CA2215732C - Quinazoline derivatives - Google Patents

Abstract

The invention concerns quinazoline derivatives of the formula (I) wherein n is 1, 2 or 3 and each R2 is independently halogeno, trifluoromethyl or (1-4C)alkyl; R3 is (1-4C)alkoxy; and R1 is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)alkoxy-(2-4C)alkoxyl]amino-(2-4C)alkoxy, thiamorpholino-(2-4C)alkoxy, 1-oxothiamorpholino-(2-4C)alkoxy or 1,1-dioxothiamorpholino-(2-4C)alkoxy, and wherein any of the above-mentioned R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 group a hydroxy substituent; or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them, and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of proliferative disease such as cancer.

Description

WO 96/33980 _ 1 _ PCT/GB96/00961 QUINAZOLINE DE)EZTVATIVES
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 of 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 benefr.cial. Alternative approaches to anti-proliferative agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action.
In recent years it has been discovered that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene i.e. a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis, 1986,1, 91 ). Several such oncogenes give rise to the production of peptides which are receptors for growth factors. The grovvh factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden ~., Ann. Rev. Biochem., 1988, ~7, ~~3: Larsen et ~1. inn Reports in Med Chem 1989, Chpt. 13).
Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. T hey are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growrth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
Various classes of receptor yrosinc l:inases are known ( V'ilks, Advances in Cancer Research, 199;, ~, -l;_7 ;1 based on families of ~~r~w-th factors which hind to different receptor tyrosine kinases. The classification includes Class t receptor tyrosine hinases compn5ing the EGF
family of receptor tyrosine kinases such as the I:CJF. TCrFu. '.vEt'. crhli. lmrh. 1 iER
and let'_' WO 96/33980 _ 2 _ PCT/GB96/00961 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 PDGFcc, PDGF(3 and colony-stimulating factor 1 (CSF1) receptors. It is known that Class I kinases such as the EGF family of receptor tyrosine kinases are frequently present in common human cancers such as breast cancer (Sainsbtuy etet al., J. Cancer, 1988, 5,$, 458; Guerin ~ ~, Oncogene Res., 1988, ~, 21 and Klijn ., Breast Cancer Res. Treat., 1994, ~, 73), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny ., Brit. J. Cancer, 1986, ~, 265; Reubi g~., Int. J. Cancer, 1990, ~, 269; and Rusch g~., Cancer Research, 1993, 5~, 2379) and squamous cell cancer of the lung (Hendler g~., Cancer Cells, 1989, Z, 347), bladder cancer (Neat ., Lancet, 1985, 366), oesophageal cancer (Mukaida etet al., Cancer, 1991, 4$, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen etet al., OncQgene Res., 1987, ~, 149), cancer of the prostate (Visakorpi ~ja ., Histochem. J., 1992, ~4_, 481), leukaemia (Konaka etet al., ~, 1984, ~, 1035) and ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400586). As further human tumour tissues are tested for the EGF family of receptor tyrosine kinases it is expected that their widespread prevalance will be established in further cancers such as thyroid and uterine cancer. It is also known that EGF type tyrosine kinase activity is rarely detected in normal cells whereas it is more frequently detectable in malignant cells (Hunter, ~1_, 1987, .~Q, 823). It has been shown more recently (W J Gullick, Brit. Med. Bull., 1991, ~7, 87) that EGF receptors which possess tyrosine kinase activity are overexpressed in many human cancers such as brain, lung squamous cell. bladder, gastric, 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 ~t ~],, Science, 1988, ~~, 933). Support for this view is provided by the demonstration that erbstatin. an EGF receptor tyrosine kinase inhibitor, specifically attenuates the growth in athymic nude mice of a transplanted human mamman~ carcinoma which expresses EGF
receptor tyrosine kinase but is without effect on the growth of another carcinoma which does not express EGF receptor tyrosine kinase (Toi ~ ~1,., Eur. J. Cancer C1111.
Oncol., 1990, ;~, 722.) Various derivatives of smrene are also stated to possess mrosine kinase inhibitory properties (European Patent Application Nos. 0211363, 0304493 and 0322738) and to be of use as anti-tumour agents. The i11 vivo inhibitory effect of two such styrene derivatives which are EGF receptor tyrosine kinase inhibitors has been demonstrated against the growth of human squamous cell carcinoma inoculated into nude mice (Yoneda ~ ~,1., Cancer Research, 1991, ,~, 4430). Various known tyrosine kinase inhibitors are disclosed in a more recent review by T R Burke .Jr. (Drugs of the Future, 1992, ~, 119).
It is known from European Patent Applications Nos. 0520722, 0566226 and 0635498 that certain quinazoline derivatives which bear an anilino substituem at the 4-position possess receptor tyrosine kinase inhibitory activity. It is further known from European Patent Application No. 0602851 that certain quinazoline derivatives which bear a heteroarylamino subs'tituent at the 4-position also possess receptor tyrosine kinase inhibitory activity.
It is further known from International Patent Application WO 92/20642 that certain aryl and heteroaryl compounds inhibit EGF andlor PDGF receptor tyrosine kinase.
There is the disclosure of certain quinazoline derivatives therein but no mention is made of 4-anilinoquinazoline derivatives.
The jg vitro anti-proliferative effect of a 4-anilinoquinazoline derivative has been disclosed by Fry ~t ~1_., Science, 1994, '~ 5, 1093. It was stated that the compound 4-(3'-bromoanilino)-6.7-dimethoxyquinazoline was a highly potent inhibitor of EGF receptor tyrosine kinase.
The i~ ~ inhibitory effect of a 4.5-dianilinophthalimide derivative which is an inhibitor of the EGF family of receptor tyrosine kinases has been demonstrated against the growth in BALB/c nude mice of a human epidermoid carcinoma A-431 or of a human ovarian carcinoma SKOV-3 (Buchdunger ~ ~., Proc. Nat. Acad. Sci.. 1994, 91, 2334).
It is further known from European Patent Application No. 0635507 that certain tricyclic compounds which comprise a 5- or 6-membered ring fused to the benzo-ring of a quinazoline possess receptor tyrosine kinase inhibitory activim. It is also known from European Patent Application No. 0635498 that certain quinazoline derivatives which carry an amino group at the b-position and a halogeno group at the 7-position possess receptor tyrosine kinase inhibitory activity.
:~ccordinglv it has been indicated that Class I receptor mrosine kinase inhibitors will prove to hr useful in the treatment of a vanetv of human cancers EGF type receptor tyrosine kinases have also been implicated in non-:malignant proliferative disorders such as psoriasis (Elder et al., Science, 1989, 243, 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 TGFa is believed to be the most important growth factor), benign prostatic hypertrophy (BPH), atherosclerosis and restenosis.
There is no disclosure in these documents of quinazoline derivatives which bear at the 4-position an anilino substituent and which also bear an alkoxy substituent at the 7-position and a dialkylaminoalkoxy substituent at the 6-position. We have now found that such compounds possess potent in vivo anti-proliferative properties which are believed to arise from their Class I receptor tyrosine kinase inhibitory activity.
According to the present invention there is provided a quinazoline derivative of the formula I
~R2O
HN
R' N' ~~'~. i R3 N
wherein n is l, 2 or 3 and each R' is independently halogeno or trifluoromethyl;
R' is (1-4C)alkoxy; and R~ is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, thiamorpholino-(2-4C)alkoxy, 1-oxothiamorpholino-(~-4C)alkoxy or 1,1-dioxothiamorpholino-(2-4C)alkoxy, and wherein any of the above-mentioned R' substituents comprising a CHZ
(methylene) group which is not attached to a N or (J atom optionally bears on said CHI group a hydroxy substituent;
or a pharmaceutically-acceptable salt thereof.
According to a further aspect of the present invention there is provided a quinazoline derivative of the formula I

7588?-223 wherein n is l, 2 or 3 and each R' is independently halogeno or trifluoromethyl;
R3 is (1-~C)alkoxy; and R~ is di-[(1-4C)alkyl]amino-(2-~1C )alkoxy, pyrrolidin-1-vl-(2-:1C)alkoxy, piperidino-(?-4C)alkoxy, morpholino-(?-4C)alkoxy, piperazin-1-yl-('?-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy or di-[( 1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, and wherein any of the above-mentioned R~ substituents comprising a CHZ
(methylene) group which is not attached to a N or O atom optionally bears on said CHZ group a hydroxy substituent;
or a pharmaceutically-acceptable salt thereof.
In this specification the term "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. For example when R~ is a di-[( 1-~C)alkyl]amino-(?-~C)alkoxy group, suitable values for this generic radical include ''-dimethylaminoethoxy, 3-dimethylaminopropoxy, ~-dimethylaminopropoxv and 1-dimethylaminoprop-2-yloxy. An analogous convention applies to other generic terms.
Within the present invention it is to be understood that, insofar as certain of the compounds of the formula I may exist in optically active or racemic forms by virtue of one or more substituents containing an asymmetric carbon atom, the invention encompasses any such optically active or racemic form which possesses anti-proliferative 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 quinazolines of the formula I are unsubstituted at the 2-, 5- and 8-positions.
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.

A suitable value for R' when it is halogeno is, for example fluoro, chloro.
bromo or iodo.
A suitable value for R3 when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.
Suitable values for each R' substituent which may be present on the quinazoline ring include, for example:-for di-[(1-4C)alkyl]amino-(2-4C)alkoxy: 2-dimethylaminoethoxy, 2-,~1-ethyl-N-methylamino)ethoxy, ?-diethvlaminoethoxy, 2-dipropylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, ?-dimethylaminopropoxy, ?-diethylaminopropoxy.
1-dimethylaminoprop-2-yloxy, 1-diethvlaminoprop-'_'-yloxy, L -dimethylamino-?-methylprop-2-yloxy, ?-dimethylamino-?-methylpropoxy.

4-dimethylaminobutoxy, =~-diethylaminobutoxy, 3-dimethylaminobutoxy, 3-diethylaminobutoxy, ?-dimethylaminobutoxy, ?-diethylaminobutoxy.
1-dimethylaminobut-2-yloxy and 1-diethylaminobut-2-yloxy;
for pyrrolidin-1-yl-(2-4C)-alkoxy: 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy and 4-(pyrrolidin-1-yl)butoxy;

for piperidino-(2-4C)alkoxy:2-piperidinoethoxy, 3-piperidinopropoxy and 4-piperidinobutoxy;

for morpholino-(2-4C)alkoxy:?-morpholinoethoxy, 3-morpholinopropoxy and 4-morpholinobutoxy;

for piperazin-1-yl-(2-4C)alkoxy:2-(piperazin-1-yl)ethoxy, 3-(piperazin-1-yl)propoxy and 4-(piperazin-1-yl)butoxy;

WO 96/33980 - ~ - PCTlGB96/00961 for 4-(1-4~C)alkylpiperazin-1-yl-(2-4C)alkoxy: 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy and 4-(4-methylpiperazin-1-yl)butoxy;
for imidazol-1-yl-(2-~1C)alkoxy: 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy ' and 4-(imidazol-1-yl)butoxy;
for di-[(1-4C)alkoxy-(2-4C)-alkyl]amino-(2-4C)alkoxy: 2-[di-(2-methoxyethyl)amino]ethoxy, 3-[di-(2-methoxyethyl)amino]propoxy, 2-[di-(3-methoxypropyl)amino]ethoxy and 3-[di-(3-methoxypropyl)amino]propoxy;
for thiamorpholino-(?-4C)alkoxy: 2-thiamotpholinoethoxy.
3-thiamorpholinopropoxy and 4-thiamorpholinobutoxy;
for 1-oxothiamorpholino-(2-4C)alkoxy: 2-(I-oxothiamorpholino)ethoxy, 3-( 1-oxothiamorpholino)propoxy and 4-( 1-oxothiamorpholino)butoxy;
for l, l-dioxothiamorpholino-(2-4C)alkoxy: 2-( 1. I -dioxothiamorpholino )ethoxy.
3-( 1. I -dioxothiamorpholino )propoxv and -1-~ 1.1-dioxothiamorpholinolbutosy.
Suitable substituents formed when any of the R~ substituents comprising a CH, group which is not attached to a N or O atom bears on said CHI group a hydroxv substituent include. for example. substituted di-[(1--1C)alkvl]amino-(?-4C)alkoxy groups.
for example hydroxy-di-[(I-~C)alkyl]amino-(2-4C)alkoxv groups such as 3-dimethylamino-?-hydroxypropoxy.
' 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 hasic. fer example. a mono- ~r d~-acid-addition salt with. for example. an inorganic or organic acid. for example hydrochloric. by drobromic. sulphuric.
phosphoric.
trifluoroacetic, citric. malefic. tartaric. fumaric. methane,ulphomr or .~-toluenesulphon~c aca _g_ Particular novel compounds of the invention include, for example, quinazoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:-(a) n is 1 or 2 and each R" is independently tluoro, chloro, bromo or trifluoromethyl;
and R' and Rl have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(b) n is l, 2 or 3 and each R' is independently tluoro, chloro or bromo; and R3 and R' have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(c) R' is methoxy or ethoxy; and n, R' and R' have any of the meanings defined hereinbefore or in this section relatin~,~ to particular novel compounds of the invention;
(d) R~ is ?-dimethylaminoethoxy, ~'-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, ?-(pyrrolidin-1-yl)ethoxy. 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, ?-morpholinoethoxy, ~-morpholinopropoxy, 2-(piperazin-1-yl)ethoxy, 3-(piperazin-l-yl)propoxy, ?-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy, 2-[di-(2-methoxyethyl)amino]ethoxy, s-[di-(?-methoxvethyl)amino]propoxy, 3-dimethylamino-?-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy, 3-(pyrrolidin-1-yl)-?-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy, 3-morpholino-2-hydroxypropoxy, 3-(piperazin-1-yl)-?-hydroxypropoxy or 3-(4-methylpiperazin-1-yl)-2-hvdroxypropoxy;
and n, R'' and R3 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(e) R~ is 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-piperidinopropoxy, ~-morpholinopropoxy, 3-(piperazin-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)propoxy, 3-(imidazol-1-yl)propoxy, 3-[di-(2-methoxyethyl)amino]propoxy, 3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy, 3-(pyrrolidin-1-yl)-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy, ~-morpholino-2-hydroxypropoxy, 3-(piperazin-1-yl)-2-hydroxypropoxy or 3-(~-methylpiperazin-1-yl)-2-hydroxypropoxy;
and n, R~ and R3 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

Rl is 3-dimethylaminopropoxy, 3-diethvlaminopropoxy, 3- .{pyrrolidin-1-yl)propoxy, 3-momholinopropoxy or 3-morpholino-?-hydroxypropoxy; and n, R~ and R3 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(g) Rl is 3-morpholinopropoxy; and n, RZ and R' have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention.
A preferred compound of the invention is a quinazoline derivative of the formula I wherein {R')" is 3'-fluoro-4'-chloro or 3'-chloro-4'-lluoro;
R3 is methoxy; and Rl is ?-dimethylaminoethoxy, ?-diethylaminoethoxy, p-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-{pyrrolidin-1-yl)ethoxy. 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, ~-morpholinopropoxy, 2-(4-methylpiperazin-1-vl)ethoxy, ~'-(irnidazol-1-yl)ethoxy, 3-{imidazol-1-yl)propoxy, 2-[di-{2-methoxyethyl)amino]ethoxv or p-morpholino-?-hydroxypropoxy;
or a pharmaceutically-acceptable mono- or di-acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (RZ)" is 3'-chloro, 3'-bromo, 2',4'-difluoro, 2',4'-dichloro, 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-=1'-t7uoro:
R3 is methoxy; and R~ is 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-Ipyrrolidin-1-yl)propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 2-[di-{?-methoxyethyl)a~nino]ethoxy or 3-morpholino-2-hydroxypropoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (RZ)~ is 3'-chloro, 3'-bromo, 2',4'-difluoro, 2',4'-dichloro, 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro;
R3 is methoxy; and WO 96/33980 - I p _ PCTlGB96/00961 R' is 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-morpholinopropoxy or 3-morpholino-2-hydroxypropoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (R2)n is 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro;
R3 is methoxy; and Rl is 3-morpholinopropoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.
A specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-pyrrolidin-1-ylethoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-morpholinoethoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-[2-(4-methylpiperazin-1-y 1)ethoxy]quinazoline:
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6- { 2-[di-(2-methoxvethyl )amino]ethoxy } -quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the im~ention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-6-(2-dimethylaminoethoxy)-7-methoxvquinazoline:
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the iw ention is the following quinazoline derivative of the formula I:-WO 96/33980 - 11 _ PCT/GB96100961 4-(3'-chloro-4'-fluoroanilino)-6-(2-diethylaminoethoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(2',4'-difluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-6-(2-hydroxy-3-morpholinopropoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(2',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-6-(2-imidazol-1-ylethoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-6-(3-diethylaminopropoxy)-7-methoxyquinazoline:
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-vlpropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative: of the formula I:-.l-(3'-chloro--1'-f7uoroanilino?-~-( ~-dimethylaminopropoxv 1-7-methowquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred comFound of the invention is the following quinazoline derivative of the formula I:-4-(3',4'-difluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-6-(3-diethylaminopropoxy)-4-(3',4'-difluoroanilino)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-piperidinopropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-piperidinoethoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further specific preferred compound of the invention is the following quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino )-6-(3-imidazol-1-ylpropoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.
In a further aspect of the invention it has been found that certain of the compounds of the invention possess not only the property of potent 'fit vivo anti-proliferative activity wherebs~ the rate of growth of tumour tissue is slowed but also the property of being able to arrest the growth of tumour tissue and. at higher doses, of being able to cause shrinkage of the original tumour volume.
According to this aspect of the invention there is provided the quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropow )quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

WO 96/33980 - 13 _ PCTIGB96/00961 There is also provided the hydrochloride salt of the quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline.
There is also provided the dihydrochloride salt of the quinazoline derivative of the formula I:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline.
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, 0635498 and 0635507.
Such processes, when used to prepare a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, n, R2, R3 and R1 have any of the meanings defined hereinbefore for a quinazoline derivative of the formula I. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(a) The reaction, conveniently in the presence of a suitable base. of a quinazoline of the formula II
Z
N / \ R, ~N ~ R3 II
wherein Z is a displaceable group. with an aniline of the formula III
~R2~n i H.,N III

WO 96/33980 _ 14 - PCT/GB96/00961 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.
A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, I~-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Alternatively a suitable base is, for example, an alkali metal or alkaline earth metal amide, for example sodium amide or sodium bis(trimethylsilyl)amide. .
The reaction is preferably 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 ~LI,L~1-dimethylformamide, ~1,Z,I-dimethylacetamide, ~[-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 10 to 150°C. preferably in the range 20 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. When it is desired to obtain the free base from the salt. the salt may be treated with a suitable base as defined hereinbefore using a conventional procedure.
(b) For the production of those compounds of the formula I wherein R~ is an amino-substituted (2-4C)alkoxy group, the alkylation. conveniently in the presence of a suitable base as defined hereinbefore, of a quinazoline derivative of the formula I wherein R~
is a hydroxy group.
A suitable alkylating agent is, for example. any anent knowm in the art for the alkylation of hydroxy to amino-substituted alkoxy, for example an amino-substituted alkyl halide, for example an amino-substituted (2-4C)alkvl chloride. bromide or iodide. in the presence of a suitable base as defined hereinbefore. in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the ranee. for example. I U to I
40°C.
conveniently at or near 80°C.

(c) For the production of those compounds of the formula I wherein R' is an amino-substituted (2-4C)alkoxy group, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula I wherein R' is a hydroxy-(2-4C)alkoxy group, or a reactive derivative thereof. with an appropriate amine.
A suitable reactive derivative of a compound of the formula I wherein R' is a hydroxy-(2-4C)alkoxy group is, for example, a halogeno- or sulphonyloxy-(2-4C)alkoxy group such as a bromo- or methanesulphonyloxy-(2-4C)alkoxy group.
The reaction is preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 50°C.
(d) For the production of those compounds of the formula I wherein R' is a hydroxy-amino-(2-4C)alkoxy group, the reaction of a compound of the formula I
wherein R' is a 2,3-epoxypropoxy or 3,4-epoxybutoxy group with an appropriate amine.
The reaction is preferably carried out in the presence of a suitable inert solvent or diluent a.s defined hereinbefore and at a temperature in the range, for example, I O to 150°C, conveniently at or near 70°C.
When a pharmaceutically-acceptable salt of a quinazoline derivative of the formula I is required. for example a mono- or di-acid-addition salt of a quinazoline derivative of the formula I, it may be obtained. for example. by reaction of said compound with, for example. a suitable acid using a con~~entional procedure.
As stated hereinbefore the quinazoline derivatives defined in the present invention possess anti-proliferative activity which is believed to arise from the Class I
receptor tyrosine kinase inhibitory activity of the compounds. These properties may be assessed, for example. using one or more of the procedures set out below:-(a) An inyitro assay which determines the ability of a test compound to inhibit the enzyme EGF receptor tyrosine kinase. Receptor tyrosine kinase was obtained in partially purified form from A-431 cells (derived from human vulva) carcinoma) by the procedures described below which are related to those described by Carpenter et ,~j_. J.
F3iol. Chem., 1979, ~~-I. ~8$~l. Cohen ~t ~. J. l3iol. Chem.. 198'_'. ''~7. 1 ~'_'3 and by Braun ~t ~t~., ,t. Biol. Cltem., 1984, a;9, '_'O51.
A-431 cells were grown to confluence using LW lbecco's modified Eagle's medium ! D~'IE\'I ) containrn!~ ~° ° fetal calm scrum ( FCS 1. The ohtarned 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. 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 ~~. hour at 0-4°C, and recentrifuged at 100,000 g for 1 hour at 0-4°C. The supernatant, containing solubilised receptor tyrosine kinase, was stored in liquid nitrogen.
For test purposes 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 ~1 of 25 mM DTT and 80 ~l of a mixture of 12.5 mM manganese chloride, 125 mM magnesium chloride and disti:Lled water. There was thus obtained the test enzyme solution.
Each test compound was dissolved in dimethyl-sulphoxide (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.
[,~-3zP]ATP (3000 Ci/mM, 250 ~,Ci) was diluted to a volume of 2 ml by the addition of a solution of ATP (100 ~,M) in distilled water. An equal volume of a 4 mg/ml solution of the peptide Arg-Arg-Leu-:Lle-Glu-Asp-Ala-Glu-Tyr-Ala-A.la-Arg-Gly in a mixture of 40 mM Hepes buffer at pH 7.4, 0.1%
Triton X-100 and 10% glycerol was added.
*Trademark 16a The 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 m_ix.ture was incubated at 25°C for 10 minutes. The phosphorylation reaction was terminated by the addition of 5°s tr:ichloroacetic acid (40 ~1) and bovine serum albumin (BSA; 1 mg/ml, 5 ~l). 'The mixture was allowed to stand at 4°C for 30 minutes and then centrifuged. An aliquot (40 ~l) of the supernatant was placed onto a strip of Whatman* p 81 phosphocellulose paper.
The strip was washed in 75 mM phosphoric acid (4x10 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:
*Trademark WO 96/33980 - 1 ~ - PCT/GB96/00961 100-(A-B) Inhibition = x 100 C-B
- The extent of inhibition was then determined at a range of concentrations of test compound to give an ICSo value.
(b) An in vitro assay which determines the ability of a test compound to inhibit the EGF-stimulated growth of the human naso-pharyngeal cancer cell line KB.
KB cells were seeded into wells at a density of 1 x 10't - 1.~ 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
tetrazoli.um 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 ICso value could then be calculated.
(c) An in-vivo assay in a group of athymic nude mice (strain ONL~:AIpk) which determines the abilivty of a test compound (usually administered orally as a ball-milled suspension in 0.5% polysorbate) to inhibit the growth of xenografts of the human vulval epidermoid carcinoma cell line A-431.
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 taller approximately 9 to 1-1 days), fragments of tumour tissue were transplanted in 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). In some studies the dosing of the test compound was continued beyond test day 19. for example to test day '?6. In each case. on the following test day the animals were killed and the final tumour volume was calculated from measurements of the length and width of th.:
tumours. Results were calculated as a percenta<: a inhibition of tumour wlume relative to untreated controls.
Although the pharmacological properties of the compounds of the formula I vary with structural chan_=a as rxpected. in general actives pe~sscssed by compounds e~t~ the formula WO 96/33980 - 1 g - PCT/GB96/00961 I may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b) and (c):-Test (a):- ICso in the range, for example, 0.01-1 ~M; .
Test (b):- ICso in the range, for example, 0.05-1 ~.M;
Test (c):- 20 to 90% inhibition of tumour volume from a daily dose in the range, for example, 12.5 to 200 mg/kg.
Thus, by way of example, the compounds described in the accompanying Examples possess activity at approximately the following concentrations or doses in tests (a) and (b).
Example Test (al Test (bl ICso (wM) ICso (!~M) 1 0.02 0.1 2 0.09 0.7 3 0.01 0.4 4 0.01 0.1 0.06 0.2 6 0.01 0.1 7 0.09 0.3 8 0.48 0.9 9 0.01 0.1 12 0.06 0.16 13 0.07 0.12 14 0.67 0.3 0.07 0.6~

17 0.0~ 0. I

18 0.''7 0.39 19 0.5'_' O..ls ''U 0.67 0.~

E7Cam~ Test fal Test fbl ICso (N~M) ICso (wM) ' 21 0.08 0.12 22 0.1 0.19 23 0.08 0.16 In addition all of the compounds described in the accompanying Examples possess activity in test (c) with EDso values of less than or equal to 200 mg/kg/day. In particular, the compound described in Example 1 hereinafter possesses activity in test (c) with an EDso value of approximately 12.~ mg/kg.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinazoline derivative of the formula I. or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intraveous.
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.
In general the above 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 ~-10000 mg per square meter body area of the animal, i.e. approximately 0.1-200 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 mgikg is employed. For the quinazoline derivative of Example 1. or a pharmaceutically-acceptable salt thereof. a daily dose of approximately 1 to 20 mg/kg. preferably of 1 to ~ mgrl:g is employed.
However the daily dose will necessarily he varied depending upon the host treated. the particular route of administration. and the severity of the illness being treated. .accordin~_ly the optimum dosage may be determined by the practitioner who is treating am particular patient.

According to a iiirther aspect of the present invention there is provided 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.
We have found that the compounds of the present invention possess anti-proliferative properties such as anti-cancer properties which are believed to arise from their Class I 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 kinases, 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. Thus the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of Class I receptor tyrosine kinases, 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 psoriasis and/or cancer by providing an anti-proIiferative 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.
Thus according to this aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
According to a further aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the production of an anti-proliferative effect in a warm-blooded animal such as man.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular proliferative disease will necessarily be varied depending on the host treated, the route of administrat,on and the severity of the illness being treated. A unit dose in the range, for example, I-200 mg/kg, preferably 1-100 mg/kg, more preferably 1-10 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, one or more other anti-tumour substances, for example cytotoxic or cytostatic anti-tumour :>ubstances, for example those selected from, for example, mitotic inhibitors, for example vinblastine, vindesine and vinorelbine; tubulin disassembly inhibitors such as Taxol.*; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide;
antimetabolites, for example 5-fluorouracil, tegafur, methotrexate, cytosine ax-abinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Applicat.i_on No. 239362 such as N-{5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl~-L-glutamic acid; intercalating antibiotics, for example adriamiycin, 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 antiandrogins such as 4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluorometr~yl)-propionanilide or, for example LHRH antagonists or LHR~:: agonists such as goserelin, leuprorelin or buserelin and hormone synthesis inhibitors, for example aromatase inhibitors such as those disclosed in European Patent Application No. 0296749, for example 2,2'-[5-(1H-1,2,4-triazol-1-yl.methyl)-1,3-phenylene]bis(2-methylpropionitrile), and, for example, inhibitors of 5a-reductase such as 17~i- (I~'-tert-butylcarbamoyl) -4-aza-5a-androst-1-en-3-one. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. According to this aspect of the invention there is provided a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore and an additional *Trademark anti-tumour substance a:~ defined hereinbefore for the conjoint treatment of cancer.
As stated above the quinazoline derivative defined in the present invention is an effective anti-cancer agent, which property is believed to arise from its Class I
receptor tyrosine kinase inhibitory properties. Such a quinazoline derivative c>f= 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. Thus it is expected that a quinazoline derivative of the invention will possess anti-cancer activity against these cancers. It is in addition expected that a quinazoline deri~~ative 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 invention will possess activity against other diseases involving excessive cellular proliferation such as psoriasis and bE~nign prostatic hypertrophy (BPH).
It is also to be expected that 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 or non-receptor tyrosine kinase enzymes, including as yet unidentified tyrosine ki.nase enzymes, are involved. Such disorders include, for example, inflammation, angiogenesis, 22a vascular restenosis, immunological disorders, pancreatitis, kidney disease and blast:ocyte maturation and implantation.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration, unless otherwise stated magnesium sulphate was used as a drying agent for organic solutions;
(ii) operations were carried out at ambient temperature, that is in t:he range 18-25°C and under an atmosphere of an inert c~as such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep* RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) melting points were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Koffler riot plate apparatus.
(vi) the struc:t:ures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques;
proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, si.nglet; d, doublet; t, triplet; m, *Trademark 22b multiplet, unless otherwise stated end-products of the formula I were dissolved. in CD3SOCD3 for the determination of NMR values:

(vii) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), infra-red (IR) or NMR analysis;
(viii) the following abbreviations have been used:-DMF N,,~1-dimethylformamide;
DIVISO dimethylsulphoxide;
THF tetrahydrofuran;
DMA N,N-dimethylacetamide.

Exam~e 1 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1 g), 3-morpholinopropyl chloride (J. A_m__er. Chem.Soc., 1945, ~~, 736; 0.62 g), potassium carbonate (2.5 g) and DMF (50 ml) was stirred and heated to 80°C for 2 hours. A further portion (0.1 g) of 3-morpholinopropyl chloride was added and the mixture was heated to 80°C
for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 4:1 mixture of ethyl acetate and methanol as eluent. The material so obtained was recrystallised from toluene. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.69 g, 50%), m.p. 119-120°C;
NMR Spectrum: 2.0 (m, 2H), 2.4~ (m. 6H), 3.6 (m, 4H), 3.95 (s, 3H), 4.2 (t.
2H), 7.2 (s, 1H), 7.4 (t. 1 H), 7.8 (m. 2H). 8.1 (m. 1 H). 8.5 (s, 1 Hl, 9.5 (s. 1 H);
Elemental Analysis: Found C, 58.7; H. ~.3; N. 1?.2;
C2~H,4C1FN.~03 requires C. X9.1: H, 5.4; N, 12.5%.
The 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows:-6.7-Dimethoxy- 3.4-dihydroquinazolin-4-one (European Patent Application No.
0 566 ??6. Example 1 thereof: ?6.~ g) was added portionwise to stirred methanesulphonic acid ( 17~ ml ). L-Methionine ('_''_' ~~ ) was added and the resultant mixture was stirred and heated to reflux for ~ hours. The mixture was cooled to ambient temperature and poured onto a mixture ( 7s0 ml ) of ice and water. The mixture was neutralised by the addition of a concentrated (40%) aqueous sodium hydroxide solution. The precipitate was isolated, washed with water and dried. There was thus obtained 6-hydroxy-7-methoxy-3.4-dihydroquinazolin-4-one ( 1 1.~ g).
After repetition of the previous reaction. a mixture of 6-hydroxy-7-methoxy-3.4-dihydroquinazolin--1-one ( 1-1.18 g). acetic anhydride ( 1 10 ml) and pyridine ( 1-I ml) ~~as stirred and heated to 100°C for '_' hours. The mixture was poured onto a mixture ('_'00 ml) of ice and ' water. The precipitate was isolated. washed with water and dried. There was thus obtained b-acetoxv-7-methsw-:.-1-dihvdroquinazolin--1-one t I 3 ~~. 7~°0):

WO 96/33980 - 25 _ PCT/GB96/00961 NMR Spectrum: 2.3 (s, 3H), 3.8 (s, 3H), 7.3 (s, 1H), 7.8 (s, 1H), 8.1 (s, 1H), 12.2 (broad s, 1 H).
After repetition of the previous steps, a mixture of 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one ( 15 g), thionyl chloride (215 ml) and DMF (4.3 ml) was stirred and heated to 90°C for 4 hours. The mixture was cooled to ambient temperature and the thionyl chloride was evaporated. There was thus obtained 6-acetoxy-4-chloro-7-methoxyquinazoline, hydrochloride salt, which was used without further purification.
A mixture of the material so obtained, 3-chloro-4-fluoroaniline (9.33 g) and isopropanol (420 ml) was stirred and heated to 90°C for 5 hours. The mixture was cooled to ambient temperature and the precipitate was isolated, washed in turn with isopropanol and methanol and then dried. There was thus obtained 6-acetoxy-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline hydrochloride salt ( 14 g, 56%);
NMR Spectrum: 2.4 (s, 3H). 4.0 (s. 3H), 7.5 (t. 1 H), 7.6 (s. I H ). 7.75 (m.
1 H). 8.05 (m. 1 H), 8.8 (s, 1 H), 8.95 (s, 1 H), 11.5 (broad s, 1 H).
A concentrated aqueous ammonium hydroxide solution (30% weightJvolume, 7.25 ml) was added to a stirred mixture of the material so obtained and methanol (520 ml).
The mixture was stirred at ambient temperature for 17 hours and then heated to 100°C for 1.5 hours. The mixture was cooled and the precipitate was isolated and dried.
There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 10.6?
~~, 95%).
m.p. >270°C (decomposes);
NMR Spectrum: 4.0 (s. 3H). 7.? (s. I H), 7.4 ( t. 1 H). 7.8 ( s. 1 H ). 7.85 ( m. 1 H). 8.? (m. 1 H ), 8.5 (s, 1 H), 9.45 (s. 1 H), 9.65 (s. 1 H).
Exarr~nle 2 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (1.14 g),''-(pyrrolidin-I-yl)ethyl chloride hydrochloride (0.607 ~~1.
potassium carbonate (3 g) and DMF (?8.5 ml) w-as stirred and heated to 90°C for 5 hour. The mixture was cooled to ambient temperature and poured into water. The precipitate was isolated. dried and purified by column chromato'_raphv using a 9:1 mixture ot~ methylene chloride and methanol as eluent.
The material so obtained was recrystallised from cthanc~l. Them was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-pyrrolidin-1-ylethoxy)quinazoline (0.813 g, 55%), m.p. 187-188°C;
NMR Spectrum: 1.7 (m, 4H), 2.6 (m, 4H), 2.9 (t, 2H), 3.9 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1 H), 7.8 (m, 2H), 8.1 (m, 1 H), 8.5 (s, 1 H), 9.5 (s, 1H);
Elemental Analysis: Found C, 60.1; H, 5.4; N, 13.4;
CZ,H22C1FN402 requires C, 60.5; H, 5.3; N, 13.4%.
A mixture of 4-(3'-chloro-4'-fluoro~:nilino)-6-hydroxy-7-methoxyquinazoline ( 1.62 g), 2-morpholinoethyl chloride hydrochloride (0.95 g), potassium carbonate (3.6 g) and DMF (40 ml) was stirred and heated to 90°C for 1.5 hours. The mixture was cooled to ambient temperature and poured into water. The precipitate was isolated. dried and purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent.
The material so obtained was recrystallised from isopropanol. There w-as thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-morpholinoethoxy)quinazoline ( I
.2 g, 55%), m.p. 229-230°C;
NMR Spectrum: 2.6 (m, 4H), 2.85 (t, 2H), 3.6 (m, 4H), 3.9 (s, 3H), 4.3 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1H), 7.8 (m, 2H), 8.1 (m. 1H), 8.5 (s. 1H). 9.5 (s, IH):
Elemental Analysis: Found C. 57.5; H, 4.9; N. 12.7;
C,,HZ,C1FN40; 0.25H,0 requires C. 57.6; H, 5.1: N, 12.8%.
ExarnPle ~i A mixture of I-methylpiperazine (43 ml), 6-(2-bromoethoay)-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline (1.6 g) and ethanol (48 ml) was stirred and heated to reflux for 20 hours. The mixture was evaporated and the residue was purified by column chromatography using a 4: I mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in a mixture of methylene chloride and methanol and a saturated aqueous sodium bicarbonate solution was added. The miwure was stirred and heated to reflux. The mixture was cooled to ambient temperature and the precipitate was isolated and dried. There was thus obtained -1-( s'-chlor~--l'-tluoroanilino )-methoxy-6-[2-(4-methUpiperazin-1-vl)ethoxy]quinazoline l0 9~c~ ~.
~8°°). m.p. 88-92°C.

NMR Spectrum: 2.15 (s, 3H), 2:3 (broad m, 4H), 2.5 (broad m, 4H), 2.8 (t, 2H), 3.9 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1 H), 7.4 (t, 1 H), 7.8 (m, 2H), 8.1 (m, 1 H), 8.5 (s, 1 H), 9.5 (s, 1 H);
Elemental Analysis: Found C, 57.3; H, 5.6; N, 15.1;
C22HZSC1FN502 0.75H20 requires C, 57.5; H, 5.8; N, 15.2%.
The 6-(2-bromoethoxy)-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline used as a starting material was obtained as follows:-A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (10 g), 1,2-dibromoethane (27 ml), potassium carbonate (20 g) and DMF (1 litre) was stirred and heated to 85°C for 2.5 hours. The mixture was filtered and the filtrate was evaporated.
The residue was purified by column chromatography using ethyl acetate as eluent. There was thus obtained 6-(2-bromoethoxy)-4-(3'-chloro- 4'-fluoroanilino)-7-methoxyquinazoline (10.26 g, 77%), m.p. 232°C (decomposes);
NMR Spectrum: 3.9 {m, 2H), 3.95 (s, 3H), 4.5 (m, 2H), 7.2 (s. 1 H), 7.4 (t, 1 H). 7.75 (m, 1 H), 7.85 (s, 1. H), 8.1 (m, 1 H), 8.5 (s, 1 H), 9.5 (s, 1 H);
Elemental Analysis: Found C, 48.0; H, 3.3; N, 9.8;
C,~H,4BrC1FN30z requires C, 47.9; H, 3.3; N, 9.8%.
A mixture of di-(2-methoxyethyl)amine ( 1.66 ml), 6-(2-bromoethoxy)-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline ( 1.6 g) and ethanol (48 ml ) was stirred and heated to reflux for 18 hours. A second portion (0.53 ml) of di-(2-methoxyethvl)amine was added and the mixture was heated to reflux for a further 18 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (Na,SO.,) and evaporated. The residue was purified by column chromatography using a 97:3 mixture of methvlene chloride and methanol as eluent. The material so obtained was dissolved in isopropanol.
water was added and the mixture was stirred for 1 hour. The precipitate mas isolzted and dried. There was thus obtained .1-( :'-chloro--1'-fluoroanilino)-7-methoxv-6-; 3-[di-i ~-methc~xv-ethvl)amino)ethoxv;quinazoline (0.95 ~=, 53°.0). m.p. 7~-7.1°C:

WO 96/33980 - 28 - PCT/GB96l00961 NMR Spectrum: 2.6 (t, 4H), 3.05 (t, 2H), 3.25 (s, 6H), 3.45 (t, 4H), 3.95 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1 H), 7.4 (t, 1 H), 7.8 (m, 2H), 8.1 (m, 1 H), 8.5 (s, 1 H), 9.5 (s, 1 H);
Elemental Analysis: Found C, 56.2; H, 6.2; N, 11.3;
C23HZ8C1FN404 0.7H~0 requires C, 56.2; H, 6.0; N, 11.4%. -A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (3 g), 2-dimethylaminoethyl chloride hydrochloride ( 1.5 g), potassium carbonate (7.5 g) and DMF (60 ml) was stirred and heated to 80°C for 5 hours. The mixture was cooled to ambient temperature and poured into water. The precipitate was isolated and dried. ~
The material so obtained was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether and recrystallised from aqueous ethanol. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-6-(2-dimethylaminoethoxy)-7-methoxyquinazoline ( 1.7 g, 46%), m.p. 133-135°C;
NMR Spectrum: 2.3 (s, 6H), 2.75 (t, 2H), 4.0 (s, 3H), 4.25 (t. 2H), 7.2 (s. 1 H), 7.3 (m, 2H), 7.4 (t, 1 H), 8.1 (m, 2H), 8.5 (s. 1 H), 9.5 (broad s, 1 H);
Elemental Analysis: Found C. 58.''; H. 5.2; Iv. 14.3:
Ct9H,oCIFN.~O, requires C. 58.4: H. 5.1: N, 14.3%.
xant A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.5 g), 2-diethylaminoethyl chloride hydrochloride (0.82 g), potassium carbonate (3.5 g) and DMF (38 ml) was stirred and heated to 90°C for 2 hours. The mixture was cooled to ambient temperature and poured onto ice (75 ml). The precipitate was isolated. rect-ystallised from a 2:1 mixture of isopropanol and water and dried. There was thus obtained 4-(3'-chloro-4'-lluoroanilino)-6- (?-diethylaminoethoxv >-7-methoxyquinazoline (0.98 <~.
50%). m.p. 154-156°C:
NMR Spectrum: 1.U tt. 6,1i), '_'.6 tm. 4H). '?.9 (t. '?H). 3.9 ts. 3H1. -1.'_' tt. ~'ll). 7.? ts, I l1). 7.-1 tt. 11-i), 7.8 (m.'_'1-1). 8.1 tm. 111). S.5 (s. 111). ~.s ts. 1H1:

WO 96/3a980 - 29 - PCT/GB96/00961 Elemental Analysis: Found C, 60.0; H, 5.7; N, 13.2;
CzlHz4C1FN40z requires C, 60.2; H, 5.8; N, 13.4%.
' xaxnDl<e ~3_ A mixture of 4-(2',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.36 g), 3-dimethylaminopropyl chloride hydrochloride (0.82 g), potassium carbonate (3 g) and DMF
(50 ml) was stirred and heated to 80°C for 4 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgS04) and evaporated. The residue was triturated under a mixture of hexane and ethyl acetate. There was thus obtained 4-(2',4'-difluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline (0.56 g, 32%), m.p. 131-134°C:
NMR Spectrum: 1.85-2.05 (m, 2H), 2.35 (s, 6H), 2.42 (t, 2H), 3.95 (s, 3H).
4.16 (t. 2H), 7.13 (m, 1 H), 7.16 (s. 1 H). 7.35 (m, 1 H), 7.5~ (m. 1 H), 7.75 (s. 1 H). 8.3 (s.
1 H), 9.5 (broad s, 1 H);
Elemental Analysis: Found C, 60.9; H, 5.7; N. 14.1;
C20H22F2N40? 0.3H~0 requires C, 61.0; H, 5.7; N, 14.2%.
The 4-(2',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows:-A mixture of 6-acetoxv-4-chloro-7-methowquinazoline hydrochloride (~.4 g), 2.4-difluoroaniline (''.~ ml) and isopropanol ( 100 ml ) was stirred and heated to reflux for '?
hours. The precipitate was isolated. washed ~.~ith acetone and with diethyl ether and dried.
There was thus obtained 6-acetoxy-4-(2',4'-difluoroanilino)-7-methoxvquinazoline hydrochloride (3.9 g, 53%), m.p. 207-210°C;
NMR Spectrum: 2.4 (s, 3H), 4.0~ (s. 3H), 7.25 (m, 1H). 7..18 (m. IH), 7.~~ (s.
1H). 7.63 (m, 1 H), 8.7 (s, 1 H). 8.8~ (s. 1 H), 1 1.6 (broad s. 1 H).
A mixture of a portion (3.7 g) of the material so obtained. a concentrated aqueous ammonium hydroxide solution (30°ro weight/volume. ~' ml) and methanol ( 1-10 tlll) was stirred at ambient temperature for'_' hours. The precipitate was isolated and washed with diethyl ether. There was thus obtained -1-('_''.-1'-difluoroanilino 1-(,-hvdrow-7-methoyquinazoline ( 1. 3 t,. 40°io):

NMR Spectrum: 3.97 (s, 3H), 7.1 (m, 1 H), 7.2 (s, 1 H), 7.54 (m, 1 H), 7.67 (s, 1 H), 8.3 (s, 1 H), 9.3 (s, 1H), 9.65 (broad s, 1H).
Exams A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-(2,3-epoxypropoxy)-7-methoxyquinazoline (2 g), morpholine (0.5 ml) and isopropanol (20 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature and evaporated.
The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The material so obtained was recrystallised from ethyl acetate. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-6-(2-hydroxy-3-morpholinopropoxy)-7-methoxyquinazoline ( 1.4 g, 57%), m.p. 206-207°C;
NMR Spectrum: 2.5 (broad m. 6H). 3.6 (t. 4H), 3.9 (s. 3H). 4.1 (broad m. 3H), 5.0 (broad m, 1 H), 7.2 (s, 1 H), 7.4 (t, 1 H). 7.8 (m, 2H), 8.1 (m. 1 H). 8.5 (s, 1 H). 9.~
(s. 1 H);
Elemental Analysis: Found C. 57.0: H. 5.'?; N. 11.9;
CzaHzaC1FN404 requires C, 57.1: H, 5.2; N, 12.1%.
The 4-(3'-chloro-4'-tluoroanilino)-6-(2,3-epoxypropoxy)-7-methoxyquinazoline used as a starting material was obtained as follows:-A mixture of 4-( :'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (5 g), '_'.3-epoxypropyl bromide ( I .6 ml). potassium carbonate (~ ~) and DMSO (~0 ml) was stirred at ambient temperature for 16 hours. The mixture was poured onto a mixture of ice and water. The precipitate was isolated. washed with water and dried. There was thus obtained the required starting material which was used without further purification and gave the following characterising data:-m.p. 125-126°C (decomposes);
NMR Spectrum: 2.8 (m. 1H), ?.9 (m. 11-1), 3.5 (m. 1H). 4.0 (s. 3H). 4.1 (m.
1H), 4.5 (m, 1H), 7.2 (s. 1H). 7.4 (t. 1H). 7.8 (m. IH). 7.85 (s. IH), 8.1 (m. I1-i). 8.~ (s.
1H). 9.5 (s. IH).

WO 96/33980 _ 31 _ PCT/GB96/00961 Examr~le .~Q
A mixture of morpholine (13.75 ml), 6-(3-bromopropoxy)-4-(3'-chloro-~4'-fluoroanilino)-7-methoxyquinazoline (2.94 g) and DMF (67 mlj was stirred at ambient temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with brine, dried (Na,S04j and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The material so obtained was recrvstallised from toluene. There was thus obtained 4-(3'-chloro-4'-fluoroa.nilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.78 g, 27%);
NMR Spectrum: 2.0 (m. 2H), 2.45 (m. 6H), 3.6 (m, 4H), 3.95 (s, 3H). 4.2 (t.
2H). 7.2 (s, 1H), 7.4 (t, 1 H), 7.8 (m, 21-1), 8.1 (m, 1 H), 8.5 (s, 1 H), 9.5 (s, 1 H).
The 6-(3-bromopropoxy)-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline used as a starting material was obtained as follows:-A mixture of 4-(3'-chloro-4'-fluoroanilinol-6-hydroxv-7-methoxyquinazoline (2 g), 1,3-dibromopropane (6.36 ml), potassium carbonate (4 g) and DMF (200 ml) was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using ethyl acetate as eluent. There was thus obtained 6-(3-bromopropoxy)-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline in quantitati~~e yield which was used without further purification:
NMR Spectrum: 2.4 im.'_'ll). 3.7 (t. 2H). 3.9~ (s, 3H). 4.3 (t. 2H), 7.2 (s.
IH). 7.4 (t. 1H). 7.8 (m. 2H). 8.1 (m, 1H). 8.s (s. 1H). 9.~ (s. 1H).
Exam lp a l l11 A mixture of morpholine (0.17 ml), 6-(2-bromoethoxy)-4-( 3'-chloro-4'-fluoroanilino)-7-methoxvquinazoline (0.4 g) and ethanol (12 mll was stirred and heated to reflux for 27 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine. dried (Na~SO~) and evaporated. The residue was purified by column chromato~~raphy usin<~ a ~):1 mixture of methvlen~ chloride and methanol as eluent. There was thus ubtaim.3 -1-( :'-chloro--1'-tluoroanilinu~-i-methow-f,-(2-morpholinoethoxviyuinaroline ((1.1-t ;~. ~~°,r>:

NMR Spectrum: 2.6 (m, 4H), 2.85 (t, 2H), 3.6 (m, 4H), 3.9 (s, 3H), 4.3 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1 H), 7.8 (m, 2H), 8.1 (m, 1 H), 8.5 (s, 1 H), 9.5 (s, 1 H).
Exam 1 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.1 g), 3-diethylaminopropyl chloride hydrochloride (0.7 g), potassium carbonate (3 g) and ' DMF (30 ml) was stirred and heated to 80°C for 3 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography using a 4:1 mixture of methylene chloride and methanol as eluent. The material so obtained was triturated under a 5:1 mixture of methanol and water.
The solid so obtained was dried. There was thus obtained 4-(3'-chloro--1'- fluoroanilino)-6-(3-diethylaminopropoxy)-7-methoxyquinazoline ( I .03 g, 70%);
NMR Spectrum: 0.9~ (t, 6H), 1.9 (m, 2H), 2.~ (m, 6H). 3.9~ (s. 3H). 4.2 (t.
2H). 7.2 (s, 1H).
7.4 (t, 1 H), 7.8 (m, ''H), 8.1 (m, 1 H). 8.5 (s, 1 H). 9.5 ( s. 1 H).
Elemental Analysis: Found C, 59.4; H, 6.2; N, 12.5;
CzzH26C1FN402 0.7H20 requires C. 59.4; H, 6.2; N, 12.6%.
Exarr~le 13 A mixture of4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.28 g). 3-(pyrrolidin-I-yl)propyl chloride hydrochloride CChem. Abs., $s.
X7736: I.~ g), potassium carbonate (?.8 g) and DMF (?0 ml) was stirred and heated to 80°C for ~ hours.
The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water. dried (MgSO,~) and e~~aporated. The residue was purified by column chromatography using a 20:3 mixture of methylene chloride and methanol as eluent. The material so obtained (I .I g) was triturated under ethyl acetate to give 4-(3'-chloro--1'-fluoroanilino)-7-tnethoxy-6-(3-pyrrolidin-1-~~lpropow )quinazoline (0.09-1 g). The organic solution was evaporated and the residual solid was recrystallised from acetonitrile. There was thus obtained a second crop 10.8 ~~) of the same product. The ' material ~~ave the ti~llowin~= characterising data:-m.p. 1 ~~-111 °C:

NMR Spectrum: 1.95 .(m, 4H), 3.3 (m, 6H), 3.95 (s, 3H), 4.3 (t, 2H), 7.2 (s, 1H), 7.4 (t, 1H), 7.9 (m, 1 H), 8.1 (s, 1 H), 8.2 (m, 1 H), 8.5 (s, 1 H), 9.8 (broad s, 1 H);
Elemental Analysis: Found C, 61.0; H, 5.7; N, 13.1;
C22H24C1FN4O~ requires C, 61.3; H, 5.6; N, 13.0%.
Exam lp ~ 14_ A mixture of 4-(2',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline (2.5 g), 3-morpholinopropyl chloride hydrochloride (1.6 g), potassium carbonate (6 g) and DMF (100 ml) was stirred and heated to 60°C for 1 hour. 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 (MgS04) and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent.
There was thus obtained 4-(2',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline (1.05 g, 30%), m.p. 151-153°C; ' NMR Spectrum: 2.0 (m, 2H), 2.35-2.67 (m, 6H), 3.58 (t, 2Hj. 3.94 (s. 3H).
.x.16 (t. ?H), 7.13 (m, 1 H), 7.16 (s, 1 H), 7.33 (m, 1 H), 7.54 (m, 1 H), 7.78 (s, 1 H), 8.1 (s, 1 H). 9.4 (broad s, 1 H);
Elemental Analysis: Found C. 61.4; H, 5.5; N. 12.8;
C22HzaFzNaC3 requires C. 61.4: H. 5.6; N. 13.0%.
Example 15 A mixture of 4-(3'-chloro-4'-fluoroanilino )-6-hvdroxv-7-metho~yquinazoline (1.24 g), 2-(imidazol-1-yl)ethyl chloride (European Patent Application \o.
04'_'1'10: ~'.61 g).
potassium carbonate ( 1.~ g) and DMF (31 ml) was stirred and heated to 90°C for 4 hours and then stored at ambient temperature for 16 hours. The mixture was poured into a mixture of ice and water. The precipitate was isolated, dried and purified by column chromatography using a 9:1 mixture of methvlene chloride and methanol as eluent. The solid so obtained was triturated under methanol. There was thus obtained 4-( 3'-chloro--~'-flu~roanilinm-6-(2-imidazol-1-vlethoxy)-7-methoxyquinazoline (0.33 ~~. 34°~0~. m.p. '_' ~~-~-11'C:
NMR Spectrum: 4.U ( s. 31i ). -1..1 1 t. '_' H ). ~1.~ l t. '_' 1'i ). 6.y U
a. I I-I i. ; .'_' v s. 1 HI ). a. : n s. 1 I-i ~. 7.-I t t.
1H). 7.7 (s. 1H). ;'.7~ (m. 11-i). 7.81s. IFII. 8.1 cm. 11_l~. S.~ ta. 111.
~~.~ i,. Ifl~.

Elemental Analysis: Found C, 57.5; H, 4.3; N, 16.7;
C2oHt7C1FN502 requires C, 58.0; H, 4.1; N, 16.9%.
Exam I~ , A mixture of imidazole (0.128 g), 6-(2-bromoethoxy)-4-(3'-chloro-4'-fluoroanilino)-7-methoxyquinazoline (0.4 g) and ethanol (12 ml) was stirred and heated to ' reflux for 66 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase «~as washed with water, dried (Na.,S04) and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-6-(2-imidazol-1-ylethoxy)-7-methoxyquinazoline (0.13 g, 33%);
NMR Spectrum: 4.0 (s. 3H), 4.4 (t, 2H), 4.5 (t. 2H). 6.9 (s. 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.4 (t, 1H), 7.7 (s, 1H). 7.75 (m. 1H), 7.8 (s. 1H), 8.1 (m. 1H). 8.5 (s, 1H), 9.5 (s, 1H).
Exams li a 17 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (2 g), 3-dimethylaminopropyl chloride hydrochloride (0.99 g), potassium carbonate (5 g) and DMF ( 100 ml) was stirred and heated to 90°C for '? hours. The mixture was cooled to ambient temperature and poured into water. The precipitate was isolated and recrystallised from toluene. The resultant solid was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There ~~as thus obtained .1-(3'-chloro-4'-fluoroanilinol-6-(3-dimeth~~laminoproposy)-7-methoxyquinazoline (0.97 g);
NMR Spectrum: 1.95 (m. 2H). '_'.'_' (s. 6H), ~'.~5 (t. 21--1), 3.95 (s. 3H), 4.18 (t. ?H), 7.2 (s. 1H), 7.42 (t, 1H), 7.8 (m, 2H), 8.12 (m. 1H). 8.5 (s. 1H), 9.5 (s. 1H);
Elemental Analvsis: Found C. 59.1: H. 5.3: I~. 13.6:
C~oH"C1FN.~0, requires C. 59.3: H. ~.5: N. 13.8%.
A mixture of-1-(3'.-1'-ditlueroanilino)-t>-hvdroxv-7-methoxyquinazoline ( 1.8 g).
3-dimethvlamin~propy chloride hvdrochloria~ (0.x-1 ~=1. potassium carbonate 1-1.5 g) and D3~1F I i)U ml ) w as stirred and hcate~3 ti, 90°C ii~r 1 hour The mixture was cc,oled to ambient WO 96/33980 - 3$ - PCT/GS96/00961 temperature and poured into water. The resultant precipitate was isolated and purified by column chromatography using a 4:1 mixture of methylene chloride and methanol as eluent.
The material so obtained was recrystallised from toluene. There was thus obtained 4-(3',4'-difluoroanilino)-6-(3-d.imethylaminopropoxy)-7-methoxyquinazoline (0.93 g);
NMR Spectrum: 2.0 (rn, 2H), 2.2 (s, 6H), 2.45 (m, 2H), 3.9 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1 H), 7.4 (m, 1 I-I), 7.55 (m, 1 H), 7.8 (s, 1 H), 8.05 (m, 1 H), 8.5 (s, 1 H), 9.5 5 (broad s, 1 H);
Elemental Analysis: Found C, 61.6; H, 5.7; N, 14.1;
C~oHZZF2N40z requires C, 61.8; H, 5.7; N, 14.4%.
The 4-(3',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows:-A mixture of 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride [obtained from 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (6 g) and thionyl chloride (87 ml)], 3,4-difluoroaniline (2.9 ml) and isopropanol ( 170 ml) was stirred and heated to reflux for 4 hours. The precipitate was isolated, washed with isopropanol and dried. There was thus obtained 6-acetoxy-4-(3',4'-difluoroanilino)-7-methoxyquinazoline hydrochloride (7.5 g);
NMR Spectrum: 2.4 (s, 3H), 4.0 (s, 3H), 7.45-7.6 (m, 3H), 7.95 (m, 1 H), 8.8 (s, 1 H), 8.95 (s, 1 H), 11.5 (broad s, 1 H).
A mixture of the material so obtained, a concentrated aqueous ammonium hydroxide solution (30% weight/volume. 3.9 ml) and methanol (?80 ml) was stirred at ambient temperature for 20 hours. The precipitate was isolated and washed with methanol. There was thus obtained 4-(3',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline ( ~.~
~):
NMR Spectrum: 4.0 (s. 3H). 7.2 (s, 1 H). 7.4 (q, 1 H), 7.6~ ( m. 1 H). 7.8 1 s. I H). 8.1 (m. 1 H).
8.45 (s, 1 H), 9.4~ (s, 1 H), 9.6 (s, I H).
A mixture of 4-(3',4'-difluoroanilino)-6-hydroxy-7-methoayquinazoline ( I .'?
1;).
3-morpholinopropyl chloride (0.7~' g). potassium carbonate ('_' ~=) and D~II ( ,0 ml) was stirred and heated to 80°C for ~' hours. .A further portion (0. ~ ~~) of :-morpholinopropyl chloride was added and the mixture was heated to 80°C for a further ~
hours. ~I-he mixture was cooled to ambient temperature. filtered and the filtrate was evaporated.
The residue was purified by column chromatography using a -1: I miwurc ~f ethv I aretat~ and methanol as eluent. There was thus obtained 4-(3',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (0.84 g);
NMR Spectrum: 2.0 (m, 2H), 3.6 (t, 4H), 3.95 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1 H), 7.4 (m, 1 H), 7.57 (m; 1H), 7.82 (s, 1H), 8.05 (m, 1H), 8.48 (s, 1H), 9.55 (s, 1H);
Elemental Analysis: Found C, 61.1; H, 5.4: N, 12.8;
CZ~H24F2N403 requires C, 61.4, H, 5.6; N, 13.0%.
A mixture of 4-(3',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.2 g), 3-diethylaminopropyl chloride hydrochloride (0.81 g), potassium carbonate (3.5 g) and DMF
(30 ml) was stirred and heated to 80°C for ? hours. The mixture was cooled to ambient temperature, filtered and evaporated. The residue was purified by column chromatography using a 4:1 mixture of methylene chloride and methanol as eluent. There was thus obtained 6-(3-diethylaminopropoxy)-4-(3'.4'-difluoroanilino)-7-methoxyquinazoline ( I
.14 g);
NMR Spectrum: 0.8 (t, 6H), 1.8 (m, 2H), 3.78 (s, 3H), 4.0 (t, 2H), 7.1 (s, 1H), 7.3 (m, 1H), 7.45 (m, 1 H), 7.65 (s, 1 H), 7.9 (m, 1 H), 8.34 (s, 1 H), 9.4 (broad s, 1 H);
Elemental Analysis: Found C, 63.4; H, 6.3; N, 13.6;
C22H,6F,N40~ requires C, 63.4: H, 6.3; N, 13.5%.
~xam~le 21 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoayquinazoline ( I
.? g).
3-piperidinopropyl chloride hydrochloride (0.8'_' ~:.), potassium carbonate (3 g) and DMF ( 30 ml) was stirred and heated to 80°C for ? hours. The mixture was cooled to ambient temperature, filtered and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The solid so obtained was triturated under diethyl ether. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-piperidinopropoxy)quinazoline (0.94 g):
NMR Spectrum: l.-1-1.7 (m, 6H1.'_'.0 (m.'?H). p.9~ (s. 3H). -1.3 tt.'_'H~.
7.'_' ts. 1H). 7.-1 (t, 1H), 7.8-8.O tm. ?1-i). 8.1 (m. IH), 8.~ (s. 111). ~).~~ (s. 1H1:
Elemental :'~nalvsis: Found C. 61.8: 11. ~.8: ~. 1?.6:
C"H,hCIFN,O, requires C. 6'_'. I : 11. ~.u: '.s. I '_'.6° o.

WO 96/x; 980 - 37 - PCT/GB96/00961 A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.5 g), 2-piperidinoethyl chloride hydrochloride (0.86 g), potassium carbonate (3 g) and DMF (40 ~ ml) was stirred and heated to 90°C for 1 hour. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as ~eluent. The material so obtained was recrystallised from toluene. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-piperidinoethoxy)quinazoline (0.77 g);
NMR Spectrum: 1.3-1.6 (m, 6H), 2.8 (t, 2H), 3.95 (s, 3H), 4.25 (t, 2H), 7.2 (s, 1H), 7.45 (t, 1 H), 7.8 (m, 2H), 8.12 (m, 1 H), 8.48 (s, 1 H), 9.5 (s, 1 H);
Elemental Analysis: Found C, 61.0; H. 5.7; N, 13.0;
C,2H2~C1FN40, requires C, 61.3; H, 5.6; N, 13.0%.
A mixture of 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline ( 1.5 g), 3-(imidazol-1-yl)propyl chloride (0.67 g), potassium carbonate (3 g) and DMF
(40 ml) was stirred and heated to 90°C for 1 hour. A second portion (0.12 g) of the propyl chloride was added and the mixture was heated to 90°C for a further hour. The mixture was cooled to ambient temperature, filtered and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-6-(3-imidazol-1-ylpropoxv)-7-methoxyquinazoline (0.66 g);
NMR Spectrum: '_'.5 (m, 2H), 4.12 (s, 3H), 4.25 (t. 2H). 1.35 (t. 2H), 7.08 (s. 1 HI. 7.4 (d. 2H).
7.6 (t, 1 H), 7.8 (s. 1 I-I), 7.95 (m, 2H), 8.25 (m, 1 H), 8.65 (s, 1 H). 9.7 (broad s. 1 H ):
Elemental Analysis: Found C, 58.2: H, 4.6; N, 16.6:
C,~H~9C1FNs0, 0.?H,O requires C. 58.5; H. 4.5; N. 16.'_'°,'°.
' The 3-(imidazol-1-~~1)propyl chloride used as a starting= material was obtained as follo~~~s:-A solution ol~imidazole (5.-1 t,) in DMF ('_'0 mll was added dropwise to a stirred miature~ of sodium hydride (60°.o dispersion in mineral oil. :. ~ <~:
which was washed unh WO 96/33980 _ 38 _ PCT/GB96/0096t petroleum ether (b.p. 40-60°C)] in DMF ( 10 ml). The resultant solution was added to a solution of 3-bromochloropropane ( 13 g) in DMF (70 ml) which had been cooled in an ice bath. The mixture was stirred at 0°C for 1 hour. The mixture was poured into a saturated aqueous sodium bicarbonate solution. The resultant mixture was filtered and the filtrate was extracted with ethyl acetate. The organic extract was dried (Na2S04) and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride ' and methanol as eluent. There was thus obtained 3-(imidazol-I-yl)propyl chloride (8.3 g);
NMR Spectrum: 2.2 (m. 2H), 3.55 (t. 2H), 4.1 fit. 2H), 6.9 (s, 1H). 7.18 (s, ll~i), 7.6 (s, 1H).
E~ In a 24 A 1 M solution of hydrogen chloride in diethyl ether (6~ ml) was added to a solution of 4-(3'-ehloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxv)quinazoline (30.1 g) in diethyl ether (545 ml) and DMF (250 ml). The mixture was stirred at ambient temperature for 1 hour. The precipitate was isolated, washed with diethyl ether and dried.
There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline hydrochloride salt (32.1 g), m.p. 251-25~°C:
NMR Spectrum: 2.3 (m, 2H), 3.2-3.4 (m. 6H). 3.9 (broad s, 4H), 3.95 (s. 3H), 4.35 (t, 2H), 7.22 (s, I H). 7.4 (t, 1 H), 7.9 (m. I H). 8.1'? (s. 1 H). 8.'? (m. I H). 8.~~
(s. 1 H). 10.0 (s, 1 H);
Elemental Analysis: Found C. J-l.J: H. ~.3: ;s. 11.7:
C"H24C1FN,~0~ 1 HCI 0.08H,0 requires C. ~-1.3: H. ~.'_': :vT. I I
.6°r.
Exam l A I M solution of hydrogen chloride in diethyl ether ( I 3 ml ) was added to a solution of 4-(3'-chloro-4'-fluoroanilino)-7-methoxv-6-( :-morpholinopropoy)quinazoline (2.2 g) in DMF (20 ml) and the mixture was stirred at ambient temperature for '_' hours.
The precipitate was isolated. washed with diethyl ether and dried under vacuum at 80°C.
There was thus obtained 4-(3'-chloro--1'-fluoroanilino)-7-methow-E>-( ~-morpholinopropomOquinazoline dihydrochloride salt (~'.3 g):
NMR Spectrum: '_'.: (m.'_'ll). _ .'_'-:.e~ lm. 61i~. -~.l) Im. 71i). -I.=~ tt.
'_'li~. 7.-I ts. 1H). 7.>s (t.
1H1.7.81t11. Ilil. S.1~ im. Ili). S.t~ va. lli~. S ~~ (~. Ilii:

Elemental.Analysis: Found C, 50.7; H, 5.0; N, 10.5; Cl, 13.1;
C22H24C1~4~3 2HCl requires C, 50.8; H, 5.0; N, 10.8; Cl, 13.6%.
A solution of L-(2R,3R)-(+)-tartaric acid ( 1.03 g) in THF (50 ml) was added to a solution of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline ( 1.53 g) in THF ( 100 ml) and the mixture was stirred at ambient temperature for 2 hours. The mixture vvas filtered, washed with THF and dried. There was thus obtained 4-(3'-chloro-4'-fluoroani:lino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline di-L-tartaric acid salt (2 g), m.p. 136-140°C (phase change at 111°C);
NMR Spectrum: 2.2 (m, 2H), 2.5-2.6 (m, 6H). 3.6 (t. 4H), 3.9~ (s, 3H), 4.2 (t, ?H), 4.3 (s, 4H), 7.2 (s, 1H). 7.45 (t, 1H). 7.8 (m, 2H), 8.1~ (m. IH). 8.5 (s, 1H), 9.5 (s. 1H);
Elemental Analysis: Found C, 48.8; H. 5.?; N, 7.6;
Cz2HzaCIFN403 2 tartaric acid requires C, 48.4; H, 4.6: N, 7.5%.
Exam Ip c 27 A solution of fumaric acid (0.8 g) in a mixture of methylene chloride and DMF
was added to a solution of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline ( 1.~ g) in a mixture of methylene chloride (~0 ml) and sufficient DMF to complete the dissolution. The mixture was stirred at ambient temperature for ?
hours. The precipitate was isolated. washed with methylene chloride and dried. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropox~~)quinazoline difumaric acid salt (2.12 g), m.p. 199-201 °C;
NMR Spectrum: 2.0 (m, 2H), 2.5-2.7 (m. 6H). 3.6 (t, 4H). 3.95 (s. 3H). 4.2 (t, 2H), 6.6 (s, 2H), 7.2 (s, 1 H). 7.42 (t, 1 H), 7.8 (m, 2H), 8.2 (m. I H). 8.48 (s. 1 H). 9.~ (s. I H);
Elemental Analysis: Found C. 51.8: H. 4.7; Iv. 8.3:
C"H,,~CIFNaO, 1 H,O 2 fumaric acid requires C. ~ I .~: H. ~.'?: N_ 8.0°,~0.
Example 2R
. .
.A solution of ~-1-( s'-chloro-.~'-tluoroanilino ~-7-methom-6-( 3-morpholinopropow 1-quinazoline ( 1 ..~ g1 in the m~nitnum wlume of TI-iF mas added to a solution of citric acid (1.5 g) in THF (30 ml). The resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated and triturated under acetone. There was thus obtained 4-(3'-chloro-4'-tluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline containing 1.8 equivalents of citric acid (1.3 g), m.p. 160-163°C; -NMR Spectrum: 2.1 (m, 2H), 2.6-2.8 (m, 8H), 3.65 (t, 4H), 3.95 (s, 3H), 4.2 (t, 2H), 7.2 (s, 1 H), 7.4 (t, 1 H), 7.8 (m, 2H), 8.2 (m, 1 H), 8.48 (s, 1 H), 9.6 (s, 1 H);
Elemental Analysis: Found C, 50.0: H, 5.2; N, 7.2:
CzzHzaC1FN403 1.8 citric acid requires C, 49.7; H, 4.9; N, 7.1%.
F~~t A solution of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline (~ g) in THF (?50 ml) was added to a stirred solution of methanesulphonic acid (2.4 g) in THF (100 ml). The resultant mixture was stirred at ambient temperature for 1 hour.
The precipitate was isolated. slurred in acetone and re-isolated. There was thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline di-methanesulphonic acid salt (6.5 g), m.p. 242-245°C;
NMR Spectrum: 2.3 (m, 2H), 2.45 (s, 6H), 3.0-3.8 (m, lOH), 4.1 (s, 3H), 4.35 (t, 2H), 7.4 (s, 1 H). 7.55 (t, 1 H), 7.75 (m. 1 H), 8.0 (m. 1 H), 8.15 (s. 1 H), 8.9 (s. 1 H). 9.6 (s, 1 H), 11.0 (s. IH):
Elemental Analysis: Found C. ~~.1: H. ~.'_': I~'. 8.6:
CzzH,.~C1FN.~03 1.13H,0 '_'CH~SOzH requires C. X3.7: H. ~.'?: N. 8.~%.
Fxarxl l A solution of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline ( 1.5 g) in a mixture of DMA ( 10 1111) and methylene chloride (50 ml) was added to a mixture of concentrated sulphuric acid ( 1.~ ml ) and methylene chloride (20 ml ). The resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated. washed with acetone and dried. There was thus obtained 4-( 3'-chloro--1'-tluoroanilino)-7-methow-V-(3-morpholinopropow)quinazoline di-sulphuric acid salt ('_'.7 g).
m.p. ~'_'~0°C:

NMR Spectrum: 2.3 (m, 2H), 3.0-3.8 (m, lOH), 4.02 (s, 3H), 4.35 (t, 2H), 7.38 (s, 1H), 7.53 (t, 1 H), 7.77 (m, 1 H), 8.05 (m, 1 H), 8.15 (s, 1 H), 8.92 (s, 1 H);
Elemental Analysis: Found C, 39.0; H, 4.2; N, 8.2;
' Cz2H2aC1FN4O3 2H~0 2H~S04 requires C, 38.9: H, 4.75; N, 8.3%.
Exam lp a 3_1 A solution of 4-toluenesulphonic acid monohydrate ( 1.12 g) in THF (20 ml) was added to a solution of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline ( 1.3 g) in THF (60 ml). The resultant mixture was stirred at ambient temperature for 4 hours. The precipitate was isolated, washed in turn with THF and acetone and dried.
There wa.s thus obtained 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline di-4-toluenesulphonic acid salt (1.54 g), m.p. 169-173°C:
NMR Spectrum: 2.3 (m, 8H), 3.0-3.8 (m, lOH), 4.0 (s, 3H), 4.3 (t, 2H), 7.1 (d, 4H), 7.34 (s, 1 H), 7.5 (d, 4H), 7.54 (t, 1 H), 7.7 (m, 1 H), 7.95 (m, 1 H), 8.1 (s, 1 H), 8.9 (s, 1 H), 11.0 (broad s, 1 H);
Elemental Analysis: Found C, 52.8; H, 4.9; N, 6.8;
C22H2aCIFN403 1.SH20 2CH3C6H4S03H requires C, 52.8; H, 5.3; N, 6.85%.
Example 32 The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically-acceptable salt thereof (hereafter compound X). for therapeutic or prophylactic use in humans:
(a) Tablet I /ta t Compound X.............................................. 100 Lactose Ph.Eur........................................... 182.7 Croscarmellose sodium.............................. 1?.0 Maize starch paste (5% wW paste) ............
Magnesium stearate ................................... 3.0 WO 96/33980 _ 42 _ PCT/GB96/00961 (b) Tablet II mg/tablet Compound X.............................................. 50 Lactose Ph.Eur........................................... 223.75 Croscarmellose sodium.............................. 6.0 Maize starch............................................... 15.0 Polyvinylpyrrolidone ................................. 2.25 Magnesium stearate ................................... 3.0 (c) Tablet III /mg tablet Compound X.............................................. I .0 Lactose Ph.Eur........................................... 93.25 Croscarmellose sodium.............................. 4.0 Maize starch paste (5% w/v paste) ............ 0.75 Magnesium stearate 1.0 (d) Cansu(g ~1g/capsule Compound X.............................................. 10 Lactose Ph. Eur.......................................... 488.5 Maenesium stearate ................................... I .5 (e) ~ecti I (50 mg/ml) Compound X.............................................. 5.0% w/v I M Sodium hydroxide solution ................. I 5.0% w/v 0.1 M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 ............................ 4.5% w/v Water for injection to 100%

(fj j~iection II (10 m~/mll Compound X.............................................. 1.0 /o w/v Sodium phosphate BP................................ 3.6 /o w/v 0.1 M Sodium hydroxide solution .............. 15.0°/a v/v Water for injection to 100%
(g) Infection III (lmg/ml.buffered to pH6) Compound X.............................................. 0.1 /o w/v Sodium phosphate BP................................ 2.26% w/v Citric acid................................................... 0.38% w/v Polyethylene glycol 400 ............................ 3.5 /o w/v Water for injection to 100%
Note 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.

Claims (19)

1. A quinazoline derivative of the formula I
wherein n is 1, 2 or 3 and each R2 is independently halogeno or trifluoromethyl;
R3 is (1-4C)alkoxy; and R1 is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, thiamorpholino-(2-4C)alkoxy, 1-oxothiamorpholino-(2-4C)alkoxy or 1,1-dioxothiamorpholino-(2-4C)alkoxy, and wherein any of the above-mentioned R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 group a hydroxy substituent;
or a pharmaceutically-acceptable salt thereof.

2. A quinazoline derivative of the formula I as claimed in claim 1 wherein n is 1, 2 or 3 and each R2 is independently halogeno or trifluoromethyl;
R3 is (1-4C)alkoxy; and R1 is di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy or di-[(1-4C)alkoxy-(2-4C)alkyl]amino-(2-4C)alkoxy, and wherein any of the above-mentioned R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 group a hydroxy substituent;

or a pharmaceutically-acceptable salt thereof.

3. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R2)n is 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro;
R3 is methoxy; and R1 is 2-dimethytaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy, 2-[di-(2-methoxyethyl)amino]ethoxy or 3-morpholino-2-hydroxypropoxy;
or a pharmaceutically-acceptable mono- or di-acid-addition salt thereof.

4. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R2)n is 3'-chloro, 3'-bromo, 2',4'-difluoro, 3',4'-dichloro, 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro:
R3 is methoxy; and R1 is 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 2-[di-(2-methoxyethyl)amino]ethoxy or 3-morpholino-2-hydroxypropoxy:
or a pharmaceutically-acceptable acid-addition salt thereof.

5, A quinazoline derivative of the formula I as claimed in claim 1 wherein (R2)n is 3'-chloro, 3'-bromo, 2',4'-difluoro, 2',4'-dichloro, 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro;
R3 is methoxy; and R1 is 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-morpholinopropoxy or 3-morpholino-2-hydroxypropoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.

6. A quinazoline derivative of the formula I as claimed in claim 1 wherein (R2)n is 3',4'-difluoro, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro;
R3 is methoxy; and R1 is 3-morpholinopropoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

7. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-pyrrolidin-1-ylethoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

8. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(2-morpholinoethoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

9, The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-6-(3-diethylaminopropoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

10. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-pyrrolidin-1-ylpropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

11. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

12. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3',4'-difluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

13. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-piperidinopropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

14. The quinazoline derivative of the formula I as claimed in claim 1 being:-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline;
or a pharmaceutically-acceptable acid-addition salt thereof.

15. The hydrochloride salt of the quinazoline derivative of the formula I as claimed in claim 14.

16. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 which comprises:-(a) the reaction of a quinazoline of the formula II

wherein Z is a displaceable group, with an aniline of the formula III
(b) for the production of those compounds of the formula I wherein R1 is an amino-substituted (2-4C)alkoxy group, the alkylation of a quinazoline derivative of the formula I wherein R1 is a hydroxy group;
(c) for the production of those compounds of the formula I wherein R1 is an amino-substituted (2-4C)alkoxy group, the reaction of a compound of the formula I wherein R1 is a hydroxy-(2-4C)alkoxy group, or a reactive derivative thereof, with an appropriate amine; or (d) for the production of those compounds of the formula I wherein R1 is a hydroxy-amino-(2-4C)alkoxy group, the reaction of a compound of the formula I
wherein R1 is a 2,3-epoxypropoxy or 3.4-epoxybutoxy group with an appropriate amine.
and when a pharmaceutically-acceptable salt of a quinazoline derivative of the formula I is required it may be obtained by reaction of said compound with a suitable acid using a conventional procedure.

17. A pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 15 in association with a pharmaceutically-acceptable diluent or carrier.

18. The use of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 15 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal.

19. The use of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 15 for the production of an anti-proliferative effect in a warm-blooded animal.