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WO2002002534A1 - Quinazolines a usage therapeutique - Google Patents

Quinazolines a usage therapeutique Download PDF

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Publication number
WO2002002534A1
WO2002002534A1 PCT/GB2001/002874 GB0102874W WO0202534A1 WO 2002002534 A1 WO2002002534 A1 WO 2002002534A1 GB 0102874 W GB0102874 W GB 0102874W WO 0202534 A1 WO0202534 A1 WO 0202534A1
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alkyl
group
formula
amino
mixture
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PCT/GB2001/002874
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2002216758A priority Critical patent/AU2002216758A1/en
Publication of WO2002002534A1 publication Critical patent/WO2002002534A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention concerns a new use of certain novel quinazoline derivatives, or pharmaceutically-acceptable salts thereof, which have been found to possess anti-tumour activity and are accordingly useful in methods of tieatment of the human or animal body, 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.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication.
  • EGF epidermal growth factor
  • Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases.
  • the classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF , Neu and erbB receptors, Class ⁇ receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR) and Class HI receptor tyrosine kinases comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the 5 PDGF , PDGF ⁇ and colony-stimulating factor 1 (CSF1) receptors.
  • EGF EGF family of receptor tyrosine kinases
  • TGF TGF
  • Neu and erbB receptors Class ⁇ receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR)
  • tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and invasiveness and subsequently metastatic tumour growth (Ullrich et ah, Cell, 1990, 61, 203-
  • Non-receptor tyrosine kinases including the Src family such as the Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
  • Src family members for example c-Src tyrosine kinase
  • c-Src tyrosine kinase is frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer (Cartwright et al, Proc. ⁇ atl. Acad. Sci. USA. 1990, 87, 558-562 and Mao et al, Oncogene.
  • 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.
  • c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility.
  • 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.
  • colon tumour progression from localised to disseminated, invasive metastatic disease has been correlated with c-Src non-receptor tyrosine kinase activity (Brunton et al., Oncogene. 1997, 14, 283-293, Fincham et al, EMBO J, 1998, 17, 81-92 and Nerbeek 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.
  • 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. It is disclosed by K. H. Gibson et al, Bioorganic & Medicinal Chemistry Letters,
  • 5 -substituted quinazoline derivatives may be useful as inhibitors of serine/threonine protein kinases.
  • 4-amino-5-phenoxyquinazolines there is the disclosure of three 4-ureido-5-phenoxyquinazolines, namely of :- l-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea, l-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea and l-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea.
  • 4-aminopyrazolo[3,4-rf]pyrimidine derivatives possess growth inhibitory activity against cultured L1210 leukaemia cells.
  • the disclosed compounds include:- l-phenyl-3-(pyrazolo[3,4- ⁇ pyrimidin-4-yl)urea, l-(2-chlorophenyl)-3-(pyrazolo[3,4- ⁇ i]pyrimidin-4-yl)urea, l-(3-chlorophenyl)-3-(pyrazolo[3,4- ⁇ flpyrimidin-4-yl)urea, l-(4-chlorophenyl)-3-(pyrazolo[3,4- ]pyrimidin-4-yl)urea, l-(2-fluorophenyl)-3-(pyrazolo[3,4- ⁇ pyrimidin-4-yl)urea, l-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and l-
  • 3-cyanoquinoline derivatives may be useful as protein tyrosine kinase inhibitors. Almost all of the 398 disclosed examples were 3-cyano-4-anilinoquinoline or
  • HFGAN72 receptor a G-protein coupled neuropeptide receptor, and hence may be of potential use in the treatment of obesity.
  • HFGAN72 receptor a G-protein coupled neuropeptide receptor
  • Q 1 is a quinazoline-like ring such as a group of the formula la, lb, Ic or Id
  • Y 1 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S;
  • Y together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S; m is O, 1, 2, 3 or 4; each R 1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbony
  • X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ), CO, CH(OR 4 ), CON(R 4 ), N(R 4 )CO, SO 2 N(R 4 ), N(R 4 )SO 2 , OC(R 4 ) 2 , SC(R 4 ) 2 and N(R 4 )C(R 4 ) 2 , wherein R 4 is hydrogen or (l-6C)alkyl, and Q 3 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, or (R ⁇ m is (l-3C)
  • X 2 is a direct bond or is selected from CO and N(R 6 )CO, wherein R 6 is hydrogen or (l-6C)alkyl, and Q 4 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 substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (
  • X 3 is a direct bond or is selected from O, S, SO, SO 2 , N(R 7 ), CO, CH(OR 7 ), CON(R 7 ), N(R 7 )CO, SO 2 N(R 7 ), N(R 7 )SO 2 , C(R 7 ) 2 O, C(R 7 ) 2 S and N(R 7 )C(R 7 ) 2 , wherein R 7 is hydrogen or (l-6C)alkyl, and Q 5 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl- (l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl- (l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl
  • X 5 is a direct bond or is selected from O and N(R 10 ), wherein R 10 is hydrogen or (l-6C)alkyl, and Q 6 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and any Q 6 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (l-6C)alkyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R 1 optionally bears 1 or 2 oxo or thioxo substituents; R 2 is hydrogen or (l-6C)alkyl and R 3 is hydrogen or (l-6C)alkyl, or R 2 and R 3 together form a CH 2 , (CH 2 ) 2 or (CH 2 ) 3 group;
  • Z is O, S, N(C ⁇ N) or N(R ⁇ ), wherein R 11 is hydrogen or (l-6C)alkyl; and 2 is aryl, aryl-(l-3C)alkyl, aryl-(3-7C)cycloalkyl, heteroaryl, heteroaryl-(l-3C)alkyl or heteroaryl-(3-7C)cycloalkyl wherein each aryl group is phenyl or naphthyl and each heteroaryl group is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Q 2 is optionally substituted with 1, 2, 3 or 4 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (l-6C)alkyl
  • X 8 is a direct bond or is selected from O and N(R 16 ), wherein R 16 is hydrogen or (l-6C)alkyl, and R 15 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, and wherein any heterocyclyl group within a substituent on Q 2 optionally bears 1 or 2 oxo or thioxo substituents; or a pharmaceutically-acceptable salt thereof; in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
  • a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinazoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.
  • a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a quinazoline derivative of the Formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • a method for the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
  • a method for providing a c-Src kinase inhibitory effect 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.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
  • An analogous convention applies to other generic terms.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • lt is to be understood that the hydrogen atom which is shown at the 2-position in each of the part structures of the formulae la, lb, Ic and Id indicates that that position remains unsubstituted by any R 1 group.
  • Suitable values for the generic radicals referred to above include those set out below.
  • a suitable value for any one of the 'Q' groups (Q 2 to Q 7 ) 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 a (3-7C)cycloalkyl group within Q 2 or for Q 3 or Q 4 when it is (3-7C)cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2. l]heptyl and a suitable value for Q 3 or Q 4 when it is (3-7C)cycloalkenyl is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • a suitable value for Q 2 when it is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or nap
  • a suitable value for any one of the 'Q' groups, Q 3 to Q 7 ,when it is heteroaryl or for the heteroaryl group within a 'Q' group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, be
  • a suitable value for any one of the 'Q' groups, Q 3 to Q 7 , 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, tetiahydrofuranyl, tetrahydropyranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetiahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • a suitable value for a 'Q' group when it is heteroaryl-(l-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.
  • the invention comprises corresponding suitable values for 'Q' groups when, for example, rather than a heteroaryl-(l-6C)alkyl group, an aryl-(l-6C)alkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl-(l-6C)alkyl or heterocyclyl-(l-6C)alkyl group is present.
  • ring Y 1 is suitably unsaturated or partially unsaturated wherein a -CH - group can optionally be replaced by a -CO- group and a ring nitrogen atom may optionally bear a (l-6C)alkyl group.
  • Diradicals of suitable fused Y 1 rings include thiendiyl, furandiyl, imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, 1,2,3-oxadiazolediyl, 1,2,3-triazolediyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl and 1,3,4-triazinediyl.
  • Suitable bicyclic rings of formula Ic formed by the fusion of ring Y 1 to the adjacent pyrimidine ring include furopyrimidinyl, thienopyrimidinyl, purinyl, pyrrolopyrimidinyl, pyrrolinopyrimidinyl, oxopyrrolinopyrimidinyl, oxazolopyrimidinyl, oxazolinopyrimidinyl, oxooxazolinopyrimidinyl, isoxazolopyrimidinyl, thiazolopyrimidinyl, thiazolinopyrimidinyl, oxothiazolinopyrimidinyl, isothiazolopyrimidinyl, oxoimidazolinopyrimidinyl, pyrazolopyrimidinyl, pyrazolinopyrimidinyl, oxopyrazolinopyrimidinyl, pyridopyrimidin
  • the bicyclic ring of formula Ic is furo[3,2-d]pyrimidinyl, furo[2,3-d]pyrimidinyl, thieno[3,2- ]pyrimidinyl, thieno[2,3- ⁇ ]pyrimidinyl, 6-purinyl, pyrrolo[2,3- ⁇ i]pyrir---idinyl, oxazolo[5,4- ⁇ ]pyrimidinyl, oxazolo[4,5-d]pyrimidinyl, thiazolo[5,4- ]pyrimidinyl, thiazolo[4,5-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4- ⁇ i]pyrimidinyl, pyrido[4,3- ]pyrimidinyl, pyrido[3,2- ]pyrimidinyl, pyrimido[4,5-rf]pyrimidinyl, pyrimi
  • bicyclic ring of formula Ic is 6-oxopyrrolino[2,3- ⁇ pyrimidin-4-yl, 6-oxopyrrolino[3,2- ⁇ pvrimidin-4-yl, 2-oxooxazolino[5,4- ⁇ 2]pyrimidin-7-yl, 2-oxothiazolino[5,4-cT]pyrimidin-7-yl, 2-oxooxazolino[4,5-rf]pyrimidin-7-yl, 2-oxothiazolino[4,5-c Jpyrimidin-7-yl, 2-oxoimidazolino[4,5--i]pyrimidin-7-yl, 3-oxopyrazolino[3,4- ⁇ i]pyrimidin-4-yl or 3-oxopyrazolino[4,3-( ]pyrimidin-7-yl.
  • bicyclic rings of formula Ic include thieno[3,2-rf]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thiazolo[5,4- ⁇ i]pyrimidinyl, 6-purinyl, pyrido[2,3-rf]pyrimidinyl, pyrido[3,4- ⁇ ]pyrimidinyl, pyrido[4,3- ⁇ f]pyrimidinyl, pyrido[3,2- ]pyrimidinyl and pteridinyl, more specifically thieno[3,2- ⁇ pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, thiazolo[5,4- ⁇ pyrimidin-7-yl, pyrido[2,3-d]pyrimidin-4-yl, pyrido[3,4-d]pyrimidin-4-yl, pyrido[4,3-cT
  • ring Y 2 When, as defined hereinbefore,Y 2 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S, ring Y 2 is suitably unsaturated or partially unsaturated wherein a -CH 2 - group can optionally be replaced by a -CO- group and a ring nitrogen atom may optionally bear a (l-6C)alkyl group.
  • Diradicals of suitable fused Y rings include thiendiyl, furandiyl, imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, 1,2,3-oxadiazolediyl, 1,2,3-triazolediyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl and 1,3,4-triazinediyl.
  • Suitable tricyclic rings of formula Id formed by the fusion of ring Y 2 to the adjacent quinazoline ring include imidazoquinazolinyl, oxazoloquinazolinyl, thiazoloquinazolinyl, [l,2,3]triazoloquinazohnyl, pyrazoloquinazolinyl, pyrroloquinazolinyl, oxoimidazolinoquinazolinyl, oxooxazolinoquinazolinyl, oxothiazolinoquinazolinyl and oxopyrazolinoquinazolinyl.
  • the tricyclic ring of formula Id is 3H-imidazo[4,5-g]quinazolinyl, oxazolo [4,5-g]quinazolinyl, thiazolo [4,5-g]quinazolinyl, 3H-[l,2,3]triazolo[4,5-g]quinazolinyl, lH-pyrazolo[3,4-g]quinazolinyl, 6H-pyrrolo[2,3-g]quinazolinyl, 2-oxo-l,2-dihydro-3H-imidazo[4,5-g]quinazolinyl, 2-oxo-l,2-dihydrooxazolo[4,5-g]quinazolinyl, 2-oxo-l,2-dihydrothiazolo[4,5-g]quinazolinyl, 3-oxo-2,3-dihydro-lH-pyrazolo[3,4-g]qui
  • tricyclic ring of formula Id is 3H ⁇ imidazo[4,5-g]quinazolin-8-yl, oxazolo[4,5-g]quinazolin-8-yl, thiazolo[4,5-g]quinazolin-8-yl, 3H-[l,2,3]triazolo[4,5-g]quinazolin-8-yl, lH-pyrazolo[3,4-g]quinazolin-8-yl, 6H-pyrrolo[2,3-g]quinazolin-4-yl, 2-oxo- l,2-dihydro-3H-imidazo[4,5-g]quinazolin-8-yl, 2-oxo-l,2-dihydrooxazolo[4,5-g]quinazolin- 8-yl, 2-oxo-l,2-dihydrothiazolo[4,5-g]quinazolin-8-yl, 3-oxo-2,3-
  • tricyclic rings of formula Id include 3-methyl-3H-imidazo[4,5-g]quinazolin-8-yl, 3-methyl-3H-[l,2,3]triazolo[4,5-g]quinazolin-8-yl, 3-methyl-2-oxo-l,2-dihydro- 3H-imidazo[4,5-g]quinazolin-8-yl, pyrazino[2,3-g]quinazolin-4-yl and 9-methyl-8-oxo- 8,9-dihydropyrazino[2,3-g]quinazolin-4-yl.
  • Suitable values for any of the 'R' groups (R to R ), or for various groups within an R 1 substituent, or within a substituent on Q 2 include:- for halogeno fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, 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, e
  • N-methylamino and diisopropylamino for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(l-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
  • N-methylethanesulphonylamino for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(l-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido;
  • N-(l-6C)alkyl-(3-6C)alkynoylamino N-methylpropiolamido
  • amino-(l-6C)alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl and
  • a suitable value for (R ) m or for a substituent on Q when it is (l-3C)alkylenedioxy is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
  • an R 1 group forms a group of the formula Q ⁇ X 1 - and, for example, X 1 is a OC(R 4 ) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R 4 ) hnking group which is attached to the quinazoline-like ring such as the ring of formula la and the oxygen atom is attached to the Q 3 group.
  • adjacent carbon atoms in any (2-6C)alkylene chain within a R 1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R 5 ) or C ⁇ C.
  • a group such as O, CON(R 5 ) or C ⁇ C.
  • insertion of a C ⁇ C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
  • suitable R 1 substituents so formed include, for example, N-[heterocyclyl- (l-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-l-ylethyl)carbamoylvinyl or N-[heterocyclyl-(l-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin- l-ylethyl)carbamoylethynyl.
  • any CH 2 or CH 3 group within a R 1 substituent optionally bears on each said CH 2 or CH 3 group one or more halogeno substituents, there are suitably 1 or 2 halogeno substituents present on each said CH 2 group and there are suitably 1, 2 or 3 halogeno substituents present on each said CH 3 group.
  • R 1 substituents so formed include, for example, hydroxy-substituted heterocyclyl- (l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy- 3-morpholinopropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (l-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl- (l-6C)alkylamino groups such as 2-hydroxy-3-piperid
  • hydroxy-substituted (l-6C)alkoxy groups such as 2-hydroxyethoxy, (l-6C)alkoxy-substituted (l-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (l-6C)alkylsulphonyl-substituted (l-6C)alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • Particular compounds of the Formula I include, for example,
  • 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, (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)alky
  • 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 7 ), CON(R 7 ), N(R 7 )CO and C(R 7 ) 2 O, wherein R 7 is hydrogen or (l-6C)alkyl
  • Q 5 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, (l-6C)alkoxy, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl,
  • m is 1, 2 or 3, and each R 1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoy
  • X is a direct bond or is CO, NHCO or N(Me)CO and Q is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-morpholinomethyl
  • X 3 is a direct bond or is selected from O, NH, CONH, NHCO and CH 2 O and Q 5 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperidin
  • m is 1 or 2 and the R 1 groups, which may be the same or different, are located at the 6- and/or 7-positions and are selected from hydroxy, amino, methyl, ethyl ! ropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, benzyloxy, cyclopropylmethoxy, 2-imidazol-l-ylethoxy, 3-imidazol- 1 -ylpropoxy, 2-(l ,2,3-triazol- 1 -yl)ethoxy, 3-( 1 ,2,3-triazol- 1 -yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid
  • Q 4 -X 2 - wherein X 2 is a direct bond or is NHCO or N(Me)CO and Q 4 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 4-pyrrolidin-l-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperidin
  • (f) Z is O, S or N(R ⁇ ), wherein R 11 is hydrogen or (l-6C)alkyl;
  • (g) Z is O, S, N(R ⁇ ), wherein R 11 is hydrogen, methyl, ethyl or propyl; (h) Z is O; (i) Q 2 is phenyl, benzyl, ⁇ -methylbenzyl, phenethyl, naphthyl, l-(l-naphthyl)ethyl or 2-phenylcyclopropyl which is optionally substituted with 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, m-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l
  • X 6 is a direct bond or is selected from O and N(R 13 ), wherein R 13 is hydrogen or (l-6C)alkyl, and R 12 is hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl or di-[(l-6C)alkyl]amino-(l-6C)alkyl, or from a group of the formula :
  • X 7 is a direct bond or is selected from O, N(R 14 ), CO, CON(R 14 ), N(R 14 )CO and C(R 14 ) O, wherein each R 1 is hydrogen or (l-6C)alkyl, and Q 7 is phenyl, benzyl, heteroaryl or heteroaryl-(l-6C)alkyl, and wherein any phenyl or heteroaryl group within a substituent on Q 2 optionally bears
  • substituents which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, (l-6C)alkyl and (l-6C)alkoxy;
  • Q is phenyl, benzyl, ⁇ -methylbenzyl or phenethyl which is optionally substituted with 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, hydroxy, methyl, ethyl, propyl, tert-butyl, vinyl, ethynyl and methoxy, or from a group of the formula :
  • X 7 is a direct bond or is selected from O and CO
  • Q 7 is phenyl, benzyl, pyridyl or pyridylmethyl, and wherein any phenyl or pyridyl group within a substituent on Q 2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl and methoxy
  • Q 2 is phenyl, benzyl or phenethyl which is substituted with 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, hydroxy, methyl, ethyl, propyl, tert-butyl, vinyl, ethynyl and methoxy provided that at least one substituent is located at an ortho position (for example the 2-position on a phen
  • each of m, R 1 , R 2 , R 3 , Z and Q 2 has any of the meanings defined hereinbefore or in any of the paragraphs (a) to (1) immediately hereinbefore and Y 1 has any of the meanings defined hereinbefore or in paragraphs (a) to (c) hereinafter :- (a) bicyclic rings formed by the fusion of ring Y 1 to the adjacent pyrimidine ring include thieno[3,2-J]pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, thiazolo[5,4-d]pyrimidin-7-yl, pyrido[2,3- ⁇ pyrimidin-4-yl, pyrido[3,4-rf]pyrimidin-4-yl, pyrido[4,3-d]pyrimidin-4-
  • bicyclic rings formed by the fusion of ring Y 1 to the adjacent pyrimidine ring include thieno[3,2- ⁇ pyrimidin-4-yl, pyrido[3,4- ⁇ pyrimidin-4-yl, pyrido[4,3- ⁇ pyrimidin-4-yl and pyrido[3,2-rf]pyrimidin-4-yl; and
  • each of m, R 1 , R 2 , R 3 , Z and Q 2 has any of the meanings defined hereinbefore or in any of the paragraphs (a) to (1) immediately hereinbefore and Y 2 has any of the meanings defined hereinbefore or in paragraphs (a) and (b) hereinafter :- (a) tricyclic rings formed by the fusion of ring Y 2 to the adjacent quinazoline ring include 3H-i ⁇ nidazo[4,5-g]quinazolin-8-yl and 2-oxo-l,2-dihydro-3H-imidazo[4,5-g]quinazolin-8-yl; and
  • a further particular compound of the invention is a quinazoline derivative of the Formula II wherein : m is 1 and the R 1 group is located at the 6- or 7-position and is selected from methoxy, benzyloxy, cyclopropylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3 -ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3 -pyrid-3 -ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-l -ylethoxy,
  • Q is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, nitro, methyl, ethyl and methoxy provided that at least one substituent is located at an ortho position; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Formula II wherein : m is 1 or 2 and the R 1 groups, which may be the same or different, are located at the 6- and/or 7-positions and are selected from methoxy, benzyloxy, 2-(l,2,3-triazol-l-yl)ethoxy, 3-(l,2,3-triazol-l-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3 -ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3 -pyrid-3 -ylpropoxy, 3-pyrid- 4-ylpropoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, pyrrolidin-3 -yloxy, l-methylpyrrolidin-3-y
  • R is hydrogen or methyl
  • R is hydrogen; Z is O;
  • Q 2 is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl and methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the Formula II wherein : m is 1 and the R 1 group is located at the 7-position and is selected from 3-(l,2,3-triazol-l-yl)propoxy, 2-pyrid-4-ylethoxy, 2-pyrrolidin-l -ylethoxy, 3 -pyrrolidin-1 -ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(l , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)ethoxy, 3-( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin- 4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3 -ylmethoxy,
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen; Z is O, S , NH or N(Et); and
  • Q 2 is phenyl which bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, nitro, methyl, ethyl and methoxy provided that at least one substituent is located at an ortho position; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is a quinazoline derivative of the
  • m is 1 and the R 1 group is located at the 7-position and is selected from 3-(l,2,3-triazol-l-yl)propoxy, 2-pyrid-4-ylethoxy, 3-pyrrolidin-l -ylpropoxy, 3-morpholinopropoxy, 3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy,
  • R 1 group is located at the 7-position and is selected from the groups defined immediately hereinbefore and the other R 1 group is a 6-methoxy group;
  • R is hydrogen or methyl;
  • R 3 is hydrogen;
  • Z is O; and
  • Q 2 is phenyl which bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo and trifluoromethyl provided that at least one substituent is located at an ortho position; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a further particular compound of the invention is, for example, a quinazoline derivative of the Formula II selected from :- l-(2,6-dichlorophenyl)-3-[7-(3-morpholinopropoxy)quinazolin-4-yl]urea, l-(2,6-dichlorophenyl)-3- ⁇ 7-[3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy]quinazolin-
  • a further particular compound of the invention is a pyrimidine derivative of the Formula IN wherein the fusion of ring Y 1 to the adjacent pyrimidine ring forms a thieno[3,2- ]pyrimidin-4-yl group; m is 0, or m is 1 and the R 1 group is a methyl, ethyl, vinyl or ethynyl group which is located at the 6-position and bears a substituent selected from carboxy, carbamoyl, ⁇ -(2-methylaminoethyl)carbamoyl, N-(2-dimethylaminoethyl)carbamoyl, N-(3-methylaminopropyl)carbamoyl or N-(3-dimethylaminopropyl)carbamoyl, or from a group of the formula :
  • Q 4 -X 2 - wherein X 2 is NHCO or N(Me)CO and Q 4 is 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-pyridylmethyl, 4-pyridylmethyl, 2-pyrid-2-ylethyl, 2-pyrrolidin-l-ylethyl, 2-(2-oxopyrrolidin- 1 -yl)ethyl, 3-pyrrolidin-l-ylpropyl, 3-(2-oxopyrrolidin- 1 -yl)propyl, pyrrolidin-2-ylmethyl, 1 -methylpyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 2-( 1 -methylpyrrolidin-2-yl)ethyl, 3-pyrrolidin-2-ylpropyl, 3-( 1 -methylpyrrolidin-2-yl)propyl, 2-morpholinoethyl,
  • R is hydrogen; Z is O;
  • Q is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl and methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
  • R is hydrogen or methyl; R 3 is hydrogen;
  • Z is O
  • Q 2 is phenyl which bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo and trifluoromethyl provided that at least one substituent is located at the ortho position; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a particular compound of this aspect of the invention is, for example, a pyrimidine derivative of the Formula IV selected from:- l-(2,6-dichlorophenyl)-3-(thieno[3,2-d]pyrimidin-4-yl)urea and (E)-3- ⁇ 4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2- ]pyrimidin-6-yl ⁇ - N-(3-dimethylaminopropyl)acrylamide; or a pharmaceutically-acceptable acid-addition salt thereof.
  • a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a quinazoline derivative of the Formula I are illustrated by the following representative process variants in which, unless otherwise stated, Q 1 , R 2 , Z, R 3 and Q 2 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.
  • 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, alkoxide or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium ethoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl- lithium or a dialkylamino-lithium, for example lithium di-isopropylamide.
  • an alkali or alkaline earth metal carbonate, alkoxide or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium ethoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide
  • an alkali metal hydride for example sodium hydride or potassium hydride
  • 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, an ether such as tetrahydrofuran or 1,4-dioxan, or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.
  • a suitable inert solvent or diluent for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or
  • a suitable conventional chemical equivalent of an isocyanate of the Formula VII is, for example, a compound of the Formula VHI L-CO-NH-Q 2 VIE wherein Q has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable or leaving group.
  • Q has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable or leaving group.
  • the compound of the Formula VHI reacts to form the desired isocyanate of the Formula VII.
  • a suitable displaceable or leaving group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable conventional chemical precursor of an isocyanate of the Formula VH is, for example, an acyl azide of the Formula IX
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy- lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri (lower alkyl)silyl-(
  • Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage.
  • hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl) ; lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
  • amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl) ; alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
  • aryl-lower alkyl groups for example
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • groups such as 2-nitrobenzyloxycarbonyl
  • hydrogenation for groups such as benzyl
  • photolytically for groups such as 2-nitrobenzyloxycarbonyl.
  • the reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2 nd Edition, by T. Green et al., also published by John Wiley & Son, for general guidance on protecting groups.
  • the compound of the Formula VHI may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of phosgene with an amine of the Formula X.
  • the compound of the Formula IX may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XI.
  • a metal azide such as sodium azide
  • a suitable conventional chemical equivalent of an isothiocyanate of the Formula XH is, for example, a compound of the Formula XDI
  • a suitable conventional chemical precursor of an isothiocyanate of the Formula XH is, for example, an acyl azide of the Formula XIV
  • N 3 -CS-Q 2 XIV wherein Q has any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • the thioacyl azide of the Formula XIV decomposes and rearranges to form the desired isothiocyanate of the Formula XH.
  • the compound of the Formula XHI may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of thiophosgene with an amine of the Formula X.
  • the compound of the Formula XTV may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XV.
  • a suitable conventional chemical equivalent of an isocyanate of the Formula XVII is, for example, a compound of the Formula XVDI wherein Q 1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable group as defined hereinbefore.
  • Q 1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary
  • L is a suitable displaceable group as defined hereinbefore.
  • the compound of the Formula XVIII reacts to form the desired isocyanate of the Formula XVII.
  • a suitable conventional chemical precursor of an isocyanate of the Formula XVII is, for example, an acyl azide of the Formula XIX
  • the compound of the Formula XVHI may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of phosgene with an amine of the Formula XX.
  • NHfe XX The compound of the Formula XIX may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XXI.
  • a suitable conventional chemical precursor of an isothiocyanate of the Formula XXH is, for example, an acyl azide of the Formula XXTV wherein Q 1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • the thioacyl azide of the Formula XXIV decomposes and rearranges to form the desired isothiocyanate of the Formula XXH.
  • the compound of the Formula XXHI may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of thiophosgene with an amine of the Formula XX.
  • the compound of the Formula XXIV may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XXV.
  • a metal azide such as sodium azide
  • a suitable reactive derivative of a compound of Formula I wherein a substituent on Q 1 or Q 2 is a carboxy group is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester formed by the reaction of the acid and an ester such as pentafluorophenyl trifluoroacetate or an ester formed by the reaction of the acid and an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride;
  • a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region -10 to 40°C, typically at ambient temperature of about 20°C.
  • an organic solvent preferably an anhydrous polar aprotic organic solvent
  • a compound of Formula I wherein a substituent on Q 1 or Q 2 is a carboxy group may conveniently be prepared by the cleavage of the corresponding ester such as a (l-12C)alkyl ester, for example by acid-, base- metal- or enzymatically-catalysed cleavage.
  • Suitable protecting groups for an amino-(l-6C)alkyl group are, for example, any of the protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore.
  • a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis.
  • Typical reaction conditions include the use of ammonium formate or hydrogen gas in the presence of a catalyst, for example a metallic catalyst such as palladium-on-carbon.
  • a dissolving metal reduction may be carried out, for example using iron in the 10 presence of an acid, for example an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric or acetic acid.
  • the reaction is conveniently carried out in the presence of an organic solvent (preferably a polar protic solvent) and preferably with heating, for example to about 60°C. Any functional groups are protected and deprotected as necessary.
  • a pharmaceutically-acceptable salt of a quinazoline derivative of the Formula I 15 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.
  • the following assays can be used to measure the effects of the compounds of the Formula I as c-Src tyrosine kinase inhibitors, as inhibitors in vitro of the proliferation of c-Src 20 tiansfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue, (a) In Vitro Enzyme Assay
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa 25 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 30 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150 ⁇ l of a 5% solution in PBS) were transferred into each substrate-coated assay well and incubated for 1 hour at ambient temperature to block non specific binding. The assay plate wells were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and with Hepes pH7.4 buffer (50mM, 300 ⁇ l/well) before being blotted dry.
  • PBS Bovine Serum Albumin
  • test compound was dissolved in dimethyl sulphoxide and diluted with distilled water to give a series of dilutions (from lOO ⁇ M to O.OOl ⁇ M). Portions (25 ⁇ l) of each dilution of test compound were transferred to wells in the washed assay plates. "Total" control wells contained diluted DMSO instead of compound. Aliquots (25 ⁇ l) of an aqueous magnesium chloride solution (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.
  • phosphate-citrate pH5 buffer 50mM containing 0.03% sodium perborate.
  • An aliquot (50ml) of this buffer was mixed with a 50mg tablet of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; Boehringer Catalogue No. 1204 521). Aliquots (lOO ⁇ l) of the resultant solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density value of the "total" control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1.0.
  • This assay determined the ability of a test compound to inhibit the proliferation of National Institute of Health (NIH) mouse 3T3 fibroblast cells that had been stably-transfected with an activating mutant (Y530F) of human c-Src.
  • NASH National Institute of Health
  • 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 O.lmg/ml streptomycin in 0.9% aqueous sodium chloride solution.
  • DMEM Dulbecco's modified Eagle's medium
  • FCS foetal calf serum
  • test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots of the stock solution were diluted with the DMEM medium described above and added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which test compound was not added were included on each plate. The plates were incubated overnight at 37°Cin a humidified (7.5% CO 2 : 95% air) incubator. BrdU labelling reagent (Boehringer Mannheim Catalogue No.
  • This assay determines the ability of a test compound to inhibit the migration of adherent mammalian cell lines, for example the human tumour cell line A549.
  • RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose (Difco Catalogue No. 0142-01) was warmed to 37°C in a waterbath.
  • a stock 2% aqueous agar solution was autoclaved and stored at 42°C.
  • An aliquot (1.5 ml) of the agar solution was added to RPMI medium (10 ml) immediately prior to its use.
  • A549 cells (Accession No. ATCC CCL185) were suspended at a concentration of 2 x 10 7 cells/ml in the medium and maintained at a temperature of 37°C.
  • a droplet (2 ⁇ l) of the cell/agarose mixture was transferred by pipette into the centre of each well of a number of 96-well, flat bottomed non-tissue-culture-treated microtitre plate (Bibby Sterilin Catalogue No. 642000). The plates were placed briefly on ice to speed the gelling of the agarose-cantaining droplets. Aliquots (90 ⁇ l) of medium which had been cooled to 4°C were transferred into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (lO ⁇ l) of the diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% CO 2 : 95% air) incubator for about 48 hours.
  • a migratory inhibitory IC 5 o was derived by plotting the mean migration measurement against test compound concentration.
  • This test measures the ability of compounds to inhibit the growth of the A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain).
  • a total of about 5 x 10 6 A549 cells in matrigel (Beckton Dickinson Catalogue No. 40234) were injected subcutaneously into the left flank of each test mouse and the resultant tumours were allowed to grow for about 14 days. Tumour size was measured twice weekly using callipers and a theoretical volume was calculated. Animals were selected to provide control and treatment groups of approximately equal average tumour volume.
  • Test compounds were prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth was assessed.
  • a pharmaceutical composition for the compounds of the Formula I comprises a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable 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
  • 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 compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • c-Src non-receptor tyrosine kinase the predominant role of c-Src non-receptor tyrosine kinase is to regulate cell motility which is necessarily required for a localised tumour to progress through the stages of dissemination into the blood siteam, invasion of other tissues and initiation of metastatic tumour growth.
  • quinazoline derivatives of the Formula I possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the non-receptor tyrosine-specific protein kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.
  • the quinazoline derivatives of the Formula I 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 Formula I are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease.
  • the compounds of the Formula I 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 Formula I 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 Formula I are expected to be useful in the prevention or treatment of solid tumour disease.
  • the anti-invasive 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 urokinase plasminogen activator receptor function
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitiosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734 such as (2S)-2- ⁇ o-fluoro-p-[N- ⁇ 2J-dimethyl-4-oxo-3 ,4
  • 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
  • topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal
  • 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.
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; and
  • 2,6-Dichlorophenyl isocyanate (0.075 g) was added to a solution of 4-amino- 6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.093 g) in a mixture of methylene chloride (2 ml) and DMF (0.1 ml) and the reaction mixture was stirred at ambient temperature for 16 hours.
  • the resultant solid was isolated, redissolved in a 20:1 mixture of methylene chloride and methanol and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1% aqueous ammonium hydroxide solution as eluent.
  • the 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline used as a starting material was prepared as follows :- A solution of di-tert-butvl dicarbonate (41.7 g) in ethyl acetate (75 ml) was added dropwise to a stirred solution of ethyl piperidine-4-carboxylate (30 g) in ethyl acetate (150 ml) which had been cooled to 0 to 5°C in an ice-bath. The resultant mixture was stirred at ambient temperature for 48 hours. The mixture was poured into water (300 ml).
  • the organic layer was separated, washed in turn with water (200 ml), 0.1N aqueous hydrochloric acid solution (200 ml), a saturated aqueous sodium bicarbonate solution (200 ml) and brine (200 ml), dried over magnesium sulphate and evaporated.
  • N-tert-butoxycarbonyl-4-hvdroxymethylpiperidine (36.3 g); NMR Spectrum: (CDC1 3 ) 1.05-1.2 (m, 2H), 1.35-1.55 (m, 10H), 1.6-1.8 (m, 2H), 2.6-2.8 (t, 2H), 3.4-3.6 (t, 2H), 4.0-4.2 (br s, 2H).
  • l,4-Diazabicyclo[2.2.2]octane (42.4 g) was added to a solution of N-tert-butoxycarbonyl-4-hydroxymethylpiperidine (52.5 g) in tert-butyl methyl ether (525 ml) and the mixture was stirred at ambient temperature for 15 minutes.
  • N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine (76.7 g)
  • a portion (40 g) of the material so obtained was added to a suspension of ethyl
  • the solid was dissolved in methylene chloride (500 ml) and hydrogen chloride (3M solution in diethyl ether; 30 ml) was added followed by diethyl ether (500 ml). The resultant solid was collected and dried under vacuum at 50°C.
  • aqueous layer was further extracted with a 1:1 mixture of ethyl acetate and diethyl ether and the organic extracts were combined, washed in turn with water and brine, dried over magnesium sulphate and evaporated.
  • the residue was triturated under a mixture of petroleum ether (b.p. 60-80°C) and diethyl ether.
  • the solid so obtained was isolated, washed with petroleum ether and dried under vacuum at 60°C. There was thus obtained ethyl 2-amino-5-methoxy- 4-(N-methylpiperidin-4-ylmethoxy)benzoate (2.58 g), m.p.
  • the solid was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1 % aqueous ammonium hydroxide solution (20: 1 :0 to 10: 1 :0 to 10: 1 : 1) as eluent.
  • a portion (0.5 g) of the material so obtained was dissolved in a 1M solution of ammonia in isopropanol (10 ml). Liquid ammonia (1 ml) was added and the reaction mixture was sealed in a Carius tube. The reaction mixture was heated to 120°C for 16 hours. The Carius tube was cooled and opened and the reaction mixture was evaporated. The residue was stirred under a 2N aqueous sodium hydroxide solution for 1 hour. The resultant solid was isolated and washed in turn with water and methyl tert-butyl ether.
  • the 4-amino-7-(3-morpholinopropoxy)quinazoline used as a starting material was prepared as follows :-
  • the 4-amino-7-[3-(l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl)propoxy]quinazoline used as a starting material was prepared as follows :- A mixture of 3-aminopropan-l-ol (0.650 ml) and divinyl sulphone (1 g) was heated to 110°C for 45 minutes. The mixture was allowed to cool to ambient temperature and was purified by column chromatography on silica usin a 19:1 mixture of methylene chloride and methanol as eluent.
  • the 4-amino-7-(4-morpholinobut-2-yn-l-yloxy)quinazoline used as a starting material was prepared as follows :- Diethyl azodicarboxylate (2.46 ml) was added dropwise to a stirred mixture of
  • a portion (3 g) of the material so obtained was dissolved in a 1M solution of ammonia in isopropanol (50 ml). Liquid ammonia (5 ml) was added and the reaction mixture was sealed in a Carius tube. The reaction mixture was heated to 120°C for 16 hours. The Carius tube was cooled and opened and the reaction mixture was evaporated. The residue was stirred under a 2N aqueous sodium hydroxide solution for 1 hour. The resultant solid was isolated and washed in turn with water and methyl tert-butyl ether.
  • triphenylphosphine (0.105 g), N-(2-hydroxyethyl)piperidine (0.02 g) and diethyl azodicarboxylate (0.062 ml) were added and reaction mixture was stirred at ambient temperature for a further 30 minutes. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent.
  • the 4-amino-6-methoxy-7-(3-morpholinopropoxy)quinazoline used as a starting material was prepared by the reaction of 4-amino-7-hydroxy-6-methoxyquinazoline and N-(3-hydroxypropyl)morpholine using an analogous procedure to that described in the last paragraph of Note [16] above.
  • the 4-amino-6-methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinazoline used as a starting material was prepared by the reaction of 4-amino-7-hydroxy-6-methoxyquinazoline and l-(3-hydroxypropyl)-4-methylpiperazine using an analogous procedure to that described in the last paragraph of Note [16] above.
  • the 4-amino-6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline used as a starting material was prepared by the reaction of 4-amino-7-hydroxy-6-methoxyquinazoline and N-(3-hydroxypropyl)pyrrolidine using an analogous procedure to that described in the last paragraph of Note [16] above.
  • the 4-amino-7- [3 -( 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4-yl)propoxy] - 6-methoxyquinazoline used as a starting material was prepared by the reaction of 4-amino- 7-hydroxy-6-methoxyquinazoline and N-(3-hydroxypropyl)- 1 , 1-dioxotetrahydro- 4H-l,4-thiazine using an analogous procedure to that described in the last paragraph of Note [16] above.
  • the 4-amino-6-methoxy-7- ⁇ 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy ⁇ - quinazoline used as a starting material was prepared by the reaction of 4-amino-7-hydroxy- 6-methoxyquinazoline and 2-[N-(2-methoxyethyl)-N-methylamino]ethanol using an analogous procedure to that described in the last paragraph of Note [16] above.
  • the 4-amino-6-methoxy-7-(3-mesylpropoxy)quinazoline used as a starting material was prepared by the reaction of 4-amino-7-hydroxy-6-methoxyquinazoline and 3-mesylpropanol using an analogous procedure to that described in the last paragraph of
  • the 3-mesylpropanol used as a starting material was prepared as follows :- 3-Chloroperoxybenzoic acid (25 g) was added in portions to a solution of
  • the 4-amino-6-methoxy-7-[2-(4-pyridyl)ethoxy] quinazoline used as a starting material was prepared by the reaction of 4-amino-7-hydroxy-6-methoxyquinazoline and 4-(2-hydroxyethyl)pyridine (Zhur. Obshchei. Khim., 1958, 28, 103-110) using an analogous procedure to that described in the last paragraph of Note [16] above.
  • 3-(4-methylpiperazin-l-yl)propyl chloride used as an intermediate was prepared by the reaction of 1-methylpiperazine with l-bromo-3-chloropropane using an analogous procedure to that described in Note [42] hereinafter for the preparation of 3-morpholinopropyl chloride.
  • the 4-amino-6-methoxy-7-(3-morpholinopropoxy)quinazoline used as a starting material was prepared as follows :- 4-(4-Bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was reacted with
  • the 4-amino-6-methoxy-7-[2-(2-oxoimidazolidin-l-yl)ethoxy]quinazoline used as a starting material was prepared as follows :- 4-(4-Bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was reacted with
  • the 4-amino-6-methoxy-7-(2-morpholinoethoxy)quinazoline used as a starting material was prepared as follows :- 4-(4-Bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was reacted with 2-morpholinoethyl chloride using an analogous procedure to that described in the second last paragraph of Note [38] above to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy- 7-(2-mor ⁇ holinoethoxy)quinazoline; NMR Spectrum: (CDC1 3 ) 2.63 (t, 4H), 2.98 (t, 2H), 3.76 (t, 4H), 4.06 (s, 3H), 4.34 (t, 2H), 7.22 (t, IH), 7.32 (s, IH), 7.41 (t, 2H), 7.52 (s, IH), 8.6 (s, IH); Mass Spectrum: M+H 4" 478 & 480.
  • the 4-amino-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]quinazoline used as a starting material was prepared as follows :- 4-(4-Bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was reacted with 2-(2-methoxyethoxy)ethyl tosylate (prepared from 2-(2-methoxyethoxy)ethanol and tosyl chloride) using an analogous procedure to that described in the second last paragraph of Note [38] above to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy- 7-[2-(2-methoxyethoxy)ethoxy]quinazoline; NMR Spectrum: (CDC1 3 ) 3.4 (s, 3H), 3.6 (m, 2H), 3.76 (m, 2H), 4.03 (m, 5H), 4.39 (t, 2H), 7.21 (m, IH), 7.34 (s, IH), 7.41 (t, 2H), 7.
  • Diethyl azodicarboxylate (3.3 ml) was added dropwise to a stirred mixture of 4-amino-7-hydroxyquinazoline (5.16 g), triphenylphosphine (16.8 g) and methylene chloride (260 ml) which had been cooled to 0°C. The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 50:45:5 mixture of methylene chloride, ethyl acetate and methanol as eluent.
  • N-(7-hydroxyquinazolin-4-yl)imide (0.2 g), N-(2-hydroxyethyl)pyrrolidine (0.081 g) and methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 1 hour. Diethyl ether (10 ml) was added and the mixture was filtered through diatomaceous earth. The filtrate was evaporated and the residue was purified by column chromatography on silica using as eluent a 48:50:2 mixture of methylene chloride, ethyl acetate and a saturated ammonia solution in methanol.
  • the 4-amino-7-(2-piperidinoethoxy)quinazoline used as a starting material was prepared as follows :- Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with
  • Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with l-(2-hydroxyethyl)-4-methylpiperazine using an analogous procedure to that described in the second last paragraph of Note [74] above to give triphenylphosphine
  • the l-(2-hydroxyethyl)-4-methylpiperazine used as a starting material was prepared as follows :- A mixture of 2-bromoethanol (2.36 g), N-methylpiperazine (1.26 g), potassium carbonate (5.0 g) and ethanol (150 ml) was stirred and heated to reflux for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under a mixture of methylene chloride and acetone.
  • Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with
  • Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with
  • N-(3-hydroxypropyl)pyrrolidine used as a starting material was prepared as follows :- A mixture of 3-chloropropanol (66 g), pyrrolidine (50 g), potassium carbonate (145 g) and acetonitrile (1 L) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by distillation to give the required starting material as an oil (62 g); NMR Spectrum: (CDC1 3 )
  • the 4-amino-7-(3-morpholinopropoxy)quinazoline used as a starting material was prepared as follows :-
  • Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with
  • the 4-amino-7-[3-(4-methylpiperazin-l-yl)propoxy]quinazoline used as a starting material was prepared as follows :- Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with l-(3-hydroxypropyl)-4-methylpiperazine using an analogous procedure to that described in the second last paragraph of Note [74] above to give triphenylphosphine N- ⁇ 7-[3-(4-methylpiperazin-l-yl)propoxy]quinazolin-4-yl ⁇ imide in 44% yield; Mass Spectrum: M+H 4 562. The material so obtained was reacted with aqueous acetic acid using an analogous procedure to that described in the last paragraph of Note [74] above to give the required starting material; Mass Spectrum: M+H 4 302.
  • the l-(3-hydroxypropyl)-4-methylpiperazine used as a starting material was prepared as follows :- A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate (83 g) and ethanol (200 ml) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The resultant mixture was filtered and the filtrate was evaporated.
  • Triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide was reacted with N_ 3-hydroxypropyl)-l,2,3-triazole using an analogous procedure to that described in the second last paragraph of Note [74] above to give triphenylphosphine N- ⁇ 7-[3-(l,2,3-triazol- l-yl)propoxy]quinazolin-4-yl ⁇ imide in 18% yield; Mass Spectrum: M+H 4" 531. The material so obtained was reacted with aqueous acetic acid using an analogous procedure to that described in the last paragraph of Note [74] above to give the required starting material; Mass Spectrum: M+H 4" 271.
  • the ⁇ -(S-hydroxypropy ⁇ -l ⁇ -triazole used as a starting material was prepared as follows :-
  • the (E)-4-pyrrolidin-l-ylbut-2-en-l-ol used as a starting material was prepared as follows :- Thionyl chloride (9.3 ml) was added portionwise to a stirred mixture of 2-butyne-l,4-diol (10 g), pyridine (10.3 ml) and toluene (15 ml) which had been cooled to 0°C. The mixture was stirred at ambient temperature for 3.5 hours and then poured onto a mixture of ice and water. The mixture was extracted with diethyl ether. The organic extract was washed with a saturated aqueous sodium bicarbonate solution and with brine, dried over magnesium sulphate and evaporated.
  • Trifluoromethanesulphomc anhydride (0.05 ml) was added dropwise to a stirred mixture of triphenylphosphine N-(7-hydroxyquinazolin-4-yl)imide (0.1 g), pyridine (0.5 ml) and methylene chloride (1 ml) which had been cooled to 0°C. The reaction mixture was stirred at 0°C for 2 hours. A second portion (0.012 ml) of trifluoromethanesulphonic anhydride was added and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic solution was dried over magnesium sulphate and evaporated.
  • the 4-amino-6-methoxy-7-(6-morpholino-l-hexynyl)quinazoline used as a starting material was prepared as follows:
  • 6-Morpholino-l-hexyne was obtained by the reaction of 6-mesyloxy- 1-hexyne with morpholine using an analogous procedure to that described in J. Heterocyclic Chemistry, 1994, 31, 1421. [117] DMF was used as the reaction solvent and 4-dimethylaminopyridine (0.1 equivalents) was added to catalyse the reaction.
  • 6-(2-Methylimidazol-l-yl)-l-hexyne was obtained by the reaction of 6-mesyloxy- 1-hexyne with 2-methylimidazole using an analogous procedure to that described in J. Heterocyclic Chemistry, 1994, 31, 1421. [119] DMF was used as the reaction solvent and 4-dimethylaminopyridine
  • the 4-amino-6-methoxy-7-[6-(N- ⁇ nethylpiperazin-l-yl)hexyl]quinazoline used as a starting material was prepared as follows :- A mixture of 4-amino-6-methoxy-7-[6-(N-methylpiperazin-l-yl)-
  • the 4-amino-6-methoxy-7-[3-(pyrrolidin-l-yl)propyl]quinazoline used as a starting material was prepared by the hydrogenation of 4-amino-6-methoxy-7-[3-(pyrrolidin-l-yl)- 1 -propynyl] quinazoline using an analogous procedure to that described in Note [139] above.
  • the 4-amino-6-methoxy-7- ⁇ N-[3-(N-methylpiperazin-l- yl)propyl] carbamoyl ⁇ quinazoline used as a starting material was prepared by the reaction of 7-carboxy-6-methoxy-4-(2,4,6-trimethoxybenzylamino)quinazoline and 3-(l-imidazolyl)propylamine and subsequent cleavage of the 2,4,6-trimethoxybenzyl group using analogous procedures to those described in Note [142] above.
  • the 4-amino-7-(3-methoxypropylan ⁇ no)-6-methoxyquinazoline used as a starting material was prepared from as follows :-
  • Example 4 l-(2,6-dichIorophenyl)-3-(6,7-dimethoxyquinazolin-4-yl)urea Using an analogous procedure to that described in Example 3, 2,6-dichlorophenyl isocyanate was reacted with 4-amino-6J-dimethoxyquinazoline (European Patent Application No.
  • 6-Methoxy-4-methylamino-7-(N-methylpiperidin-4-ylmethoxy)quinazoline (0.195 g) was added to 2,6-dichlorophenyl isocyanate (0.3 g) under argon and the solids were mixed together using a spatula. The mixture was heated to 85°C with gentle mixing for 40 minutes. The mixture was cooled to ambient temperature, dissolved in a mixture of chloroform (15 ml) and methanol (5 ml) and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 1% aqueous ammonium hydroxide solution as eluent.
  • 6-methoxy-4-methylamino-7-Qi-methylpiperidin-4-ylmethoxy)quinazoline used as a starting material was obtained as follows :- A mixture of 4-chloro-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline
  • 2,6-Dichlorophenyl isocyanate (0.075 g) was added to a mixture of 4-aminothieno[3,2- ]pyrimidine (Tetrahedron, 1971, 27, 487; 0.201 g) and acetonitrile (16 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated and washed in turn with diethyl ether and methanol.
  • Example 8 (E)-3- ⁇ 4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2- ⁇ f]pyrimidin-6-yl ⁇ acrylic acid Hydrogen chloride gas was bubbled during 3 hours through a stirred solution of tert-butyl (E)-3- ⁇ 4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2- ]pyrimidin-6-yl ⁇ acrylate (1.4 g) in methylene chloride (200 ml) which had been cooled in an ice-bath to 0°C.
  • the tert-butyl (E)-3- ⁇ 4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2-rf] ⁇ yrimidin- 6-yl ⁇ acrylate used as a starting material was obtained as follows :- A mixture of methyl 3-aminothiophene-2-carboxylate (94 g), formamidine acetic acid salt (187 g) and 2-hydroxyethyl methyl ether (1 L) was stirred and heated to reflux for 3 hours. The mixture was cooled to ambient temperature and water (400 ml) was added. The resultant solid was isolated, washed thoroughly with water and with diethyl ether and dried under vacuum.
  • tert-Butoxycarbonylmethvlenetriphenylphosphorane (20.6 g) was added portionwise to a solution of 6-formyl-4-methylthiothieno[3,2-(i]pyrimidine (9.6 g) in methylene chloride (500 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated to half of its original volume and poured onto a column of silica. The column was eluted initially with methylene chloride followed by a 19: 1 mixture of methylene chloride and ethyl acetate. The material so obtained was triturated under petroleum ether (b.p. 60- 80°C), re-isolated and dried under vacuum.
  • Example 10 Using an analogous procedure to that described in Example 9, the appropriate amine was reacted with (E)-3- ⁇ 4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2- ⁇ i]pyrimidin- 6-yl ⁇ acrylic acid to give the compounds described in Table H.
  • Example 14 l-[6-methoxy-7-(N-methyIpiperidin-4-yImethoxy)quinazoIin-4 «yl]- 3-(trans-2-phenylcyclopropyI)urea tr ⁇ ns-2-Phenylcyclopropyl isocyanate (0.2 ml) was added to a stirred mixture of 4-amino-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (0.1 g) and chloroform (3 ml) and the resultant mixture was stirred at ambient temperature for 20 hours.
  • reaction mixture was diluted with chloroform (3 ml) and tris-(2-aminoethyl)amine polystyrene resin (0.5 g) was added.
  • the mixture was stirred at ambient temperature for 1 hour.
  • 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 2M methanolic ammonia as eluent.
  • Example 17 l-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]- 3-[l-(l-naphthyl)ethyl]urea Using an analogous procedure to that described in Example 14, l-(l-naphthyl)ethyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin- 4-ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDC1 3 ) 1.41-1.57 (m, 2H), 1.76 (m, partially obscured by water peak), 1.86-2.05 (m, 5H), 2.02 (s, 3H), 2.91 (s, 2H), 3.87 (s, 3H), 4.02 (d, 2H), 5.95 (s, IH), 7.19 (s, IH), 7.23 (s, IH), 7.39-7.52 (m, 3H), 7.6 (d, IH
  • Example 24 l- ⁇ 7-[3-(4-aminomethylpiperidin-l-yl)propoxy]-6-methoxyquinazolin- 4-yl ⁇ -3-(2-chloro-6-methylphenyl)urea
  • l- ⁇ 7-[3-(4-tert-butoxycarbonylaminomethylpiperidin-l-yl)propoxy]-6-methoxyquinazolin- 4-yl ⁇ -3-(2-chloro-6-methylphenyl)urea was reacted with trifluoroacetic acid to give the title compound;
  • 6-(3-morpholinopropoxy)quinazoline (0.614 g); NMR Spectrum: (CDC1 3 ) 2.12 (m, 2H), 2.5 (br s, 4H), 2.59 (t, 2H), 3.73 (t, 4H), 4.05 (s, 3H), 4.27 (t, 2H), 7.33 (s, IH), 7.4 (s, IH), 8.86 (s, IH).
  • a mixture of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (1.6 g) and isopropanol (50 ml) was placed in a Carius tube which was cooled to -78°C prior to the addition of liquid ammonia (10 ml).
  • the Carius tube was sealed and heated to 130°C for 20 hours.
  • the Carius tube was cooled to ambient temperature, opened and the mixture was evaporated. The residue was triturated under diethyl ether.
  • 4-amino- 7-methoxy-6-(3-morpholinopropoxy)quinazoline (containing 2.9 equivalents of ammonium chloride; 1.54 g) which was used without further purification.
  • a portion of the material was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent.
  • N-diphenylmethylene-6-(3-piperidinopropoxy)- 7-methoxyquinazolin-4-amine (0.277 g); NMR Spectrum: (DMSOde) 1.3 (br s, 2H), 1.42 (br s, 4H), 1.88 (t, 2H), 2.28 (br s, 4H), 2.38 (t, 2H), 3.92 (s, 3H), 4.07 (t, 2H), 7.0 (s, IH), 7.23 (s, IH), 7.2-7.65 (br m, 10H), 8.62 (s, IH); Mass Spectrum: M+H 4 481.
  • Trifluoroacetic acid (1 ml) was added to a mixture of the material so obtained, triethylsilane (0.093 g) and methylene chloride (0.15 ml) and the reaction mixture was stirred and heated to reflux for 2 minutes. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic soultion was evaporated to give 4-amino-7-methoxy-6-[N-(3-morpholino ⁇ ropyl)carbamoyl]quinazoline (0.129 g); Mass Spectrum: M+H 4 346.
  • the 4-amino-7-methoxy-6-[2-(2-methoxyethoxy)ethoxy]quinazoline used as a starting material was prepared from N-diphenylmethylene-6-hydroxy-7-methoxyquinazolin-4-amine and 2-(2-methoxyethoxy)ethyl chloride using analogous procedures to those described in the last two paragraphs of Note (e) above. In a further preparation, 2-(2-methoxyethoxy)ethyl 4-toluenesulphonate was used.
  • N-methylamino)-l-hexynyl]-6-methoxyquinazolin-4-yl ⁇ urea (0.1 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and a solution of hydrogen chloride gas in ethyl acetate was added. Toluene was added and the mixture was evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated.
  • 6-Mesyloxy- 1-hexyne was reacted with methylamine using an analogous procedure to that described in J. Heterocyclic Chemistry, 1994, 31, 1421 to give 6-methylamino- 1-hexyne which was reacted di-tert-butyl dicarbonate using a conventional procedure.
  • Example 28 Using an analogous procedure to that described in Example 27, the appropriate
  • Example 31 l-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]- 3-[(R)-(+)- ⁇ -methylbenzyl]guanidine Using an analogous procedure to that described in Example 29, l-[6-methoxy-
  • the l-(6J-dimethoxyquinazolin-4-yl)-3-(2-nitrophenyl)urea used as a starting material was prepared by the reaction of 2-nitrophenylisocyanate and 4-amino- 6J-dimethoxyquinazoline using an analogous procedure to that described in Example 1.
  • Compound X the active ingredient being termed "Compound X"
  • Maize starch paste (5% w/v paste) 2.25
  • Citric acid 0.38% w/v

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Abstract

L'invention concerne l'utilisation de dérivés de quinazoline dans la fabrication d'un médicament destiné à être utilisé comme agent anti-invasif dans le confinement et/ou le traitement d'une tumeur solide. Ces dérivés sont représentés par la formule (I) dans laquelle Q1 comprend un noyau quinazoline éventuellement substitué par un groupe constitué par halogéno, trifluorométhyle et cyano, ou par un groupe représenté par la formule: Q3-X1- dans laquelle X1 comprend une liaison directe et O et Q3 comprennent aryle, aryle-alkyle (1-6C), hétérocyclyle et hétérocyclyle-alkyle(1-6); R2 et R3 représentent chacun hydrogène ou alkyle(1-6C); Z comprend O, S et NH; et Q2 comprend aryle et aryle-alkyle (1-3C) ou leur sel pharmaceutiquement acceptable.
PCT/GB2001/002874 2000-07-03 2001-06-28 Quinazolines a usage therapeutique WO2002002534A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037789A2 (fr) * 2002-10-24 2004-05-06 Merck Patent Gmbh Derives de methylene uree
US7498335B2 (en) 2000-03-06 2009-03-03 Astrazeneca Ab Method of producing an antiangiogenic or vascular permeability reducing effect
US7632840B2 (en) 2004-02-03 2009-12-15 Astrazeneca Ab Quinazoline compounds for the treatment of hyperproliferative disorders
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
CN102250112A (zh) * 2010-05-18 2011-11-23 上海再启生物技术有限公司 7-溴-4-氨基噻吩并嘧啶的制备方法
CN103232429A (zh) * 2013-04-26 2013-08-07 绍兴民生医药有限公司 (e)-n-[3-(甲氨基)丙基]-3-(噻吩-2-基)丙烯酰胺及其盐的制备方法
CN103265481A (zh) * 2013-06-14 2013-08-28 苏州明锐医药科技有限公司 4-氨基-3-喹啉甲腈衍生物的制备方法
WO2014147246A1 (fr) 2013-03-21 2014-09-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique pour l'utilisation dans le traitement de maladies hépatiques chroniques associées à une faible expression d'hepcidine
JP2019526568A (ja) * 2016-08-26 2019-09-19 カーテナ ファーマシューティカルズ，インク． Ｏｌｉｇ２活性の阻害
CN118359621A (zh) * 2024-04-16 2024-07-19 上海陶术生物科技有限公司 加利司伟及加利司伟中间体的制备方法和相应的加利司伟中间体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998038984A2 (fr) * 1997-03-05 1998-09-11 Sugen, Inc. Preparations d'agents pharmaceutiques hydrophobes
WO1998043960A1 (fr) * 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
WO1998050370A1 (fr) * 1997-05-02 1998-11-12 Sugen, Inc. Procedes de modulation de la fonction proteine kinase de la famille serine/threonine avec des composes a base de quinazoline
WO1999009024A1 (fr) * 1997-08-14 1999-02-25 Smithkline Beecham Plc Derives de phenyluree et de phenylthiouree utilises en tant qu'antagonistes de hfgan72

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998038984A2 (fr) * 1997-03-05 1998-09-11 Sugen, Inc. Preparations d'agents pharmaceutiques hydrophobes
WO1998043960A1 (fr) * 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
WO1998050370A1 (fr) * 1997-05-02 1998-11-12 Sugen, Inc. Procedes de modulation de la fonction proteine kinase de la famille serine/threonine avec des composes a base de quinazoline
WO1999009024A1 (fr) * 1997-08-14 1999-02-25 Smithkline Beecham Plc Derives de phenyluree et de phenylthiouree utilises en tant qu'antagonistes de hfgan72

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7498335B2 (en) 2000-03-06 2009-03-03 Astrazeneca Ab Method of producing an antiangiogenic or vascular permeability reducing effect
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US8536184B2 (en) 2000-11-01 2013-09-17 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
USRE43098E1 (en) 2000-11-01 2012-01-10 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US8410143B2 (en) 2002-10-24 2013-04-02 Merck Patent Gmbh Methylene urea derivatives
WO2004037789A3 (fr) * 2002-10-24 2004-10-28 Merck Patent Gmbh Derives de methylene uree
JP2006506454A (ja) * 2002-10-24 2006-02-23 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング メチレン尿素誘導体
US7589112B2 (en) 2002-10-24 2009-09-15 Merck Patent Gmbh Methylene urea derivatives
WO2004037789A2 (fr) * 2002-10-24 2004-05-06 Merck Patent Gmbh Derives de methylene uree
JP2010254714A (ja) * 2002-10-24 2010-11-11 Merck Patent Gmbh メチレン尿素誘導体
JP4690889B2 (ja) * 2002-10-24 2011-06-01 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング メチレン尿素誘導体
US7632840B2 (en) 2004-02-03 2009-12-15 Astrazeneca Ab Quinazoline compounds for the treatment of hyperproliferative disorders
CN102250112A (zh) * 2010-05-18 2011-11-23 上海再启生物技术有限公司 7-溴-4-氨基噻吩并嘧啶的制备方法
WO2014147246A1 (fr) 2013-03-21 2014-09-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique pour l'utilisation dans le traitement de maladies hépatiques chroniques associées à une faible expression d'hepcidine
CN103232429A (zh) * 2013-04-26 2013-08-07 绍兴民生医药有限公司 (e)-n-[3-(甲氨基)丙基]-3-(噻吩-2-基)丙烯酰胺及其盐的制备方法
CN103265481A (zh) * 2013-06-14 2013-08-28 苏州明锐医药科技有限公司 4-氨基-3-喹啉甲腈衍生物的制备方法
JP2019526568A (ja) * 2016-08-26 2019-09-19 カーテナ ファーマシューティカルズ，インク． Ｏｌｉｇ２活性の阻害
US11242323B2 (en) 2016-08-26 2022-02-08 Curtana Pharmaceuticals, Inc. Inhibition of OLIG2 activity
JP7028860B2 (ja) 2016-08-26 2022-03-02 カーテナ ファーマシューティカルズ，インク． Ｏｌｉｇ２活性の阻害
US12145913B2 (en) 2016-08-26 2024-11-19 Curtana Pharmaceuticals, Inc. Inhibition of Olig2 activity
CN118359621A (zh) * 2024-04-16 2024-07-19 上海陶术生物科技有限公司 加利司伟及加利司伟中间体的制备方法和相应的加利司伟中间体

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