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  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
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  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
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  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • 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
  • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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  • 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
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

• the invention relates to quinazoline derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-proliferative activity such as anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body.
• the invention also relates to processes for the manufacture of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
• Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial.
• Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
• EGF epidermal growth factor
• Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research. 1993, £0_, 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, transforming growth factor ⁇ (TGF ⁇ ). NEU, erbB. Xmrk, DER and let23 receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin, IGFI and insulin-related receptor (IRR) receptors and Class III receptor tyrosine kinases comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF ⁇ , PDGF ⁇ and colony-stimulating factor 1 (CSF1) receptors.
• EGF EGF family of receptor tyrosine kinases
• TGF ⁇ transforming growth factor ⁇
• NEU erbB. Xmrk, DER and let23 receptors
• Class II receptor tyrosine kinases comprising the insulin family
• Class I kinases such as the EGF family of receptor tyrosine kinases are frequently present in common human cancers such as breast cancer (Sainsbury elal., Brit. J. Cancer. 1988, 5_8_, 458; Guerin et aL, Oncogene Res., 1988, 1, 21 and Klijn el al., Breast Cancer Res. Treat.. 1994, 22, 73), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny el al., Brit. J. Cancer. 1986, 5_4_, 265; Reubi el al., Int. J. Cancer. 1990, 4_5_, 269 and Rusch el al-, Cancer Research.
• NSCLCs non-small cell lung cancers
• EGF receptors which possesses tyrosine kinase activity are overexpressed in many human cancers such as brain, lung squamous cell, bladder, gastric, colorectal, breast, head and neck, oesophageal, gynaecological and thyroid tumours. Accordingly it has been recognised that an inhibitor of receptor tyrosine kinases should be of value as a selective inhibitor of the growth of mammalian cancer cells (Yaish el aL Science. 1988, 242. 933).
• EGF type receptor tyrosine kinases have also been implicated in non-malignant 0 proliferative disorders such as psoriasis (Elder el al., Science. 1989, 241, 811). It is therefore expected that inhibitors of EGF type receptor tyrosine kinases will be useful in the treatment of non-malignant diseases of excessive cellular proliferation such as psoriasis (where TGF ⁇ is believed to be the most important growth factor) and benign prostatic hypertrophy (BPH), atherosclerosis and restenosis. 5 It is known from European Patent Applications Nos.
• Q 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen, nitrogen and sulphur, and Q 2 optionally bears up to 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (l-4C)alkoxycarbonyl, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino, di-[(l-4C)alkyl]amino, (2-4C)alkanoylamino,
• N-(l-4C)alkylcarbamoyl and N,N-di-(l-4C)alkylcarbamoyl, or Q is a group of the formula II
• X 2 is a group of the formula CO, C(R 3 ) 2 , CH(OR 3 ), C(R 3 ) 2 -C(R 3 ) 2 .
• C(R 3 ) C(R 3 ), C ⁇ C, CH(CN), O, S, SO, SO 2 , N(R 3 ), CON(R 3 ), SO 2 N(R 3 ), N(R 3 )CO, N(R 3 )SO 2 , OC(R 3 ) 2 , SC(R 3 ) 2 , C(R 3 ) 2 O or C(R 3 ) 2 S
• each R 3 is independently hydrogen or (l -4C)alkyl
• Q 3 is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur, which heteroaryl moiety is a single ring or is fused to a benzo ring, and wherein said phenyl or naphthy
• alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl” are specific for the straight chain version only.
• R is a hydroxy-(2-4C)alkoxy group
• suitable values for this generic radical include 2-hydroxyethoxy, 2-hydroxypropoxy, l-hydroxyprop-2-yloxy and 3-hydroxypropoxy.
• An analogous convention applies to other generic terms.
• a quinazoline derivative of the formula I may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses anti-proliferative activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
• the quinazolines of the formula I are unsubstituted at the 2-position thus it is to be understood that the R 1 groups are located only on the benzo portion of the quinazoline ring. It is also to be understood that certain quinazoline derivatives of the formula I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess anti-proliferative activity. Suitable values for the generic radicals referred to above include those set out below. i 2 3
• a suitable value for a substituent on Q , Q or Q , for a substituent on a CH 2 group within a substituent on Q 1 , or for R 1 , R , R or R when it is halogeno is, for example, fluoro, chloro, bromo or iodo; when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl; when it is (l-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; when it is (l-4C)alky lamino is, for example, methylamino, ethylamino or propylamino; when it is di-[(l-4C)alkyl]amino is, for example, dimethylamino, diethylamino,
• N-ethyl-K-methylamino or dipropy lamino when it is (2-4C)alkanoy lamino is, for example, acetamido, propionamido or butyramido; when it is (l-4C)alkoxycarbonyl is, for example, methoxycarbonyl, ethoxy carbonyl, propoxy carbonyl, butoxcarbonyl or tert-butoxycarbony 1 : when it is N-(l-4C)alkylcarbamoyl is, for example, N_-methylcarbamoyl or N-ethylcarbamoyl; and when it is N,N-di-[(l-4C)alkyl]carbamoyl is, for example, N.,N-dimethylcarbamoyl, M-ethyl-N-methylcarbamoyl and H ⁇ i-diethylcarbamoyl.
• Suitable values for each substituent which may be present on Q l include, for example:- for (2-4C)alkenyloxy: vinyloxy and allyloxy; for (2-4C)alkynyloxy: 2-propynyloxy; for ( 1 -3 C)alky lenedioxy : methylenedioxy, ethylenedioxy and propylenedioxy; for 4-(l-4C)alkyl- piperazin- 1-yl: 4-methylpiperazin-l-yl and 4-ethylpiperazin- 1 -y 1 ; for amino-(l-4C)alkyl: aminomethyl, 2-aminoethyl and 3 -aminopropyl; for (l-4C)alkylamino-(l-4C)alkyl: methylaminomethyl, 2-methylaminoethyl and 3 -methy laminopropy 1 ; for di-[(l-4C)alkyl]amino-(l-4C)alkyl: di
• H-( 1 -4C)alkyl-( 1 -4C)alkoxy- (2-4C)aIkylamino N-methyl-M-(2-methoxyethyl)amino, N-methy l-H-(3 -methoxypropy l)amino and M-ethyl-K-(2-methoxyethyl)amino; for halogeno-(2-4C)alkanoy lamino: 2-chloroacetamido, 2-bromoacetamido, 3-chloropropionamido and 3-bromopropionamido; for hydroxy-(2-4C)alkanoylamino: 2-hydroxyacetamido, 3-hydroxypropionamido and 4-hydroxy buty ramido ;
• the R 1 substituent is preferably located at the 7-position of the quinazoline ring.
• Suitable substituents formed when any of the substituents on Q comprising a CH 2 group which is not attached to a halogeno, SO or SO 2 group or to a N, O or S atom bears on said CH 2 group a substituent selected from hydroxy, amino, (l-4C)alkoxy, (l ⁇ 4C)alkylamino and di-[(l-4C)alkyl]amino include, for example, substituted (l-4C)alkylamino-(2-4C)alkoxy or di-[(l-4C)alkyl]amino-(2-4C)alkoxy groups, for example hydroxy-( 1 -4C)alkylamino-(2-4C)alkoxy or hydroxy-di-[( 1 -4C)alkyl]amino-(2-4C)alkoxy groups such as 3-methylamino-2-hydroxypropoxy and 3-dimethyla
• a suitable value for Q and Q 3 when it is a naphthyl group is, for example, 1 -naphthyl or 2-naphthyl.
• a suitable value for Q when it is 9- or 10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a benzo-fused heterocyclic moiety such as indolyl, isoindolyl, indolizinyl, lH-benzimidazolyl, lH-indazolyl, benzoxazolyl, benzofcjisoxazoiyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, lH-benzotriazolyl, benzo [c] furazanyl, benzo[c][2,l,3]thiadiazolyl, benzo[d][l,2,3]oxadiazolyl, benzo[d][l,2,3]thiadiazolyl, quinolyl
• the heterocyclic moiety may be attached through any available position including from either of the two rings of the bicyclic heterocyclic moiety.
• the heterocyclic moiety may bear a suitable substituent such as a (l-4C)alkyl substituent on an available nitrogen atom.
• X 1 is, for example, a group of the formula C(R ) 2 O, it is the C atom which is attached to the quinazoline ring and the O atom which is attached to Q .
• X is, for example, a group of the formula N(R 3 )SO 2
• X is, for example, a group of the formula CON(R 2 )
• it is the CO group which is attached to the quinazoline ring and the N atom which is attached to Q 1 .
• a suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention is, for example, an acid-addition salt of a quinazoline derivative of the invention which is sufficiently basic, for example, a mono- or di-acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
• a suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, mo ⁇ holine or tris-(2-hydroxyethyl)amine.
• novel compounds of the invention include, for example, quinazoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Q 1 , X 1 , m, R 1 and Q has any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention:- (a) X 1 is a direct link;
• X 1 is a group of the formula CH 2 , CH 2 CH 2 , O, S, SO, SO 2 , NH, NHCO, NHSO 2 , OCH 2 or NHCH 2 ;
• Q 1 is phenyl optionally substituted as defined hereinbefore;
• Q 1 is a 5- or 6-membered monocyclic heteroaryl moiety containing up to 3 heteroatoms selected from oxygen, nitrogen and sulphur which is optionally substituted as defined hereinbefore;
• Q 1 is furyl, pyrrolyl, thienyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazoiyi, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,3-triazolyl or 1 ,2,4-triazolyl which is attached from any available position including from a nitrogen atom and which is optionally substituted as defined hereinbefore;
• Q bears 1 or 2 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino, di-[(l-4C)alkyl]amino and (2-4C)alkanoy lamino;
• Q ' bears a substituent selected from amino-( 1 -4C)alkyl, ( 1 -4C)alky lamino-
• (l-4C)alkyl di-[(l-4C)alkyl]amino-(l-4C)alkyl, pyrrolidin-l-yl-(l-4C)alkyl, piperidino-(l-4C)alkyl, mo ⁇ holino-(l-4C)alkyl, piperazin- l-yl-(l-4C)alkyl and 4-( 1 -4C)alkylpiperazin- 1 -y l-( 1 -4C)alkyl;
• Q is phenyl which is optionally substituted as defined hereinbefore;
• X is a group of the formula CO, CH 2 , CH(OH), S, SO 2 NH or OCH 2
• Q 3 is phenyl or pyridyl which optionally bears 1 or 2 substituents selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy, n is 1 and R 4 is hydrogen, halogeno, (l-4C)alkyl or (l-4C)alkoxy;
• Q is a group of the formula II wherein X 2 is a group of the formula CO, Q 3 is phenyl which optionally bears 1 or 2 substituents selected from halogeno, ( 1 -4C)alkyl and ( 1 -4C)alkoxy, n is 1 and R is hydrogen, halogeno or (l-4C)alkyl; and (o) Q 2 is a group of the formula II wherein X 2 is a group of the formula OCH 2 , Q 3 is pyridyl, n is 1 and R is hydrogen, halogeno or (l-4C)alkyl; provided that when Q 1 is optionally-substituted phenyl, X 1 is not N(R 2 )CO, N(R 2 )SO 2 ,
• a preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link or a group of the formula CH 2 , CH 2 CH 2 , NH, NHCO, NHSO 2 ,
• OCH 2 , SCH 2 NHCH 2 , CH 2 O or CH 2 S;
• Q' is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-oxazolyl,
• 5-isothiazolyl or 1 ,2,3-triazol-4-yl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, piperidinomethyl, 2-piperidinoethyl, mo ⁇ holinomethyl, 2-mo ⁇ holinoethyl, piperazin- 1-ylmethyl, 2-piperazin-l-ylethyl, 4-methylpiperazin-l-ylmethyl and
• X is a group of the formula CO or OCH 2
• Q is phenyl or 2-pyridyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo, methyl and methoxy
• n is 1 and R is hydrogen, fluoro, chloro, bromo or methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
• a further preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link or a group of the formula NHCO, OCH 2 or NHCH 2 ; Q l is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-oxazolyl, 5-isoxazolyl or
• 4-imidazolyl which optionally bears a substituent selected from aminomethyl, mo ⁇ holinomethyl and 2-mo ⁇ holinoethyl; m is 1 and R 1 is hydrogen or methoxy; and Q 2 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
• a specific especially preferred compound of the invention is the quinazoline derivative of the formula I:- 4-(3-chloro-4-fluoroanilino)-6-(3-furyl)quinazoline,
• a further preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link;
• Q is thienyl which bears a substituent selected from amino-(l-4C)alkyl, (l-4C)alkylamino- (l-4C)alkyl, di-[(l-4C)alkyl]amino-(l-4C)alkyl, pyrrolidin-l-yl-(l-4C)alkyl, piperidino-(l-4C)alkyl, mo ⁇ holino-(l-4C)alkyi, piperazin- l-yl-(l-4C)alkyl and
• a further preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link;
• Q is 2-thienyl which optionally bears a substituent selected from methyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-l-ylethyl, piperidinomethyl, 2-piperidinoethyl, mo ⁇ holinomethyl, 2-mo ⁇ holinoethyl, piperazin- 1-ylmethyl, 2-piperazin-l-ylethyl, 4-methylpiperazin- 1-ylmethyl and 2-(4-methylpiperazin-l-yl)ethyl; m is 1 and R 1 is hydrogen or methoxy; and Q is phenyl which optionally bears 1, 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy; or a pharmaceutically-acceptable acid-
• a further preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link;
• Q is 2-thienyl which optionally bears a substituent selected from aminomethyl, mo ⁇ holinomethyl and 2-mo ⁇ holinoethyl; m is 1 and R is hydrogen or methoxy; and Q is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo and methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
• a further specific especially preferred compound of the invention is the quinazoline derivative of the formula I:- 4-(3-chloro-4-fluoroanilino)-6-[5-(2-mo ⁇ holinoethyl)thien-2-yl]quinazoline; or a pharmaceutically-acceptable acid-addition salt thereof.
• a further preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link or a group of the formula O;
• Q is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, bromo, amino, cyano, nitro, aminomethyl, methylaminomethyl, dimethylaminomethyl, diethylaminomethyl, pyrrolidin- 1-ylmethyl, piperidinomethyl, mo ⁇ holinomethyl, piperazin- 1-ylmethyl and 4-methylpiperazin- 1-ylmethyl; m is 1 and R is hydrogen or methoxy; and
• Q is phenyl which optionally bears 1 , 2 or 3 substituents selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy, or Q 2 is a group of the formula II wherein X 2 is a group of the formula OCH 2 , Q 3 is 2-pyridyl, n is 1 and R 4 is hydrogen, fluoro, chloro or methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
• a further preferred compound of the invention is a quinazoline derivative of the formula I wherein X 1 is a direct link or a group of the formula O;
• Q 1 is phenyl which optionally bears 1 or 2 substituents selected from amino, aminomethyl, diethylaminomethyl, pyrrolidin- 1-ylmethyl, piperidinomethyl and mo ⁇ holinomethyl; m is 1 and R 1 is hydrogen; and Q is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro and methyl; or a pharmaceutically-acceptable acid-addition salt thereof.
• a further specific especially preferred compound of the invention is the quinazoline derivative of the formula I:- 4-(3-methylanilino)-6-phenylquinazoline,
• 6-(4-aminomethylphenyl)-4-(3-chloro-4-fluoroanilino)quinazoline 6-(4-aminophenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline, 6-(4-aminomethylphenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline or 4-(3-chloro-4-fluoroanilino)-6-(4-mo ⁇ holinomethylphenoxy)quinazoline; 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. Suitable processes include, for example, those illustrated in European Patent Applications Nos. 0520722, 0566226, 0602851, 0635507 and 0635498, and Intemational Patent Applications WO 96/15118 and WO 96/16960.
• Z is a displaceable group, with an aniline of the formula Q -NH 2 .
• a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine,
• H-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride.
• a suitable displaceable group Z is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
• the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol. isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N.,H-dimethylformamide, N,N_-dimethylacetamide, N.-methylpyr ⁇ oIidin-2-one or dimethylsulphoxide.
• a suitable inert solvent or diluent for example an alkanol or ester such as methanol, ethanol. isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride
• the reaction is conveniently carried out at a temperature in the range, for example, 10 to 250°C, preferably in the range 40 to 80°C.
• the quinazoline derivative of the formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-Z wherein Z has the meaning defined hereinbefore.
• the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N_-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
• a suitable base for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N_-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene
• an alkali or alkaline earth metal carbonate or hydroxide for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium
• Z is a displaceable group as defined hereinbefore, with an organoboron reagent of the ffoorrmmuullaa QQ''--BB((LL')(L 2 ) wherein each L 1 and L 2 , which may be the same or different, is a suitable ligand.
• a suitable value for the ligands L and L which are present on the boron atom include, for example, a hydroxy, (l-4C)alkoxy or (l-6C)alkyl ligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand.
• the ligands L 1 and L 2 may be linked such that, together with the boron atom to which they are attached, they form a ring.
• L and L together may define an oxy-(2-4C)alkylene-oxy group, for example an oxyethyleneoxy or oxytrimethyleneoxy group such that, together with the boron atom to which they are attached, they form a cyclic boronic acid ester group.
• Particularly suitable organoboron reagents include, for example, compounds of the formulae Q'-B(OH) 2 , Q'-B(OPr') 2 and Q'-B(Et) 2 .
• a suitable catalyst for the reaction includes, for example, a metallic catalyst such as a palladium(O), palladium(II), nickel(O) or nickel(II) catalyst, for example tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride, palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride. nickel(II) bromide or bis(triphenylphosphine)nickel(II) chloride.
• a free radical initiator may conveniently be added, for example an azo compound such as azo(bisisobutyronitrile).
• the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran, 1 ,4-dioxan or 1 ,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol, and the reaction is conveniently carried out at a temperature in the range, for example 10 to 250°C, preferably in the range 60 to 120°C.
• a suitable inert solvent or diluent for example an ether such as tetrahydrofuran, 1 ,4-dioxan or 1 ,2-dimethoxyethane, an aromatic solvent such as benzene, toluene or xylene, or an alcohol such as methanol or ethanol
• Organoboron reagents of the formula Q -B(L )(L ) may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist, for example by the reaction of an organometallic compound of the formula Q'-M, wherein M is, for example, lithium or the magnesium halide portion of a Grignard reagent, with an ⁇ organoboron compound of the formula Z-B(L )(L ) wherein Z is a displaceable group as defined hereinbefore.
• the compound of the formula Z-B(L')(L 2 ) is, for example, boric acid or a tri-(l-4C)alkyl borate such as tri-isopropyl borate.
• the organoboron compound of the formula Q -B(L )(L ) may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist, for example by the reaction of an organometallic compound of the formula Q'-M, wherein M
• Q -B(L )(L ) may be replaced with an organometallic compound of the formula Q'-M wherein M is a metal atom or a metallic group (i.e. a metal atom bearing suitable ligands).
• M is a metal atom or a metallic group (i.e. a metal atom bearing suitable ligands).
• Suitable values for the metal atom include, for example, lithium and copper.
• Suitable values for the metallic group include, for example, groups which contain a tin, silicon, zirconium, aluminium, magnesium or mercury atom.
• Suitable ligands within such a metallic group include, for example, hydroxy groups, (l-6C)alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl groups, halogeno groups such as chloro, bromo and iodo groups, and (l-6C)alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
• a particular organometallic compound of the formula Q -M is, for example, an organotin compound such as a compound of the formula Q -SnBu 3 , an organosilicon compound such as a compound of the formula Q'-Si(Me)F 2 , an organozirconium compound such as a compound of the formula Q'-ZrCl 3 , an organoaluminium compound such as a compound of the formula Q -AIEt 2 , an organomagnesium compound such as a compound of the formula Q'-MgBr, or an organomercury compound such as a compound of the formula Q -HgBr.
• an organotin compound such as a compound of the formula Q -SnBu 3
• an organosilicon compound such as a compound of the formula Q'-Si(Me)F 2
• an organozirconium compound such as a compound of the formula Q'-ZrCl 3
• an organoaluminium compound such
• each of L and L which may be the same or different, is a suitable ligand as defined hereinbefore, with a compound of the formula Q -Z wherein Z is a displaceable group as defined hereinbefore.
• the reaction is conveniently carried out in a suitable inert solvent or diluent and at a suitable temperature in an analogous manner to the conditions described in paragraph (b) hereinbefore.
• the quinazoline of the formula V may conveniently be obtained by analogous procedures to those described hereinbefore for the preparation of the organoboron reagent of the formula Q'-BfL'XL 2 ).
• a suitable reactive derivative of a carboxylic acid of the formula Q 1 -CO 2 H 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 such as pentafluorophenyl trifluoroacetate or an alcohol such as methanol, ethanol, isopropanol, butanol or H-hydroxybenzotriazole; an acyl azide.
• 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 anhydr
• an azide formed by the reaction of the acid and azide such as diphenylphosphoryl azide
• an acyl cyanide for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide
• the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.
• Analogously suitable reactive derivatives of the sulphonic acid of the formula Q -SO 2 OH may be obtained.
• the reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 120°C, preferably at or near ambient temperature.
• reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near 80°C.
• Z is a displaceable group as defined hereinbefore.
• reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 to 150°C, preferably in the range 20 to 70°C.
• a suitable reducing agent is, for example, an alkali metal aluminium hydride such as lithium aluminium hydride.
• the reduction is conveniently carried out in a suitable inert solvent or diluent such as diethyl ether or tetrahydrofuran and at a temperature in the range, for example,
• 0 to 80°C preferably in the range 15 to 50°C.
• the reduction may conveniently be carried out by any of the many procedures known for such a transformation.
• the reduction may be carrried out, for example, by the hydrogenation of a solution of the nitro compound in an inert solvent or diluent as defined hereinbefore in the presence of a suitable metal catalyst such as palladium or platinum.
• a further suitable reducing agent is, for example, an activated metal such as activated iron
• the reduction may be carried out by heating a mixture of the nitro compound and the activated metal in a suitable solvent or diluent such as a mixture of water and an alcohol, for example, methanol or ethanol, to a temperature in the range, for example,
• a suitable reducing agent is, for example, a hydride reducting agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
• a hydride reducting agent for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride.
• the reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
• a suitable inert solvent or diluent for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride.
• the coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore, preferably in N_,N-dimethylformamide, N,N_-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
• a pharmaceutically-acceptable salt of a quinazoline derivative of the formula I when required, for example a mono- or di-acid-addition salt, it may be obtained, for example, by reaction of said compound with, for example, a suitable acid using a conventional procedure.
• the quinazoline derivative defined in the present invention possesses anti-proliferative activity such as anti-cancer activity which is believed to arise from the Class I receptor tyrosine kinase inhibitory activity of the compound.
• anti-proliferative activity such as anti-cancer activity which is believed to arise from the Class I receptor tyrosine kinase inhibitory activity of the compound.
• Receptor tyrosine kinase was obtained in partially purified form from A-431 cells (derived from human vulval carcinoma) by the procedures described below which are related to those described by Ca ⁇ enter el a , J. Biol. Chem., 1979, 254, 4884, Cohen el a , J. Biol. Chem.. 1982, 2 ⁇ 2, 1523 and by Braun el al» J. Biol. Chem., 1984, 252, 2051.
• A-431 cells were grown to confluence using Dulbecco's modified Eagle's medium DMEM) containing 5% fetal calf serum (FCS). The obtained cells were homogenised in a hypotonic borate/EDTA buffer at pH 10.1. The homogenate was centrifuged at 400 g for 10 minutes at 0-4°C. The supernatant was centrifuged at 25,000 g for 30 minutes at 0-4°C.
• DMEM Dulbecco's modified Eagle's medium
• FCS fetal calf serum
• the pelleted material was suspended in 30 mM Hepes buffer at pH 7.4 containing 5% glycerol, 4 mM benzamidine and 1% Triton X-100, stirred for 1 hour at 0-4°C, and recentrifuged at 100,000 g for 1 hour at 0-4°C.
• test pu ⁇ oses 40 ⁇ l of the enzyme solution so obtained was added to a mixture of 400 ⁇ l of a mixture of 150 mM Hepes buffer at pH 7.4, 500 ⁇ M sodium orthovanadate, 0.1% Triton X-100, 10% glycerol, 200 ⁇ l water, 80 ⁇ l of 25 mM DTT and 80 ⁇ l of a mixture of 12.5 mM manganese chloride, 125 mM magnesium chloride and distilled water. There was thus obtained the test enzyme solution.
• test compound was dissolved in dimethylsulphoxide (DMSO) to give a 50 mM solution which was diluted with 40 mM Hepes buffer containing 0.1% Triton X-100, 10% glycerol and 10% DMSO to give a 500 ⁇ M solution. Equal volumes of this solution and a solution of epidermal growth factor (EGF; 20 ⁇ g/ml) were mixed.
• EGF epidermal growth factor
• [ ⁇ - 3 P]ATP 3000 Ci/mM, 250 ⁇ Ci
• test compound EGF mixture solution (5 ⁇ l) was added to the test enzyme solution (10 ⁇ l) and the mixture was incubated at 0-4°C for 30 minutes.
• the ATP/peptide mixture (10 ⁇ l) was added and the mixture was incubated at 25 °C for 10 minutes.
• the phosphorylation reaction was terminated by the addition of 5% trichloroacetic acid (40 ⁇ l) and bovine serum albumin (BSA; 1 mg/ml, 5 ⁇ l).
• BSA bovine serum albumin
• the strip was washed in 75 mM phosphoric acid (4 x 10 ml) and blotted dry. Radioactivity present in the filter paper was measured using a liquid scintillation counter (Sequence A). The reaction sequence was repeated in the absence of the EGF (Sequence B) and again in the absence of the test compound (Sequence C).
• Receptor tyrosine kinase inhibition was calculated as follows :-
• KB cells were seeded into wells at a density of 1 x 10 ⁇ - 1.5 x 10 ⁇ cells per well and grown for 24 hours in DMEM supplemented with 5% FCS (charcoal-stripped). Cell growth was determined after incubation for 3 days by the extent of metabolism of MTT tetrazolium dye to furnish a bluish colour. Cell growth was then determined in the presence of EGF (10 ng/ml) or in the presence of EGF (10 ng/ml) and a test compound at a range of concentrations. An IC 50 value could then be calculated.
• test compound (usually administered orally as a ball-milled suspension in 0.5% polysorbate) to inhibit the stimulation of liver hepatocyte growth caused by the administration of the growth factor TGF ⁇ (400 ⁇ g/kg subcutaneously, usually dosed twice, 3 and 7 hours respectively after the administration of the test compound).
• TGF ⁇ causes on average a 5-fold stimulation of liver hepatocyte growth.
• A-431 cells were maintained in culture in DMEM supplemented with 5% FCS and 2mM glutamine. Freshly cultured cells were harvested by trypsinization and injected subcutaneously (10 million cells/0.1 ml/mouse) into both flanks of a number of donor nude mice. When sufficient tumour material was available (after approximately 9 to 14 days), fragments of tumour tissue were transplanted into the flanks of recipient nude mice (test day 0). Generally, on the seventh day after transplantation (test day 7) groups of 7 to 10 mice with similar-sized tumours were selected and dosing of the test compound was commenced. Once-daily dosing of test compound was continued for a total of 13 days (test days 7 to 19 inclusive).
• Test (d) - 20 to 70% inhibition of tumour volume from a daily dose in the range, for example, 50 to 400 mg kg.
• the compound 4-(3-chloro-4-fluoroanilino)-6-[5-(2- mo ⁇ holinoethyl)thien-2-yl]quinazoline has an IC 50 of 0.04 ⁇ M in Test (a), an IC 50 of 0.19 ⁇ M in Test (b) and gives 64% inhibition in Test (d) at a dosage of 50 mg/kg/day.
• a pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
• the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• compositions may be prepared in a conventional manner using conventional excipients.
• the quinazoline derivative will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
• a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
• Preferably a daily dose in the range of 1-100 mg/kg is employed.
• the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
• a quinazoline derivative of the formula I as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
• the compounds of the present invention possess anti-proliferative properties which are believed to arise from their Class I (EGF type) receptor tyrosine kinase inhibitory activity. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by Class I receptor tyrosine kinase enzymes, i.e. the compounds may be used to produce a Class I receptor tyrosine kinase inhibitory effect in a warm-blooded animal in need of such treatment.
• the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of Class I receptor tyrosine kinase enzymes, i.e.
• the compounds may be used to produce an anti-proliferative effect mediated alone or in part by the inhibition of Class I receptor tyrosine kinase. Accordingly the compounds of the present invention are expected to be useful in the treatment of cancer by providing an anti-proliferative effect, particularly in the treatment of Class I receptor tyrosine kinase sensitive cancers such as cancers of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary. The compounds of the present invention are also expected to be useful in the treatment of other cell-proliferation diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
• other cell-proliferation diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
• 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 production of an anti-proliferative effect in a warm-blooded animal such as man.
• a method for producing an anti-proliferative effect 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 as defined immediately above.
• the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
• a unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
• the anti-proliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinazoline derivative of the invention, conventional radiotherapy or one or more other anti-tumour substances, for example cytotoxic or cytostatic anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine, vindesine and vinorelbine; alkyiating agents, for example cis-platin, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, tegafur, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No.
• cytotoxic or cytostatic anti-tumour substances for example those selected from, for example, mitotic inhibitors, for example vinblastine, vindesine and vinorelbine
• alkyiating agents for example cis-platin, carboplatin and cyclophos
• antibiotics for example adriamycin, mitomycin and bleomycin
• enzymes for example asparaginase
• topoisomerase inhibitors for example etoposide and camptothecin
• biological response modifiers for example interferon
• anti-hormones for example antioestrogens such as tamoxifen, for example antiandrogens such as 4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'- (trifluorornethyl)propionanilide or, for example LHRH antagonists or LHRH agonists such as goserelin, leuprorelin or buserelin and hormone synthesis inhibitors, for example
• the quinazoline derivative defined in the present invention is an effective anti-cancer agent, which property is believed to arise from its Class I (EGF type) receptor tyrosine kinase inhibitory properties.
• Class I EGF type
• Such a quinazoline derivative of the invention is expected to possess a wide range of anti-cancer properties as Class I receptor tyrosine kinases have been implicated in many common human cancers such as leukaemia and breast, lung, colon, rectal, stomach, prostate, bladder, pancreas and ovarian cancer.
• a quinazoline derivative of the invention will possess anti-cancer activity against these cancers.
• a quinazoline derivative of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, prostate and pancreas. It is further expected that a quinazoline derivative of the present invention will possess activity against other cell-proliferation diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
• a quinazoline derivative of the invention will be useful in the treatment of additional disorders of cellular growth in which aberrant cell signalling by way of receptor tyrosine kinase enzymes, including as yet unidentified receptor tyrosine kinase enzymes, are involved.
• Such disorders include, for example, inflammation, angiogenesis, vascular restenosis, immunological disorders, pancreatitis, kidney disease and blastocyte maturation and implantation.
• (v) melting points were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Koffier hot plate apparatus.
• Tetrakis(triphenylphosphine)palladium(0) (0.04 g) was added to a stirred mixture of 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt (0.25 g), a saturated aqueous sodium bicarbonate solution (1.5 ml), di-isopropyl 4-cyanophenylboronate and DME (10 ml). The resultant mixture was stirred and heated to reflux for 3 hours. The mixture was cooled to ambient temperature.
• Tetrakis(triphenylphosphine)palladium(0) (0.019 g) and a solution of phenylboronic acid (0.083 g) in ethanol (1 ml) were added in turn to a stirred mixture of 6-bromo-4-(3- methylanilino)quinazoline hydrochloride salt (European Patent Application No. 0520722, Example 9 thereof. 0.245 g), a saturated aqueous sodium carbonate solution (0.4 ml) and toluene ( 1.2 ml).
• the resultant mixture was stirred and heated to reflux for 6 hours.
• the mixture was cooled to ambient temperature and partitioned between methylene chloride and water.
• Example 3 Lithium aluminium hydride (IM in diethyl ether, 20 ml) was added dropwise to a stirred mixture of 4-(3-chloro-4-fluoroanilino)-6-(4-cyanophenyl)quinazoline (0.706 g), diethyl ether (25 ml) and THF (25 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was cooled to 0°C. Water (2 ml), 5M aqueous sodium hydroxide solution (2 ml) and water (6 ml) were added in turn and the mixture was allowed to warm to ambient temperature. The mixture was filtered and the filtrate was evaporated.
• Tetrakis(triphenylphosphine)palladium(0) (0.05 g) and a saturated aqueous sodium bicarbonate solution (5 ml) were added in turn to a stirred mixture of 6-bromo-4-(3-chloro-4- fluoroanilino)quinazoline hydrochloride salt (0.35 g), 3-furylboronic acid (J. Het. Chem.. 1975, 195; 0.208 g) and DME (15 ml).
• the resultant mixture was stirred and heated to reflux for 2 hours.
• the mixture was cooled to ambient temperature and partitioned between ethyl acetate and water.
• the organic phase was washed with water and with brine, dried (MgSO 4 ) and evaporated.
• Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added to a stirred mixture of
• 6-bromo-4-(3-chloro-4-fluoroaniIino)quinazoline hydrochloride salt (0.613 g), a saturated aqueous sodium bicarbonate solution (10 ml), di-isopropyl 2-furylboronate and DME (20 ml).
• the di-isopropyl 2-furylboronate used as a starting material was obtained as follows :- n-Butyllithium (1.6M in hexane, 2.75 ml) was added dropwise to a stirred solution of furan (0.25 g) in THF (10 ml) which had been cooled to 0°C. The resultant mixture was stirred at ambient temperature for 20 minutes. The mixture was cooled to -78°C and tri- isopropyl borate (1 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was evaporated to give the required starting material which was used without further purification.
• the di-isopropyl 5-(2-mo ⁇ holinoethyl)thien-2-ylboronate used as a starting material was obtained as follows :- 2-(2-Thienyl)acetyl chloride (16 g) was added slowly to a stirred mixture of mo ⁇ holine (17.5 ml) and methylene chloride (150 ml). A further portion (5 ml) of mo ⁇ holine was added and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was washed in turn with 2M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried and evaporated.
• Example 9 Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 2 hours, 6-bromo-4-(3-chloro-4- fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 5- mo ⁇ holinomethylthien-3-ylboronate. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by column chromatography using a 25:1 mixture of methylene chloride and methanol as eluent. The resultant product was recrystallised from ethyl acetate.
• aqueous phase was basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extract was dried (MgSO 4 ) and evaporated to give 4-bromo-2-mo ⁇ holinomethylthiophene (3.2 g); NMR Spectrum: 2.4 (t, 4H), 3.55 (t, 4H), 3.65 (s, 2H), 6.95 (d, IH), 7.5 (d, IH).
• Example 10 A mixture of 6-(2-chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline (0.5 g) and formamide (2 ml) was stirred and heated to 140°C for 2 hours. The mixture was cooled to ambient temperature and water was added. The precipitate was isolated and purified by column chromatography on a C18 reversed-phase silica column using decreasingly polar mixtures of water and methanol (containing 0.2% of trifluoroacetic acid) as eluent. There were thus obtained in turn:-
• Triphenylphosphine (0.063 g) was added to a stirred mixture of 6-bromo-4-(3- chloro-4-fluoroanilino)quinazoline hydrochloride salt (2.34 g), triethylamine (3.4 ml), (trimethylsilyl)acetylene (1.33 ml) palladium(II) chloride (0.021 g), cuprous iodide (0.045 g) and DMF (15 ml). The mixture was stirred and heated to 90°C for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 4-(3-chloro- 4-fluoroanilino)-6-(2-trimethylsilylethynyl)quinazoline (2.2 g).
• Chlorine gas was led into a stirred mixture of 6-acetyl-4-(3-chloro-4-fluoroanilino)- quinazoline (0.1 1 g), methylene chloride (40 ml) and ethanol (60 ml) and the mixture was cooled to a temperature in the range 20 to 25°C. After 10 minutes the supply of chlorine was stopped and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-(2-chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoiine (0.1 14 g) which was used without further purification.
• Example 11 A mixture of 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline (0.5 g), 2-pyridyl-tri- n-butyltin ( J. Het. Chem.. 1990, 2165; 0.8 g), tetrakis(triphenylphosphine)palladium(0) (0.05 g) and THF (20 ml) was stirred and heated to 60°C for 4 days. The mixture was evaporated and the residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and methanol as eluent.
• Diethyl-3-pyridylborane (0.176 g) was added to a mixture of 6-bromo-4-(3-chloro-4- fluoroanilino)quinazoline (0.53 g), powdered potassium hydroxide (0.202 g), tetra-n- butylammonium bromide (0.042 g), tetrakis(triphenylphosphine)palladium(0) (0.069 g) and THF (10 ml). The resultant mixture was stirred and heated to reflux for 16 hours. The mixture was evaporated and the residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and methanol as eluent.
• the 2-fluoroimidazole 4-toluenesulphonic acid salt used as a starting material was obtained from 2-aminoimidazole using analogous procedures to those described in J. Het. CJieriL, 1978, 1227 and J. Amer. Chem. Soc. 1973, 4619.
• Example 15 l-Methylimidazole-4-sulphonyl chloride (0.181 g) was added to a stirred mixture of 6-amino-4-(3-methylanilino)quinazoline (0.25 g) and pyridine (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residual oily solid was washed with methylene chloride and with a saturated aqueous sodium bicarbonate solution. The solid was then washed with water and with acetone and dried. There was thus obtained 4-(3-methylanilino)-6-(l-methylimidazole-4-sulphonamido)quinazoline (0.07 g), m.p. >250°C;
• Example 17 Sodium cyanoborohydride (0.126 g) was added portionwise to a stirred mixture of
• 6-amino-4-(3-methylanilino)quinazoline (0.25 g), 2-imidazolecarbaldehyde (0.192 g), glacial acetic acid (0.114 ml) and ethanol (20 ml).
• the resultant mixture was stirred at ambient temperature for 3 hours.
• the mixture was basified by the addition of a saturated aqueous sodium bicarbonate solution and evaporated. The residue was washed with water and dried. There was thus obtained 6-(2-imidazolylmethylamino)-4-(3-methylanilino)quinazoline (0.096 g), m.p. 235-237°C;
• Lithium aluminium hydride (IM in diethyl ether, 7.1 ml) was added dropwise to a stirred mixture of 4-(3-chloro-4-fluoroanilino)-6-(thiophene-2-carboxamido)quinazoline hydrochloride salt (1 g) and THF (200 ml). The mixture was stirred at ambient temperature for 2 hours and then heated to 45 °C for 1 hour. The mixture was cooled to ambient temperature and glacial acetic acid (5 ml) was added to destroy the excess of reducing agent. The mixture was evaporated and the residue was partitioned between methylene chloride and a 5M aqueous sodium hydroxide solution. The organic phase was washed with brine, dried and evaporated.
• Example 22 Using an analogous procedure to that described in Example 18, 6-amino-4-(3- chloro-4-fluoroanilino)quinazoline was reacted with 5-isoxazolecarbonyl chloride to give 4- (3-chloro-4-fluoroanilino)-6-(isoxazole-5-carboxamido)quinazoline hydrochloride salt in 87% yield, m.p. >250°C; NMR Spectrum: 7.4 (d, IH), 7.5 (t, IH), 7.65 (m, 2H), 8.0 (m, 2H), 8.85 (d, IH), 8.9 (s, IH), 1 1.4 (s, IH);
• Example 23 M,N_' -Dicyclohexylcarbodiim.de (0.416 g) was added portionwise to a stirred mixture of l,2,3-triazole-4-carboxylic acid (0.226 g) and DMA (10 ml). The resultant mixture was stirred at ambient temperature for 2 hours. A solution of 6-amino-4-(3-chloro-4- fluoroanilino)quinazoline (0.576 g) in DMA (5 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography using a 9:1:0.2 mixture of methylene chloride: methanol: triethylamine as eluent. There was thus obtained 4-(3-chloro-4-fluoroanilino)-6-( 1,2,3- triazole-4-carboxamido)quinazoline (0.145 g);
• 3-Pyridinecarbonyl chloride hydrochloride salt (0.107 g) was added portionwise to a stirred mixture of 6-amino-4-(3-chloro-4-fluoroanilino)-7-methylaminoquinazoline (European Patent Application No. 0635507, within Example 3 thereof; 0.11 g), triethylamine (0.101 g) and DMA (1 ml). The mixture was heated to 100°C for 3 hours. The mixture was evaporated and the residue was purified by column chromatography using a Cl 8 reversed-phase silica column and decreasingly polar mixtures of water and methanol (containing 0.2% trifluoroacetic acid) as eluent.
• a concentrated aqueous ammonium hydroxide solution (30% weight/volume, 35 ml) ' was added to a stirred mixture of 6-acetoxy-4-(3-chloro-4-fluoroanilino)quinazoline (22 g) and methanol (200 ml) and the mixture was heated to reflux for 3 hours. The mixture was evaporated and water (300 ml) was added to the residue. The solid was isolated, washed in turn with water (100 ml) and ethanol (60 ml) and dried. There was thus obtained 4-(3-chloro- 4-fluoroanilino)-6-hydroxyquinazoline (16.1 g, 93%);
• Example 31 A mixture of 6-bromomethyl-4-(3-methylanilino)quinazoline (European Patent
• Example 33 Using an analogous procedure to that described in Example 32, 4-(3-chloro-4- fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-chloromethylpyridine, hydrochloride salt to give 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-pyridylmethoxy)- quinazoline in 18% yield; NMR Spectrum: 3.93 (s, 3H), 5.28 (s, 2H), 7.16 (s, IH), 7.4 (m, 2H), 7.75 (m, IH), 7.95 (m, IH), 8.1 (m, 2H), 8.4 (s, IH), 8.6 (m, IH), 8.75 (m, IH); Elemental Analysis: Found C, 61.0; H, 3.9; N, 13.5; C 21 H 16 ClFN 4 O 2 requires C, 61.4; H, 3.9; N, 13.6%.
• Example 34 Example 34
• Example 39 Using an analogous procedure to that described in Example 5, 6-bromo-4-[3- methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di ⁇ isopropyl 3-furylboronate to give 6-(3-furyl)-4-[3-methyl-4-(2-pyridylmethoxy)anilino]- quinazoline in 55% yield, m.p.
• the di-isopropyl 3-furylboronate used as a starting material was obtained as follows:- n-Butyllithium (1.6M in hexane, 1 ml) was added dropwise to a stirred mixture of 3-bromofuran (0.21 g), tri-isopropyl borate (0.4 ml) and THF (5 ml) which had been cooled to -78°C. The mixture was stirred and allowed to warm to ambient temperature. The mixture was evaporated to give the required starting material which was used without further purification.
• the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
• the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

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