloro- 7-(3-chloropropoxy)-6-methoxyquinazoline was reacted with 3-amino-2-chloro- 5-methoxypyridine to give the title compound as a solid in 76% yield; NMR Spectrum: (DMSOd6) 2.3 (m, 2H), 3.84 (t, 2H), 3.89 (s, 3H), 4.0 (s, 3H), 4.32 (t, 2H), 7.31 (s, IH), 7.77 (s, IH), 8.03 (s, IH), 8.19 (s, IH), 8.69 (s, IH); Mass Spectrum: M+H4" 409 and 411.
The 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline used as a starting material was prepared as follows :-
Ammonium formate (45 g) was added portionwise over 1.25 hours to a stined 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 stined for an additional 30 minutes. The catalyst was removed by filtration and the solvent was evaporated. There was thus obtained 7-hydroxy- 6-methoxy-3,4-dihydroquinazolin-4-one (8.65 g); NMR Spectrum: (DMSOd6) 3.9 (s, 3H), 7.0 (s, IH), 7.45 (s, IH), 7.9 (s, IH). A mixture of the material so obtained, acetic anhydride (63 ml) and pyridine (7.5 ml) was heated to 100°C for 4.5 hours. The resultant mixture was allowed to stand at ambient temperature for 16 hours. The mixture was poured into a stined mixture (400 ml) of ice and water. The resultant precipitate was isolated and dried under vacuum. Analysis revealed that hydrolysis of the acetate group on the 4 position of the quinazoline was incomplete. The mixture was therefore further hydrolysed with water (150 ml) and pyridine (a few drops) at 90°C for 15 minutes. The resultant mixture was cooled to ambient temperature and the solid was collected by filtration, washed with water and dried under vacuum. There was thus obtained 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (7.4 g); NMR Spectrum: (DMSOd6) 2.3 (s, 3H), 3.9 (s, 3H), 7.45 (s, IH), 7.65 (s, IH), 8.05 (s, IH).
A mixture of a portion (2 g) of the material so obtained, thionyl chloride (32 ml) and DMF (5 drops) was stined and heated to reflux for 1.5 hours. The mixture was cooled to ambient temperature and the excess of thionyl chloride was evaporated. Toluene was added to the residue and evaporated. The resultant residue was diluted with methylene chloride (15 ml) and a 10% ammonia solution in methanol (80 ml) was added and the mixture was heated to 80°C for 10 minutes. The mixture was cooled to ambient temperature and evaporated. Water was added to the residue and the mixture was neutralised by the addition of dilute aqueous hydrochloric acid solution. The resultant precipitate was collected by filtration and dried under vacuum at 35°C for 16 hours. There was thus obtained 4-chloro- 7-hydroxy-6-methoxyquinazoline (1.65 g); NMR Spectrum: (DMSOd6) 4.0 (s, 3H), 7.25 (s, IH), 7.4 (s, IH), 8.8 (s, IH).
Di-tert-butyl azodicarboxylate (2.3 g) was added portionwise over a few minutes to a stined 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 stined 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. There was thus obtained 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline as a white solid (2 g); NMR Spectrum: (DMSOd6) 2.3 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.4 (m, 2H), 7.45 (s, IH), 7.55 (s, IH), 8.9 (s, IH).
Example 9
4-(2-chloro-5-methoxypyridin-3-yIamino)-7-(2,4-dimethoxybenzyloxy)- 5-isopropoxyquinazoIine
A mixture of 4-chloro-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline (1.5 g), 3-amino-2-chloro-5-methoxypyridine (0.64 g) and isopropanol (15 ml) was stined and heated to 80°C for 45 minutes. The resultant mixture was allowed to cool to ambient temperature. Diethyl ether was added and the solid was isolated. There was thus obtained the title compound (1.81 g) as ahydrochloride salt; NMR Spectrum: (CDC13) 1.58 (s, 3H), 1.59 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 3.94 (s, 3H), 4.92 (m, IH), 5.25 (s, 2H), 6.25 (m, 2H), 6.74 (s, IH), 7.37 (d, IH), 7.67 (s, IH), 8.0 (s, IH), 8.32 (s, IH), 8.66 (s, IH); Mass Spectrum: M+H4" 51 l and 513.
The 4-chloro-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline used as a starting material was prepared as follows :-
A mixture of 7-fluoro-5-isopropoxy-3,4-dihydroquinazolin-4-one (61 g), 2,4-dimethoxybenzyl alcohol (138 g), potassium tert-butoxide (185 g) and THF (1.5 litres) was stined and heated to reflux for 18 hours. After cooling, the solvent was evaporated and a mixture of methylene chloride (400 ml) and water (600 ml) was added. With cooling, the 2-phase mixture was neutralised by the addition of 2N aqueous hydrochloric acid. The mixture was filtered and the organic phase was separated, dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether. There was thus obtained 7-(2,4-dimethoxybenzyloxy)-5-isopropoxy-3,4-dihydroquinazolin-4-one (68 g); NMR
Spectrum: (DMSOd6) 1.28 (s, 6H), 3.78 (s, 3H), 3.82 (s, 3H), 4.63 (m, IH), 5.06 (s, 2H), 6.55 (m, 2H), 6.62 (s, IH), 6.71 (s, IH), 7.33 (d, IH), 7.88 (s, IH); Mass Spectrum: M+H4" 371.
A mixture of a portion (4 g) of the material so obtained, phosphoryl chloride (1.98 g), N,N-diisopropyl-N-ethylamine (3.6 g) and methylene chloride (100 ml) was stined and heated to 75 °C for 3 hours. The mixture was cooled and evaporated. The residue was dried under vacuum for 1 hour and purified by column chromatography on silica using a 20:3 mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained 4-chloro-7-(2,4-dimethoxybenzyloxy)-5 isopropoxyquinazoline as a solid (2.63 g); NMR Spectrum: (CDC13) 1.46 (s, 3H), 1.47 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.68 (m, IH), 5.16 (s, 2H), 6.52 (m, 2H), 6.65 (s, IH), 7.06 (s, IH), 7.33 (d, IH), 8.78 (s, IH); Mass Spectrum: M+H+ 389.
Example 10 4-(2-chloro-5-methoxypyridin-3-ylamino)-7-hydroxy-5-isopropoxyquinazoline Trifluoroacetic acid (3 ml) was added to a solution of 4-(2-chloro-5-methoxypyridin-
3-ylamino)-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline hydrochloride (1.81 g) in methylene chloride (27 ml) and the reaction mixture was stined at ambient temperature for 1 hour. The solvents were evaporated. Toluene was added and the mixture was evaporated. A 7M methanolic ammonia solution (30 ml) was added and the mixture was stined for 20 minutes. The solvents were evaporated, the precipitate was suspended in a 10:1 mixture of methylene chloride and methanol and the mixture was stined vigorously for 2 hours. The solid so obtained was filtered off and the filtrate was evaporated. There was thus obtained the title compound (2.31 g); Mass Spectrum: M+H1" 361 and 363.
Example 11 4-(2-chϊoro-5-methoxypyridin-3-yIamino)-7-(3-chloropropoxy-5-isopropoxy)quinazoline
Using an analogous procedure to that described in Example 6, 4-(2-chloro- 5-methoxypyridin-3-ylamino)-7-hydroxy-5-isopropoxyquinazoline was reacted with l-bromo-3-chloropropane to give the title compound as a solid in 65% yield; Mass Spectrum: M+H4" 437 and 439.
Example 12 4-(2-chloro-5-methoxypyridin-3-ylamino)-7-(2-chloroethoxy-5-isopropoxy)quinazoIine
Using an analogous procedure to that described in Example 7, 4-(2-chloro- 5-methoxypyridin-3-ylamino)-7-hydroxy-5-isopropoxyquinazoline was reacted with 1,2-dichloroethane to give the title compound as a solid in 68% yield; Mass Spectrum: M+H4" 423 and 425.
Example 13
4-(2-chIoro-5-methoxypyridin-3-ylamino)-7-[3-(4-methylpiperazin-l-yl)propoxy]-
5-tetrahydropyran-4-yloxyquinazoline
A mixture of 4-(2-chloro-5-methoxypyridin-3-ylamino)-7-(3-chloropropoxy)- 5-tetrahydropyran-4-yloxyquinazoline (0.069 g), 1-methylpiperazine (0.05 g), potassium iodide (0.042 g) and DMA (1 ml) was stined and heated to 90°C for 4 hours. 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. There was thus obtained the title compound as a solid (0.012 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.05 (m, 2H), 2.15 (m, 2H), 2.26 (m, 2H), 2.6 (m, 8H), 2.96 (s, 3H), 3.45 (m, 2H), 3.54 (m, 2H), 3.92 (s, 3H), 3.97 (m, 2H), 4.33 (m, 2H), 5.16 (m, IH), 6.96 (s, IH), 7.15 (s, IH), 8.07 (s, IH), 8.2 (s, IH), 8.93 (s, IH); Mass Spectrum: M+H1" 543 and 545.
Example 14 Using an analogous procedure to that described in Example 13, the appropriate chloroalkoxy substituted quinazoline was reacted with the appropriate heterocycle to give the compounds described in Table H. Unless otherwise stated, each compound described in Table H was obtained as a free base and, generally, the products were obtained in a yield in the range of 15% to 70%. Table II
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000067_0001
Notes
[1] The product was obtained in 49% yield and gave the following characterising data;
NMR Spectrum: (DMSOd6) 1.85 (m, 2H), 1.96 (m, 2H), 1.99 (s, 3H), 2.15 ( , 2H), 2.4-2.3 (m, 4H), 2.5 (m, 2H), 3.3 (m, 2H), 3.42 (m, 2H), 3.52 (m, 2H), 3.89 (s, 3H), 3.92 (m, 2H), 4.2
(m, 2H), 5.06 (m, IH), 6.87 (s, IH), 6.97 (s, IH), 7.94 (s, IH), 8.53 (s, IH), 8.61 (s, IH), 9.88
(s, IH); Mass Spectrum: M+H4" 571 and 573.
[2] After the reaction mixture was cooled to ambient temperature, water (2 ml) was added.
The solid was isolated, washed in turn with water and with diethyl ether and dried. The product so obtained in 85% yield gave the following characterising data; NMR Spectrum:
(DMSOd6 and CF3CO2D) 2.03 (m, 2H), 2.14 (m, 2H), 2.26 (m, 2H), 3.17 (m, 2H), 3.36 (m,
2H), 3.55 (m, 4H), 3.71 (m, 2H), 3.92 (s, 3H), 3.96 (m, 2H), 4.05 (m, 2H), 4.33 (m, 2H), 5.17
(m, IH), 6.94 (s, IH), 7.16 (s, IH), 8.07 (s, IH), 8.20 (s, IH), 8.92 (s, IH); Mass Spectrum:
M+H1" 530 and 532. [3] The product gave the following characterising data; NMR Spectrum: (DMSOdg and
CF3CO2D) 2.05 (m, 2H), 2.15 (m, 2H), 2.5 (m, 8H) 2.95 (s, 3H), 3.53 (m, 2H), 3.77 (m, 2H),
3.92 (s, 3H), 3.98 (m, 2H), 4.63 (m, 2H), 5.13 (m, IH), 7.0 (s, IH), 7.17 (s, IH), 8.07 (s, IH),
8.2 (s, IH), 8.93 (s, IH); Mass Spectrum: M+H4" 529 and 531. [4] The product gave the following characterising data; NMR Spectrum: (DMSOd6 and
CF3CO2D) 2.03 (m, 2H), 2.15 (m, 2H), 3.28 (m, 2H), 3.55 (m, 4H), 3.73 (m, 4H), 3.91 (s,
3H), 3.97 (m, 2H), 4.02 (m, 2H), 4.63 (m, 2H), 5.15 (m, IH), 7.0 (s, IH), 7.18 (s, IH), 8.06 (s,
IH), 8.2 (s, IH), 8.93 (s, IH); Mass Spectrum: M+H4" 516 and 518. 5 [5] The product gave the following characterising data; NMR Spectrum: (DMSOd6 and
CF3CO2D) 1.95 (m, 2H), 2.06 (m, 4H), 2.17 (m, 2H), 3.21 (m, 2H), 3.55 (m, 2H), 3.70 (m,
4H), 3.92 (s, 3H), 3.98 (m, 2H), 4.60 (m, 2H), 5.18 (m, IH), 7.00 (s, IH), 7.20 (s, IH), 8.07 (s,
IH), 8.20 (s, IH), 8.95 (s, IH); Mass Spectrum: M+H4" 500 and 502.
[6] The product gave the following characterising data; NMR Spectrum: (DMSOd6 and 10 CF3CO2D) 1.45 (m, 2H), 1.75 (m, 2H), 1.88 (m, 2H), 2.04 (m, 2H), 2.17 (m, 2H), 3.08 (m,
2H), 3.65-3.5 (m, 6H), 3.92 (s, 3H), 3.98 (m, 2H), 4.63 (m, 2H), 5.18 (m, IH), 7.0 (s, IH), 7.2
(s, IH), 8.08 (s, IH), 8.2 (s, IH), 8.95 (s, IH); Mass Spectrum: M+H4" 514 and 516.
[7] The product was obtained in 26% yield and gave the following characterising data;
HPLC RT: 1.29 minutes; Mass Spectrum: M+H4" 430 and 432. 15 [8] The product was obtained in 24% yield and gave the following characterising data;
HPLC RT: 1.41 minutes; Mass Spectrum: M+H1" 444 and 446.
[9] The product was obtained in 24% yield and gave the following characterising data;
HPLC RT: 1.56 minutes; Mass Spectrum: M+H4" 446 and 448.
[10] The product was obtained in 18% yield and gave the following characterising data; 20 HPLC RT: 1.3 minutes; Mass Spectrum: M+H+ 459 and 461.
[11] The product was obtained in 15% yield and gave the following characterising data;
HPLC RT: 1.62 minutes; Mass Spectrum: M+H4" 483 and 485.
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 25 10 minutes to a stined mixture of 1 -tert-butoxycarbonylpiperazine (50 g), potassium carbonate (74.2 g) and acetonitrile (2 litres) that had been cooled to 0°C. The mixture was stined for 1.5 hours and allowed to warm to ambient temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There 30 was thus obtained tert-butyl 4-prop-2-ynylpiperazine-l -carboxylate as an oil (45.5 g); NMR
Spectrum: (CDC13) 1.4 (s, 9H), 2.2 (s, IH), 2.45 (m, 4H), 3.3 (s, 2H), 3.45 (m, 4H).
A solution of the material so obtained in methylene chloride (100 ml) was added slowly to a solution of hydrogen chloride gas in 1,4-dioxane (4M, 450 ml). The reaction was slightly exothermic and a precipitate formed as carbon dioxide gas was evolved. The mixture was stined at ambient temperature for 1 hour. The resultant mixture was evaporated and the residue was suspended in methylene chloride. A solution of ammonia gas in methanol (7M, 110 ml) was added and the mixture was stined at ambient temperature for 15 minutes. The mixture was filtered and the filtrate was evaporated. An oil was obtained which crystallised on standing. There was thus obtained l-prop-2-ynylpiperazine (23 g); NMR Spectrum: (CDCI3) 2.2 (s, IH), 2.5 (br s, 4H), 2.85 (m, 4H), 3.25 (s, 2H).
[12] The product was obtained in 21% yield and gave the following characterising data; HPLC RT: 1.36 minutes; Mass Spectrum: M+H4" 444 and 446. [13] The product was obtained in 30% yield and gave the following characterising data; HPLC RT: 1.38 minutes; NMR Spectrum: (DMSOd6) 1.96 (m, 2H), 2.39 (m, 4H), 2.46 (t, 2H), 3.59 (m, 4H), 3.87 (s, 3H), 3.95 (s, 3H), 4.19 (t, 2H), 7.21 (s, IH), 7.72 (s, IH), 7.81 (s, IH), 8.09 (s, IH), 8.36 (s, IH), 9.6 (s, IH); Mass Spectrum; M+H4" 460 and 462. [14] The product was obtained in 19% yield and gave the following characterising data; HPLC RT: 1.19 minutes; Mass Spectrum: M+H+ 473 and 475.
[15] The product was obtained in 30% yield and gave the following characterising data; HPLC RT: 1.55 minutes; Mass Spectrum: M+H4" 501 and 503.
[16] The product was obtained in 17% yield and gave the following characterising data; HPLC RT: 1.48 minutes; Mass Spectrum: M+H4" 497 and 499. [17] The product was obtained in 15% yield and gave the following characterising data; HPLC RT: 1.41 minutes; Mass Spectrum: M+H+ 458 and 460.
[18] The product was obtained in 17% yield and gave the following characterising data; NMR Spectrum: (CDCI3) 1.57 (s, 3H), 1.59 (s, 3H), 2.02 (m, 2H), 2.33 (s, 3H), 2.55 (m, 10H), 3.92 (s, 3H), 4.15 (t, 2H), 4.89 (m, IH), 6.57 (s, IH), 6.85 (s, IH), 7.82 (s, IH), 8.59 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H4" 501 and 503.
[19] The product was obtained in 20% yield and gave the following characterising data; NMR Spectrum: (CDCI3) 1.58 (s, 3H), 1.59 (s, 3H), 2.04 (m, 2H), 2.1 (s, 3H), 2.47 (m, 4H), 2.58 (t, 2H), 3.49 (m, 2H), 3.63 (m, 2H), 3.92 (s, 3H), 4.17 (t, 2H), 4.89 ( , IH), 6.57 (s, IH), 6.86 (s, IH), 7.82 (s, IH), 8.59 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H4" 529 and 531. [20] After the reaction mixture was cooled to ambient temperature, the solvent was evaporated under vacuum. The residue was triturated under water and the resultant solid was isolated and dried. The product so obtained in 55% yield gave the following characterising data; NMR Spectrum: (CDCI3) 1.58 (s, 3H), 1.59 (s, 3H), 1.9 (m, 4H), 2.9 (m, 4H), 3.17 (m, 2H), 3.92 (s, 3H), 4.35 (m, 2H), 4.92 (m, IH), 6.80 (br s, IH), 6.84 (s, IH), 7.82 (s, IH), 8.59
(s, IH), 8.81 (s, IH); Mass Spectrum: M+H4" 458 and 460.
[21] The product, which was obtained in 51% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDC13) 1.5 (m, 2H), 1.57 (s, 3H), 1.58 (s, 3H), 1.65 (m, 4H), 2.55 (m, 4H), 2.86 (m, 2H), 3.92 (s, 3H),
4.25 (t, 2H), 4.88 (m, IH), 6.63 (s, IH), 6.84 (s, IH), 7.82 (s, IH), 8.6 (s, IH), 8.82 (s, IH);
Mass Spectrum: M+H" 472 and 474.
[22] The product, which was obtained in 57% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDCI3) 1.57 (s, 3H), 1.58 (s, 3H), 2.6 (m, 4H), 2.89 (t, 2H), 3.76 (m, 4H), 3.92 (s, 3H), 4.25 (t, 2H), 4.89
(m, IH), 6.62 (s, IH), 6.85 (s, IH), 7.82 (s, IH), 8.6 (s, IH), 8.82 (s, IH); Mass Spectrum:
M+H4" 474 and 476.
[23] The product, which was obtained in 62% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDC13) 1.57 (s, 3H), 1.59 (s, 3H), 2.32 (s, 3H), 2.8-2.5 (m, 8H), 2.89 (t, 2H), 3.92 (s, 3H), 4.24 (t, 2H),
4.89 (m, IH), 6.61 (s, IH), 6.84 (s, IH), 7.82 (s, IH), 8.6 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H4" 487 and 489.
[24] The product, which was obtained in 53% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDC13) 1.57 (s, 3H), 1.58 (s, 3H), 2.26 (s, IH), 2.67 (m, 8H), 2.90 (m, 2H), 3.32 (s, 2H), 3.92 (s, 3H), 4.25 (t, 2H), 4.89 (m, IH), 6.62 (s, IH), 6.84 (s, IH), 7.82 (s, IH), 8.6 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H4" 511 and 513.
[25] The product, which was obtained in 55% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDC13) 1.58 (s, 3H), 1.59 (s, 3H), 1.93 (m, 4H), 2.21 (m, 2H), 2.9-2.7 (m, 6H), 3.92 (s, 3H), 4.18 (t, 2H),
4.90 (m, IH), 6.59 (s, IH), 6.84 (s, IH), 7.82 (s, IH), 8.59 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H4" 472 and 474.
[26] The product, which was obtained in 67% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDC13) 1-57 (s, 3H), 1.59 (s, 3H), 2.04 (m, 2H), 2.50 (m, 4H), 2.56 (m, 2H), 3.74 (m, 4H), 3.92 (s, 3H), 4.17 (t, 2H), 4.89 ( , IH), 6.57 (s, IH), 6.86 (s, IH), 7.82 (s, IH), 8.59 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H+ 488 and 490. [27] The product, which was obtained in 68% yield using an analogous work-up to that described in Note [20], gave the following characterising data; NMR Spectrum: (CDC13) 1.57 (s, 3H), 1.59 (s, 3H), 2.04 (m, 2H), 2.5 (m, 4H), 2.56 (m, 2H), 3.74 (m, 4H), 3.92 (s, 3H), 4.17 (t, 2H), 4.89 (m, IH), 6.57 (s, IH), 6.86 (s, IH), 7.82 (s, IH), 8.59 (s, IH), 8.82 (s, IH); Mass Spectrum: M+H4" 525 and 527.

Claims

1. A quinazoline derivative of the Formula I
Figure imgf000072_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-6C)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-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl- (3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino,
N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonylamino and N-(l-6C)alkyl-(l-6C)alkanesulphonylamino, or from a group of the formula : cZ-x1- wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (l-6C)alkyl, and Q1 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R^m is (l-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH=CH and C≡C wherein R5 is hydrogen or (l-6C)alkyl or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula :
Q2-X2- wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (l-6C)alkyl, and Q2 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, 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)S02, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (l-6C)alkyl, and Q3 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)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-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino- (l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl or (l-6C)alkoxycarbonylamino-(l-6C)alkyl, or from a group of the formula :
-X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (l-6C)alkyl, and Q4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
R is hydrogen or halogeno; R is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy;
Rc is (l-6C)alkoxy; and
R is hydrogen, halogeno, (l-6C)alkyl or (l-6C)alkoxy; or a pharmaceutically-acceptable salt thereof.
2. A quinazoline derivative of the Formula I according to claim 1 wherein :-
Z is O or NH; m is 2 and each R1 substituent has any of the meanings defined in claim 1 provided that the R1 substituents are located at the 6- and 7-positions on the quinazoline ring;
Ra is chloro or bromo; R is hydrogen;
Rc is methoxy or ethoxy; and R is hydrogen; or a pharmaceutically-acceptable salt thereof.
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 R 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-pynolidin- 1 -ylethoxy, 3 -pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, pynolidin-3-yloxy, pynolidin-2-ylmethoxy, 2-pynolidin-2-ylethoxy,
3-pynolidin-2-ylpropoxy, 2-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, 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-l -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin- 1 -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 pynolidin-2-yl, pynolidin-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 hydrogen, chloro or bromo; R is hydrogen, chloro or bromo; R is methoxy or ethoxy; and R 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-pynolidin- 1 -ylethoxy, 3-pynolidin-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- 1 -yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy and 3-(4-acetylpiperazin-l-yl)propoxy; and Ra is chloro; R is hydrogen;
Rc is methoxy; and R 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, pynolidin-3-yloxy, pynolidin-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-ρynolidin- 1 -ylethoxy, 3-pynolidin- 1 -ylpropoxy, 4-pynolidin- 1 -ylbutoxy, 2-pyrrolidin-2-ylethoxy, 3 -pynolidin-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-l-ylethoxy, 3 -homopiperidin- 1 -ylpropoxy, 3-(l,2,3,6-tetrahydropyridin- l-yl)propoxy, 2-piperazin-l -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 2-homopiperazin- 1 -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 pynolidin-2-yl, pynolidin-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;
R is hydrogen, chloro or bromo;
R is hydrogen, chloro or bromo; Rc is 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, tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first R1 group is located at the 5-position and is selected from the group of substituents listed immediately above, and the second R1 group is located at the 7-ρosition and is selected from 2-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -ylpropoxy, 2- [(3RS ,4SR)-3 ,4-methylenedioxypynolidin- 1 -yl] ethoxy, 3-[(3RS,4SR)-3,4-methylenedioxypynolidin-l-yl]propoxy, 2-morpholinoethoxy, 3 -morpholinopropoxy, 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, 2-piperazin-l -ylethoxy, 3 -piperazin- 1 -ylpropoxy, 4-piperazin- 1-ylbutoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-l-yl)propoxy, 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-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin- 1 -yl)propoxy, 2-(4-isobutyrylpiperazin- 1 -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 -yl]propoxy ; and R is chloro or bromo;
R is hydrogen or chloro;
R is methoxy or ethoxy; and
R 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-pynolidin- 1 -ylethoxy, 3 -pynolidin-1 -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 or chloro;
Rc is methoxy; and
R 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 quinazoline of the Formula H
Figure imgf000079_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 imgf000079_0002
wherein Z is O, S, or N(R ) and R , 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
Figure imgf000079_0003
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 imgf000079_0004
wherein m, R1, Z, Ra, R , Rc and R 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 imgf000080_0001
wherein L is a displaceable group and Z, R , R , R and R 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;
(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; or
(g) for the production of those compounds of the Formula I wherein an R1 group contains an N-acylated heterocyclic group, the acylationof a quinazoline derivative of the Formula I wherein the R1 group contains a heterocyclic group having an unsubstituted NH 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. A quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 for use in a method of treatment of the human or animal body by therapy.
11. 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.
12. A method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1.
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