CA2086968C - Quinazoline derivatives - Google Patents

Quinazoline derivatives

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Publication number
CA2086968C
CA2086968C CA002086968A CA2086968A CA2086968C CA 2086968 C CA2086968 C CA 2086968C CA 002086968 A CA002086968 A CA 002086968A CA 2086968 A CA2086968 A CA 2086968A CA 2086968 C CA2086968 C CA 2086968C
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alkyl
alkoxy
amino
quinazoline
alkylamino
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French (fr)
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CA2086968A1 (en
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Andrew John Barker
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AstraZeneca UK Ltd
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Zeneca Ltd
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Priority claimed from GB929201095A external-priority patent/GB9201095D0/en
Priority claimed from GB929213572A external-priority patent/GB9213572D0/en
Priority claimed from GB929223735A external-priority patent/GB9223735D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Cosmetics (AREA)
  • Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention concerns quinazoline derivatives of the formula I

(see fig. I) wherein m is 1, 2 or 3 and each R1 includes hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkoxyamino, (2-4C)alkanoyloxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy and (1-3C)alkylenedioxy;
n is 1 or 2 and each R2 includes hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano and (1-4C)alkyl;
or a pharmaceutically-acceptable salt 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 cancer.

Description

8 ~6 8 QUINAZOLINE DERIVATIVES

The invention relates to quinazoline derivatives, or pharmaceutically-acceptable salts thereof, which possess 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-cancer effect in a warm-blooded animal such as man.

Many of the current treatment regimes for cancer utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on the rapidly dividing tumour cells can be beneficial. Alternative approaches to anti-cancer agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action against cancer cells.
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 growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57, 443;
Larsen et al. Ann. Reports in Hed. Chem. 1989, Chpt. 13).
Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation. It is known that such kinases are CA 02086968 l997-06-l8 - 2 _ 2 G~

frequently present in common human cancers such as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149), leukaemia (Konaka et al., Cell, 1984, 37, 1035) and ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400586). As further human tumour tissues are tested for receptor tyrosine kinase activity it is expected that its widespread prevalance will be established in further cancers such as thyroid and uterine cancer. It is also known that tyrosine kinase activity is rarely detected in normal cells whereas it is more frequently detectable in malignant cells (Hunter, Cell, 1987, 50, 823). It has been shown more recently (~ J Gullick, Brit. Med. Bull., 1991, 47, 87) that epidermal growth factor receptor which possesses tyrosine kinase activity is 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 kinase should be of value as a selective inhibitor of the growth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933). Support for this view is provided by the demonstration that erbstatin, a receptor tyrosine kinase inhibitor, specifically attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor (EGF) receptor tyrosine kinase but is without effect on the growth of another carcinoma which does not express EGF receptor tyrosine kinase (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722.) Various derivatives of styrene are also stated to possess tyrosine kinase inhibitory properties (European Patent Application Nos. 0211363, 0304493 and 0322738) and to be of use as anti-tumour agents. The in vivo inhibitory effect of two such styrene derivatives has been demonstrated against the growth of human squamous cell carcinoma inoculated into nude mice (Yoneda et al., Cancer Research, 1991, 51, 4430). Accordingly it has been indicated that receptor tyrosine kinase inhibitors will prove to be useful in the treatment of a variety of human cancers. Various known tyrosine kinase inhibitors _ 3 _ 20S~

are disclosed in a more recent review by T R Burke Jr. (Dru~s of the Future, 1992, 17, 119).
We have now found that certain quinazoline derivatives possess anti-cancer properties which are believed to arise from their receptor tyrosine kinase inhibitory properties.
Many quinazoline derivatives are already known but we are not aware of any public disclosure that any such quinazoline derivative possesses anti-cancer properties arising from receptor tyrosine kinase inhibitory properties.
It is known from UK Patent Application No. 2033894 that certain quinazoline derivatives possess analgesic and anti-inflammatory properties. The compounds, and pharmaceutical compositions containing them, are disclosed by way of a generic formula II (set our hereinafter) wherein R1 is hydrogen, halogeno, trifluoromethyl or nitro;
R is hydrogen, halogeno, alkyl or alkoxy; and R is hydrogen or alkyl.
With one exception, all of the examples or named compounds therein require R1 to be a substituent other than hydrogen. The exception is the compound 4-(N-methylanilino)quinazoline i.e. each of R1 and R2 is hydrogen and R3 is methyl. It is believed that the quinazoline derivatives disclosed hereinafter do not embrace any of the specifically disclosed compounds of UK Patent Specification No.
2033894.
Further known quinazoline derivatives mentioned in UK
2033894 include the compounds 4-anilinoquinazoline and 4-anilino-6-chloroquinazoline [J. Org. Chem., 1976, 41, 2646 and US
Patent No. 3985749 respectivelyl, known for use in the treatment of coccidiosis.
It is known from Chemical Abstracts, volume 107, abstract number 134278h, that certain 4-(4'-hydroxyanilino)quinazoline derivatives have been tested for antiarrythmic properties. Compounds mentioned as chemical intermediates include 4-(4'-hydroxyanilino)-6-methoxyquinazoline and 4-(4'-hydroxyanilino)-6,7-methylenedioxy-quinazoline. It is known from Chemical Abstracts, volume 70, abstract number 68419u, that certain 4-aminoquinazoline derivatives possess 2 ~

bronchodilator and/or hypotensive properties. One such compound disclosed is 4-anilino-6,7-dimethoxyquinazoline. It is further known from Chemical Abstracts, volume 92, abstract number 76445u, that certain 6,7,8-trimethoxyquinazoline derivatives possess antimalarial properties. One compound mentioned as a chemical intermediate is 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline.
It is further known from Chemical Abstracts, volume 58, abstract number 9268, that certain 4-(4'-azoanilino)quinazoline derivatives are dyestuffs. A compound mentioned therein as an intermediate is 6-amino-4-(4'-aminoanilino)quinazoline. It is also known from J. Chem. Soc., 1962, 4679 that 4-chloro-6-methylquinazoline reacts with aniline to furnish 4-anilino-6-methylquinazoline.
According to one aspect of the invention there is provided a quinazoline derivative of the formula I (set out hereinafter) wherein m is 1, 2 or 3 and each R1 is independently hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyllcarbamoyl, hydroxyamino, (1-4C)alkoxyamino, (2-4C)alkanoyloxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, halogeno-(1-4C)alkyl (other than trifluoromethyl), hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-1(1-4C)alkyll-carbamoyl-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, phenoxy-(1-4C)alkyl, anilino-(1-4C)alkyl, phenylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, 2 D ~

halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, (2-4C)alkanoyloxy, hydroxy-(2-4C)alkanoyloxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, phenoxy-(2-4C)alkoxy, anilino-(2-4C)alkoxy, phenylthio-(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, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, carboxy-(1-4C)alkylamino, (1-4C)alkoxycarbonyl-(1-4C)alkylamino, carbamoyl-(1-4C)alkylamino, N-(1-4C)alkylcarbamoyl-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, phenyl-(1-4C)alkylamino, phenoxy-(2-4C)alkylamino, anilino-(2-4C)alkylamino, phenylthio-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino, carbamoyl-(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl-(2-4C)alkanoyl-amino, N,N-di-[(1-4C)alkyl]carbamoyl-(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent or any anilino, phenoxy or phenyl group in a R1 substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
n is 1 or 2 and each R is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, ?086 96~

(1-4C)alkylsulphlnyl, (l-4C)alkylsulphonyl, (2-4C)alkanoyl-amlno, benzamldo or (2-4C)alkanoyl, and whereln said benzamldo group may optlonally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substltuents;
or a pharmaceutlcally-acceptable salt thereof;
except that 4-(4'-hydroxyanlllno)-6-methoxyqulnazollne, 4-(4'-hydroxyanlllno)-6,7-methylenedloxyqulnazollne, 4-(4'-hydroxy-anlllno)-6,7,8-trlmethoxyqulnazollne, 4-(4'-methoxyanlllno)-8-methoxyqulnazollne, 4-(4'-chloroanlllno)-8-methoxyqulnazollne, 8-hydroxy-4-(4'-methoxyanlllno)qulnazollne, 4-(4'-chloro-anlllno)-8-hydroxyqulnazollne, 6-amlno-4-(4'-amlnoanlllno)-qulnazollne, 4-anlllno-6-methylqulnazollne or the hydro-chlorlde salt thereof and 4-anlllno-6,7-dlmethoxyqulnazollne or the hydrochlorlde salt thereof are excluded.
Accordlng to a further aspect of the lnventlon there ls provlded a qulnazollne derlvatlve of the formula I as deflned herelnbefore whereln each R2 ls lndependently hydrogen, hydroxy, halogeno, trlfluoromethyl, amlno, nltro, cyano (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamlno, dl-[(1-4C) alkyl]amlno, (1-4C)alkylthlo, (1-4C)alkylsulphlnyl or (1-4C)-alkylsulphonyl;
or a pharmaceutlcally-acceptable salt thereof.
Accordlng to a further aspect of the lnventlon there ls provlded a qulnazollne derlvatlve of the formula I whereln m ls l, 2 or 3 and each Rl ls lndependently hydroxy, amlno, carboxy, carbamoyl, ureldo, (1-4C)alkoxycarbonyl, N-(1-4C)-alkylcarbamoyl, N,N-dl-[(1-4C)alkyl]carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedloxy, (1-4C)alkylamlno, dl-~(1-4C)alkyl]amlno, (1-4C)alkylthlo, (1-4C)alkylsulphlnyl, (1-4C)alkylsulphonyl, halogeno-(1-4C)alkyl (other than trlfluoromethyl), hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-dl-[(1-4C)alkyl~-carbamoyl-(1-4C)alkyl, amlno-(1-4C)alkyl, (1-4C)alkylamlno-(1-4C)alkyl, dl-[(1-4C)alkyllamlno-(1-4C)alkyl, plperldlno-(1-4C)alkyl, morphollno-(1-4C)alkyl, plperazln-1-yl-(1-4C)-alkyl, 4-(1-4C)alkylplperazln-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C) alkoxy-(2-4C)alkoxy-(1-4C)-alkyl, hydroxy-(2-4C)alkylamlno-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamlno-(1-4C)alkyl, (1-4C)alkylthlo - 6a -'~' 2Gg~

(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-l(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyllamino-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, carboxy-(1-4C)alkylamino, (1-4C)alkoxycarbonyl-(1-4C)alkylamino, carbamoyl-(1-4C)alkylamino, N-(1-4C)alkylcarbamoyl-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino, carbamoyl-(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl-(2-4C)alkanoyl-amino, N,N-di-l(1-4C)alkyllcarbamoyl-(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-1(1-4C)alkyllamino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyllamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl;
or a pharmaceutically-acceptable salt thereof;
except that 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxy-quinazoline or the hydrochloride salt thereof are excluded.

2~Ci~8 According to a further aspect of the invention there is provided a quinazoline derivative of the formula I wherein m is 1 or 2 and each R1 is independently hydroxy, amino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-l(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-l(1-4C)alkyl]amino-(1-4C)alkyl, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, (2-4C)alkanoylamino, (1-4C)alkylsulphonylamino, benzamido or benzenesulphonamido, and wherein said last 2 substituents may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-l(1-4C)alkyllamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl;
or a pharmaceutically-acceptable salt thereof;
except that 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxy-quinazoline or the hydrochloride salt thereof are excluded.
The chemical formulae referred to herein by Roman numerals are set out for convenience on a separate sheet hereinafter. 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. An analogous convention applies to other generic terms.
Within the present invention it is to be understood that a quinazoline of the formula I may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses anti-cancer activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.

- 9 - ~0~ 8 The quinazolines of the formula I are unsubstituted at the 2-position. This is specifically indicated in formula I by the hydrogen atom at the 2-position. It is to be understood that the R1 groups are located only on the benzo position of the quinazoline ring.
It is also to be understood that certain quinazolines 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-cancer activity.
Suitable values for the generic radicals referred to above include those set out below.

A suitable value for R1 or R2 when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; when it is (1-4C)alkylamino is, for example, methylamino, ethylamino or propylamno; when it is di-[(1-4C)alkyl]amino is, for example, dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino or dipropylamino; when it is (1-4C)alkylthio is, for example, methylthio, ethylthio or propylthio; when it is (1-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl or propylsulphinyl; when it is (1-4C)alkylsulphonyl is, for example, methylsulphonyl, ethylsulphonyl or propylsulphonyl; and when it is (2-4C)alkanoylamino is, for example, acetamido, propionamido or butyramido.

Suitable values for each R1 substituent which may be present on the quinazoline ring include, for example:-for (1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl;
for N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl;
for N,N-di-[(1-4C)alkyl]-carbamoyl: N,N-dimethylcarbamoyl, - 10 - 20~J 3~

N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;
for (1-4C)alkoxyamino: methoxyamino, ethoxyamino and propoxyamino;
for (2-4C)alkanoyloxyamino: acetoxyamino, propionyloxyamino and butyryloxyamino;
for (1-3C)alkylenedioxy: methylenedioxy, ethylenedioxy and propylenedioxy;
for 4-(1-4C)alkyl-piperazin-l-yl: 4-methylpiperazin-1-yl and 4-ethylpiperazin-1-yl;
for halogeno-(1-4C)alkyl: fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2-fluoroethyl, 2-chloroethyl and 2-bromoethyl but trifluoromethyl is excluded;
for hydroxy-(1-4C)alkyl: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl;
for (2-4C)alkanoyloxy-(1-4C)-alkyl: acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl and 3-acetoxypropyl;
for (1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
for carboxy-(1-4C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 3-carboxypropyl;
for (1-4C)alkoxycarbonyl-(1-4C)alkyl: methoxycarbonylmethyl, ethoxy-carbonylmethyl, tert-butoxy-carbonylmethyl, 1-methoxycarbonyl-ethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and - 11 - 2~ô~3J~8 3-ethoxycarbonylpropyl;
for carbamoyl-(1-4C)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl;
for N-(1-4C)alkylcarbamoyl-(1-4C)alkyl: N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1-(N-methylcarbamoyl)ethyl, l-(N-ethylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl;
for N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl: N,N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl, N,N-diethylcarbamoylmethyl, 1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl and 3-(N,N-dimethylcarbamoyl)propyl;
for amino-(1-4C)alkyl: aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl;
for (1-4C)alkylamino-(1-4C)-alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylamino-ethyl, 2-ethylamimoethyl and 3-methylaminopropyl;
for di-l(1-4C)alkyl]amino-(1-4C)alkyl: dimethylaminomethyl, diethylamino-methyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl;
for piperidino-(1-4C)alkyl: piperidinomethyl and 2-piperidino-ethyl;

- 12 - ~ ~ ~ ~
~or morpholino-(1-4C)alkyl: morpholinomethyl and 2-morpholino-ethyl;
for piperazin-1-yl-(1-4C)alkyl: piperazin-1-ylmethyl and 2-(piperazin-1-yl)ethyl;
for 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl: 4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl, 2-(4-methylpiperazin-1-yl)ethyl and 2-(4-ethylpiperazin-1-yl)ethyl;
for hydroxy-(2-4C)alkoxy-(1-4C)alkyl: 2-hydroxyethoxymethyl, 3-hydroxy-propoxymethyl, 2-(2-hydroxy-ethoxy)ethyl and 2-(3-hydroxy-propoxy)ethyl;
for (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl: 2-methoxyethoxymethyl, 2-ethoxy-ethoxymethyl, 3-methoxypropoxy-methyl, 3-ethoxypropoxymethyl, 2-(2-methoxyethoxy)ethyl and 2-(2-ethoxyethoxy)ethyl;
for hydroxy-(2-4C)alkylamino-(1-4C)alkyl: 2-hydroxyethylaminomethyl, 3-hydroxypropylaminomethyl, 2-(2-hydroxyethylamino)ethyl and 2-(3-hydroxypropylamino)ethyl;
for (1-4C)alkoxy-(2-4C)-alkylamino-(1-4C)alkyl: 2-methoxyethylaminomethyl, 2-ethoxyethylaminomethyl, 3-methoxypropylaminomethyl, 2-(2-methoxyethylamino)ethyl and 2-(2-ethoxyethylamino)ethyl;
for (1-4C)alkylthio-(1-4C)alkyl: methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl and 3-ethylthiopropyl;
for hydroxy-(2-4C)alkylthio-2~ ,~ C ~ ~ 8 (1-4C)alkyl: 2-hydroxyethylthiomethyl, 3-hydroxypropylthiomethyl, 2-(2-hydroxyethylthio)ethyl and 2-(3-hydroxypropylthio)ethyl;
for (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl: 2-methoxyethylthiomethyl, 2-ethoxyethylthiomethyl, 3-methoxypropylthiomethyl, 2-(2-methoxyethylthio)ethyl and 2-(2-ethoxyethylthio)ethyl;
for phenoxy-(1-4C)alkyl: phenoxymethyl, 2-phenoxyethyl and 3-phenoxypropyl;
for anilino-(1-4C)alkyl: anilinomethyl, 2-anilinoethyl and 3-anilinopropyl;
for phenylthio-(1-4C)alkyl; phenylthiomethyl, 2-phenylthioethyl and 3-phenylthiopropyl;
for cyano-(1-4C)alkyl: cyanomethyl, 2-cyanoethyl and 3-cyanopropyl;
for halogeno-(2-4C)alkoxy: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy and 3-chloropropoxy;
for hydroxy-(2-4C)alkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy and 4-hydroxybutoxy;
for (2-4C)alkanoyloxy-(2-4C)-alkoxy: 2-acetoxyethoxy, 2-propionyloxy-ethoxy, 2-butyryloxyethoxy and 3-acetoxypropoxy;
for (1-4C)alkoxy-(2-4C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy and 4-methoxybutoxy;
for carboxy-(1-4C)alkoxy: carboxymethoxy, 1-carboxyethoxy, 2-carboxyethoxy and 3-carboxypropoxy;
for (1-4C)alkoxycarbonyl-(1-4C)alkoxy: methoxycarbonylmethoxy, ethoxy-carbonylmethoxy, 1-methoxy-2 0 ~ û ~ ~8 carbonylethoxy, 2-methoxy-carbonylethoxy, 2-ethoxy-carbonylethoxy and 3-methoxy-carbonylpropoxy;
for carbamoyl-(1-4C)alkoxy: carbamoylmethoxy, 1-carbamoylethoxy, 2-carbamoylethoxy and 3-carbamoylpropoxy;
for N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy: N-methylcarbamoylmethoxy, N-ethylcarbamoylmethoxy, 2-(N-methylcarbamoyl)ethoxy, 2-(N-ethylcarbamoyl)ethoxy and 3-(N-methylcarbamoyl)propoxy;
for N,N-di-l(1-4C)alkyll-carbamoyl-(1-4C)alkoxy: N,N-dimethylcarbamoylmethoxy, N-ethyl-N-methylcarbamoylmethoxy, N,N-diethylcarbamoylmethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy, 2-(N,N-diethylcarbamoyl)ethoxy and 3-(N,N-dimethylcarbamoyl)propoxy;
for amino-(2-4C)alkoxy: 2-aminoethoxy and 3-aminopropoxy;
for (1-4C)alkylamino-(2-4C)-alkoxy: 2-methylaminoethoxy, 2-ethyl-aminoethoxy, 2-propylaminoethoxy, 3-methylaminopropoxy and 3-ethylaminopropoxy;
for di-[(1-4C)alkyl]amino-(2-4C)alkoxy: 2-dimethylaminoethoxy,2-(N-ethyl-N-methyl)ethoxy, 2-diethylaminoethoxy, 2-dipropylaminoethoxy, 3-dimethylaminopropoxy and 3-diethylaminopropoxy;
for (2-4C)alkanoyloxy: acetoxy, propionyloxy and butyryloxy;
for hydroxy-(2-4C)alkanoyloxy: 2-hydroxyacetoxy, 2 ~ i 8 3-hydroxypropionyloxy and 4-hydroxybutyryloxy;
for (1-4C)alkoxy-(2-4C)-alkanoyloxy: 2-methoxyacetoxy, 2-ethoxyacetoxy and 3-methoxypropionyloxy;
for phenyl-(1-4C)alkoxy: benzyloxy, 2-phenylethoxy and 3-phenylpropoxy;
for phenoxy-(2-4C)alkoxy: 2-phenoxyethoxy, 3-phenoxypropoxy and 4-phenoxybutoxy;
for anilino-(2-4C)alkoxy: 2-anilinoethoxy, 3-anilinopropoxy and 4-anilinobutoxy;
for phenylthio-(2-4C)alkoxy: 2-phenylthioethoxy, 3-phenylthiopropoxy and 4-phenylthiobutoxy;
for piperidino-(2-4C)alkoxy: 2-piperidinoethoxy and 3-piperidinopropoxy;
for morpholino-(2-4C)alkoxy: 2-morpholinoethoxy and 3-morpholinopropoxy;
for piperazin-1-yl-(2-4C)alkoxy: 2-(piperazin-1-yl)ethoxy and 3-(piperazin-1-yl)propoxy;
for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy: 2-(4-methylpiperazin-1-yl)ethoxy and 3-(4-methylpiperazin-1-yl)propoxy;
for halogeno-(2-4C)alkylamino: 2-fluoroethylamino, 2-chloroethylamino, 2-bromoethylamino, 3-fluoropropylamino and 3-chloropropylamino;
for hydroxy-(2-4C)alkylamino: 2-hydroxyethylamino, 3-hydroxypropylamino and 4-hydroxybutylamino;
for (2-4C)alkanoyloxy-(2-4C)alkylamino: 2-acetoxyethylamino, 2-propionyloxyethylamino, 2-butyryloxyethylamino and 3-acetoxypropylamino;

2 ~

for (1-4C)alkoxy-(2-4C)alkyl-amino: 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino;
for carboxy-(1-4C)alkylamino: carboxymethylamino, 1-carboxyethylamino, 2-carboxyethylamino and 3-carboxypropylamino;
for (1-4C)alkoxycarbonyl-(1-4C)alkylamino: methoxycarbonylmethylamino, ethoxycarbonylmethylamino, 1-methoxycarbonylethylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino and 3-methoxycarbonylpropylamino;
for carbamoyl-(1-4C)alkylamino: carbamoylmethylamino, 1-carbamoylethylamino, 2-carbamoylethylamino and 3-carbamoylpropylamino;
for N-(1-4C)alkylcarbamoyl-(1-4C)alkylamino: N-methylcarbamoylmethylamino, N-ethylcarbamoylmethylamino, 2-(N-methylcarbamoyl)ethylamino, 2-(N-ethylcarbamoyl)ethylamino and 3-(N-methylcarbamoyl)propylamino;
for N,N-di-[(1-4C)alkyl]
carbamoyl-(1-4C)alkylamino: N,N-dimethylcarbamoylmethylamino, N-ethyl-N-methylcarbamoylmethylamino N,N-diethylcarbamoylmethylamino, 2-(N,N-dimethylcarbamoyl)ethylamino, 2-(N,N-diethylcarbamoyl)ethylamino and 3-(N,N-dimethylcarbamoyl)propyl-amino;
for amino-(2-4C)alkylamino: 2-aminoethylamino, 3-aminopropyl-amino and 4-aminobutylamino;

2 G ~ 8 for (1-4C)alkylamino-(2-4C)alkylamino: 2-methylaminoethylamino, 2-ethyl-aminoethylamino, 2-propylamino-ethylamino, 3-methylaminopropyl-amino, 3-ethylaminopropylamino and 4-methylaminobutylamino;
for di-[(1-4C)alkyllamino-(2-4C)alkylamino: 2-dimethylaminoethylamino, 2-(N-ethyl-N-methylamino)ethylamino, 2-diethylaminoethylamino, 2-dipropylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino and 4-dimethylaminobutylamino;
for phenyl-(1-4C)alkylamino: benzylamino, phenethylamino and 3-phenylpropylamino;
for phenoxy-(2-4C)alkylamino: 2-phenoxyethylamino and 3-phenoxypropylamino;
for anilino-(2-4C)alkylamino: 2-anilinoethylamino and 3-anilinopropylamino;
for phenylthio-(2-4C)alkylamino: 2-phenylthioethylamino and 3-phenylthiopropylamino;
for (1-4C)alkoxycarbonylamino: methoxycarbonylamino, ethoxy-carbonylamino and propoxy-carbonylamino;
for (1-4C)alkylsulphonylamino: methylsulphonylamino, ethyl-sulphonylamino and propyl-sulphonylamino;
for halogeno-(2-4C)alkanoylamino: 2-chloroacetamido, 2-bromoacetamido, 3-chloropropionamido and 3-bromo-propionamido;
for hydroxy-(2-4C)alkanoylamino: 2-hydroxyacetamido, 3-hydroxy-propionamido and 4-hydroxybutyramido;
for (1-4C)alkoxy-(2-4C)-alkanoylamino: 2-methoxyacetamido, 2-ethoxy-~ O ~ ù~ ù8 acetamido, 2-propoxyacetamido, 3-methoxypropionamido, 3-ethoxypropionamido and 4-methoxybutyramido;
for carboxy-(2-4C)alkanoylamino: 2-carboxyacetamido, 3-carboxypropionamido and 4-carboxybutyramido;
for (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino: 2-methoxycarbonylacetamido, 2-ethoxycarbonylacetamido, 3-methoxycarbonylpropionamido and 3-ethoxycarbonylpropionamido;
for carbamoyl-(2-4C)alkanoyl-amino: 2-carbamoylacetamido, 3-carbamoylpropionamido and 4-carbamoylbutyramido;
for N-(1-4C)alkylcarbamoyl-(2-4C)alkanoylamino: 2-(N-methylcarbamoyl)acetamido, 2-(N-ethylcarbamoyl)acetamido, 3-(N-methylcarbamoyl)propionamido, 3-(N-ethylcarbamoyl)propionamido and 4-(N-methylcarbamoyl)butyramido;
for N,N-di-[(1-4C)alkyll-carbamoyl-(2-4C)alkanoylamino: 2-(N,N-dimethylcarbamoyl)acetamido, 2-(N-ethyl-N-methylcarbamoyl)-acetamido, 2-(N,N-diethylcarbamoyl)-acetamido, 3-(N,N-dimethyl-carbamoyl)propionamido, 3-(N,N-diethylcarbamoyl)-propionamido and 4-(N,N-di-methylcarbamoyl)butyramido;
for amino-(2-4C)alkanoylamino: 2-aminoacetamido, 3-amino-propionamido and 4-aminobutyramido;
for (1-4C)alkylamino-(2-4C)-alkanoylamino: 2-methylaminoacetamido, 2-ethylaminoacetamido, ~ ~ ~ U J ~ 8 2-propylaminoacetamido, 3-methylaminopropionamido, 3-ethylaminopropionamido and 4-methylaminobutyramido;
for di-[(1-4C)alkyl]amino-(2-4C)-alkanoylamino: 2-dimethyl-aminoacetamido, 2-(N-ethyl-N-methylamino)acetamido, 2-diethylaminoacetamido, 3-dimethylaminopropionamido, 3-diethylaminopropionamido and 4-dimethylaminobutyramido.

When R1 is (1-3C)alkylenedioxy the oxygen atoms of each such group occupy adjacent positions on the quinazoline ring.
Suitable values for the substituents which may be present on the phenyl ring when R1 is benzamido or benzenesulphonamido, R2 is benzamido or on a R1 substituent which contains an anilino, phenoxy or phenyl group include, for example:-for halogeno: fluoro, chloro and bromo;
for (1-4C)alkyl: methyl, ethyl and propyl;
for (1-4C)alkoxy: methoxy, ethoxy and propoxy.
A suitable value for R when it is halogeno is, for example, fluoro, chloro, bromo or iodo; and when it is (2-4C)alkanoyl is, for example, acetyl, propionyl or butyryl.

A suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention is, for example, an acid-addition salt of a quinazoline derivative of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable CA 02086968 1997-06-18 ~ ~
~ J ~ 8 cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example, quinazoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, subject to the exclusions defined hereinbefore, wherein:-(a) m is 1 or 2 and each R1 is independently hydroxy,(1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy or (1-3C)alkylenedioxy; and n and R2 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

(b) m is 1 or 2 and each R1 is independently hydroxy, amino, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, halogeno-(1-4C)alkyl (but trifluoromethyl is excluded), (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)-alkylamino, (2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino or (1-4C)alkoxy-(2-4C)alkanoylamino; and n and R2 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

(c) m is 1 or 2 and each R1 is independently hydroxy, (1-4C)alkoxy, (1-3C)alkylenedioxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy or di-[(1-4C)alkyl]amino-(2-4C)alkoxy;
and n and R have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

2~G~v8 (d) m is 1 or 2 and each Rl is independently amino, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino or (1-4C)alkoxy-(2-4C)alkanoylamino; and n and R2 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

(e) m is 1, 2 or 3 and each R1 is independently hydroxy, amino, carboxy, ureido, (1-4C)alkoxycarbonyl, hydroxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, piperidino, morpholino, piperazin-l-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, halogeno-(1-4C)alkyl (but trifluoromethyl is excluded), (1-4C)alkoxy-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-l-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, anilino-(1-4C)alkyl, phenylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, phenoxy-(2-4C)alkoxy, anilino-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-1(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, benzamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino or (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino; and n and R2 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

(f) m is 1 or 2 and each R1 is independently hydroxy, amino, - 22 - 2 ~ 8 ureido, (1-4C)alkoxycarbonyl, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, piperidino, morpholino, (1-4C)alkylthio, halogeno-(1-4C)alkyl (but trifluoromethyl is excluded), cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carbamoyl-(1-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, anilino-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkylamino, (2-4C)alkanoylamino, halogeno-(2-4C)alkanoylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl or (1-4C)alkoxy-(2-4C)alkanoylamino; and n and R2 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

(g) n is 1 or 2 and each R2 is independently hydrogen, halogeno, trifluoromethyl, nitro, cyano, (1-4C)alkyl, di-[(1-4C)alkyl]amino or (1-4C)alkylthio; and m and R1 have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;

(h) n is 1 or 2 and each R2 is independently halogeno, trifluoromethyl or (1-4C)alkyl; and m and R1 have any of the -~ningS
defined hereinbefore or in this section relating to particular novel compounds of the invention; or (i) n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano or (1-4C)alkyl; and m and R1 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 m is 1 or 2 and each R1 is independently hydroxy, methyl, ethyl, methoxy, ethoxy or methylenedioxy;
n is 1 and R2 is hydrogen, fluoro, chloro, bromo, iodo, methyl or ethyl;
or a pharmaceutically-acceptable acid-addition salt thereof;

2~S t, ~ ~8 except that 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxyquinazoline or the hydrochloride salt thereof are excluded.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-methyl, 7-methyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy or 6,7-methylenedioxy;
and (R2)n is 3'-chloro, 3'-bromo or 3'-methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A specific preferred compound of the invention is the following quinazoline derivative of the formula I, or a pharmaceutically-acceptable acid-addition salt thereof:-6,7-dimethoxy-4-(3'-methylanilino)quinazoline, 6,7-dimethoxy-4-(3'-chloroanilino)quinazoline, 6,7-dimethoxy-4-(3'-bromoanilino)quinazoline, 6,,'-methylenedioxy-4-(3'-methylanilino)quinazoline, 7-methoxy-4-(3'-methylanilino)quinazoline, 7-hydroxy-4-(3'-methylanilino)quinazoline, 6-methyl-4-(3'-methylanilino)quinazoline or 7-methoxycarbonyl-4-(3'-methylanilino)quinazoline.

A further preferred compound of the invention is a quinazoline derivative of the formula I wherein m is 1 or 2 and each R1 is independently hydroxy, amino, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, dibromomethyl, dimethylaminomethyl, piperazin-l-ylmethyl, 2-hydroxyethylthiomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, 2-methoxyacetamido or 2-ethoxyacetamido;

- 24 - 2~ 8 n is 1 or 2 and each R2 is independently fluoro, chloro, bromo, trifluoromethyl, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-methyl, 6,7-dimethyl, 7-methoxy, 6,7-dimethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6,7-methylenedioxy, 6-(2-hydroxyethylthiomethyl), 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 7-carbamoylmethoxy-6-methoxy, 7-(2-dimethylaminoethoxy)-6-methoxy, 6-(2-methoxyethylamino), 6-acetamido or 7-(2-methoxyacetamido); and (R )n is 4'-fluoro, 3'-chloro, 3'-bromo, 3'-methyl, 3'-trifluoromethyl or 4'-fluoro-3'-trifluoromethyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (R1)m is 6-amino, 7-amino, 6-(2-methoxyethylamino), 6-acetamido or 7-(2-methoxyacetamido); and (R )n is 3'-chloro, 3'-methyl or 3'-trifluoromethyl;
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, or a pharmaceutically-acceptable acid-addition salt thereof:-6,7-dimethoxy-4-(3'-trifluoromethylanilino)quinazoline, 6-hydroxy-7-methoxy-4-(3'-methylanilino)quinazoline, 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline, 7-amino-4-(3'-methylanilino)quinazoline, 6-amino-4-(3'-methylanilino)quinazoline, 6-amino-4-(3'-chloroanilino)quinazoline, 6-acetamido-4-(3'-methylanilino)quinazoline, 6-(2-methoxyethylamino)-4-(3'-methylanilino)quinazoline, 7-(2-methoxyacetamido)-4-(3'-methylanilino)quinazoline, 7-(2-hydroxyethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline or 7-(2-methoxyethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline.
A further preferred compound of the invention is a 2~Sû~8 quinazoline derivative of the formula I
wherein m is 1, 2 or 3 and each R1 is independently hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, bromomethyl, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyacetoxy, benzyloxy, 2-anilinoethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, benzamido, 3-phenylureido, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetamido or 2-ethoxyacetamido;
n is 1 or 2 and each R2 is independently hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-dimethylamino, 6-methoxymethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 2 ~ ~ u ~ ~ ~

6,7-di-(2-methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamino), 6-acetamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido); and (R2)n is hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3',4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl;
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, or a pharmaceutically-acceptable acid-addition salt thereof:-4-(3'-chloro-4'-fluoroanilino)-6,7-dimethoxyquinazoline, 4-(3',4'-dichloroanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-4-(3'-nitroanilino)quinazoline, 6,7-diethoxy-4-(3'-methylanilino)quinazoline, 6-methoxy-4-(3'-methylanilino)quinazoline, 4-(3'-chloroanilino)-6-methoxyquinazoline, 6,7-ethylenedioxy-4-(3'-methylanilino)quinazoline, 6-amino-7-methoxy-4-(3'-methylanilino)quinazoline, 4-(3'-methylanilino)-6-ureidoquinazoline or 6-(2-methoxyethoxymethyl)-4-(3'-methylanilino)quinazoline.

A further preferred compound of the invention is a quinazoline derivative of the formula I
wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-methylamino, 7-methylamino, 6-dimethylamino, 6-amino-7-methylamino, 6-methoxymethyl, 6-bromomethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 6-methylthiomethyl, 6-phenylthiomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-bromoethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(2-methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 20Su~

6-(2-methoxyethylamino), 6-acetamido, 6-benzamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido); and (R2)n is hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3',4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl;
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, or a pharmaceutically-acceptable acid-addition salt thereof:-6,7-di-(2-methoxyethoxy)-4-(3'-methylanilino)quinazoline, 6-dimethylamino-4-(3'-methylanilino)quinazoline or 6-benzamido-4-(3'-methylanilino)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. A suitable process is, for example, illustrated by that used in UK Patent Application No. 2033894. 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, Rl, m, n and R2 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 III (set out hereinafter), wherein Z is a displaceable group, with an aniline of the formula IV.
A suitable displaceable group Z is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, -2~u~8 methoxy, phenoxy, methanesulphonyloxy or toluene-P-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, N-methylmorpholine or diazabicyclo[5.4.0~undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
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 N,N-dimethylformamide, N,N-dimethylacetamide, N-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 R1 or R2 is hydroxy, the cleavage of a quinazoline derivative of the formula I wherein R1 or R2 is (1-4C)alkoxy.
The cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation. The reaction may be carried out, for example, by treatment of the quinazoline derivative with an alkali metal (1-4C)alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide. Alternatively the cleavage reaction may conveniently be carried out, for example, by treatment of the quinazoline derivative with a boron or aluminium & 8 trihalide such as boron tribromide. Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a suitable temperature as illustrated in the accompanying Examples.

(c) For the production of those compounds of the formula I
wherein R1 or R2 is a (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl group, the oxidation of a quinazoline derivative of the formula I
wherein R1 or R2 is a (1-4C)alkylthio group.
A suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinium. The oxidation is generally carrried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups. In general the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, -25 to 50~C, conveniently at or near ambient temperature, that is in the range 15 to 35~C. When a compound carrying a sulphinyl group is required a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I containing a (1-4C)alkylsulphonyl group is required, it may be obtained by oxidation of the corresponding (1-4C)alkylsulphinyl compound as well as of the corresponding (1-4C)alkylthio compound.

(d) For the production of those compounds of the formula I
wherein R1 is amino, the reduction of a quinazoline derivative of the formula I wherein R1 is nitro.
The reduction may conveniently be carried out by any of the many procedures known for such a transformation. The reduction may be -2 ~ ~ û ~ ô ~

carrried out, for example, by the hydrogenation of a solution of the nitro compound in an inert solvent or diluent as defined hereinbefore in the presence of a suitable metal catalyst such as palladium or platinum. A further suitable reducing agent is, for example, an activated metal such as activated iron (produced by washing iron powder with a dilute solution of an acid such as hydrochloric acid).
Thus, for example, the reduction may be carried out by heating a mixture of the nitro compound and the activated metal in a suitable solvent or diluent such as a mixture of water and an alcohol, for example, methanol or ethanol, to a temperature in the range, for example, 50 to 150~C, conveniently at or near 70~C.

(e) For the production of those compounds of the formula I
wherein R1 is (2-4C)alkanoylamino or substituted (2-4C)alkanoylamino, ureido, 3-phenylureido or benzamido, or R2 is acetamido or benzamido, the acylation of a quinazoline derivative of the formula I wherein or R is amino.
A suitable acylating agent is, for example, any agent known in the art for the acylation of amino to acylamino, for example an acyl halide, for example a (2-4C)alkanoyl chloride or bromide or a benzoyl chloride or bromide, conveniently in the presence of a suitable base, as defined hereinbefore, an alkanoic acid anhydride or mixed anhydride, for example a (2-4C)alkanoic acid anhydride such as acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and a (1-4C)alkoxycarbonyl halide, for example a (1-4C)alkoxycarbonyl chloride, in the presence of a suitable base as defined hereinbefore. For the production of those compounds of the formula I wherein R1 is ureido or 3-phenylureido, a suitable acylating agent is, for example, a cyanate, for example an alkali metal cyanate such as sodium cyanate or, for example, an isocyanate such as phenyl isocyanate. In general the acylation is carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature, in the range, for example, -30 to 120~C, conveniently at or near ambient temperature.

(f) For the production of those compounds of the formula I

- 31 - 2 ~ ~ 8 wherein R1 is (1-4C)alkoxy or substituted (1-4C)alkoxy or R1 is (1-4C)alkylamino or substituted (1-4C)alkylamino, the alkylation, preferably in the presence of a suitable base as defined hereinbefore, of a quinazoline derivative of the formula I wherein R1 is hydroxy or amino as appropriate.
A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (1-4C)alkyl chloride, bromide or iodide or a substituted (1-4C)alkyl 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 range, for example, 10 to 140~C, conveniently at or near ambient temperature.

(g) For the production of those compounds of the formula I
wherein R1 is a carboxy substituent or a substituent which includes a carboxy group, the hydrolysis of a quinazoline derivative of the formula I wherein R1 is a (1-4C)alkoxycarbonyl substituent or a substituent which includes a (1-4C)alkoxycarbonyl group.
The hydrolysis may conveniently be performed, for example, under basic conditions as illustrated in the accompanying Examples.

(h) For the production of those compounds of the formula I
wherein R1 is an amino-, oxy-, thio- or cyano-substituted (1-4C)alkyl substituent, the reaction, preferably in the presence of a suitable base as defined hereinbefore, of a quinazoline derivative of the formula I wherein R1 is a (1-4C)alkyl substituent bearing a displaceable group as defined hereinbefore with an appropriate amine, alcohol, thiol or cyanide.
The reaction is preferably carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 100~C, conveniently at or near ambient temperature.

~hen a pharmaceutically-acceptable salt of a quinazoline - 32 - 2 ~3 ~ 8 derivative of the formula I is required, it may be obtained, for example, by reaction of said compound with, for example, a suitable acid using a conventional procedure.

Many of the intermediates defined herein are novel, for example, those of the formula III and these are provided as a further feature of the invention. Horeover some of the starting materials for use in process variant (d) described hereinbefore, namely those compounds of the formula I wherein m is 2 or 3 and one of the R1 groups is nitro, are not only novel but also active as inhibitors of receptor tyrosine kinase. Accordingly these compounds are provided as a further feature of the invention.

As stated hereinbefore the quinazoline derivative defined in the present invention possesses anti-cancer activity which is believed to arise from the receptor tyrosine kinase inhibitory activity of the compound. These properties may be assessed, for example, using one or more of the procedures set out below:-(a) An in vitro assay which determines the ability of a testcompound to inhibit the enzyme receptor tyrosine kinase. Receptor tyrosine kinase was obtained in partially purified form from A-431 cells (derived from human vulval carcinoma) by procedures related to those described by Carpenter et al., J. Biol. Chem., 1979, 254, 4884, Cohen et al., J. Biol. Chem., 1982, 257, 1523 and by Braun et al., J. Biol. Chem., 1984, 259, 2051.
A-431 cells were grown to confluence using Dulbecco's modified Eagle's medium (DMEM) containing 5% fetal calf serum (FCS).
The obtained cells were homogenised in a hypotonic borate/EDTA buffer at pH 10.1. The homogenate was centrifuged at 400 g for 10 minutes at 0-4~C. The supernatant was centrifuged at 25,000 g for 30 minutes at 0-4~C. The pelleted material was suspended in 30 mM Hepes buffer at pH 7.4 containing 5% glycerol, 4 mM benzamidine and 1% Triton X-100, stirred for 1 hour at 0-4~C, and recentrifuged at 100,000 g for 1 hour at 0-4~C. The supernatant, containing solubilised receptor tyrosine kinase, was stored in liquid nitrogen.

_ 33 _ 208696~
For test purposes 40 ~l of the enzyme solutlon so obtained was added to a mixture of 400 ~l of a mlxture of 150 mM Hepes buffer at pH 7.4, 500 ~M sodlum orthovanadate, 0.1% Triton X-100 , 10% glycerol, 200 ~1 water, 80 ~l of 25 mM
DTT and 80 ~l of a mixture of 12.5 mM manganese chlorlde, 125 mM magnesium chloride and distllled water. There was thus obtalned the test enzyme solution.
Each test compound was dissolved in dimethylsulphoxide (DMSO) to give a 50 mM solutlon which was diluted wlth 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 epldermal growth factor (EGF; 20 ~g/ml) were mixed.
[y-32]ATP (3000 Ci/mM, 250 ~C1) was diluted to a volume of 2 ml by the addltlon of a solution of ATP (100 ~M) ln distilled water. An equal volume of a 4 mg~ml solution of the peptide Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arq-Gly in a mixture of 40 mM Hepes buffer at pH 7.4, 0.1% Triton X-100 and 10~ glycerol was added.
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 mixture was incubated at 25~C for 10 minutes. The phosphorylation reaction was terminated by the addition of 5% trichloroacetic acid (40 ~l) and bovine serum albumin (BSA; 1 mg/ml, 5 ~l). The mlxture was allowed to stand at 4~C for 30 minutes and then centrifuged. An aliquot * Trade-mark B

- 33a - 208696~
(40 ~l) of the supernatant was placed onto a strlp of Whatman p 81 phosphocellulose paper. The strlp was washed in 75 mM
phosphoric acid (4 x 10 ml) and blotted dry. Radioactivity present in the filter paper was measured using a liquid scintillation counter (Sequence A). The reactlon 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:-100 - (A-B) Inhibition = x 100 C - B

~ 75887-139 "~

CA 02086968 l997-06-l8 34 ~û~iJ8 The extent of inhibition was then determined at a range of concentrations of test compound to give an IC50 value.

(b) An in vitro assay which determines the ability of a test compound to inhibit the growth of the human naso-pharyngeal cancer cell line KB.
KB cells were seeded into wells at a density of 1 X 104 - 1. 5 x 104 cells per well and grown for 24 hours in DMEN
supplemented with 5Z FCS (charcoal-stripped). Cell growth was determined after incubation for 3 days by the extent of metabolism of MTT tetrazolium dye to furnish a bluish colour. Cell growth was then determined in the presence of EGF (10 ng/ml) or in the presence of EGF
(10 ng/ml) and a test compound at a range of concentrations. An IC50 value could then be calculated.

(c) An in vivo assay in a group of male rats which determines the ability of a test compound (usually administered orally as a ball-milled suspension in 0.5% polysorbate) to inhibit the stimulation of liver hepatocyte growth caused by the administration of the growth factor TGFa (400 ~g/kg subcutaneously, usually dosed twice, 3 and 7 hours respectively after the administration of the test compound).
In a control group of rats, the administration of TGFa causes on average a 5-fold stimulation of liver hepatocyte growth.
Cell-growth in the control and test animals is determined as follows:-On the morning of the day after the dosing of the testcompound (or 0.5% polysorbate in the control group), the animals are dosed with bromodeoxyuridine (BrdU; 100 mg/kg intraperitoneally). The animals are killed four hours later and the livers are excised.
Slices are cut from each liver and the uptake of BrdU is determined by a conventional immunohistochemical technique similar to that described on pages 267 and 268 of an article by Goldsworthy et al. in Chemically Induced Cell Proliferation: Implications for Risk Assessment, Wiley-Liss Inc., 1991, pages 253-284.

-2G ~ ~ 3 ~ ~

Further tests were carried out using a range of doses of the test compounds to allow the calculation of an approximate ED50 value for the inhibition of liver hepatocyte proliferation as determined by inhibition of the uptake of BrdU.

Although the pharmacological properties of the compounds of the formula I vary with structural change as expected, in general activity possessed by compounds of the formula I may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b) and (c):-Test (a):- IC50 in the range, for example, 0.0005-1 ~M;
Test (b):- IC50 in the range, for example, 0.01-10 ~M;
Test (c):- ED50 in the range, for example, 1-100 mg/kg.

Thus, by way of example, the compound 6,7-dimethoxy-4-(3'-methylanilino)quinazoline has an IC50 of 0.005 ~M in Test (a), an IC50 of 0 05 ~M in Test (b) and an ED50 of <5 mg/kg in Test (c);
the compound 6,7-dimethoxy-4-(3'-trifluoromethylanilino)quinazoline has an IC50 of 0.01 ~M in Test (a) and an IC50 of 0 3 ~M in Test (b);
the compound 6-amino-4-(3'-methylanilino)quinazoline has an IC50 of 0.055 ~M in Test (a), an IC50 of 1 ~M in Test (b) and an ED50 ~f <5 mg/kg in Test (c); the compound 6-acetamido-4-(3'-methylanilino)-quinazoline has an IC50 of 0.01 ~M in Test (a) and an IC50 of 0.65 ~M
in Test (b); and the compound 7-(2-hydroxyethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline has an IC50 of 0.005 ~M in Test (a) and an IC50 of 0.14 ~M in Test (b).

As stated hereinbefore the compound 4-anilino-6,7-dimethoxy-quinazoline is known and is stated to possess bronchodilator and/or hypotensive properties. There is no disclosure that the other quinazoline derivatives excluded from the definition of the invention possess pharmacological properties.
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 - 36 - ~ &S~V3 thereof, as defined hereinbefore or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxy-anilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline and 4-anilino-6-methylquinazoline or the hydrochloride salt thereof, 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 will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose. A
unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
According to a further 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 now found that the compounds of the present invention and those known compounds excluded from the definition of the compounds of the invention possess anti-cancer properties which are believed to arise from their receptor tyrosine kinase inhibitory activity.
Thus according to this aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a 2 ~ 3 pharmaceutically-acceptable salt thereof, as defined hereinbefore or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxy-quinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxyquinazoline or the hydrochloride salt thereof in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative as defined immediately above.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular cancer will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
The anti-cancer 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 those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 239362 such as N-{5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-_-methylamino]-2-thenoyl}-L-glutamic acid;
intercalating antibiotics, for example adriamycin and bleomycin;
enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; biological response modifiers, for example interferon; and anti-hormones, for example antioestrogens such as 'NOLVADEX' (tamoxifen) or, for example antiandrogens such as 'CASODEX' (4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'--- 38 - 2 0 ~ ~ ~ ô ~

(trifluoromethyl)propionanilide. 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 or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxyquinazoline or the hydrochloride salt thereof and an additional anti-tumour substance as 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 receptor tyrosine kinase inhibitory properties. Such a quinazoline derivative of the invention is expected to possess a wide range of anti-cancer properties as 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 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.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:-(i) evaporations were carried out by rotary evaporationin vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at ambient temperature, that is in the range 18-25~C and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and - 3g - 2086~6~
medium pressure llquid chromatography (MPLC) were performed on Merck Kieselgel silica ~Art. 9385) or Merck Llchroprep RP-18 (Art. 9303~ reversed-phase sllica obtalned from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maxlmum attainable;
(v) meltlng polnts are uncorrected and were determined using a Mettler SP62 automatlc melting point apparatus, an oll-bath apparatus or a Koffler hot plate apparatus.
(vl) the structures of the end-products of the formula I were conflrmed by nuclear ~generally proton) magnetlc resonance (NMR) and mass spectral techniques; proton magnetlc resonance chemlcal shift values were measured on the delta scale and peak multipliclties are shown as follows s, slnglet; d, doublet; t, trlplet; m, multiplet;
(vil) lntermedlates were not generally fully characterlsed and purity was assessed by thln layer chromatography (TLC), lnfra-red (IR) or NMR analysls;
(viii) the following abbreviations have been used:-DMF N,N-dlmethylformamlde;
DMA N,N-dlmethylacetamide;
THF tetrahydrofuran.

* Trade-mark ~3 ~ U ~ U J U 8 esal ple 1 A mixture of 4-chloro-6,7-dimethoxyquinazoline (0.3 g), 3-methylaniline (0.143 g) and isopropanol (5 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was filtered off and washed with cold isopropanol and with diethyl ether. There was thus obtained 6,7-dimethoxy-4-(3'-methylanilino)quinazoline hydrochloride (0.226 g, 51Z), m.p. 248-249~C.
NNR Spectrum: (CD3SOCD3) 2.36 (s, 3H), 3.99 (s, 3H), 4.02 (s, 3H), 7.13 (d, lH), 7.38 (s, lH), 7.39 (t, lH), 7.49 (s, 2H), 8.34 (s, lH), 8.80 (s, lH);
Elemental Analysis: Found C, 61.4; H, 5.4; N, 12.5;
C17H17N3O2. HCl requires C, 61.4; H, 5.4; N, 12.7%.

The 4-chloro-6,7-dimethoxyquinazoline used as a starting material was obtained as follows:-A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10 ml) was stirred and heated to 190~C for 5 hours. The mixture was allowed to cool to approximately 80~C and water (50 ml) was added. The mixture was stored at ambient temperature for 3 hours.
The precipitate was isolated, washed with water and dried. There was thus obtained 6,7-dimethoxyquinazolin-4-one (3.65 g).
A mixture of a portion (2.06 g) of the material so obtained, thionyl chloride (20 ml) and DMF (1 drop) was stirred and heated to reflux for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, dried (NgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained the required starting material (0.6 g, 27%).

Example 2 The procedure described in Example 1 was repeated except that the appropriate aniline was used in place of 3-methylaniline and, where appropriate, the appropriate substituted 4-chloroquinazoline was 2~S~8 used in place of 4-chloro-6,7-dimethoxyquinazoline. There were thus obtained, as hydrochloride salts, the compounds described in the following table, the structures of which were confirmed by proton magnetic resonance spectroscopy and by elemental analysis.

- - -- 42 - 2 ~ & ~ 3 ~ 8 TABLE I
H N/ ~ _ R2 H ~ ~ ~ ( R 1 ) m Lxa~ple 2 (Rl)~ R2 m.p.
Coopd. No. (~C) 1 6,7-dimethoxy 3'-chloro 245-247 2a 6,7-dimethoxy 3'-bromo >250 (decomposes) 3b 6,7-methylenedioxy 3'-methyl >280 4c 7-methoxy 3'-methyl 232-233 5d 7-methoxycarbonyl 3'-methyl 206-211 Notes a. The product gave the following analytical data: Found C, 48.3; H, 3.6; N, 10.4; C16H14BrN302. HCl requires C, 48.4; H, 3.8; N, 10.6%;
and the following characteristic NMR data: (CD3SOCD3) 4.0 (s, 3H), 4.22 (s, 3H), 7.36 (s, lH), 7.5 (m, 2H), 7.76 (m, lH), 8.02 (m, lH), 8.35 (s, lH), 8.66 (s, lH).

b. The product gave the following analytical data: Found C, ~Oô~u8 60.3; H, 4.3; N, 13.3; C16H13N302. 1.08HCl requires C, 60.2, H, 4.4;
N, 13.2X.
and the following characteristic NMR data (CD3SOCD3) 2.36 (s, 3H), 6.37 (s, 2H), 7.13 (d, 2H), 7.35 (t, lH), 7.37 (s, lH), 7.49 (m, 2H), 8.28 (s, lH), 8.78 (s, lH).
The 4-chloro-6,7-methylenedioxyquinazoline used as a starting material was obtained from 4,5-methylenedioxyanthranilic acid using analogous procedures to those described in the portion of Example 1 which is concerned with the preparation of starting materials.

c. The 4-chloro-7-methoxyquinazoline used as a starting material was obtained from 4-methoxyanthranilic acid using analogous procedures to those described in the portion of Example 1 which is concerned with the preparation of starting materials.

d. The reaction mixture was heated to reflux for 2 hours. A
precipitate was not deposited when the mixture was cooled to ambient temperature. The mixture was poured into water (50 ml) and a saturated aqueous ammonium hydroxide solution was added dropwise. The resultant precipitate was isolated, washed with water and dried.
There was thus obtained 7-methoxycarbonyl-4-(3'-methylanilino)-quinazoline in 47% yield.
The product gave the following analytical data: Found C, 69.8; H, 5.2; N, 13.9; C17H15N302 requires C, 69.6; H, 5.2; N, 14.3%;
and the following characteristic NMR data:
(CD3SOCD3) 2.36 (s, 3H), 3.95 (s, 3H), 6.98 (d, lH), 7.29 (t, lH), 7.67 (m, 2H), 8.08 (m, lH), 8.29 (d, lH), 8.68 (s, lH), 8.70 (s, lH).
The 4-chloro-7-methoxycarbonylquinazoline used as a starting material was obtained as follows:-Using an analogous procedure to that described in the firstparagraph of the portion of Example 1 which is concerned with the preparation of starting materials, 4-carboxyanthranilic acid (14.2 g) was reacted with formamide to give 7-carboxyquinazolin-4-one (8.5 g).
A mixture of a portion (4 g) of the material so obtained, methanol (40 2 0 ~ ' G ~

ml) and concentrated sulphuric acid (2 ml) was stirred and heated to reflux for 6 hours. The mixture was cooled to ambient temperature and the precipitate was isolated. There was thus obtained 7-methoxycarbonylquinazolin-4-one (5.7 g).
A mixture of a portion (0.5 g) of the material so obtained, phosphoryl chloride (2 ml) and DMF (1 drop) was stirred and heated to reflux for 2 hours. The mixture was evaporated to give 4-chloro-7-methoxycarbonylquinazoline which was used without further purification.

Exa~ple 3 A mixture of 4-chloro-6-methylquinazoline (0.5 g), 3-methylaniline (0.33 g) and isopropanol (10 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was filtered off and washed with cold isopropanol and with diethyl ether. There was thus obtained 6-methyl-4-(3'-methylanilino)quinazoline (0.61 g, 76%), m.p.
243-245~C.
NMR Spectrum: (CD3SOCD3) 2.38 (s, 3H), 2.57 (s, 3H), 7.1-8.0 (m, 6H), 8.77 (s, lH), 8.88 (s, lH);
Elemental Analysis: Found C, 67.0; H, 5.5; N, 14.5;
C16H15N3. HCl requires C, 67.2; H, 5.6; N, 14.7%.

The 4-chloro-6-methylquinazoline used as a starting material was obtained as follows:-A mixture of 6-methylquinazolin-4-one (10 g; J. Ned. Chem., 1989, 32, 847), phosphoryl chloride (12.5 ml), _,N-dimethylaniline (14.25 ml) and toluene (150 ml) was stirred and heated to reflux for 2.5 hours. The mixture was poured onto ice and the organic layer was separated, washed with water, dried (MgS04) and evaporated. There was thus obtained the required starting material as a solid (10.4 g, 93%) which was used without further purification.

example 4 A mixture of 7-methoxy-4-(3'-methylanilino)quinazoline (0.106 g), sodium ethanethiolate (0.336 g) and DMF (5 ml) was stirred -~0~~8 and heated to 140~C for 4 hours. The mixture was evaporated and the residue was purified by column chromatography using a 45:55:0.2 v/v mixture of water, methanol and trifluoroacetic acid as eluent. There was thus obtained 7-hydroxy-4-(3'-methylanilino)quinazoline (0.068 g, 41Z), m.p. 52-60~C.
Elemental Analysis: Found C, 51.6; H, 3.6; N, 10.3;
C15H13N30. 1.4CF3C02H requires C, 52.0; H, 3.5; N, 10.2%.

Example 5 Using an analogous procedure to that described in Example 4, 6,7-dimethoxy-4-(3'-chloroanilino)quinazoline was reacted with sodium ethanethiolate to give 6,7-dihydroxy-4-(3'-chloroanilino)quinazoline in 68% yield, m.p. 233-235~C.
Elemental Analysis: Found C, 46.3; H, 2.7; N, 10.0;
C14H1oClN302. 1.18CF3C02H requires C, 46.6; H, 2.7; N, 10.0%.

Example 6 The procedure described in Example 1 was repeated except that the appropriate aniline was used in place of 3-methylaniline and, where appropriate, the appropriate substituted 4-chloroquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. There were thus obtained, as hydrochloride salts, the compounds described in the following table, the structures of which were confirmed by proton magnetic resonance spectroscopy and by elemental analysis.

- 46 - 2 G ~ G J

TABLE II
R ) n J
H N/~/' Hi\N"~

Exa~ple 6 (R1)~ (R2)n ~-p-Co~pd. No. (~C) la 6,7-dimethoxy 3'-trifluoromethyl 261-262 2b 6,7-dimethoxy 4'-fluoro-3'- 260-261 trifluoromethyl 3c 6,7-dimethoxy 4'-fluoro 227-230 4d,e 6,7-dimethyl 3'-methyl 263-272 5d,f 6,7-dimethyl 3'-chloro 6g 6-dibromomethyl 3'-methyl 247-252 Notes a. The product gave the following analytical data: Found C, 52.9; H, 4.0; N, 10.6; C17H14F3N302. HCl. 0.1(CH3)2CHOH requires C, 53.0; H, 4.0; N, 10.7%; and the following characteristic NMR data:
(CD3SOCD3) 4.0 (s, 3H), 4.03 (s, 3H), 7.37 (s, lH), 7.64 (d, lH), 7.73 (t, lH), 8.09 (d, lH), 8.16 (s, lH), 8.39 (s, lH), 8.89 (s, lH), 11.59 2G$~8 (broad s, lH).

b. The product gave the following analytical data: Found C, 50.3; H, 3.7; N, 9.9; C17H13F4N302. HCl. 0.5EtOH requires C, 50.7; H, 3.6; N, 9.9X; and the following characteristic NMR data: (CD3SOCD3) 4.0 (s, 3H), 4.03 (s, 3H), 7.37 (s, lH), 7.65 (t, lH), 8.1-8.25 (m, 2H), 8.44 (s, lH), 8.89 (s, lH), 11.76 (s, lH).

c. The product, obtained initially as the hydrochloride salt, was converted into the corresponding free base as follows. The salt was partitioned between ethyl acetate and lN aqueous sodium hydroxide solution. The organic phase was washed with brine, dried (MgS04) and evaporated. The material so obtained was triturated under ethyl acetate. There was thus obtained the required free base, m.p.
227-230~C;
NMR Spectrum: (CD3SOCD3) 3.94 (s, 3H), 3.98 (s, 3H), 7.16-7.25 (m, 3H), 7.7-7.8 (m, 3H), 8.40 (s, lH), 9.5 (s, lH);
Elemental Analysis: Found C, 64.1; H, 4.7; N, 13.8;
C16H14FN302 requires C, 64.2; H, 4.7; N, 14.0%.

d. Two equivalents of triethylamine were added to the reaction mixture prior to the reaction mixture being heated to reflux for 3 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was dried (MgS04) and evaporated. The residue was recrystallised from isopropanol to give the required product.

e. The product gave the following analytical data: Found C, 70.7; H, 6.3; N, 14.3; C17H17N3. 0.7HCl requires C, 70.7; H, 6.15; N, 14.5X;
and the following characteristic NMR data:
(CD3SOCD3) 2.36 (s, 3H), 2.5 (s, 6H), 7.1-7.7 (m, 5H), 8.56 (s, lH), 8.77 (s, lH).
The 4-chloro-6,7-dimethylquinazoline used as a starting material was obtained from 4,5-dimethylanthranilic acid (Acta Chemica Scand., 1967, 21, 983) using analogous procedures to those described - 48 - 2086~68 in the portion of Example 1 which is concerned with the preparation of starting materials.
f. The product gave the following analytical data:
Found C, 58.2; H, 5.9; N, 10.6; C16H14ClN3. 1.3 HCl.
0.8(CH3)2CHOH requires C, 58.2; H, 5.8; N, 11.0%;
and the following characteristic NMR data: (CD3SOCD3) 2.5 (s, 6H), 7.37 (m, lH), 7.51 (t, lH), 7.73 (s, lH), 7.78 (m, lH), 7.96 (t, lH), 8.74 (s, lH), 8.92 ~s, lH), 11.5 (broad s, lH).
g. The product gave the following analytical data:

Found C, 41-4; H, 3-4; N, 9.1; C16H13BrN3. HCl. l.lH2O
requires C, 41.4; H, 3.5; N, 9.1;
and the followlng characteristic NMR data:
~CD3SOCD3) 2.38 (s, 3H), 7.18 (d, lH), 7.40 (t, lH), 7.49 (m, 2H), 7.51 (s, lH), 7.94 (d, lH), 8.29 (m, lH), 8.gl (s, lH), 9.10 (d, lH), 11.7 (s, lH).
The 4-chloro-6-dibromomethylquinazoline used as a starting material was obtained as follows:-A mixture of 4-chloro-6-methylquinazoline (7.3 g) [obtained by the reactlon 6-methyl-4-oxo-3,4-dihydroquinazoline (European Patent Application No. 0204529, published December 10, 1986 with thionyl chloride], N-bromosuccinimlde (7.32 g) dibenzoyl peroxide (0.1 g) and carbon tetrachloride (200 ml) was stirred and heated to reflux for 6 hours. The mlxture was evaporated and the resldue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent.
There were thus obtained in turn 4-chloro-6-dibromo-- 48a - 208 6 96 methylquinazoline (0.5 g) and 6-bromomethyl-4-chloroquinazoline (4 g).

Example 7 Ammonium formate (3.6 g) was added to a stlrred mlxture of 4-(3'-methylanlllno)-7-nltroqulnazollne (4 g), 10 palladium-on-charcoal catalyst (0.4 g) and ethanol (200 ml) and the mixture was stlrred at ambient temperature for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase B

2ûôû~&8 was dried (HgS04) and evaporated. The residue was recrystallised from ethanol. There was thus obtained 7-amino-4-(3'-methylanilino)-quinazoline (3.39 g), m.p. 196-197~C.
NMR Spectrum: (CD3SOCD3) 2.32 (s, 3H), 5.96 (broad s, 2H), 6.7-6.9 (m, 3H), 7.23 (t, lH), 7.6 (m, 2H), 8.21 (d, lH), 8.38 (s, lH);
Elemental Analysis: Found C, 69.1; H, 6.8; N, 19.0; C15H14N4. C2H5OH
requires C, 69.1; H, 6.8; N, 18.9~~.

The 4-(3'-methylanilino)-7-nitroquinazoline used as a starting material was obtained as follows:-Using an analogous procedure to that described in theportion of Example 1 which is concerned with the preparation of starting materials, 4-nitroanthranilic acid was converted into 4-chloro-7-nitroquinazoline. Using an analogous procedure to that described in Example 1 except that the reactants were stirred together at ambient temperature for 20 minutes, 4-chloro-7-nitroquinazoline was reacted with 3-methylaniline to give 4-(3'-methylanilino)-7-nitro-quinazoline.

Example 8 Using an analogous procedure to that described in Example 7, 4-(3'-methylanilino)-6-nitroquinazoline was reduced to give 6-amino-4-(3'-methylanilino)quinazoline in 43% yield, m.p. 205-206~C.
NMR Spectrum: (CD3SOCD3) 2.32 (s, 3H), 5.6 (broad s, 2H), 6.8 (d, lH), 7.2-7.7 (m, 6H), 8.34 (s, lH);
Elemental Analysis: Found C, 71.7; H, 5.7; N, 22.4; C15H14N4 requires C, 72.0; H, 5.6; N, 22.4%.

The 4-(3'-methylanilino)-6-nitroquinazoline used as a starting material was obtained as follows:-Using an analogous procedure to that described in the firstparagraph of the portion of Example 1 which is concerned with the preparation of starting materials, 5-nitroanthranilic acid was reacted with formamide to give 6-nitroquinazolin-4-one in 82% yield, m.p.
268-271~C.
A mixture of 6-nitroquinazolin-4-one (10 g), phosphorus 2 &~ G~ ~8 pentachloride (16.4 g) and phosphoryl chloride (20 ml) was heated to reflux for 2 hours. The mixture uas cooled to ambient temperature and hexane (700 ml) was added. The mixture was stored at O~C for 16 hours. The precipitate was isolated and partitioned between chloroform (700 ml) and water (550 ml). The aqueous layer was basified by the addition of 2N aqueous sodium hydroxide solution and extracted with chloroform (2 x 200 ml). The combined organic solutions were dried (MgSO4) and evaporated. There was thus obtained 4-chloro-6-nitroquinazoline (1.6 g) which was used without further purification.
3-Methylaniline (0.139 g) was added to a mixture of 4-chloro-6-nitroquinazoline (0.25 g) and isopropanol (5 ml) and the mixture was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained an oil which solidified on trituration under a mixture of diethyl ether and isopropanol. There was thus obtained 4-(3'-methylanilino)-6-nitro-quinazoline (0.09 g, 26%), m.p. 248-249~C.
Hass Spectrum: (P+l) m/e 281.
Elemental Analysis: Found C, 64.0; H, 4.5; N, 18.6;
C15H12N4O2. O.25(CH3)2CHOH requires C, 64.1; H, 4.8; N, 18.9%.

~xample 9 Using an analogous preocedure to that described in Example 7, 4-(3'-chloroanilino)-6-nitroquinazoline was reduced to give 6-amino-4-(3'-chloroanilino)quinazoline in 18% yield, m.p. >150~C
(decomposes).
NMR Spectrum: (CD3SOCD3) 7.27 (m, lH), 7.39 (d, lH), 7.45 (m, 2H), 7.66 (d, lH), 7.74 (d, lH), 7.97 (t, lH), 8.60 (s, lH);
Elemental Analysis: Found C, 56.4; H, 4.5; N, 18.4;
C14HllClN4. 0.5 HCl. 0.5H2O requires C, 56.4; H, 4.2; N, 18.8%.

The 4-(3'-chloroanilino)-6-nitroquinazoline used as a starting material was obtained as follows:-Triethylamine (2.53 g) and 3-chloroaniline (3.35 g) were added in turn to a stirred mixture of 4-chloro-6-nitroquinazoline (5 g) and isopropanol (40 ml). The mixture was stirred and heated to 80~C for 1 hour. The mixture was cooled to ambient temperature and the precipitate was isolated and washed with diethyl ether. There was thus obtained the required starting material (5.09 g), m.p. 272-274~C.

Example 10 Using an analogous procedure to that described in Example 7, 6-nitro-4-(3'-trifluoromethylanilino)quinazoline was reduced to give 6-amino-4-(3'-trifluoromethylanilino)quinazoline in 38% yield, m.p.
190-192~C.
NMR Spectrum: (CD3SOCD3) 5.7 (broad s, 2H), 7.28 (m, lH), 7.38 (d, lH), 7.40 (d, lH), 7.6 (m, 2H), 8.23 (d, lH), 8.35 (s, lH), 8.42 (s, lH);
Elemental Analysis: Found C, 57.4; H, 3.6; N, 17.6;
C15H11F3N4. 0.5H20 requires C, 57.5; H, 3.8; N, 17.9%.

The 6-nitro-4-(3'-trifluoromethylanilino)quinazoline used as a starting material was obtained as follows:-Triethylamine (3.46 g) and 3-trifluoromethylaniline (3.46 g) were added in turn to a stirred mixture of 4-chloro-6-nitroquinazoline (4.5 g) and isopropanol (30 ml). The mixture was heated to 80~C for 1 hour. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained the required starting material (1.76 g), m.p. 206-207~C.

~xaDple 11 Acetic anhydride (0.204 g) was added to a stirred solution of 6-amino-4-(3'-methylanilino)quinazoline (0.5 g) in DMA (5 ml) and the mixture was stirred at ambient temperature for 24 hours. The mixture was evaporated and the residue was recrystallised from a 4:1:2 mixture of isopropanol, acetone and water. There was thus obtained 6-acetamido-4-(3'-methylanilino)quinazoline (0.413 g).

2 0 (~ 8 NMR Spectrum: (CD3SOCD3) 2.12 (s, 3H), 2.33 (s, 3H), 6.93 (d, lH), 7.28 (t, lH), 7.6 (m, 2H), 7.73 (d, lH), 7.84 (m, lH), 8.49 (s, lH), 8.64 (d, lH), 9.68 (s, lH);
Elemental Analysis: Found C, 69.6; H, 5.5; N, 19.1;
C17H16N4O requires 69.8; H, 5.5; N, 19.2%.

Exa~ple 12 Using an analogous procedure to that described in Example 11, 6-amino-4-(3'-chloroanilino)quinazoline was reacted with acetic anhydride to give 6-acetamido-4-(3'-chloroanilino)quinazoline in 50X
yield, m.p. 260-262~C.
NMR Spectrum: (CD3SOCD3) 2.13 (s, 3H), 7.13 (m, lH), 7.39 (t, lH), 7.8 (m, 3H), 8.03 (s, lH), 8.56 (s, lH), 8.66 (d, lH), 9.87 (broad s, lH), 10.24 (broad s, lH);
Elemental Analysis: Found C, 61.2; H, 4.1; N, 18.0;
C16H13ClN4O requires C, 61.4; H, 4.2; N, 17.9%.

~xample 13 2-Methoxyacetyl chloride (0.094 g) was added to a stirred solution of 7-amino-4-(3'-methylanilino)quinazoline (0.206 g) in DMA
(4 ml). The mixture was stirred and heated to 100~C for 1 hour. The mixture was cooled to ambient temperature and poured into a mixture of methylene chloride and water. The mixture was basified to pH 9 by the addition of dilute aqueous sodium hydroxide solution. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially a 100:1 mixture of methylene chloride and ethanol and then increasingly polar mixtures of methylene chloride and ethanol as eluent. There was thus obtained 7-(2-methoxyacetamido)-4-(3'-methylanilino)quinazoline (0.085 g), m.p.
222~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 3.42 (s, 3H), 4.08 (s, 2H), 6.9-7.9 (m, 4H), 8.21 (d, lH), 8.48 (d, lH), 8.52 (s, lH), 9.6 (s, lH), 10.2 (s, lH);
Elemental Analysis: Found C, 66.6; H, 5.7; N, 17.0;
C18H18N4O2. 0.1H2O requires C, 66.7; H, 5.6; N, 17.3%.

2 ~ u 8 Exa~ple 14 Using an analogous procedure to that described in Example 13 except that the reaction mixture was stirred at ambient temperature rather than being heated to 100~C, 6-amino-4-(3'-chloroanilino)-quinazoline was reacted with 2-methoxyacetyl chloride to give 6-(2-methoxyacetamido)-4-(3'-chloroanilino)quinazoline in 41X yield, m.p. 177-180~C.
NHR Spectrum: (CD3SOCD3) 3.44 (s, 3H), 4.09 (s, 2H), 7.17 (m, lH), 7.44 (t, lH), 7.8 (m, 2H), 8.0 (m, 2H), 8.61 (s, lH), 8.71 (d, lH), 9.9 (s, lH), 10.05 (s, lH);
Elemental Analysis: Found C, 59.7; H, 4.4; N, 16.2;
C18H18N402 requires C, 59.6; H, 4.4; N, 16.3%

Example 15 Benzenesulphonyl chloride (0.158 g) was added to a stirred mixture of 7-amino-4-(3'-methylanilino)quinazoline (0.2 g), triethylamine (0.181 g) and methylene chloride (10 ml) which had been cooled to 3~C. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 7-benzenesulphonamido-4-(3'-methylanilino)quinazoline (0.05 g), m.p. 180-185~C (decomposes).
Elemental Analysis: Found C, 61.5; H, 4.8; N, 13.4;
C21H18N402S. H20 requires C, 61.7; H, 4.4; N, 13.7%.

Example 16 2-Bromoethanol (0.109 g) was added to a mixture of 7-amino-4-(3'-methylanilino)quinazoline (0.2 g), potassium carbonate (0.218 g) and DMA (6 ml). The mixture was stirred and heated to 110~C
for 1 hour. Further portions of 2-bromoethanol (3 x 0.109 g) were added periodically and the mixture was heated to 110~C for 5 hours.
The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethanol as eluent. The product so obtained was further purified by reverse phase column chromatography using initally a 25:75:0.2 2 ~ ~ ~J ~ ~ ~

mixture of methanol, water and trifluoroacetic acid and finally a 50:50:0.2 mixture of these solvents as eluent. There was thus obtained 7-(2-hydroxyethylamino)-4-(3'-methylanilino)quinazoline (0.027 g).
NMR Spectrum (CD3SOCD3) 2.36 (s, 3H), 3.77 (t, 2H), 4.34 (t, 2H), 6.8-7.5 (m, 7H), 8.37 (d, lH), 8.61 (s, lH), 10.79 (s, lH).

~xa~ple 17 Using an analogous procedure to that described in Example 16, 6-amino-4-(3'-methylanilino)quinazoline was reacted with 2-bromoethyl methyl ether to give 6-(2-methoxyethylamino)-4-(3'-methylanilino)quinazoline in 20% yield, m.p. 163-167~C.
NMR Spectrum: (CD3SOCD3 + CD3C02D) 2.39 (s, 3H), 3.36 (s, 3H), 3.44 (t, 2H), 3.63 (t, 2H), 7.17 (d, lH), 7.4-7.7 (m, 6H), 8.6 (s, lH);
Elemental Analysis: Found C, 56.4; H, 5.0; N, 13.1;
C18H20N4O. CF3C02H requires C, 56.8; H, 5.0; N, 13.3X.

~xa~ple 18 Using an analogous procedure to that described in Example 7, 7-(3-dimethylaminopropylamino)-4-(3'-methylanilino)-6-nitroquinazoline was reduced to give 6-amino-7-(3-dimethylaminopropylamino)-4-(3'-methylanilino)quinazoline in 56% yield, m.p. 60-66~C.
NMR Spectrum: (CD3SOCD3) 1.84 (m, 2H), 2.28 (s, 6H), 2.30 (s, 3H), 2.31 (m, 2H), 3.23 (m, 2H), 6.58 (s, lH), 6.81 (d, lH), 7.19 (t, lH), 7.31 (s, lH), 7.63 (m, 2H), 8.24 (s, lH);
Elemental Analysis: Found C, 66.5; H, 7.6; N, 22.8;
C20H26N6. 0.66H2O requires C, 66.3; H, 7.6; N, 23.2%.

The 7-(3-dimethylaminopropylamino)-4-(3'-methylanilino)-6-nitroquinazoline used as a starting material was obtained as follows:-A mixture of 4-chloroanthranilic acid (17.2 g) and formamide (10 ml) was stirred and heated to 130~C for 45 minutes and to 175~C
for 75 minutes. The mixture was allowed to cool to approximately 100~C and 2-(2-ethoxyethoxy)ethanol (50 ml) was added. The solution 2~oû~v8 so formed was poured into a mixture (250 ml) of ice and water. The precipitate was isolated, washed with water and dried. There was thus obtained 7-chloroquinazolin-4-one (15.3 g, 85%).
A portion (6 g) of the material so obtained was added portionwise to a stirred mixture of concentrated sulphuric acid (12 ml) and fuming nitric acid (12 ml). The mixture was heated to 110~C
for 30 minutes. The mixture was cooled to ambient temperature and poured onto ice. The solid was isolated, washed with water and dried.
There was thus obtained 7-chloro-6-nitroquinazolin-4-one (6.89 g, 92X).
A mixture of a portion (4 g) of the material so obtained, thionyl chloride (30 ml), phosphoryl chloride (5 ml) and DMF (10 drops) was stirred and heated to reflux for 4 hours. The mixture was evaporated. A mixture of the residue, 3'-methylaniline (1.89 g) and isopropanol (25 ml) was stirred and heated to reflux for 2 hours. The mixture was filtered and the solid was washed with isopropanol and with diethyl ether. There was thus obtained 7-chloro-4-(3'-methyl-anilino)-6-nitroquinazoline (3.74 g, 67%), m.p. 271-274~C.
NHR Spectrum: (CD3SOCD3) 2.37 (s, 3H), 7.13 (d, lH), 7.47 (t, lH), 7.57 (m, 2H), 8.20 (s, lH), 8.83 (s, lH), 9.72 (s, lH).
3-Dimethylaminopropylamine (2.44 g) was added to a stirred solution of a portion (0.75 g) of the material so obtained in DMA (20 ml). The mixture was heated to 70~C for 1 hour and to 90~C for a further hour. The mixture was evaporated. The residue was triturated under water to give a solid. The solid was taken into hot methanol.
Water was added and the solution was allowed to cool. The resultant precipitate was isolated and dried. There was thus obtained 7-(3-dimethylaminopropylamino)-4-(3'-methylanilino)-6-nitroquinazoline (0.47 g, 52%), m.p. 112-118~C.
NMR Spectrum: (CD3SOCD3) 1.61 (m, 2H), 2.2-2.3 (3 s's, 9H), 2.39 (t, 2H), 3.39 (m, 2H), 6.93 (s, lH), 6.96 (d, lH), 7.27 (t, lH), 7.61 (s, lH), 7.63 (d, lH), 8.36 (t, lH), 8.42 (s, lH), 9.50 (s, lH), 10.07 (broad s, lH).

Example 19 A mixture of 6,7-dimethoxy-4-(3'-methylanilino)quinazoline - 56 - 2&~ 8 (4 g), sodium ethanethiolate (9.8 g) and DMF (100 ml) uas stirred and heated to 80~C for 6 hours. The mixture was cooled and poured into a mixture of ethyl acetate and water. The mixture was acidified to pH7 by the addition of dilute aqueous hydrochloric acid. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. The oil so obtained was triturated under diethyl ether to give a solid. There was thus obtained 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (1.02 g), m.p.
139-149~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3.97 (s, 3H), 6.90 (m, lH), 7.05 (s, lH), 7.26 (m, lH), 7.5-7.7 (m, 2H), 7.84 (s, lH), 8.39 (s, lH), 9.34 (broad s, lH);
Elemental Analysis: Found C, 66.5; H, 5.7; N, 13.7;
C16H15N302. 0.15Et20. 0.5H2O requires C, 66.3; H, 5.5; N, 14.0%.

example 20 A mixture of 6,7-dimethoxy-4-(3'-methylanilino)quinazoline (4 g), sodium ethanethiolate (9.8 g) and DMF (100 ml) was stirred and heated to 80~C for 3 hours. The mixture was cooled to ambient temperature and acidified to pH4 by the addition of glacial acetic acid. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-hydroxy-7-methoxy-4-(3'-methylanilino)quinazoline (0.3 g), m.p.
265-267~C.
NMR Spectrum: (CD3SOCD3) 2.32 (s, 3H), 3.97 (s, 3H), 6.90 (m, lH), 7.15-7.30 (m, 2H), 7.66 (m, 2H), 7.80 (s, lH), 8.41 (s, lH), 9.24 (broad s, lH), 9.53 (broad s, lH);
Elemental Analysis: Found C, 65.2; H, 5.2; N, 14.0;
C16H15N3O2. 0.67H20 requires C, 65.5; H, 5.6; N, 14.3Z.

example 21 Ethyl bromoacetate (0.033 g) was added dropwise to a stirred mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.05 g), potassium carbonate (0.074 g) and DHF (1 ml). The mixture was 2 0 ~ û ~' u 3 stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 7-(ethoxycarbonylmethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.051 g), m.p. 165-168~C.
NMR Spectrum: (CD3SOCD3) 1.24 (t, 3H), 2.35 (s, 3H), 3.99 (s, 3H), 4.99 (q, 2H), 4.33 (s, 2H), 6.9-7.9 (m, 6H), 8.43 (s, lH), 9.40 (s, lH);
Elemental Analysis: Found C, 64.8; H, 5.9; N, 10.9;
C20H21N304. 0.2H20 requires C, 64.7; H, 5.8; N, 11.3%.

Example 22 The procedure described in Example 21 was repeated except that 2-iodoacetamide was used in place of ethyl bromoacetate. There was thus obtained 7-(carbamoylmethoxy)-6-methoxy-4-(3'-methylanilino)-quinazoline in 91X yield, m.p. 214-222~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3.99 (s, 3H), 4.65 (s, 2H), 6.9-7.9 (m, 6H), 8.45 (s, lH);
Elemental Analysis: Found C, 47.8; H, 4.9; N, 11.9;
C18H18N403. O.lHI requires C, 47.5; H, 4.8; N, 12.3%.

Example 23 A mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)-quinazoline (0.556 g), 2-bromoethanol (0.153 ml), potassium carbonate (0.819 g) and DMF (10 ml) was stirred and heated to 80~C for 3 hours.
The mixture was evaporated and the residue was purified by column chromatography using a 19:1 mixture of ethyl acetate and methanol as eluent. The product was further purified by reverse phase chromatography using a 50:50:0.2 mixture of methanol, water and trifluoroacetic acid as eluent. There was thus obtained 7-(2-hydroxyethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.154 g), m.p. 122-124~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3.81 (m, 2H), 3.97 (s, 3H), 4.17 (t, 2H), 6.9-7.9 (m, 6H), 8.45 (s, lH);
Elemental Analysis: Found C, 52.9; H, 4.9; N, 8.7;
C18H1gN303. 1.1CF3C02H. 0.5H20 requires C, 52.7; H, 4.6; N, 91%.

. CA 02086968 1997-06-18 ~V~J~

Example 24 The procedure described in Example 21 was repeated except that 2-bromoethyl methyl ether was used in place of ethyl bromoacetate and that the reaction mixture was stirred at ambient temperature for 16 hours. There was thus obtained 6-methoxy-7-(2-methoxyethoxy)-4-(3'-methylanilino)quinazoline as a colourless oil. The oil was dissolved in ethyl acetate (2 ml) and a saturated solution of hydrogen chloride in diethyl ether was added. There was thus obtained the hydrochloride salt of the product in an overall yield of 73%, m.p.
211-227~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3.34 (s, 3H), 3.78 (q, 2H), 4.01 (s, 3H), 4.31 (q, 2H), 6.9-7.6 (m, 5H), 8.23 (s, lH), 8.75 (s, lH);
Elemental Analysis: Found C, 61.2; H, 6.0; N, 10.9;
C1gH21N3O3. 0.9 HCl requires C, 61.2; H, 5.9; N, 11.3X.

Exanple 25 A mixture of 7-(ethoxycarbonylmethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.262 g), 2N aqueous sodium hydroxide solution (2 ml) and 1,4-dioxan (2 ml) was stirred at ambient temperature for 3 hours. The mixture was acidified by the addition of 2N aqueous hydrochloric acid and the acidity was reduced to pH6 by the addition of aqueous ammonium hydroxide solution. The precipitate was isolated and dried. There was thus obtained 7-(carboxymethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.159 g), m.p. 215-222~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 3.95 (s, 3H), 4.33 (s, 2H), 6.9-7.9 (m, 6H), 8.41 (s, lH);
Elemental Analysis: Found C, 53.5; H, 5.0; N, 10.5;
C18H16NaN3O4. 2.3H2O requires C, 53.6; H, 5.1; N, 10.4%.

Exanple 26 A mixture of 7-(2-hydroxyethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.23 g), DMF (1 drop) and thionyl chloride (5 ml) was heated to reflux for 2 hours. The mixture was evaporated.
The residue was dissolved in DMF (3 ml) and the solution was ~ûou~ S8 saturated with dimethylamine gas. The solution was stirred and heated to 100~C for 3 hours. The mixture was evaporated and the residue was purified by reverse phase column chromatography using a 50:50:0.2 mixture of methanol, water and trifluoroacetic acid as eluent. There was thus obtained 7-(2-dimethylaminoethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.24 g), m.p. 97-100~C.
NHR Spectrum: (CD3SOCD3) 2.37 (s, 3H), 2.93 (s, 6H), 3.66 (t, 2H), 3.98 (s, 3H), 4.57 (t, 2H), 7.1-8.2 (m, 6H), 8.78 (s, lH), 10.82 (s, lH~;
Elemental Analysis: Found C, 46.4; H, 4.2; N, 8.8;
C20H24N402. 2.6CF3C02H requires C, 46.6; H, 4.1; N, 8.6%.

exanple 27 2-Iodoethanol (0.327 ml) was added to a mixture of 6,7-dihydroxy-4-(3'-methylanilino)quinazoline (0.534 g), potassium carbonate (1.1 g) and DHA (10 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was purified by reverse phase column chromatography using a 50:50:0.2 mixture of methanol, water and trifluoroacetic acid as eluent. There was thus obtained 6,7-di-(2-hydroxyethoxy)-4-(3'-methylanilino)quinazoline (0.049 g), m.p. 96-102~C.
NHR Spectrum: (CD3SOCD3) 2.37 (s, 3H), 3.85 (m, 4H), 4.23 (m, 4H), 7.05-7.55 (m, 5H), 8.06 (s, lH), 8.76 (s, lH), 10.78 (broad s, lH);
Elemental Analysis: Found C, 49.2; H, 4.5; N, 7.9;
C1gH21N304. 1.6CF3C02H requires C, 49.5; H, 4.2; N, 7.8%.

The 6,7-dihydroxy-4-(3'-methylanilino)quinazoline used as a starting material was obtained in 77% yield from 6,7-dimethoxy-4-(3'-methylanilino)quinazoline using an analogous procedure to that described in Example 4.

exanple 28 A solution of 6-bromomethyl-4-(3'-methylanilino)quinazoline in DHF (3 ml) was saturated with dimethylamine gas and the resultant solution was stirred at ambient temperature for 16 hours. The mixture 2 ~

was evaporated and the residue was purified by column chromatography using a 17:3 mixture of methylene chloride and methanol as eluent.
The resultant solid (0.308 g) was further purified by reversed-phase column chromatography using a 3:2:0.01 mixture of water, methanol and trifluoroacetic acid as eluent. There was thus obtained 6-dimethylaminomethyl-4-(3'-methylanilino)quinazoline (0.172 g), m.p.
174-177~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 2.85 (s, 6H), 4.47 (s, 2H), 7.0-8.1 (m, 6H), 8.66 (d, lH), 8.85 (s, lH);
Elemental Analysis: Found C, 49.2; H, 4.2; N, 10.4;
C18H20N4. 2.25CF3CO2H requires C, 49.2; H, 4.1; N, 10.2%.

Example 29 Using an analogous procedure to that described in Example 28, 6-bromomethyl-4-chloroquinazoline was reacted with 3-methylaniline and the product so formed was reacted with piperazine. There was thus obtained 4-(3'-methylanilino)-6-(piperazin-1-ylmethyl)quinazoline in 45Z yield, m.p. 175-178~C.
NMR Spectrum: (CD3SOCD3) 2.38 (s, 3H), 2.73 (m, 4H), 3-17 (m, 4H), 3.86 (s, 2H), 7.1-8.1 (m, 6H), 8.66 (d, lH), 8.90 (s, lH);
Elemental Analysis: Found C, 43.0; H, 3.7; N, 9.0;
C20H23N5. 3.9CF3CO2H requires C, 42.9; H, 3.5; N, 9.0%.

~xaDple 30 Using an analogous procedure to that described in Example 28, 6-bromomethyl-4-chloroquinazoline (0.5 g) was reacted with 3-methylaniline (0.204 g) . A mixture of the product so formed and the sodium salt of 2-mercaptoethanol Iprepared by the reaction of 2-mercaptoethanol (0.38 g) with sodium hydride (60% dispersion in mineral oil, 0.17 g) in DMA (5 ml)] was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by reverse phase column chromatography using an 11:9:0.04 mixture of methanol, water and trifluoroacetic acid as eluent. There was thus obtained 6-(2-hydroxyethylthiomethyl)-4-(3'-methylanilino)quinazoline (0.38 g), m.p. 93-94~C.
NMR Spectrum: (CD3SOCD3) 2.37 (s, 3H), 2.52 (m, 2H), 3.56 (m, 2H), ~ CA 02086968 1997-06-18 2 ~

3.98 (s, 2H), 7.1-8.1 (m, 6H), 8.60 (d, lH), 8.84 (s, lH);
Elemental Analysis: Found C, 54.1; H, 4.5; N, 9.3;
C18H19N3OS. l.lCF3CO2H requires C, 53.8; H, 4.5; N, 9.3%.

Example 31 A mixture of 7-methoxycarbonyl-4-(3'-methylanilino)-quinazoline (1.3 g) and 2N aqueous sodium hydroxide solution (10 ml) was stirred and heated to 40~C for 4 hours. The mixture was cooled to ambient temperature and acidified to pH6 by the addition of glacial acetic acid. The precipitate was isolated, washed with water and dried. There was thus obtained 7-carboxy-4-(3'-methylanilino)-quinazoline (1.16 g), m.p. >280~C.
NMR Spectrum: (CD3SOCD3) 2.36 (s, 3H), 6.98 (d, lH), 7.29 (t, lH), 7.66 (m, 2H), 8.18 (m, lH), 8.28 (d, lH), 8.64 (s, lH), 8.66 (d, lH), 9.88 (s, lH);
Elemental Analysis: Found C, 67.3; H, 4.8; N, 14.8;
C16H13N3O2. 0.3H2O requires C, 67.3; H, 4.8; N, 14.7%.

Example 32 Ethyl chloroformate (0.146 g) and triethylamine (0.162 g) were added in turn to a stirred mixture of 7-carboxy-4-(3'-methylanilino)quinazoline (0.3 g) and THF (5 ml). The mixture was stirred at ambient temperature for 1 hour. Sodium borohydride (0.123 g) was added and the mixture was stirred at ambient temperature for 2 hours. The mixture was acidified by the addition of 2N aqueous hydrochloric acid and evaporated. The residue was dissolved in water and extracted with methylene chloride. The aqueous phase was basified to pH9 by the addition of a saturated aqueous ammonium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 7-hydroxymethyl-4-(3'-methylanilino)quinazoline (0.125 g), m.p. 175-177~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 4.70 (d, 2H), 5.45 (t, lH), 6.96 (d, lH), 7.2-7.7 (m, 5H), 8.50 (s, lH), 8.57 (s, lH), 9.64 (s, lH);

. CA 02086968 1997-06-18 ~OS~3 Elemental Analysis: Found C, 72.2; H, 5.8; N, 15.8;
C16H15N30 requires C, 72.4; H, 5.7; N, 15.8%.

~xample 33 Using an analogous procedure to that described in Example 11, 6-amino-4-(3'-trifluoromethylanilino)quinazoline was reacted with acetic anhydride to give 6-acetamido-4-(3'-trifluoromethylanilino)-quinazoline in 87% yield as a solid.
NMR Spectrum: (CDSOCD3) 2.14 (s, 3H), 7.45 (d, lH), 7.64 (t, lH), 7.78 (d, lH), 7.87 (m, lH), 8.18 (d, lH), 8.26 (s, lH), 8.60 (s, lH), 8.73 (d, lH);
Elemental Analysis: Found C, 58.7; H, 3.9; N, 16.1;
C17H13F3N40 requires C, 59.0; H, 3.8; N, 16.5%.

~xample 34 Using an analogous procedure to that described in Example 1, the appropriate substituted 4-chloroquinazoline was reacted with the appropriate aniline to give, as hydrochloride salts, the compounds described in the following table, the structures of which were confirmed by proton magnetic resonance spectroscopy and by elemental analysis.

. CA 02086968 1997-06-18 - 63 - 2a~ 8 TABLE III

~ ( R2 )n H N/~J

N ~ \~
ll ¦ ( R ) m HN/\~

Example 34 (Rl)m (R2)n ~.p.
Compd. No. (~C) la 6-methoxy 3'-methyl 236-240 2b 6-methoxy 3'-chloro 261-265 3c 6-hydroxy 3'-methyl 150-156 4d 6-trifluoromethyl 3'-methyl >300 5e 6,7-dimethoxy 3'-chloro-4'-fluoro >240 6f 6,7-dimethoxy 3'-chloro-4'-cyano >240 7g 6,7-dimethoxy 3',4'-dichloro >240 8h 6,7-dimethoxy 3'-nitro >240 9i 6,7-dimethoxy hydrogen 234-236 lOi 6,7-dimethoxy 4'-chloro-3'-nitro >240 llk 6,7-dimethoxy 4'-fluoro-3'-nitro >240 . CA 02086968 1997-06-18 2 ~

Notes a. The product gave the following analytical data: Found C, 63.1; H, 5.2; N, 13.5; C16H15N30. l.lHCl requires C, 62.9; H, 5.3; N, 13.8X; and the following characteristic NMR data: (CD3SOCD3) 2.37 (s, 3H), 4.01 (s, 3H), 7.16 (d, lH), 7.38 (m, lH), 7.52 (s, 2H), 7.73 (m, lH), 7.94 (d, lH), 8.43 (d, lH), 8.84 (s, lH), 11.63 (s, lH).

The 4-chloro-6-methoxyquinazoline used as a starting material was obtained from 5-methoxyanthranilic acid using analogous procedures to those described in the portion of Example 1 which is concerned with the preparation of starting materials.
The 5-methoxyanthranilic acid used as a starting material was obtained as follows:-A mixture of 5-chloro-2-nitrobenzoic acid (60.5 g) and thionyl chloride (113 ml) was stirred and heated to reflux for 4 hours. The mixture was evaporated. The material so obtained was added to a solution obtained by adding sodium (15.2 g) to methanol (250 ml). The mixture was heated to reflux for 4 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained methyl 5-methoxy-2-nitrobenzoate as an oil (22.5 g).
A mixture of the material so obtained, 10%
palladium-on-charcoal catalyst (2.1 g), ethanol (200 ml) and ammonium formate (25.2 g) was stirred and heated to 70~C for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and a dilute aqueous sodium bicarbonate solution. The organic layer was dried (MgS04) and evaporated to give methyl 2-amino-5-methoxybenzoate (15.2 g).
A mixture of the material so obtained, 2N aqueous sodium hydroxide solution (150 ml) and 1,4-dioxan (50 ml) was stirred and heated to 40~C for 3 hours. The bulk of the 1,4-dioxan was evaporated, the aqueous residue was acidified to pH4 by the addition of concentrated hydrochloric acid and the solution was extracted with . CA 02086968 1997-06-18 ~ô~ 8 ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 5-methoxyanthranilic acid (14.1 g).

b. The reaction mixture was heated to reflux for 3 hours. The product gave the following analytical data: Found C, 55.4; H, 4.0; N, 12.8; C15H12ClN3O. l.lHCl requires C, 55.2; H, 4.0; N, 12.9X; and the following characteristic NMR data: (CD3SOCD3) 4.02 (s, 3H), 7.37 (m, lH), 7.53 (m, lH), 7.67 (m, 2H), 7.95 (m, 2H), 8.51 (d, lH), 8.91 (s, lH), 11.62 (s, lH).

c. 6-Acetoxy-4-chloroquinazoline was used as the appropriate quinazoline and the reaction mixture was heated to reflux for 2.5 hours. The product gave the following analytical data: Found C, 58.6; H, 5.3; N, 13.4; C15H13N30. lHCl. 1H2O requires C, 58.9; H, 5.2; N, 13.7X;
and the following characteristic NMR data:
(CD3SOCD3) 2.36 (s, 3H), 7.14 (d, lH), 7.36 (t, lH), 7.51 (d, 2H), 7.72 (m, lH), 7.90 (d, lH), 8.07 (d, lH), 8.78 (s, lH), 10.42 (s, lH), 11.22 (s, lH).
The 6-acetoxy-4-chloroquinazoline used as a starting material was obtained as follows:-Using an analogous procedure to that described in theportion of Example 1 which is concerned with the preparation of starting materials, 5-hydroxyanthranilic acid was converted into 6-hydroxyquinazolin-4-one. Acetic anhydride (1.38 g) was added dropwise to a mixture of 6-hydroxyquinazolin-4-one (2 g), triethylamine (1.37 g) and DMF (60 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-acetoxyquinazolin-4-one which was reacted with thionyl chloride using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials.

d. The product gave the following analytical data: Found C, 54.1; H, 3.7; N, 11.7; C16H12F3N30. lHCl requires C, 54.0; H, 3.7; N, 11.8%;

2 ~ 8 and the following characteristic NMR data: (CD3SOCD3) 2.37 (s, 3H), 7.17 (s, lH), 7.38 (t, lH), 7.51 (d, 2H), 8.07 (m, 2H), 8.91 (m, 2H), 11.45 (s, lH).
The 4-chloro-6-trifluoromethoxyquinazoline used as a starting material was obtained from 5-trifluoromethoxyanthranilic acid using analogous procedures to those described in the portion of Example 1 which is concerned with the preparation of starting materials.

e. The reaction mixture was heated to reflux for 2 hours. The product gave the following analytical data: Found C, 51.7; H, 3.7; N, 11.1; C16H13ClFN3O2. lHCl requires C, 51.9; H, 3.8; N, 11.4X;
and the following characteristic NMR data: (CD3SOCD3) 4.01 (s, 3H), 4.04 (s, 3H), 7.45 (s, lH), 7.59 (t, lH), 7.84 (m, lH), 8.1 (m, lH), 8.51 (s, lH), 8.93 (s, lH), 11.74 (s, lH).

f. The reaction mixture was heated to reflux for 2 hours. The product gave the following characteristic NMR data: (CD3SOCD3) 4.04 (s, 3H), 4.08 (s, 3H), 7.35 (s, lH), 7.91 (s, lH), 8.03 (d, lH), 8.18 (m, lH), 8.47 (d, lH), 8.74 (s, lH), 9.93 (s, lH).

g. The reaction mixture was heated to reflux for 2 hours. The product gave the following analytical data: Found C, 49.7; H, 3.7; N, 11.0; C16H13C12N302. lHCl requires C, 49.7; H, 3.65; N, 10.9X;
and the following characteristic NMR data: (CD3SOCD3) 4.01 (s, 3H), 4.04 (s, 3H), 7.36 (s, lH), 7.74 (m, lH), 7.83 (m, lH), 8.17 (d, lH), 8.38 (s, lH), 8.91 (s, lH), 11.55 (s, lH).

h. The reaction mixture was heated to reflux for 2 hours. The product gave the following analytical data: Found C, 53.1; H, 4.2; N, 15-3; C16H14N4O4 lHCl requires C, 53.0; H, 4.2; N, 15.4%;
and the following characteristic NMR data: (CD3SOCD3) 4.0 (s, 3H), 4.04 (s, 3H), 7.37 (s, lH), 7.75 (t, lH), 8.11 (m, lH), 8.33 (m, lH), 8.40 (s, lH), 8.74 (m, lH), 8.88 (s, lH), 11.58 (s, lH).

i. The reaction mixture was heated to reflux for 3 hours. The . CA 02086968 1997-06-18 - 67 - 20S~v8 product gave the following analytical data: Found C, 59.1; H, 5.0; N, 12-7; C16H15N3O2. lHCl- 0-35H20 requires C, 59.3; H, 5.2; N, 13.0X;
and the following characteristic NMR data:
(CD3SOCD3) 3.99 (s, 3H), 4.02 (s, 3H), 7.1-7.6 (m, 4H), 7.68-7.75 (m, 2H), 8.43 (s, lH), 8.80 (s, lH).

j. The reaction mixture was heated to reflux for 2 hours. The product gave the following analytical data: Found C, 48.3; H, 3.5; N, 13.5;
C16H13ClN4O4. lHCl requires C, 48.4; H, 3.5; N, 14.1%;
and the following characteristic NMR data:
(CD3SOCD3) 4.01 (s, 3H), 4.05 (s, 3H), 7.34 (s, lH), 7.86 (d, lH), 7.88 (d, lH), 8.23 (m, lH), 8.48 (s, lH), 8.64 (d, lH), 8.94 (s, lH), 11.87 (s, lH).

k. The product gave the following analytical data: Found C, 50.7; H, 3.4; N, 14.2; C16H13FN4O4. lHCl requires C, 50.5; H, 3.7; N, 14.7X; and the following characteristic NMR data: (CD3SOCD3) 4.0 (s, 3H), 4.04 (s, 3H), 7.40 (s, lH), 7.71 (m, lH), 8.29 (m, lH), 8.50 (s, lH), 8.65 (m, lH), 8.92 (s, lH), 11.9 (broad s, lH).

Example 35 3-Methylaniline (0.123 g) was added dropwise to a stirred solution of 6-bromomethyl-4-chloroquinazoline (0.3 g) in DMF (3 ml).
The mixture was stirred at ambient temperature for 2 hours. Diethyl ether (10 ml) was added and the precipitate was isolated. There was thus obtained 6-bromomethyl-4-(3'-methylanilino)quinazoline in 32X
yield, m.p. >260~C (decomposes);
NMR Spectrum: (CD3SOCD3) 2.37 (s, 3H), 4.98 (s, 2H), 7.17 (d, lH), 7.39 (t, lH), 7.53 (m, 2H), 7.95 (d, lH), 8.15 (m, lH), 8.93 (s, lH), 8.96 (d, lH), 11.59 (broad s, lH);
Elemental Analysis: Found C, 56.5; H, 4.6; N, 12.3;
C16H14BrN3. 0.25HCl requires C, 56.9; H, 4.3; N, 12.4%.

The 6-bromomethyl-4-chloroquinazoline used as a starting material was obtained as described in Note g. below Table II in 2~g~J~8 Example 6.

Exanple 36 Using an analogous procedure to that described in Example 7, 6,7-dimethoxy-4-(3'-methylanilino)-5-nitroquinazoline was reduced to give 5-amino-6,7-dimethoxy-4-(3'-methylanilino)quinazoline which was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained the required product in 55% yield, m.p. 181-182~C.
NHR Spectrum: (CD3SOCD3) 2.30 (s, 3H), 3.70 (s, 3H), 3.86 (s, 3H), 6.51 (s, lH), 6.86 (d, lH), 7.10 (m, 2H), 7.19 (t, lH), 7.90 (s, lH);
Elemental Analysis: Found C, 65.4; H, 5.9; N, 17.6;
C17H18N402. 0.15H2O requires C, 65.2; H, 5.8; N, 17.9%.

The 6,7-dimethoxy-4-(3'-methylanilino)-5-nitroquinazoline used as a starting material was obtained as follows:-6,7-Dimethoxyquinazolin-4-one (10 g) was added portionwise to a stirred mixture of concentrated sulphuric acid (30 ml) and fuming nitric acid (30 ml) which had been cooled to 0~C. The mixture was stirred at ambient temperature for 1 hour. The mixture was poured onto a mixture of ice and water (500 ml). The precipitate was isolated, washed with water and dried. There was thus obtained 6,7-dimethoxy-5-nitroquinazolin-4-one (9.51 g).
Using analogous procedures to those described in Example 1, the compound so obtained was converted into 6,7-dimethoxy-4-(3'-methylanilino)-5-nitroquinazoline in 71% yield, m.p. 151-155~C.
NHR Spectrum: (CD3SOCD3) 2.30 (s, 3H), 3.86 (s, 3H), 4.02 (s, 3H), 6.75 (m, 2H), 6.88 (d, lH), 7.22 (t, lH), 7.28 (s, lH), 7.85 (s, lH).

Example 37 Using an analogous procedure to that described in Example 7, except that the reaction mixture was heated to 70~C for 2 hours, 4-(3'-methylanilino)-7-methylthio-6-nitroquinazoline was reduced to 6-amino-4-(3'-methylanilino)-7-methylthioquinazoline which was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus 2G~S8 obtained the required product in 22X yield, m.p. 217-218~C.
NMR Spectrum: (CD3SOCD3) 2.33 (s, 3H), 2.59 (s, 3H), 5.34 (broad s, 2H), 6.90 (d, lH), 7.24 (t, lH), 7.44 (s, lH), 7.50 (s, lH), 7.63 (s, 2H), 8.47 (s, lH);
Elemental Analysis: Found C, 64.8; H, 5.4; N, 18.7;
C16H16N4S requires C, 64.8; H, 5.4; N, 18.9%.

The 4-(3'-methylanilino)-7-methylthio-6-nitroquinazoline used as a starting material was obtained as follows:-A mixture of 4-chloroanthranilic acid (17.2 g) and formamide (10 ml) was stirred and heated to 130~C for 45 minutes and to 175~C
for 75 minutes. The mixture was allowed to cool to approximately 100~C and 2-(2-ethoxyethoxy)ethanol (50 ml) was added. The solution so formed was poured into a mixture (250 ml) of ice and water. The precipitate was isolated, washed with water and dried. There was thus obtained 7-chloroquinazolin-4-one (15.3 g, 85%).
After repetition of this reaction, 7-chloroquinazolin-4-one (30 g) was added portionwise to a stirred mixture of concentrated sulphuric acid (60 ml) and fuming nitric acid (60 ml) which had been cooled to 0~C. The mixture was stirred at ambient temperature for 1 hour and then heated to 110~C for 30 minutes. The mixture was cooled to ambient temperature and poured onto a mixture of ice and water (lL). The precipitate was isolated, washed with water and dried.
There was thus obtained 7-chloro-6-nitroquinazolin-4-one (38.1 g).
Using analogous procedures to those described in Example 1, the material so obtained was converted into 7-chloro-4-(3'-methylanilino)-6-nitroquinazoline in 59% yield, m.p.
271-274~C.
A portion (0.9 g) of the material so obtained was dissolved in DMA (15 ml). Sodium methanethiolate (0.44 g) was added and the mixture was stirred at ambient temperature for 1 hour. Them mixture was acidified by the addition of glacial acetic acid. The mixture was evaporated and the residue was triturated under methylene chloride.
The solid so obtained was partitioned between methylene chloride and a dilute aqueous ammonium hydroxide solution. The organic layer was dried (MgS04) and evaporated to give 4-(3'-methylanilino)-7-methyl-2D 3 ~8 thio-6-nitroquinazoline (0.473 g), m.p. 230-231~C.
NHR Spectrum: (CD3SOCD3) 2.33 (s, 3H), 2.63 (s, 3H), 6.97 (d, lH), 7.28 (t, lH), 7.61 (s, lH), 7.63 (m, 2H), 8.63 (s, lH), 9.70 (s, lH);
Elemental Analysis: Found C, 58.6; H, 4.6; N, 17.2;
C16H14N4O2S requires C, 58.8; H, 4.3; N, 17.1%.

Esample 38 A mixture of 7-methoxy-4-(3'-methylanilino)-6-nitroquinazoline (0.4 g), 10% palladium-on-charcoal catalyst (0.06 g), DHF (5 ml) and ethanol (20 ml) was stirred under an atmosphere pressure of hydrogen for 5 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on reversed-phase silica using decreasingly polar mixtures of methanol, water and trifluoroacetic acid as eluent. There were thus obtained in turn:-6-hydroxyamino-7-methoxy-4-(3'-methylanilino)quinazoline (0.038 g), m.p. 130-147~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 4.02 (s, 3H), 7.12 (d, lH), 7.19 (s, lH), 7.34 (t, lH), 7.48 (m, 2H), 8.10 (s, lH), 8.70 (s, lH);
Elemental Analysis: Found C, 44.0; H, 3.5; N, 10.5;
C16H16N4O2. lH2O. 2CF3CO2H requires C, 44.3; H, 3.7; N, 10.7%; and 6-amino-7-methoxy-4-(3'-methylanilino)quinazoline (0.049 g), m.p.
85-95~C.
NMR Spectrum: (CD3SOCD3) 2.36 (s, 3H), 4.03 (s, 3H), 7.12 (d, lH), 7.18 (s, lH), 7.35 (t, lH), 7.45 (m, 2H), 7.62 (s, lH), 8.69 (s, lH);
Elemental Analysis: Found C, 52.3; H, 4.0; N, 13.0;
C16H16N4O. 1.3CF3CO2H requires C, 52.1; H, 4.0; N, 13.1%.

The 7-methoxy-4-(3'-methylanilino)-6-nitroquinazoline used as a starting material was obtained as follows:-7-Chloro-4-(3'-methylanilino)-6-nitroquinazoline (0.35 g) was added portionwise to a methanolic solution of sodium methoxide [prepared by the addition of sodium (0.055 g) to methanol (5 ml)].
The mixture was stirred and heated to reflux for 1 hour. A second portion of sodium (0.069 g) was added and the mixture was heated to reflux for 5 hours. The mixture was evaporated and the residue was 2iS3~ô8 ' purified by column chromatography on reversed-phase silica using initially a 50:50:0.2 mixture of water, methanol and trifluoroacetic acid and then decreasingly polar mixtures of water, methanol and trifluoroacetic acid as eluent. There was thus obtained 7-methoxy-4-(3'-methylanilino)-6-nitroquinazoline (0.81 g), m.p.
149-154~C.

Example 39 1,2-Dibromoethane (10.9 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (2.5 g), potassium carbonate (3.69 g) and DMF (60 ml). The mixture was stirred at ambient temperature for 30 minutes and then heated to 80~C for 2 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 7-(2-bromoethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (2.8 g), m.p. 86-89~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3-89 (t, 2H), 3-99 (s, 3H), 4.51 (t, 2H), 7.21 (s, lH), 7.28 (t, lH), 7.58 (s, lH), 7.62 (d, lH), 7.88 (s, lH), 8.46 (s, lH), 8.94 (d, lH), 9.46 (s, lH);
Elemental Analysis: Found C, 55.7; H, 5.9; N, 11.9;
C18H18Br N3O2. 0.9DMF requires C, 55.5; H, 5.6; N, 11.7%.

Exa~ple 40 A mixture of 7-(2-bromoethoxy)-6-methoxy-4-(3'-methyl-anilino)quinazoline (0.25 g) and aniline (4 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 7-(2-anilinoethoxy)-6-methoxy-4-(3'-methylanilino)-quinazoline (0.169 g), m.p. 160-162~C.
NMR Spectrum: (CD3SOCD3) 2-35 (s, 3H), 3.51 (m, 2H), 3.97 (s, 3H), 4.30 (t, 2H), 6.58 (t, lH), 6.66 (d, 2H), 6.94 (d, lH), 7.12 (t, 2H), 7.20 (s, lH), 7.28 (t, lH), 7.58 (s, lH), 7.63 (d, lH), 7.87 (s, lH), 8.48 (s, lH), 9.50 (s, lH);

2 0 ~ ~ J ~8 Elemental Analysis: Found C, 69.6; H, 6.2; N, 13.6;
C24H24N4O2. 0.75H2O requires C, 69.6; H, 6.2; N, 13.5%.

Exanple 41 A mixture of 7-(2-bromoethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.25 g) and morpholine (4 ml) was stirred at ambient temperature for 4 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a dilute aqueous sodium bicarbonate solution. The organic phase was dried (MgS04) and evaporated. The residue was triturated under diethyl ether to give 6-methoxy-4-(3'-methylanilino)-7-(2-morpholino-ethoxy)quinazoline (0.198 g), m.p. 168-170~C.
NHR Spectrum: (CD3SOCD3 + CD3CO2D) 2.35 (s, 3H), 3.15 (t, 4H), 3.81 (t, 4H), 3.96 (s, 3H), 6.93 (d, lH), 7.21 (s, lH), 7.26 (t, lH), 7.58 (s, lH), 7.63 (d, lH), 7.84 (s, lH), 8.44 (s, lH), 9.58 (s, lH);
Elemental Analysis: Found C, 64.3; H, 6.9; N, 13.8;
C22H26N4O3. O.9H2O requires C, 64.3; H, 6.8; N, 13.6-~.

Example 42 2-Methoxyacetyl chloride (0.085 g) was added to a stirred solution of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.2 g) in DMA (1 ml) and the mixture was stirred at ambient temperature for 16 hours. A second portion of 2-methoxyacetyl chloride (0.085 g) was added and the mixture was heated to 45~C for 3 hours. The mixture was cooled to ambient temperature and ethyl acetate (5 ml) was added.
The precipitate was isolated, washed with ethyl acetate and with diethyl ether and dried under vacuum. There was thus obtained 6-methoxy-7-(2-methoxyacetoxy)-4-(3'-methylanilino)quinazoline (0.218 g)~ m.p. 215-219~C.
NHR Spectrum: (CD3SOCD3) 2.37 (s, 3H), 3.43 (s, 3H), 4.06 (s, 3H), 4.45 (s, 2H), 7.16 (d, lH), 7.33 (s, lH), 7.38 (t, lH), 7.52 (m, 2H), 8.83 (s, lH), 8.62 (s, lH);
Elemental Analysis: Found C, 53.5; H, 5.8; N, 10.0;
C19H19N3O4. lHCl. 2H20 requires C, 53.5; H, 5.6; N, 9.9X.

- ~G~63~

Exa~ple 43 A mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.25 g), benzoyl chloride (0.148 g), triethylamine (2 ml) and DHF (2 ml) was stirred and heated to 100~C for 3 hours. A further portion of benzoyl chloride (0.296 g) was added and the mixture was heated to 100~C for a further 3 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 6-benzamido-4-(3'-methylanilino)quinazoline (0.142 g), m.p.
243-245~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 6.95 (d, lH), 7.27 (m, lH), 7.6 (m, 5H), 7.79 (d, lH), 8.01 (m, lH), 8.04 (m, 2H), 8.52 (s, lH), 8.90 (d, lH), 9.80 (s, lH), 10.55 (s, lH);
Elemental Analysis: Found C, 73.2; H, 5.0; N, 15.4;
C22H18N40. 0.25H20 requires C, 73.6; H, 5.2; N, 15.6%.

Exanple 44 A mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.75 g), methyl 3-chloroformylpropionate (0.451 g), triethylamine (0.303 g) and toluene (6 ml) was stirred and heated to reflux for 4 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-(3-methoxy-carbonylpropionamido)-4-(3'-methylanilino)quinazoline (0.46 g), m.p.
202-203~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 2.68 (m, 4H), 3.61 (s, 3H), 6.95 (d, lH), 7.26 (t, lH), 7.6 (s, 2H), 7.74 (d, lH), 7.84 (m, lH), 8.52 (s, lH), 8.70 (d, lH), 9.8 (s, lH), 10.3 (s, lH);
Elemental Analysis: Found C, 65.3; H, 5.5; N, 14.8;
C20H20N403 requires C, 65.2; H, 5.5; N, 15.0%.

Example 45 A mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.5 g), methyl 4-chlorobutyrate (1 ml) and triethylamine (0.55 ml) was . CA 02086968 1997-06-18 2 0 ~ u ~ ~

stirred and heated to 100~C for 4 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic layer was dried (MgS04) and evaporated. The residue was purified by column chromatography using a 20:1 mixture of methylene chloride and methanol as eluent. There was thus obtained 6-(3-methoxycarbonylpropylamino)-4-(3'-methylanilino)quinazoline (0.32 g) NMR Spectrum: (CD3SOCD3) 1.92 (m, 2H), 2.34 (s, 3H), 3.23 (m, 4H), 3.61 (s, 3H), 6.22 (t, lH), 6.93 (d, lH), 7.18 (d, lH), 7.25 (m, lH), 7.29 (t, lH), 7.6 (s, lH), 7.65 (d, lH), 8.43 (s, lH), 9.25 (s, lH).
A mixture of the material so obtained and diphenyl ether (0.5 ml) was stirred and heated to 160~C for 3 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using a 20:1 mixture of methylene chloride and methanol as eluent. There was thus obtained 4-(3'-methylanilino)-6-(2-oxopyrrolidin-1-yl)quinazoline (0.053 g), m.p. 212-215~C.
NMR Spectrum: (CD3SOCD3) 2.15 (m, 2H), 2.35 (s, 3H), 2.59 (t, 2H), 4.01 (t, 2H), 7.02 (d, lH), 7.30 (t, lH), 7.6 (m, 2H), 7.8 (d, lH), 8.24 (d, lH), 8.55 (s, lH), 8.60 (m, lH), 9.88 (s, lH);
Elemental Analysis: Found C, 64.8; H, 5.0; N, 14.9;
ClgH18N40. 0.75CH2C12. 0.5H20 requires C, 64.4; H, 5.4; N, 14.6%.

~xample 46 Phenyl isocyanate (0.193 g) was added to a stirred mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.39 g) and THF (15 ml) which had been cooled to -2~C. The mixture was stirred at 5~C for 10 minutes and then allowed to warm to ambient temperature. The mixture was evaporated and the residue was purified by column chromatography using a 20:1 mixture of methylene chloride and methanol as eluent.
There was thus obtained 4-(3'-methylanilino)-6-(3-phenylureido)-quinazoline (0.335 g), m.p. 224-226~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 6.94 (d, lH), 7.01 (m, lH), 7.28 (m, 2H), 7.30 (t, lH), 7.51 (m, 2H), 7.62 (m, 2H), 7.73 (d, lH), 7.92 (m, lH), 8.46 (d, lH), 8.49 (s, lH), 8.90 (s, lH), 8.94 (s, lH), ~ CA 02086968 1997-06-18 20~ ~ J ~8 9.75 (s, lH);
Elemental Analysis: Found C, 65.2; H, 5.5; N, 17.2;
C22HlgN5O. 2H2O requires C, 65.2; H, 5.7; N, 17.3X.

EsaDple 47 A solution of sodium cyanate (0.195 g) in water (3 ml) was added to a stirred solution of 6-amino-4-(3'-methylanilino)quinazoline (0.25 g) in water (5 ml) and acetic acid (0.1 ml). The mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on reversed-phase silica using initially a 30:70:0.2 mixture and then a 45:55:0.2 mixture of methanol, water and trifluoroacetic acid as eluent. There was thus obtained 4-(3'-methylanilino)-6-ureido-quinazoline (0.047 g), m.p. >230~C (decomposes).
NMR Spectrum: (CD3SOCD3) 2.36 (s, 3H), 6.18 (s, 2H), 7.12 (d, lH), 7.36 (m, lH), 7.48 (m, 2H), 7.79 (d, lH), 8.01 (m, lH), 8.65 (d, lH), 8.75 (s, lH), 9.11 (s, lH), 11.12 (s, lH);
Elemental Analysis: Found C, 48.8; H, 4.1; N, 15.4;
C16H15N5O. lH2O. 1.3CF3C02H requires C, 48.6; H, 4.0; N, 15.2%.

Esample 48 Benzyl chloride (0.378 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.281 g), potassium carbonate (0.414 g) and DMA (4 ml). The mixture was stirred at ambient temperature for 10 minutes and then heated to 60~C for 1 hour. The mixture was evaporated and the residue was purified by column chromatography using initially methylene chloride and then a 100:3 mixture of methylene chloride and methanol as eluent. There was thus obtained 7-benzyloxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.225 g), m.p. 203-205~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 3.97 (s, 3H), 5.28 (s, 2H), 6.93 (d, lH), 7.27 (t, lH), 7.28 (s, lH), 7.22-7.55 (m, 5H), 7.58 (s, lH), 7.63 (d, lH), 7.87 (s, lH), 8.44 (s, lH), 9.41 (s, lH);
Elemental Analysis: Found C, 74.0; H, 5.8; N, 11.1;
C23H21N3O2 requires C, 74.4; H, 5.7; N, 11.3%.

2~&~8 ~xanple 49 Isopropyl bromide (0.246 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.281 g), potassium carbonate (0.414 g) and DHA (3 ml). The mixture was stirred at ambient temperature for 30 minutes and then heated to 70~C for 1 hour. The mixture was partitioned between ethyl acetate and water.
The organic phase was dried (MgSO4) and evaporated to give 7-isopropoxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.28 g), m.p.
218-221~C.
NMR Spectrum: (CD3SOCD3) 1.36 (d, 6H), 2.34 (s, 3H), 3.94 (s, 3H), 4.83 (m, lH), 6.94 (d, lH), 7.17 (s, lH), 7.27 (t, lH), 7.57 (s, lH), 7.64 (d, lH), 7.82 (s, lH), 8.43 (s, lH);
Elemental Analysis: Found C, 69.4; H, 6.7; N, 12.0;
ClgH21N3O2. 0.3H2O. 0.1EtOAc requires C, 69.0; H, 6.6; N, 12.4%.

~xample 50 Ethyl iodide (0.624 g) was added to a stirred mixture of 6,7-dihydroxy-4-(3'-methylanilino)quinazoline (0.534 g), potassium carbonate (0.828 g) and DMA (10 ml). The mixture was heated to 50~C
for 2 hours. A second portion of ethyl iodide (0.624 g) was added and the mixture was heated to 60~C for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6,7-diethoxy-4-(3'-methylanilino)quinazoline (0.26 g), m.p.
178-180~C.
NMR Spectrum: (CD3SOCD3) 1.43 & 1.44 (2 t's, 6H), 2.34 (s, 3H), 4.2 (m, 4H), 6.92 (d, lH), 7.14 (s, lH), 7.26 (t, lH), 7.57 (s, lH), 7.63 (d, lH), 7.82 (s, lH), 8.42 (s, lH);
Elemental Analysis: Found C, 69.1; H, 6.6; N, 12.2;
ClgH21N302. 0.48H2O requires C, 68.7; H, 6.6; N, 12.6%.

Example 51 2-Bromoethyl methyl ether (0.834 g) was added to a stirred mixture of 6,7-dihydroxy-4-(3'-methylanilino)quinazoline (0.534 g), potassium carbonate (0.828 g) and DMA (10 ml). The mixture was . CA 02086968 1997-06-18 2 & ~ 8 stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. The gum so obtained was dissolved in ethyl acetate (4 ml) and acidified by the addition of a saturated solution of hydrogen chloride in diethyl ether. The precipitate was isolated. There was thus obtained 6,7-di-(2-methoxyethoxy)-4-(3'-methylanilino)quinazoline hydrochloride (0.292 g), m.p. 218-220~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 3.36 (s, 6H), 3.75-3.8 (m, 4H), 4.1-4.5 (m, 4H), 7.14 (d, lH), 7.37 (t, lH), 7.40 (s, lH), 7.48 (m, 2H), 8.35 (s, lH), 8.79 (s, lH);
Elemental Analysis: Found C, 59.8; H, 6.4; N, 9.9;
C21H25N304. lHCl requires C, 60.0; H, 6.2; N, lO.OX.

Exa~ple 52 1,2-Dibromoethane (0.376 g) was added to a stirred mixture of 6,7-dihydroxy-4-(3'-methylanilino)quinazoline (0.534 g), potassium carbonate (0.828 g) and DMA (20 ml). The mixture was heated to 100~C
for 30 minutes. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 6,7-ethylenedioxy-4-(3'-methylanilino)quinazoline (0.23 g), m.p. 223-226~C.
NHR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 4.40 (s, 4H), 7.14 (d, lH), 7.17 (s, lH), 7.26 (t, lH), 7.66 (m, 2H), 8.10 (s, lH), 8.43 (s, lH), 9.38 (s, lH);
Elemental Analysis: Found C, 67.5; H, 5.1; N, 13.0;
C17H15N302. 0.33H20. 0.25EtOAc requires C, 67.2; H, 5.5; N, 13.1%.

Example 53 A mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.415 g) and morpholine (2 ml) was stirred and heated to 60~C for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated. The solid so obtained was partitioned . CA 02086968 1997-06-18 2 & ~ ~ ~ 68 between methylene chloride and water. The organic phase was washed with brine, dried (HgSO4) and evaporated. There was thus obtained 6-morpholinomethyl-4-(3'-methylanilino)quinazoline (0.195 g), m.p.
191-193~C.
NhR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 2.49 (t, 4H), 3.62 (t, 4H), 3.69 (s, 2H), 6.96 (d, lH), 7.29 (t, lH), 7.69 (m, 2H), 7.74 (d, lH), 7.85 (m, lH), 8.45 (s, lH), 8.55 (s, lH), 9.71 (s, lH);
Elemental Analysis: Found C, 71.2; H, 6.8; N, 16.2;
C20H22N4O requires C, 71.2; H, 6.6; N, 16.6%.

Exanple 54 A mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.3 g), aniline (0.085 g) and DMA (5 ml) was stirred and heated to 80~C for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-anilinomethyl-4-(3'-methylanilino)quinazoline as an oil (0.254 g), which was dissolved in ethyl acetate. A saturated solution of hydrogen chloride in diethyl ether was added and the precipitate so formed was isolated. There was thus obtained 6-anilinomethyl-4-(3'-methylanilino)quinazoline dihydrochloride, m.p. 216-221~C.
NHR Spectrum: (CD3SOCD3) 2.30 (s, 3H), 4.45 (s, 2H), 6.6 (t, lH), 6.7 (d, 2H), 7.05 (d, lH), 7.08 (d, lH), 7.10 (d, lH), 7.31 (m, lH), 7.5 (m, 2H), 7.88 (d, lH), 8.06 (m, lH), 8.83 (s, lH), 9.02 (s, lH);
Elemental Analysis: Found C, 60.4; H, 5.8; N, 12.9;
C22H20N4. 2HCl. 1.33H20 requires C, 60.4; H, 5.6; N, 12.8X.

Exanple 55 Sodium methoxide (0.073 g) was added to a stirred mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.3 g) and methanol (5 ml). The mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 6-methoxymethyl-4-(3'-methylanilino)quinazoline as a gum (0.045 g).
NHR Spectrum: (CD3SOCD3) 2.36 (s, 3H), 3.39 (s, 3H), 4.62 (s, 2H), . CA 02086968 1997-06-18 7.07 (d, lH), 7.35 (t, lH), 7.58 (s, 2H), 7.82 (d, lH), 7.92 (d, lH), 8.65 (s, lH), 8.76 (s, lH).

~xample 56 A mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.5 g) and 2-methoxyethanol (2.5 ml) was stirred and heated to 80~C
for 2 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was washed with brine, dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 6-(2-methoxyethoxymethyl)-4-(3'-methylanilino)quinazoline as an oil (0.211 g).
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 3.27 (s, 3H), 3.53 (m, 2H), 3.63 (m, 2H), 4.67 (s, 2H), 6.96 (d, lH), 7.28 (t, lH), 7.7 (m, 2H), 7.8 (m, 2H), 8.5 (s, lH), 8.57 (s, lH), 9.8 (s, lH);
Elemental Analysis: Found C, 68.5; H, 6.8; N, 12.5;
C19H21N302 requires C, 68.6; H, 6.7; N, 12.6%.

Example 57 Sodium methanethiolate (0.141 g) was added to a stirred mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.6 g), triethylamine (0.203 g) and DMF (2 ml). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained an oil which was triturated under a mixture of hexane and diethyl ether to give 4-(3'-methylanilino)-6-methylthiomethyl-quinazoline (0.205 g), m.p. 134-136~C.
NMR Spectrum: (CD3SOCD3) 2.01 (s, 3H), 2.34 (s, 3H), 3.88 (s, 2H), 6.97 (d, lH), 7.28 (t, lH), 7.6 (m, 2H), 7.75 (d, lH), 7.83 (m, lH), 8.45 (d, lH), 8.58 (s, lH), 9.8 (broad s, lH);
Elemental Analysis: Found C, 69.7; H, 5.8; N, 14.2;
C17H17N3S. O.lC6H14 requires C, 69-5; H, 6.1; N~ 13-8%-~ C Sû ~ ~8 Exanple 58 Triethylamine (0.1 ml) was added to a stirred mixture of 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.33 g), benzenethiol (0.11 g) and DHA (2 ml). The mixture was stirred at ambient temperature for 5 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures by methylene chloride and ethyl acetate as eluent. There was thus obtained 4-(3'-methylanilino)-6-phenylthiomethylquinazoline (0.155 g), m.p. 145-148~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 4.41 (s, 2H), 6.96 (d, lH), 7.24 (t, lH), 7.3 (s, 5H), 7.65 (m, 2H), 7.72 (d, lH), 7.86 (m, lH), 8.54 (d, lH), 8.55 (s, lH), 9.73 (s, lH);
Elemental Analysis: Found C, 73.7; H, 5.3; N, 11.5;
C22H19N3S requires C, 73.9; H, 5.4; N, 11.8%.

Exa~ple 59 Succinyl dichloride (0.207 g) was added to a mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.32 g), triethylamine (0.128 g) and toluene (5 ml). The mixture was stirred and heated to reflux for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 4-(3'-methylanilino)-6-(2,5-dioxopyrrolidin-1-yl)quinazoline (0.082 g), m.p. >150~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 2.90 (s, 4H), 6.98 (d, lH), 7.28 (t, lH), 7.61 (d, 2H), 7.75 (m, lH), 7.88 (d, lH), 8.50 (d, lH), 8.64 (s, lH), 9.95 (s, lH);
Elemental Analysis: Found C, 64.9; H, 5.2; N, 15.2;
C1gH16N4O2. 0.4HCl. 0.4CH30H requires C, 64.8; H, 5.0; N, 15.6%.

Exa~ple 60 3-Chloroacetyl chloride (0.473 g) was added to a mixture of 6-amino-4-(3'-methylanilino)quinazoline (1 g), triethylamine (0.423 g) and DHF (5 ml). The mixture was stirred and heated to 50~C for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene 2 ~ 8 chloride and methanol as eluent. There was thus obtained 6-(2-chloroacetamido)-4-(3'-methylanilino)quinazoline (0.775 g), m.p.
~290~C.
NMR Spectrum: (CD3SOCD3) 2.32 (s, 3H), 4.33 (s, 2H), 6.94 (d, lH), 7.25 (t, lH), 7.6 (m, 2H), 7.75 (d, lH), 7.84 (m, lH), 8.50 (s, lH), 8.68 (d, lH), 9.80 (s, lH), 10.57 (s, lH);
Elemental Analysis: Found C, 62.6; H, 4.5; N, 17.1;
C17H15ClN40 requires C, 62.5; H, 4.6; N, 17.1%.

Exa~ple 61 Sodium cyanoborohydride (0.2 g) was added portionwise to a mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.5 g), formaldehyde (37% solution in water, 0.8 ml) and acetonitrile (15 ml).
The mixture was stirred at ambient temperature for 45 minutes. The mixture was neutralised by the addition of glacial acetic acid and evaporated. The residue was partitioned between methylene chloride and 2N aqueous sodium hydroxide. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-dimethylamino-4-(3'-methylanilino)quinazoline (0.237 g), m.p. >200~C
(decomposes).
NMR Spectrum: (CD3SOCD3) 2.33 (s, 3H), 3.06 (s, 6H), 6.95 (d, lH), 7.26 (t, lH), 7.41 (s, lH), 7.48 (d, lH), 7.6 (m, 2H), 7.65 (d, lH), 8.37 (s, lH), 9.5 (s, lH);
Elemental Analysis: Found C, 71.2; H, 6.3; N, 19.4;
C17H18N4. 0.4H2O requires C, 71.5; H, 6.6; N, 19.6%.

Exa~ple 62 Using an analogous procedure to that described in Example 39, except that DMA was used in place of DMF and that the reaction mixture was heated to 80~C for 4 hours, 6-hydroxy-4-(3'-methylanilino)quinazoline was reacted with 1,2-dibromoethane to give 6-(2-bromoethoxy)-4-(3'-methylanilino)quinazoline in 47~~ yield, m.p.
129-135~C.

' CA 02086968 1997-06-18 2 ~ 8 NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3.92 (t, 2H), 4.52 (t, 2H), 6.95 (d, lH), 7.28 (t, lH), 7.53 (m, lH), 7.63 (m, 2H), 7.74 (d, lH), 7.96 (d, lH), 8.49 (s, lH), 9.52 (s, lH);
Elemental Analysis: Found C, 57.5; H, 4.2; N, 11.5;
C17H16BrN3O requires C, 57.0; H, 4.5; N, 11.7%.

Exanple 63 The procedure described in Example 62 was repeated except that 2-bromoethyl methyl ether was used in place of 1,2-dibromoethane.
There was thus obtained 6-(2-methoxyethoxy)-4-(3'-methylanilino)quinazoline in 52% yield, m.p.
177-179~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 3.36 (s, 3H), 3.76 (t, 2H), 4.29 (t, 2H), 6.95 (d, lH), 7.28 (m, lH), 7.51 (m, lH), 7.62 (s, lH), 7.65 (d, lH), 7.72 (d, lH), 7.95 (d, lH), 8.49 (s, lH);
Elemental Analysis: Found C, 69.4; H, 6.2; N, 13.2;
C18H1gN3O2. 0.1H2O requires C, 69.4; H, 6.2; N, 13.5%.

Exanple 64 Dimethylamine gas was led into a stirred solution of 6-(2-bromoethoxy)-4-(3'-methylanilino)quinazoline (0.237 g) in DMA (5 ml) and the mixture was stirred at ambient temperature for 16 hours.
The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-(2-dimethylaminoethoxy)-4-(3'-methylanilino)quinazoline hydrobromide (0.177 g), m.p. 83-86~C.
NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 2.5 (s, 6H), 3.09 (t, 2H), 4.35 (t, 2H), 6.96 (d, lH), 7.29 (m, lH), 7.50 (m, lH), 7.62 (m, 2H), 7.64 (d, lH), 7.98 (d, lH), 8.49 (s, lH), 9.54 (s, lH);
Elemental Analysis: Found C, 56.6; H, 5.9; N, 13.6;
C1gH22N40. lHBr requires C, 56.6; H, 5.7; N, 13.9%.

Exanple 65 Sodium cyanide (0.121 g) and triethylamine (0.303 g) were added in turn to a mixture of . CA 02086968 1997-06-18 2 0 ~ 8 6-bromomethyl-4-(3'-methylanilino)quinazoline (0.3 g) and DMA (5 ml).
The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 6-cyanomethyl-4-(3'-methylanilino)quinazoline as a solid (0.084 g).
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 4.24 (s, 2H), 6.98 (d, lH), 7.29 (t, lH), 7.61 (m, 2H), 7.83 (s, 2H), 8.56 (s, lH), 8.62 (s, lH);
Elemental Analysis: Found C, 72.7; H, 4.9; N, 19.6;
C17H14N4. 0.33H20 requires C, 72.8; H, 5.2; N, 20.0%.

~xample 66 Di-(1-imidazolyl) ketone (0.421 g) was added to a mixture of 7-carboxy-4-(3'-methylanilino)quinazoline (0.558 g), THF (40 ml) and DMF (20 ml). The mixture was stirred and heated to 40~C for 90 minutes. The mixture was cooled to 5~C and dimethylamine was led into the mixture for 40 minutes. The mixture was evaporated and the residue was triturated under water. The solid so obtained was isolated and dried. There was thus obtained 7-(_,_-dimethyl-carbamoyl)-4-(3'-methylanilino)quinazoline (0.55 g), m.p. 207-209~C.
NMR Spectrum: (CD3SOCD3 + CD3C02D) 2.35 (s, 3H), 2.96 (s, 3H), 3.07 (s, 3H), 7.04 (d, lH), 7.32 (t, lH), 7.63 (m, lH), 7.66 (s, 2H), 7.82 (d, lH), 8.60 (d, lH), 8.64 (s, lH);
Elemental Analysis: Found C, 69.6; H, 5.8; N, 18.1;
C18H18N4O. 0.2H2O requires C, 69.8; H, 5.9; N, 18.1%.

~xample 67 Using an analogous procedure to that described in Example 1, 4-chloro-6-morpholinoquinazoline was reacted with 3-methylaniline to give 4-(3'-methylanilino)-6-morpholinoquinazoline hydrochloride in 76%
yield, m.p. 276-278~C.
NMR Spectrum: (CD3SOCD3) 2.38 (s, 3H), 3.41 (m, 4H), 3.82 (m, 4H), 7.18 (d, lH), 7.38 (m, lH), 7.48 (s, lH), 7.50 (d, lH), 7.87 (s, 2H), 8.08 (s, lH), 8.75 (s, lH);
Elemental Analysis: Found C, 63.9; H, 6.0; N, 15.4;
C19H20N40. lHCl requires C, 64.1; H, 5.9; N, 15.8%.

~ CA 02086968 1997-06-18 2 û ~ 8 The 4-chloro-6-morpholinoquinazoline used as a starting material was obtained as follows:-A mixture of 5-chloro-2-nitrobenzoic acid (20.2 g) and morpholine (50 ml) was stirred and heated to reflux for 3 hours. The mixture was evaporated. Water (100 ml) was added and the mixture was acidified to pH2 by the addition of concentrated hydrochloric acid.
The precipitate was isolated, washed with water and dried. There was thus obtained 2-nitro-5-morpholinobenzoic acid (24.3 g).
A mixture of a portion (10 g) of the material so obtained, 10-~ palladium-on-charcoal catalyst (1 g) and DMA (150 ml) was heated to 40~C and stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether to give 5-morpholinoanthranilic acid (6.05 g).
A mixture of a portion (5.5 g) of the material so obtained and formamide (20 ml) was stirred and heated to 170~C for 4 hours.
The mixture was cooled to ambient temperature and the precipitate was isolated, washed in turn with formamide, ethyl acetate and diethyl ether and dried. There was thus obtained 6-morpholinoquinazolin-4-one (4.8 g), m.p. 270-273~C.
Phosphoryl chloride (0.664 g) was added to a stirred mixture of 6-morpholinoquinazoline (0.5 g), N,N-dimethylaniline (0.471 g) and toluene (10 ml). The mixture was heated to reflux for 1 hour. The mixture was cooled to ambient temperature, diluted with toluene (25 ml) and extracted with dilute aqueous ammonium chloride solution. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 4-chloro-6-morpholinoquinazoline as a solid (0.52 g).

Example 68 A mixture of 4-chloro-6,7-dimethoxyquinazoline (0.449 g), 1,3-phenylenediamine (0.433 g) and THF (16 ml) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature. The precipitate was isolated, washed with diethyl ether and dried. There was thus obtained 4-(3'-aminoanilino)-6,7-dimethoxy-2û~û~B

quinazoline hydrochloride (0.367 g), m.p. 242-243~C.
NMR Spectrum: (CD3SOCD3) 3.97 (s, 3H), 4.0 (s, 3H), 6.64 (m, lH), 6.95 (d, lH), 7.02 (d, lH), 7.16 (t, lH), 7.87 (s, lH), 8.25 (s, lH), 8.72 (s, lH), 10.99 (broad s, lH);
Elemental Analysis: Found C, 57.6; H, 5.0; N, 16.4;
C16H16N4O2. lHCl. O.lH2O requires C, 57.4; H, 5.2; N, 16.7%.

Exa~ple 69 Using an analogous procedure to that described in Example 68, 4-chloro-6,7-dimethoxyquinazoline was reacted with 3-aminophenol to give 4-(3'-hydroxyanilino)-6,7-dimethoxyquinazoline in 92X yield, m.p. 256-257~C.
NHR Spectrum: 3.98 (s, 3H), 4.02 (s, 3H), 6.75 (m, lH), 7.12 (d, lH), 7.14 (d, lH), 7.25 (t, lH), 7.42 (s, lH), 8.37 (s, lH), 8.80 (s, lH), 9.5 (broad hump, lH), 11.4 (broad s, lH);
Elemental Analysis: Found C, 57.1; H, 4.8; N, 12.1;
C16H15N3O3. lHCl. 0.25H2O requires C, 56.8; H, 4.9; N, 12.4%.

~xample 70 A mixture of 4-chloro-6-piperidinoquinazoline (0.371 g), 3,4-dichloroaniline (0.243 g), isopropanol (3 ml) and THF (4 ml) was stirred and heated to reflux for 3 hours. The mixture was allowed to cool to ambient temperature. The precipitate was isolated, washed with THF and diethyl ether and dried. There was thus obtained 4-(3',4'-dichloroanilino)-6-piperidinoquinazoline hydrochloride (0.331 g, 54%), m.p. >280~C.
NMR Spectrum: (CD3SOCD3) 1.68 (m, 6H), 3.49 (m, 4H), 7.7-8.0 (m, 5H), 8.13 (s, lH), 8.81 (s, lH);
Elemental Analysis: Found C, 56.4; H, 4.7; N, 13.6;
C19H18Cl2N4. 0.9HCl requires C, 56.3; H, 4.7; N, 13.8%.

The 4-chloro-6-piperidinoquinazoline used as a starting material was obtained as follows:-A mixture of 5-chloro-2-nitrobenzoic acid (13.7 g), piperidine (27 ml) and DMA (100 ml) was stirred and heated to 120~C
for 18 hours. The mixture was evaporated. The residue was dissolved . CA 02086968 1997-06-18 2 0 ~ 8 in water and the solution was basified to pH10 by the addition of 2N
aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The aqueous layer was acidified to pH2 by the addition of concentrated hydrochloric acid and extracted with ethyl acetate.
The organic layer was dried (MgS04) and evaporated to give 2-nitro-5-piperidinobenzoic acid (16.25 g), m.p.130-140~C.
A mixture of a portion (10 g) of the material so obtained, 10% palladium-on-charcoal catalyst (1 g) and DMA (150 ml) was heated to 40~C and stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered and the filtrate was evaporated. There was thus obtained 5-piperidinoanthranilic acid as an oil (12.1 g) which was used without further purification.
A mixture of the material so obtained and formamide (50 ml) was stirred and heated to 170~C for 90 minutes. The mixture was allowed to cool to ambient temperature. The precipitate was isolated, washed with formamide and with diethyl ether and dried. There was thus obtained 6-piperidinoquinazolin-4-one (5.95 g), m.p. 160-166~C.
Phosphoryl chloride (5.37 g) was added to a stirred mixture of 6-piperidinoquinazoline (4 g), N,_-dimethylaniline (3.81 g) and toluene (70 ml). The mixture was heated to reflux for 2 hours. The mixture was allowed to cool to ambient temperature, diluted with toluene (80 ml) and extracted with dilute aqueous ammonium chloride solution. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 4-chloro-6-piperidinoquinazoline as a solid (2.01 g).

Example 71 A mixture of 7-methylamino-4-(3'-methylanilino)-6-nitroquinazoline (1 g), 10% palladium-on-charcoal catalyst (0.1 g) and DMA (20 ml) was stirred and heated to 50~C under an atmosphere of hydrogen for 3 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was partitioned between methylene chloride and aqueous ammonium hydroxide solution. The organic phase was dried (MgS04) and evaporated. The residue was purified by column chromatography using increasingly polar ~ CA 02086968 1997-06-18 2 0 S~ ~8 mixture of methylene chloride and methanol as eluent. There was thus obtained 6-amino-7-methylamino-4-(3'-methylanilino)quinazoline (0.056 g, 6X), m.p. 229-232~C.
NMR Spectrum: (CD3SOCD3) 2.31 (s, 3H), 2.86 (d, 3H), 5.10 (broad s, 2H), 5.98 (broad s, lH), 6.65 (s, lH), 6.84 (d, lH), 7.20 (m, lH), 7.32 (s, lH), 7.60 (d, lH), 7.62 (s, lH), 8.29 (s, lH), 9.10 (broad s, lH);
Elemental Analysis: Found C, 65.9; H, 5.8; N, 23.8;
C16H17N5. O.lH2O. 0.15CH2C12 requires C, 66.2; H, 5.9; N, 23.7%.

The 7-methylamino-4-(3'-methylanilino)-6-nitroquinazoline used as a starting material was obtained as follows:-A mixture of7-chloro-4-(3'-methylanilino)-6-nitroquinazoline (10.5 g), an ethanolic solution of methylamine (30% weight/volume; 100 ml) and ethanol (100 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated to give the required starting material which was used without further purification.

Example 72 Tert-butyl nitrite (0.051 g) was added to a mixture of 6-amino-4-(3'-methylanilino)-7-morpholinoquinazoline (0.167 g) and DMF
(5 ml) which had been heated to 65~C. The mixture was heated to 65~C
for 30 minutes. A second portion (0.051 g) of tert-butyl nitrite was added and the mixture was stirred at ambient temperature for 65 hours.
The mixture was evaporated and the residue was purified by reversed-phase column chromatography using a 60:40:0.2 mixture of methanol, water and trifluoroacetic acid as eluent. There was thus obtained 4-(3'-methylanilino)-7-morpholinoquinazoline (0.066 g, 41%), m.p. 227-229~C.
NMR Spectrum: (CD3SOCD3) 2-33 (s, 3H), 3.50 (m, 4H), 3.82 (m, 4H), 6.93 (d, lH), 7.14 (d, lH), 7.56 (d, lH), 7.57 (s, lH), 7.59 (m, lH), 8.49 (d, lH), 8.75 (s, lH), 10.93 (broad s, lH).

The 6-amino-4-(3'-methylanilino)-7-morpholinoquinazoline used as a starting material was obtained as follows:-2~u~8 A mixture of 7-chloro-4-(3'-methylanilino)-6-nitro-quinazoline (1 g) and morpholine (0.306 ml) was stirred and heated to 70~C for 3 hours. The mixture was evaporated and the residue was triturated under methylene chloride. There was thus obtained 4-(3'-methylanilino)-7-morpholino-6-nitroquinazoline (1.02 g), m.p.
212-215~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 3.11 (t, 4H), 3.74 (t, 4H), 6.97 (d, lH), 7.28 (t, lH), 7.31 (s, lH), 7.62 (s, lH), 7.64 (d, lH), 8.58 (s, lH), 9.19 (s, lH), 9.90 (broad s, lH);
Elemental Analysis: Found C, 55.7; H, 16.4; N, 4.7;
ClgHlgN5O3. 0.73CH2C12 requires C, 55.4; H, 16.4; N, 4.6%.
Using an analogous procedure to that described in Example 70 except that the reaction was conducted at ambient temperature, 4-(3'-methylanilino)-7-morpholino-6-nitroquinazoline was reduced to give 6-amino-4-(3'-methylanilino-7-morpholinoquinazoline in 48X yield, m.p. 211-213~C.
N~R Spectrum: (CD3SOCD3) 2.32 (s, 3H), 2.98 (m, 4H), 3.84 (m, 4H), 5.24 (broad s, 2H), 6.92 (d, lH), 7.18 (s, lH), 7.25 (t, lH), 7.52 (s, lH), 7.62 (d, 2H), 8.38 (s, lH), 9.37 (broad s, lH);
Elemental Analysis: Found C, 67.7; H, 6.4; N, 20.5;
C19H21N5O requires C, 68.0; H, 6.3; N, 20.9%.

Example 73 Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 2 hours, the appropriate 4-chloroquinazoline was reacted with the appropriate aniline to give, as hydrochloride salts (unless otherwise stated), the compounds described in the following table, the structures of which were confirmed by proton magnetic resonance spectroscopy and by elemental analysis.

89 20~û8 TABLE IV

J~ ( R ) n H N

NJ/~
ll I ( R 1 ) m H/~N--\~

Example 73 (Rl)m (R2)n m.p.
Compd. No. (~C) la 6,7-dimethoxy 3'-cyano >240 2b 6,7-dimethoxy 3'-acetyl >240 3c 6,7-dimethoxy 2',6'-difluoro >240 4d 6-piperidino 3'-methyl 230-232 Notes a. The product, obtained initially as the hydrochloride salt, was converted into the corresponding free base as follows. The salt was treated with a mixture of methylene chloride and lN aqueous sodium hydroxide solution. The mixture was filtered and the solid so isolated was washed with a 10:1 mixture of methylene chloride and methanol and dried. There was thus obtained the required free base, m.p. >240~C;
NMR Spectrum: (CD3SOCD3) 3.97 (s, 3H), 4.0 (s, 3H), 7.22 (s, lH), 7.55 (m, lH), 7.62 (m, lH), 7.83 (s, lH), 8.16 (m, lH), 8.38 (m, lH), 8.56 (s, lH), 9.67 (broad s, lH);
Elemental Analysis: Found C, 66.0; H, 4.6; N, 18.0;

' CA 02086968 1997-06-18 C17H14N402. 0.2H20 requires C, 65.9; H, 4.7; N, 18.1%.

b. The product gave the following analytical data: Found C, 58.3; H, 5.0; N, 11.2; C18H17N303. lHCl. 0.5H20 requires C, 58.6; H, 5.2; N, 11.4%; and the following characteristic NHR data: 2.62 (s, 3H), 3.99 (s, 3H), 4.04 (s, 3H), 7.43 (s, lH), 7.62 (m, lH), 7.90 (m, lH), 8.05 (m, lH), 8.29 (m, lH), 8.47 (s, lH), 8.84 (s, lH), 11.74 (broad s, lH).

c. The product, obtained initially as the hydrochloride salt, was converted into the corresponding free base as follows. The salt was partitioned between ethyl acetate and lN aqueous sodium hydroxide solution. The organic phase was washed with brine, dried (MgS04) and evaporated. The residue was purified by column chromatography using a 19:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the required free base, m.p. >240~C;
NMR Spectrum: (CD3SOCD3) 3.82 (s, 6H), 7.05-7.35 (m, 3H), 7.72 (s, lH), 8.21 (s, lH), 9.34 (broad s, lH);
Elemental Analysis: Found C, 60.6; H, 4.1; N, 13.4; C16H13F2N302 requires C, 60.6; H, 4.1; N, 13.2%.

d. The product gave the following analytical data: Found C, 67.8; H, 6.9; N, 15.3; C20H22N4. 1.03 HCl requires C, 67.4; H, 6.5; N, 15.7%; and the following characteristic NMR data: (CD3SOCD3) 1.63 (m, 6H), 2.35 (s, 3H), 3.45 (m, 4H), 7.13 (d, lH), 7.36 (m, lH), 7.45 (m, 2H), 7.75 (d, lH), 7.84 (m, lH), 8.69 (s, lH), 8.88 (d, lH), 11.2 (broad s, lH).

Example 74 A mixture of 4-chloro-6,7-dimethoxyquinazoline (0.674 g), 1,2-phenylenediamine (0.649 g) and THF (24 ml) was stirred and heated to reflux for 40 hours. The mixture was cooled to ambient temperature. The precipitate was isolated, washed with diethyl ether and dried. There was thus obtained 4-(2'-aminoanilino)-6,7-dimethoxyquinazoline hydrochloride (0.83 g, 83%), m.p. 241-243~C.
NMR Spectrum; (CD3SOCD3) 3.98 (s, 6H), 6.68 (m, lH), 6.87 (d, lH), ' CA 02086968 1997-06-18 2 ~ S C ~ ~ 8 7.12 (m, 2H), 7.40 (s, lH), 8.29 (s, lH), 8.68 (s, lH), 11.05 (broad s, lH);
Elemental Analysis: Found C, 57.9; H, 5.2; N, 16.6;
C16H16N4O2. lHCl requires C, 57.7; H, 5.15; N, 16.8%.

Esample 75 Using an analgous procedure to that described in Example 74, 4-chloro-6,7-dimethoxyquinazoline was reacted with 1,4-phenylenediamine to give 4-(4'-aminoanilino)-6,7-dimethoxy-quinazoline hydrochloride in 85% yield, m.p. 274-276~C.
NMR Spectrum: (CD3SOCD3) 3.95 (s, 3H), 3.98 (s, 3H), 6.75 (d, 2H), 7.35 (s, lH), 7.38 (d, 2H), 8.25 (s, lH), 8.67 (s, lH), 11.05 (broad s, lH);
Elemental Analysis: Found C, 57.6; H, 5.0; N, 16.9;
C16H16N4O2. lHCl requires C, 57.7; H, 5.15; N, 16.8%.

Example 76 Sodium cyanoborohydride (0.013 g) was added to a mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.5 g), formaldehyde (37%
solution in water, 0.16 ml) and DMA (5 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was neutralised by the addition of glacial acetic acid. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-methylamino-4-(3'-methylanilino)quinazoline (0.15 g, 28X), m.p. 99-102~C.
NMR Spectrum: (CD3SOCD3) 2.34 (s, 3H), 2.85 (d, 3H), 6.32 (q, lH), 6.96 (d, lH), 7.20 (d, lH), 7.28 (m, 2H), 7.54 (d, lH), 7.6 (m, 2H), 8.48 (s, lH), 9.52 (broad s, lH);
Elemental Analysis: Found C, 70.8; H, 5.9; N, 20.5;
C16H16N4. 0.4H2O requires C, 70.7; H, 6.2; N, 20.6%.

Example 77 A mixture of 6-amino-4-(3'-methylanilino)quinazoline (0.05 g), benzaldehyde (0.02 ml) and methanol (5 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature 2 ~ û 3 and sodium borohydride (0.0076 g) was added portionwise. The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography using a 4:1 mixture of methylene chloride and ethyl acetate as eluent.
There was thus obtained 6-benzylamino-4-(3'-methylanilino)quinazoline (0.068 g).
NnR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 4.36 (d, lH), 6.67 (t, lH), 6.93 (d, lH), 7.2-7.7 (m, 11H), 8.33 (s, lH), 9.26 (broad s, lH);
Elemental Analysis: Found C, 77.3; H, 6.1; N, 16.0;
C22H20N4. 0.125H20 requires C, 77.1; H, 5.9; N, 16.4X.

Exaxple 78 DMA (3 ml) was saturated with dimethylamine gas and 6-(2-chloroacetamido)-4-(3'-methylanilino)quinazoline (0.2 g) was added. The mixture was stirred at ambient temperature for 18 hours.
The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 6-(2-dimethyl-aminoacetamido)-4-(3'-methylanilino)quinazoline (0.127 g, 62X), m.p.
146-148~C.
NMR Spectrum: (CD3SOCD3) 2.32 (s, 9H), 3.14 (s, 2H), 6.94 (d, lH), 7.26 (t, lH), 7.65 (m, 2H), 7.75 (d, lH), 8.13 (m, lH), 8.53 (s, lH), 8.61 (d, lH), 9.64 (broad s, lH), 9.89 (broad s, lH);
Elemental Analysis: Found C, 67.7; H, 6.5; N, 20.6;
C19H21N50 requires C, 68.0; H, 6.3; N, 20.9%.

Example 79 Using an analogous procedure to that described in Example 11, 4-(3'-aminoanilino)-6,7-dimethoxyquinazoline hydrochloride was reacted with acetic anhydride. The crude product was purified by column chromatography using a 150:8:1 mixture of methylene chloride, methanol and ammonia as eluent. There was thus obtained 4-(3'-acetamidoanilino)-6,7-dimethoxyquinazoline in 47X yield, m.p.
252-255~C.
NMR Spectrum: (CD3SOCD3) 2.06 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 7.18 (s, lH), 7.27-7.35 (m, 2H), 7.45 (m, lH), 7.87 (s, lH), 8.06 (s, 2 0 ~ 3 8 lH), 8.45 (s, lH), 9.5 (broad s, lH), 9.9 (broad s, lH);
Elemental Analysis: Found C, 62.9; H, 5.5; N, 16.1;
C18H18N403. 0.25H20 requires C, 63.1; H, 5.4; N, 16.3%.

Example 80 A mixture of 4-(3'-aminoanilino)-6,7-dimethoxyquinazoline hydrochloride (0.083 g), benzoyl chloride (0.042 g), triethylamine (0.101 g) and DHF (1.5 ml) was stirred at ambient temperature for 20 hours. The mixture was evaporated and the residue was purified by column chromatography using a 100:8:1 mixture of methylene chloride, methanol and ammonia as eluent. There was thus obtained 4-(3'-benzamidoanilino)-6,7-dimethoxyquinazoline (0.15 g, 15%), m.p.
239-242~C.
NHR Spectrum: (CD3SOCD3) 3.92 (s, 3H), 3.96 (s, 3H), 7.18 (s, lH), 7.34 (t, lH), 7.45-7.63 (m, 5H), 7.87 (s, lH), 7.96 (m, 2H), 8.26 (t, lH), 8.45 (s, lH), 9.52 (broad s, lH), 10.29 (broad s, lH);
Elemental Analysis: Found C, 65.9; H, 5.3; N, 13.0;
C23H20N403. 0.3CH30H. 0.75H20 requires C, 66.1; H, 5.4; N, 13.2%.

Exanple 81 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:

' CA 02086968 1997-06-18 2 0 $ ~ ~ ~ 8 (a) Tablet I mg/tablet Compound X..................................... 100 Lactose Ph.Eur................................ 182.75 Croscarmellose sodium.......................... 12.0 Maize starch paste (5% w/v paste).............. 2.25 Magnesium stearate............................. 3.0 (b) Tablet II mg/tablet Compound X...................................... 50 Lactose Ph.Eur................................ 223.75 Croscarmellose sodium.......................... 6.0 Maize starch................................... 15.0 Polyvinylpyrrolidone (5% w/v paste)............ 2.25 Magnesium stearate............................. 3.0 (c) Tablet III mg/tablet Compound X..................................... 1.0 Lactose Ph.Eur................................ 93.25 Croscarmellose sodium.......................... 4.0 Maize starch paste (5% w/v paste).............. 0.75 Magnesium stearate............................. 1.0 (d) Capsule mg/capsule Compound X.................................... 10 Lactose Ph.Eur ............................... 488.5 Hagnesium stearate ........................... 1.5 (e) Injection I (50 mg/ml) Compound X ................................... 5.0% w/v lM Sodium hydroxide solution ................. 15.0% v/v O.lM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400....................... 4.5X w/v Water for injection to 100%

2 ~ a ~ ~ ~8 (f) Injection II 10 mg/ml) Compound X .................................... 1.0Z w/v Sodium phosphate BP ........................... 3.6% w/v O.lH Sodium hydroxide solution ................ 15.0X v/v ~ater for injection to lOOX

(g) Injection III (lmg/ml,buffered to pH6) Compound X .................................... 0.1% w/v Sodium phosphate BP ........................... 2.26% w/v Citric acid ................................... 0.38% w/v Polyethylene glycol 400 ....................... 3.5% w/v ~ater for injection to 100%
~ote 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.

BST/KEB: 08DEC92 ' CA 02086968 1997-06-18 2 C ~ ~ ~ l) 8 CHE~ICAL FORHULAE
,~' " ~ 2 H N/~/J

N' -- '~

H--~N( R 1 ~ R2 \ N

N ,G", ,~
~N/~ R1 11 N ' ~ ~1 H/~N~ ,J ( R 1 ) rn I I I

H N/\~'~ ( R 2 ) I V

Claims (17)

1. A quinazoline derivative of the formula I

wherein m is 1, 2 or 3 and each R1 is independently hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkoxyamino, (2-4C)alkanoyloxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyllamino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, halogeno-(1-4C)alkyl (other than trifluoromethyl), hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, phenoxy-(1-4C)alkyl, anilino-(1-4C)alkyl, phenylthio-(1-4C)alkyl, cyano-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, (2-4C)alkanoyloxy, hydroxy-(2-4C)alkanoyloxy, (1-4C)alkoxy-(2-4C)alkanoyloxy, phenyl-(1-4C)alkoxy, phenoxy-(2-4C)alkoxy, anilino-(2-4C)alkoxy, phenylthio-(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, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, carboxy-(1-4C)alkylamino, (1-4C)alkoxycarbonyl-(1-4C)alkylamino, carbamoyl-(1-4C)alkylamino, N-(1-4C)alkylcarbamoyl-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, phenyl-(1-4C)alkylamino, phenoxy-(2-4C)alkylamino, anilino-(2-4C)alkylamino, phenylthio-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino, carbamoyl-(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl-(2-4C) alkanoylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent or any anilino, phenoxy or phenyl group in a R1 substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;

n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino, benzamido or (2-4C)alkanoyl, and wherein said benzamido group may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
or a pharmaceutically-acceptable salt thereof;
except that 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxy-anilino)-6,7,8-trimethoxyquinazoline, 4-(4'-methoxyanilino)-8-methoxyquinazoline, 4-(4'-chloroanilino)-8-methoxyquinazoline, 8-hydroxy-4-(4'-methoxyanilino)quinazoline, 4-(4'-chloro-anilino)-8-hydroxyquinazoline, 6-amino-4-(4'-aminoanilino)-quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxyquinazoline or the hydrochloride salt thereof are excluded.
2. A quinazoline derivative of the formula I as claimed in claim 1 wherein each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)-alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl; or a pharmaceutically-acceptable salt thereof; except that 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 4-(4'-methoxyanilino)-8-methoxy quinazoline, 4-(4'-chloroanilino)-8-methoxyquinazoline, 8-hydroxy-4-(4'-methoxyanilino)quinazoline, 4-(4'-chloro-anilino)-8-hydroxyquinazoline, 6-amino-4-(4'-aminoanilino)-quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxyquinazoline or the hydrochloride salt thereof are excluded.
3. A quinazoline derivative of the formula I as claimed in claim 1 wherein m is 1, 2 or 3 and each R1 is independently hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxy-carbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]-carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, halogeno-(1-4C)-alkyl (other than trifluoromethyl), hydroxy-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(l-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-dl-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)-alkyl, piperidino-(l-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, - 99a -hydroxy-(2-4C)alkoxy-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkoxy-(1-4C)alkyl, hydroxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylamino-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, hydroxy-(2-4C)alkylthio-(1-4C)alkyl, (1-4C)alkoxy-(2-4C)alkylthio-(1-4C)alkyl, halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy, halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino, (2-4C)alkanoyloxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino, carboxy-(1-4C)alkylamino, (1-4C)alkoxycarbonyl-(1-4C)alkylamino, carbamoyl-(1-4C)alkylamino, N-(1-4C)alkylcarbamoyl-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkylamino, amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino, di-[(1-4C)alkyl]amino-(2-4C)alkylamino, (2-4C)alkanoylamino, (1-4C)alkoxycarbonylamino, (1-4C)alkylsulphonylamino, benzamido, benzenesulphonamido, halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino, (1-4C)alkoxy-(2-4C)alkanoylamino, carboxy-(2-4C)alkanoylamino, (1-4C)alkoxycarbonyl-(2-4C)alkanoylamino, carbamoyl-(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl-(2-4C)alkanoyl-amino, N,N-di-[(1-4C)alkyl]carbamoyl-(2-4C)alkanoylamino, amino-(2-4C)alkanoylamino, (1-4C)alkylamino-(2-4C)alkanoylamino or di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino, and wherein said benzamido or benzenesulphonamido substituent may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl;
or a pharmaceutically-acceptable salt thereof;
except that 4-(4'-hydroxyanilino)-6-methoxyquinazoline,
4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxy-quinazoline or the hydrochloride salt thereof are excluded.

4. A quinazoline derivative of the formula I as claimed in claim 1 wherein m is 1 or 2 and each R1 is independently hydroxy, amino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, (2-4C)alkanoylamino, (1-4C)alkylsulphonylamino, benzamido or benzenesulphonamido, and wherein said last 2 substituents may optionally bear one or two halogeno, (1-4C)alkyl or (1-4C)alkoxy substituents;
n is 1 or 2 and each R2 is independently hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl;
or a pharmaceutically-acceptable salt thereof;
except that 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxy-quinazoline or the hydrochloride salt thereof are excluded.
5. A quinazoline derivative of the formula I as claimed in claim 1 and subject to the provisos stated in claim 1 wherein m is 1, 2 or 3 and each R1 is independently hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, methylthio, ethylthio, bromomethyl, dibromomethyl, methoxymethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, carbamoylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-methoxyacetoxy, benzyloxy, 2-anilinoethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 2-(piperazin-1-yl)ethoxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, acetamido, propionamido, benzamido, 3-phenylureido, 2-chloroacetamido, 2-oxopyrrolidin-1-yl, 2-hydroxyacetamido, 2-methoxyacetamido or 2-ethoxyacetamido;
n is 1 or 2 and each R2 is independently hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl or ethyl;
or a pharmaceutically-acceptable salt thereof.
6. A quinazoline derivative of the formula I as claimed in claim 1 and subject to the provisos stated in claim 1 wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino,
7-amino, 6-ureido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-dimethylamino, 6-methoxymethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(2-methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzyloxy-6-methoxy, 6-(2-methoxyethylamino), 6-acetamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido); and (R2)n is hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3',4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoromethyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.

7. A quinazoline derivative of the formula I, or a pharmaceutically-acceptable acid-addition salt thereof, as claimed in claim 1, selected from:-4-(3'-chloro-4'-fluoroanilino)-6,7-dimethoxyquinazoline, 4-(3',4'-dichloroanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-4-(3'-nitroanilino)quinazoline, 6,7-diethoxy-4-(3'-methylanilino)quinazoline, 6-methoxy-4-(3'-methylanilino)quinazoline, 4-(3'-chloroanilino)-6-methoxyquinazoline, 6,7-ethylenedioxy-4-(3'-methylanilino)quinazoline, 6-amino-7-methoxy-4-(3'-methylanilino)quinazoline, 4-(3'-methylanilino)-6-ureidoquinazoline and 6-(2-methoxyethoxymethyl)-4-(3'-methylanilino)quinazoline.
8. A quinazoline derivative of the formula I as claimed in claim 1 and subject to the provisos stated in claim 1 wherein (R1)m is 6-hydroxy, 7-hydroxy, 6,7-dihydroxy, 6-amino, 7-amino, 6-ureido, 6-trifluoromethoxy, 6-methyl, 6,7-dimethyl, 6-methoxy, 7-methoxy, 6,7-dimethoxy, 6,7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6-methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino-6,7-dimethoxy, 6-methoxy-7-isopropoxy, 6,7-methylenedioxy, 6,7-ethylenedioxy, 6-methylamino, 7-methylamino, 6-dimethylamino, 6-amino-7-methylamino, 6-methoxymethyl, 6-bromomethyl, 6-(2-methoxyethoxymethyl), 6-cyanomethyl, 6-methylthiomethyl, 6-phenylthiomethyl, 7-(2-hydroxyethoxy)-6-methoxy, 6,7-di-(2-hydroxyethoxy), 6-(2-bromoethoxy), 6-(2-methoxyethoxy), 6-methoxy-7-(2-methoxyethoxy), 6,7-di-(2-methoxyethoxy), 7-(2-bromoethoxy)-6-methoxy, 7-benzoyloxy-6-methoxy, 6-(2-methoxy-ethylamino), 6-acetamido, 6-benzamido, 6-(2-chloroacetamido), 6-(2-methoxyacetamido) or 7-(2-methoxyacetamido); and (R2)n is hydrogen, 4'-fluoro, 3'-chloro, 3'-bromo, 3',4'-dichloro, 4'-fluoro-3'-chloro, 3'-trifluoromethyl, 4'-fluoro-3'-trifluoro-methyl, 3'-nitro, 3'-nitro-4'-chloro, 3'-nitro-4'-fluoro or 3'-methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
9. A quinazoline derivative of the formula I, or a pharmaceutically-acceptable acid-addition salt thereof, as claimed in claim 1, selected from: 6,7-di-12-methoxyethoxy)-4-(3'-methylanilino)quinazoline; 6-dimethylamino-4-(3'-methylanilino)quinazoline and 6-benzamido-4-(3'-methyl-anilino)quinazoline.
10. The compound 6,7-dimethoxy-4-(3'-bromoanilino)-quinazoline or a pharmaceutically-acceptable salt thereof.
11. The compound 6,7-dimethoxy-4-(3'-bromoanilino)-quinazoline.
12. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined in any one of claims 1 to 11 which comprises:
(a) the reaction of a quinazoline of the formula III

wherein Z is a displaceable group, with an aniline of the formula IV

(b) for the production of those compounds of the formula I wherein R1 or R2 is hydroxy, the cleavage of a quinazoline derivative of the formula I wherein R1 or R2 is (1-4C)alkoxy;
(c) for the production of those compounds of the formula I wherein R1 or R2 is a (1-4C)alkylsulphinyl or (1-4C)alkyl-sulphonyl group, the oxidation of a quinazoline derivative of the formula I wherein R1 or R2 is a (1-4C)alkylthio group;
(d) for the production of those compounds of the formula I wherein R1 is amino, the reduction of a quinazoline derivative of the formula I wherein R1 is nitro;
(e) for the production of those compounds of the formula I wherein R1 is (2-4C)alkanoylamino or substituted (2-4C)-alkanoylamino, ureido, 3-phenylureido or benzamido, or R2 is acetamido or benzamido the acylation of a quinazoline derivative of the formula I wherein R1 or R2 is amino;
(f) for the production of those compounds of the formula I wherein R1 is (1-4C)alkoxy or substituted (1-4C)alkoxy or R1 is (1-4C)alkylamino or substituted (1-4C)alkylamino, the alkylation of a quinazoline derivative of the formula I
wherein R1 is hydroxy or amino as appropriate;
(g) for the production of those compounds of formula I
wherein R1 is a carboxy substituent or a substituent which includes a carboxy group, the hydrolysis of a quinazoline derivative of the formula I wherein R1 is a (1-4C)alkoxy-carbonyl substituent or a substituent which includes a (1-4C)-alkoxycarbonyl group; or (h) for the production of those compounds of the formula I wherein R1 is an amino-, oxy-, thio- or cyano-substituted (1-4C)alkyl substituent, the reaction of a quinazoline derivative of the formula I wherein R1 is a (1-4C)alkyl substituent bearing a displaceable group with an appropriate amine, alcohol, thiol or cyanide;
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.
13. 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 11, or a quinazoline derivatlve selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline and 4-anilino-6-methylquinazoline or the hydrochloride salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
14. 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 11 or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxy-quinazoline or the hydrochloride salt thereof in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal.
15. 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 11 or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof and 4-anilino-6,7-dimethoxy-quinazoline or the hydrochloride salt thereof in the manufacture of a medicament for use in the production of an anti-cancer effect in man.
16. 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 11 or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof as an anti-cancer agent in a warm-blooded animal.
17. 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 11 or a quinazoline derivative selected from 4-(4'-hydroxyanilino)-6-methoxyquinazoline, 4-(4'-hydroxyanilino)-6,7-methylenedioxyquinazoline, 4-(4'-hydroxyanilino)-6,7,8-trimethoxyquinazoline, 6-amino-4-(4'-aminoanilino)quinazoline, 4-anilino-6-methylquinazoline or the hydrochloride salt thereof as an anti-cancer agent in man.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE41065E1 (en) 1995-06-06 2009-12-29 Pfizer, Inc. Alkynl and azido-substituted 4-anilinoquinazolines
CN103382182A (en) * 2013-05-17 2013-11-06 河北医科大学 Phenylurea coupling quinazoline compound, and preparation method, pharmaceutical composition and pharmaceutical use thereof

Families Citing this family (700)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721237A (en) * 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
US6645969B1 (en) 1991-05-10 2003-11-11 Aventis Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US5710158A (en) * 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5714493A (en) * 1991-05-10 1998-02-03 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
USRE37650E1 (en) 1991-05-10 2002-04-09 Aventis Pharmacetical Products, Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US7772432B2 (en) 1991-09-19 2010-08-10 Astrazeneca Ab Amidobenzamide derivatives which are useful as cytokine inhibitors
US5763441A (en) * 1992-11-13 1998-06-09 Sugen, Inc. Compounds for the treatment of disorders related to vasculogenesis and/or angiogenesis
US5981569A (en) * 1992-11-13 1999-11-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease
US5712395A (en) * 1992-11-13 1998-01-27 Yissum Research Development Corp. Compounds for the treatment of disorders related to vasculogenesis and/or angiogenesis
US5792771A (en) * 1992-11-13 1998-08-11 Sugen, Inc. Quinazoline compounds and compositions thereof for the treatment of disease
GB9323290D0 (en) 1992-12-10 1994-01-05 Zeneca Ltd Quinazoline derivatives
PH31122A (en) * 1993-03-31 1998-02-23 Eisai Co Ltd Nitrogen-containing fused-heterocycle compounds.
GB9314893D0 (en) * 1993-07-19 1993-09-01 Zeneca Ltd Quinazoline derivatives
GB9325217D0 (en) * 1993-12-09 1994-02-09 Zeneca Ltd Pyrimidine derivatives
AU739382B2 (en) * 1993-12-10 2001-10-11 Aventis Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US5700823A (en) * 1994-01-07 1997-12-23 Sugen, Inc. Treatment of platelet derived growth factor related disorders such as cancers
IL112249A (en) 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
IL112248A0 (en) 1994-01-25 1995-03-30 Warner Lambert Co Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them
US5654307A (en) * 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6524832B1 (en) * 1994-02-04 2003-02-25 Arch Development Corporation DNA damaging agents in combination with tyrosine kinase inhibitors
CN1141633A (en) * 1994-02-23 1997-01-29 辉瑞大药厂 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent
AU2096895A (en) * 1994-03-07 1995-09-25 Sugen, Incorporated Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof
DE59500788D1 (en) * 1994-05-03 1997-11-20 Ciba Geigy Ag Pyrrolopyrimidine derivatives with antiproliferative activity
MX9702307A (en) * 1994-09-29 1998-04-30 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES AND THEIR USE.
TW321649B (en) * 1994-11-12 1997-12-01 Zeneca Ltd
GB9424233D0 (en) * 1994-11-30 1995-01-18 Zeneca Ltd Quinazoline derivatives
AU778961B2 (en) * 1995-03-30 2004-12-23 Osi Pharmaceuticals, Inc. Intermediates for the preparation of 4-(substituted phenylamino)quinazoline derivatives
ATE205483T1 (en) 1995-03-30 2001-09-15 Pfizer QUINAZOLINE DERIVATIVES
DK0819129T3 (en) * 1995-04-03 2000-10-23 Novartis Ag Pyrazole derivatives and process for their preparation
US5721277A (en) * 1995-04-21 1998-02-24 Sugen, Inc. Compounds and methods for inhibiting hyper-proliferative cell growth
GB9508565D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quiazoline derivative
JPH11507329A (en) * 1995-04-27 1999-06-29 ゼネカ リミテッド Quinazoline derivatives
GB9508537D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
GB9508535D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivative
GB9508538D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
US5639757A (en) * 1995-05-23 1997-06-17 Pfizer Inc. 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors
US6331555B1 (en) 1995-06-01 2001-12-18 University Of California Treatment of platelet derived growth factor related disorders such as cancers
US5880141A (en) 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
US5763470A (en) * 1995-06-07 1998-06-09 Sugen Inc. Benzopyran compounds and methods for their use
EP0832073B1 (en) * 1995-06-07 2002-01-16 Sugen, Inc. Quinazolines and pharmaceutical compositions
US6316635B1 (en) 1995-06-07 2001-11-13 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
US7060808B1 (en) * 1995-06-07 2006-06-13 Imclone Systems Incorporated Humanized anti-EGF receptor monoclonal antibody
US6147106A (en) 1997-08-20 2000-11-14 Sugen, Inc. Indolinone combinatorial libraries and related products and methods for the treatment of disease
US6716575B2 (en) 1995-12-18 2004-04-06 Sugen, Inc. Diagnosis and treatment of AUR1 and/or AUR2 related disorders
GB9624482D0 (en) * 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
US7119174B2 (en) 1995-12-18 2006-10-10 Sugen, Inc. Diagnosis and treatment of AUR1 and/or AUR2 related disorders
ZA9756B (en) * 1996-01-16 1997-07-17 Warner Lambert Co Process for preparing 4,6-disubstituted pyrido[3,4-d]-pyrimidines
US5760041A (en) * 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
NZ330868A (en) * 1996-02-13 2000-01-28 Zeneca Ltd 4-phenoxy, phenylthio or phenylamino substituted quinazoline derivatives ane medicaments useful as VEGF inhibitors
GB9603097D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline compounds
GB9603095D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
NZ331191A (en) * 1996-03-05 2000-03-27 Zeneca Ltd 4-anilinoquinazoline derivatives and pharmaceutical compositions thereof
DK0892789T4 (en) 1996-04-12 2010-04-06 Warner Lambert Co Irreversible inhibitors of tyrosine kinases
GB9607729D0 (en) * 1996-04-13 1996-06-19 Zeneca Ltd Quinazoline derivatives
US6391874B1 (en) * 1996-07-13 2002-05-21 Smithkline Beecham Corporation Fused heterocyclic compounds as protein tyrosine kinase inhibitors
BR9710808A (en) * 1996-08-06 1999-08-17 Pfizer Bicyclic derivatives 6,6 or 6,7 containing substituted pyrite or pyrimido
RU2196137C2 (en) * 1996-08-08 2003-01-10 Зенека Лимитед Quinazoline derivatives and their use as inhibitors of vessel endothelium growth factor
US6004967A (en) * 1996-09-13 1999-12-21 Sugen, Inc. Psoriasis treatment with quinazoline compounds
EP0954315A2 (en) * 1996-09-13 1999-11-10 Sugen, Inc. Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
EP0837063A1 (en) * 1996-10-17 1998-04-22 Pfizer Inc. 4-Aminoquinazoline derivatives
US6225318B1 (en) 1996-10-17 2001-05-01 Pfizer Inc 4-aminoquinazolone derivatives
WO1998023613A1 (en) * 1996-11-27 1998-06-04 Pfizer Inc. Fused bicyclic pyrimidine derivatives
US6002008A (en) * 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6818440B2 (en) 1997-04-28 2004-11-16 Sugen, Inc. Diagnosis and treatment of alk-7 related disorders
AR012634A1 (en) 1997-05-02 2000-11-08 Sugen Inc QUINAZOLINE BASED COMPOUND, FAMACEUTICAL COMPOSITION THAT UNDERSTANDS IT, METHOD TO SYNTHESIZE IT, ITS USE, METHODS OF MODULATION OF THE DESERINE / TREONIN PROTEIN-KINASE FUNCTION AND IN VITRO METHOD TO IDENTIFY COMPOUNDS THAT MODULATE
US5929080A (en) * 1997-05-06 1999-07-27 American Cyanamid Company Method of treating polycystic kidney disease
US6486185B1 (en) 1997-05-07 2002-11-26 Sugen, Inc. 3-heteroarylidene-2-indolinone protein kinase inhibitors
US6316429B1 (en) 1997-05-07 2001-11-13 Sugen, Inc. Bicyclic protein kinase inhibitors
US6316479B1 (en) 1997-05-19 2001-11-13 Sugen, Inc. Isoxazole-4-carboxamide compounds active against protein tryosine kinase related disorders
US6228641B1 (en) 1997-05-20 2001-05-08 Sugen, Inc. Diagnosis and treatment of PTP04 related disorders
US6987113B2 (en) 1997-06-11 2006-01-17 Sugen, Inc. Tyrosine kinase inhibitors
US6342593B1 (en) 1997-06-11 2002-01-29 Sugen, Inc. Diagnosis and treatment of ALP related disorders
US7115710B2 (en) 1997-06-11 2006-10-03 Sugen, Inc. Diagnosis and treatment of PTP related disorders
US6388063B1 (en) 1997-06-18 2002-05-14 Sugen, Inc. Diagnosis and treatment of SAD related disorders
US6313158B1 (en) 1997-06-20 2001-11-06 Sugen, Inc. Bioavailability of 3-heteroarylidenyl-2-indolinones active as protein tyrosine kinase inhibitors
US6051593A (en) * 1997-06-20 2000-04-18 Sugen, Inc. 3-(cycloalkanoheteroarylidenyl)-2- indolinone protein tyrosine kinase inhibitors
US6130238A (en) * 1997-06-20 2000-10-10 Sugen, Inc. 3-(cyclohexanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
US6114371A (en) * 1997-06-20 2000-09-05 Sugen, Inc. 3-(cyclohexanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
US6235769B1 (en) 1997-07-03 2001-05-22 Sugen, Inc. Methods of preventing and treating neurological disorders with compounds that modulate the function of the C-RET receptor protein tyrosine kinase
ZA986729B (en) * 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitors of tyrosine kinases
ZA986732B (en) 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
TW436485B (en) * 1997-08-01 2001-05-28 American Cyanamid Co Substituted quinazoline derivatives
US6251912B1 (en) 1997-08-01 2001-06-26 American Cyanamid Company Substituted quinazoline derivatives
WO1999007701A1 (en) 1997-08-05 1999-02-18 Sugen, Inc. Tricyclic quinoxaline derivatives as protein tyrosine kinase inhibitors
AU737092B2 (en) * 1997-08-15 2001-08-09 Cephalon, Inc. Combination of tyrosine kinase inhibitor and chemical castration to treat prostate cancer
AU8816298A (en) 1997-08-22 1999-03-16 Zeneca Limited Oxindolylquinazoline derivatives as angiogenesis inhibitors
DK1017384T3 (en) * 1997-09-26 2005-01-31 Zentaris Gmbh Azabenzimidazole-based compounds for modulating serine / threonine protein kinase function
US6133305A (en) * 1997-09-26 2000-10-17 Sugen, Inc. 3-(substituted)-2-indolinones compounds and use thereof as inhibitors of protein kinase activity
UA71555C2 (en) 1997-10-06 2004-12-15 Zentaris Gmbh Methods for modulating function of serine/threonine protein kinases by 5-azaquinoline derivatives
US6323209B1 (en) 1997-11-06 2001-11-27 American Cyanamid Company Method of treating or inhibiting colonic polyps
GB9800569D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
WO1999037787A2 (en) 1998-01-21 1999-07-29 Sugen, Inc. Human orthologues of wart
US6531502B1 (en) 1998-01-21 2003-03-11 Sugen, Inc. 3-Methylidenyl-2-indolinone modulators of protein kinase
JP2002504529A (en) 1998-02-27 2002-02-12 ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ シークレタリー デパートメント オブ ヘルス アンド ヒューマン サービシーズ Disubstituted lavendustine A analogs and pharmaceutical compositions containing these analogs
US20030224001A1 (en) * 1998-03-19 2003-12-04 Goldstein Neil I. Antibody and antibody fragments for inhibiting the growth of tumors
US6514981B1 (en) 1998-04-02 2003-02-04 Sugen, Inc. Methods of modulating tyrosine protein kinase function with indolinone compounds
JP2002522009A (en) 1998-04-14 2002-07-23 スージェン・インコーポレーテッド STE-20-related protein kinase
US6706721B1 (en) 1998-04-29 2004-03-16 Osi Pharmaceuticals, Inc. N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate
ZA200007412B (en) * 1998-05-15 2002-03-12 Imclone Systems Inc Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases.
WO1999061428A1 (en) * 1998-05-28 1999-12-02 Parker Hughes Institute Quinazolines for treating brain tumor
SK287132B6 (en) 1998-05-29 2009-12-07 Sugen, Inc. Pharmaceutical composition containing pyrrole substituted 2-indolinone, kit containing mentioned composition and use pyrrole substituted 2-indolinone
US6384223B1 (en) 1998-07-30 2002-05-07 American Home Products Corporation Substituted quinazoline derivatives
US6184226B1 (en) * 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US6525072B1 (en) 1998-08-31 2003-02-25 Sugen, Inc. Geometrically restricted 2-indolinone derivatives as modulators of protein kinase activity
US6680335B2 (en) 1998-09-28 2004-01-20 Sugen, Inc. Methods of modulating protein tyrosine kinase function with substituted indolinone compounds
US6288082B1 (en) 1998-09-29 2001-09-11 American Cyanamid Company Substituted 3-cyanoquinolines
US6297258B1 (en) 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
CA2344168C (en) 1998-09-29 2011-04-05 American Cyanamid Company Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors
ATE232205T1 (en) 1998-10-01 2003-02-15 Astrazeneca Ab QUINOLINE AND QUINAZOLINE DERIVATIVES AND THEIR USE AS INHIBITORS OF DISEASES INVOLVING CYTOKINE
UA71945C2 (en) 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
JP3270834B2 (en) 1999-01-27 2002-04-02 ファイザー・プロダクツ・インク Heteroaromatic bicyclic derivatives useful as anticancer agents
DK1553097T3 (en) 1999-02-10 2010-12-13 Astrazeneca Ab Quinazoline derivative as angiogenesis inhibitor and intermediates thereto
DE19911509A1 (en) * 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
CA2368097C (en) 1999-03-17 2010-01-19 Astrazeneca Ab Amide derivatives of 3,4-dihydroquinazolinone compounds useful as cytokine inhibitors
US7064114B2 (en) * 1999-03-19 2006-06-20 Parker Hughes Institute Gel-microemulsion formulations
US6258820B1 (en) 1999-03-19 2001-07-10 Parker Hughes Institute Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
RS49836B (en) 1999-03-31 2008-08-07 Pfizer Products Inc., Process and intermediates for preparing anti-cancer compounds
IT1312310B1 (en) * 1999-05-07 2002-04-15 Recordati Ind Chimica E Farma USE OF SELECTIVE 1B ADRENERGIC RECEPTOR ANTAGONISTS TO IMPROVE SEXUAL DYSFUNCTION
CA2373815A1 (en) 1999-05-14 2000-11-23 Imclone Systems Incorporated Treatment of refractory human tumors with epidermal growth factor receptor antagonists
US6126917A (en) * 1999-06-01 2000-10-03 Hadasit Medical Research Services And Development Ltd. Epidermal growth factor receptor binding compounds for positron emission tomography
CA2375259C (en) 1999-06-21 2009-04-28 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
DE60037020T2 (en) 1999-07-09 2008-08-21 Glaxo Group Ltd., Greenford ANILINOCHINAZOLINE AS PROTEIN TYROSINE KINASE INHIBITOR
US6933299B1 (en) 1999-07-09 2005-08-23 Smithkline Beecham Corporation Anilinoquinazolines as protein tyrosine kinase inhibitors
US6432979B1 (en) 1999-08-12 2002-08-13 American Cyanamid Company Method of treating or inhibiting colonic polyps and colorectal cancer
US6921763B2 (en) 1999-09-17 2005-07-26 Abbott Laboratories Pyrazolopyrimidines as therapeutic agents
US7081461B1 (en) * 1999-09-21 2006-07-25 Astrazeneca Ab Quinazoline compounds and pharmaceutical compositions containing them
AU7301000A (en) * 1999-09-21 2001-04-24 Astrazeneca Ab Quinazoline derivatives and their use as pharmaceuticals
JP3868811B2 (en) * 1999-10-01 2007-01-17 大日本住友製薬株式会社 New quinazoline derivatives
GB9924092D0 (en) * 1999-10-13 1999-12-15 Zeneca Ltd Pyrimidine derivatives
SV2002000205A (en) * 1999-11-01 2002-06-07 Lilly Co Eli PHARMACEUTICAL COMPOUNDS REF. X-01095
GB9925958D0 (en) * 1999-11-02 1999-12-29 Bundred Nigel J Therapeutic use
ATE330954T1 (en) * 1999-11-05 2006-07-15 Astrazeneca Ab QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
US7087613B2 (en) 1999-11-11 2006-08-08 Osi Pharmaceuticals, Inc. Treating abnormal cell growth with a stable polymorph of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride
UA74803C2 (en) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. A stable polymorph of n-(3-ethynylphenyl)-6,7-bis(2-methoxyetoxy)-4-quinazolinamine hydrochloride, a method for producing thereof (variants) and pharmaceutical use
US6878733B1 (en) 1999-11-24 2005-04-12 Sugen, Inc. Formulations for pharmaceutical agents ionizable as free acids or free bases
UA75055C2 (en) * 1999-11-30 2006-03-15 Пфайзер Продактс Інк. Benzoimidazole derivatives being used as antiproliferative agent, pharmaceutical composition based thereon
WO2001057008A1 (en) 2000-02-07 2001-08-09 Abbott Gesellschaft Mit Beschrankter Haftung & Company Kommanditgesellschaft 2-benzothiazolyl urea derivatives and their use as protein kinase inhibitors
GB0002952D0 (en) * 2000-02-09 2000-03-29 Pharma Mar Sa Process for producing kahalalide F compounds
NZ520640A (en) 2000-02-15 2005-04-29 Upjohn Co Pyrrole substituted 2-indolinone protein kinase inhibitors
ES2267748T3 (en) * 2000-04-07 2007-03-16 Astrazeneca Ab QUINAZOLINE COMPOUNDS.
RU2276151C2 (en) * 2000-06-06 2006-05-10 Астразенека Аб Quinazoline derivatives for tumor treatment
UA73993C2 (en) * 2000-06-06 2005-10-17 Астразенека Аб Quinazoline derivatives for the treatment of tumours and a pharmaceutical composition
CA2412592A1 (en) * 2000-06-28 2002-01-03 Astrazeneca Ab Substituted quinazoline derivatives and their use as inhibitors
AU9500201A (en) * 2000-08-09 2002-02-18 Imclone Systems Inc Treatment of hyperproliferative diseases with epidermal growth factor receptor antagonists
KR20080027400A (en) 2000-08-21 2008-03-26 아스트라제네카 아베 Quinazoline derivatives
US6617329B2 (en) 2000-08-26 2003-09-09 Boehringer Ingelheim Pharma Kg Aminoquinazolines and their use as medicaments
DE10042059A1 (en) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE60144284D1 (en) 2000-11-01 2011-05-05 Millennium Pharm Inc NITROGENIC HETEROCYCLIC COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US6582919B2 (en) 2001-06-11 2003-06-24 Response Genetics, Inc. Method of determining epidermal growth factor receptor and HER2-neu gene expression and correlation of levels thereof with survival rates
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
AR042586A1 (en) 2001-02-15 2005-06-29 Sugen Inc 3- (4-AMIDOPIRROL-2-ILMETILIDEN) -2-INDOLINONE AS INHIBITORS OF PROTEIN KINASE; YOUR PHARMACEUTICAL COMPOSITIONS; A METHOD FOR THE MODULATION OF THE CATALYTIC ACTIVITY OF PROTEINQUINASE; A METHOD TO TREAT OR PREVENT AN AFFECTION RELATED TO PROTEINQUINASE
CA2994779C (en) 2001-02-19 2020-08-25 Novartis Ag Use of 40-o-(2-hydroxyethyl)-rapamycin for inhibiting growth of a solid tumour of the brain other than lymphatic cancer
ATE340165T1 (en) * 2001-02-26 2006-10-15 Univ Mcgill COMBINATION MOLECULES WHICH HAVE AN INHIBITING EFFECT ON SIGNAL TRANSMISSION AND DNA DAMAGE PROPERTIES
US20080008704A1 (en) * 2001-03-16 2008-01-10 Mark Rubin Methods of treating colorectal cancer with anti-epidermal growth factor antibodies
MXPA03008560A (en) 2001-03-22 2004-06-30 Abbot Gmbh & Co Kg Single-stage pfc + ballast control circuit/general purpose power converter.
EP1385983A4 (en) * 2001-04-02 2005-11-16 Merck & Co Inc In vivo methods of determining activity of receptor-type kinase inhibitors
CA2444821C (en) 2001-04-24 2012-07-10 Merck Patent Gesellschaft Mit Beschraenkter Haftung Combination therapy using anti-angiogenic agents and tnfa
US20110313230A1 (en) 2001-05-11 2011-12-22 Terrance Grant Johns Specific binding proteins and uses thereof
US20100056762A1 (en) 2001-05-11 2010-03-04 Old Lloyd J Specific binding proteins and uses thereof
WO2002092771A2 (en) 2001-05-11 2002-11-21 Ludwig Institute For Cancer Research Specific binding proteins and uses thereof
WO2002092577A1 (en) * 2001-05-14 2002-11-21 Astrazeneca Ab Quinazoline derivatives
BR0209647A (en) 2001-05-16 2004-07-27 Novartis Ag A combination comprising n- {5- [4- (4-methyl-piperazine-methyl) -benzoylamido] -2-methyl-phenyl} -4- (3-pyridyl) -2-pyrimidine-amine and a chemotherapeutic agent
EP1408980A4 (en) 2001-06-21 2004-10-20 Ariad Pharma Inc Novel quinazolines and uses thereof
KR100397792B1 (en) 2001-06-28 2003-09-13 한국과학기술연구원 4-(phenylamino)-[1,4]dioxano[2,3-g]quinazoline Derivatives and Process for Preparing the Same
JP2005508953A (en) 2001-10-10 2005-04-07 スージェン・インコーポレーテッド 3- [4- (Substituted heterocyclyl) -pyrrol-2-ylmethylidene] -2-indolinone derivatives as kinase inhibitors
GB0126433D0 (en) * 2001-11-03 2002-01-02 Astrazeneca Ab Compounds
HU229477B1 (en) * 2001-12-24 2014-01-28 Astrazeneca Ab Substituted quinazoline derivatives as inhibitors of aurora kinases
EA200400816A1 (en) * 2002-01-17 2005-02-24 Ньюроджин Корпорейшн SUBSTITUTE HINAZOLIN-4-ILAMINE ANALOGUES AS CAPSAICIN MODULATORS
BR0307151A (en) 2002-02-01 2004-12-07 Astrazeneca Ab Compound or a salt thereof, process for preparing it, pharmaceutical composition, use of the compound or salt thereof, method for producing an antiangiogenic and / or vascular permeability reducing effect in a warm-blooded animal such as a human , which requires a treatment of the said type, and processes for the preparation of 5-bromo-7-azaindole, and for the production of 5-methoxy-7-azaindole
US7612077B2 (en) * 2002-02-26 2009-11-03 Astrazeneca Ab Crystalline forms of the anti-cancer compound ZD1839
GB0204392D0 (en) * 2002-02-26 2002-04-10 Astrazeneca Ab Pharmaceutical compound
DK1480679T3 (en) * 2002-02-26 2007-09-03 Astrazeneca Ab Pharmaceutical formulation of iressa comprising a water-soluble cellulose derivative
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
TW200813014A (en) * 2002-03-28 2008-03-16 Astrazeneca Ab Quinazoline derivatives
US7078409B2 (en) 2002-03-28 2006-07-18 Beta Pharma, Inc. Fused quinazoline derivatives useful as tyrosine kinase inhibitors
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
JP2005530735A (en) * 2002-04-16 2005-10-13 アストラゼネカ アクチボラグ Combination therapy for the treatment of cancer
DE10221018A1 (en) 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Use of inhibitors of EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy
PL372103A1 (en) 2002-05-16 2005-07-11 Novartis Ag Use of edg receptor binding agents in cancer
JP5111729B2 (en) 2002-06-05 2013-01-09 ジェネンテック， インコーポレイテッド Compositions and methods for liver growth and liver protection
GB0221245D0 (en) 2002-09-13 2002-10-23 Astrazeneca Ab Chemical process
GB0223854D0 (en) * 2002-10-12 2002-11-20 Astrazeneca Ab Therapeutic treatment
GB0304367D0 (en) * 2003-02-26 2003-04-02 Pharma Mar Sau Methods for treating psoriasis
PT1562955E (en) * 2002-11-04 2008-05-05 Astrazeneca Ab Quinazoline derivatives as src tyrosine kinase inhibitors
WO2004055004A1 (en) * 2002-12-13 2004-07-01 Neurogen Corporation Carboxylic acid, phosphate or phosphonate substituted quinazolin-4-ylamine analogues as capsaicin receptor modulators
WO2004056807A1 (en) 2002-12-20 2004-07-08 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
WO2004064718A2 (en) * 2003-01-23 2004-08-05 T.K. Signal Ltd. Irreversible inhibitors of egf receptor tyrosine kinases and uses thereof
US7223749B2 (en) 2003-02-20 2007-05-29 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
EP1622941A2 (en) * 2003-03-20 2006-02-08 ImClone Systems Incorporated Method of producing an antibody to epidermal growth factor receptor
GB0309850D0 (en) 2003-04-30 2003-06-04 Astrazeneca Ab Quinazoline derivatives
JP4944613B2 (en) 2003-05-19 2012-06-06 アイアールエム・リミテッド・ライアビリティ・カンパニー Immunosuppressive compounds and compositions
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
EP2348110B1 (en) 2003-05-30 2013-03-27 OncoTherapy Science, Inc. Process for screening a drug response in cancer patients
US20070036795A1 (en) 2003-06-09 2007-02-15 Samuel Waksal Method of inhibiting receptor tyrosine kinases with an extracellular antagonist and an intracellular agonist
PL1680426T3 (en) * 2003-06-10 2008-02-29 Hoffmann La Roche 1.3.4-triaza-phenalene and 1,3,4,6-tetraazaphenalene derivatives
AU2004261477A1 (en) * 2003-07-29 2005-02-10 Astrazeneca Ab Piperidyl-quinazoline derivatives as tyrosine kinase inhibitors
GB0317663D0 (en) * 2003-07-29 2003-09-03 Astrazeneca Ab Pharmaceutical composition
GB0317665D0 (en) 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
PT1663982E (en) 2003-07-31 2008-01-31 Sanofi Aventis Aminoquinoline derivatives and their use as adenosine a3 ligands
GB0318422D0 (en) 2003-08-06 2003-09-10 Astrazeneca Ab Chemical compounds
US7105562B2 (en) 2003-08-06 2006-09-12 Sugen, Inc. Geometrically restricted 3-cyclopentylidene-1,3-dihydroindol-2-ones as potent protein tyrosine kinase inhibitors
GB0321066D0 (en) * 2003-09-09 2003-10-08 Pharma Mar Sau New antitumoral compounds
AU2004272345A1 (en) * 2003-09-16 2005-03-24 Astrazeneca Ab Quinazoline derivatives
ES2305844T3 (en) * 2003-09-16 2008-11-01 Astrazeneca Ab DERIVATIVES OF QUINAZOLINE AS INHIBITORS OF THYROSINE KINASE.
EP1670782B1 (en) * 2003-09-19 2007-02-14 AstraZeneca AB Quinazoline derivatives
RU2370494C2 (en) * 2003-09-19 2009-10-20 Астразенека Аб Quinazoline derivatives
WO2005030757A1 (en) * 2003-09-25 2005-04-07 Astrazeneca Ab Quinazoline derivatives
GB0322409D0 (en) 2003-09-25 2003-10-29 Astrazeneca Ab Quinazoline derivatives
US7232824B2 (en) * 2003-09-30 2007-06-19 Scios, Inc. Quinazoline derivatives as medicaments
US7456189B2 (en) 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10349113A1 (en) 2003-10-17 2005-05-12 Boehringer Ingelheim Pharma Process for the preparation of aminocrotonyl compounds
GB0324790D0 (en) 2003-10-24 2003-11-26 Astrazeneca Ab Amide derivatives
WO2005048928A2 (en) * 2003-11-12 2005-06-02 George Mason Intellectual Property Methods for treating viral infection
US20050171171A1 (en) * 2003-11-13 2005-08-04 Ambit Biosciences Corporation Amide derivatives as FLT-3 modulators
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
JP2007537717A (en) * 2004-01-07 2007-12-27 ブリストル−マイヤーズ　スクイブ　カンパニー Biomarkers and methods for determining susceptibility to epidermal growth factor receptor modulators
ES2315834T3 (en) 2004-02-03 2009-04-01 Astrazeneca Ab DERIVATIVES OF QUINAZOLINA.
BRPI0400869B8 (en) * 2004-03-02 2021-05-25 Univ Estadual Campinas Unicamp new compounds derived from 4-anilinoquinazolines with adenosine kinase inhibiting property
CA2557433C (en) 2004-02-19 2013-05-14 Rexahn Corporation Quinazoline derivatives and therapeutic use thereof
DK1735348T3 (en) * 2004-03-19 2012-07-16 Imclone Llc Human anti-epidermal growth factor receptor antibody
EP2423331B1 (en) 2004-03-31 2019-05-08 The General Hospital Corporation Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments
BRPI0509721A (en) 2004-04-07 2007-09-25 Novartis Ag iap inhibitors
CN1972688B (en) 2004-05-06 2012-06-27 沃尼尔·朗伯有限责任公司 4-phenylamino-quinazolin-6-yl-amides
WO2005107747A2 (en) 2004-05-06 2005-11-17 Bioresponse, Llc Diindolymethane formulations for the treatment of leiomyomas
CA2566647A1 (en) * 2004-05-13 2005-12-22 Imclone Systems Incorporated Inhibition of macrophage-stimulating protein receptor (ron)
GB0512324D0 (en) 2005-06-16 2005-07-27 Novartis Ag Organic compounds
WO2006002422A2 (en) 2004-06-24 2006-01-05 Novartis Vaccines And Diagnostics Inc. Compounds for immunopotentiation
CA2581516C (en) 2004-10-12 2013-06-11 Astrazeneca Ab Quinazoline derivatives
US7947676B2 (en) 2004-12-14 2011-05-24 Astrazeneca Ab Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents
ATE497762T1 (en) 2004-12-30 2011-02-15 Bioresponse Llc USE OF DIINDOLYLMETHANE-RELATED INDOLES FOR THE TREATMENT AND PREVENTION OF DISEASES RELATED TO THE RESPIRATORY SYNCYTIAL VIRUS
US20060188498A1 (en) * 2005-02-18 2006-08-24 Genentech, Inc. Methods of using death receptor agonists and EGFR inhibitors
US20090155247A1 (en) * 2005-02-18 2009-06-18 Ashkenazi Avi J Methods of Using Death Receptor Agonists and EGFR Inhibitors
PL1854789T3 (en) 2005-02-23 2014-03-31 Shionogi & Co Quinazoline derivative having tyrosine kinase inhibitory activity
AR055564A1 (en) 2005-02-26 2007-08-22 Astrazeneca Ab QUINAZOLINE DERIVATIVES
DE602006004976D1 (en) * 2005-03-28 2009-03-12 Bristol Myers Squibb Co COMPETITIVE ATP KINASE HEMMER
US8309133B2 (en) * 2005-04-12 2012-11-13 Alkermes Pharma Ireland Limited Nanoparticulate quinazoline derivative formulations
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
US20060286103A1 (en) 2005-06-15 2006-12-21 Parag Kolhe Stable antibody formulation
DK2100614T3 (en) 2005-06-17 2013-10-28 Imclone Llc Antibody to PDGFR-alpha for use in the treatment of tumors
ATE520979T1 (en) * 2005-08-24 2011-09-15 Bristol Myers Squibb Co BIOMARRKERS AND METHODS FOR DETERMINING SENSITIVITY TO MODULATORS OF THE EGF (EPIDERMAL GROWTH FACTOR) RECEPTOR
AU2006288716A1 (en) * 2005-09-06 2007-03-15 T.K. Signal Ltd. Polyalkylene glycol derivatives of 4- (phenylamino)quinazolines useful as irreversible inhibitors of epidermal growth factor receptor tyrosine kinase
ES2354457T3 (en) 2005-09-20 2011-03-15 Astrazeneca Ab COMPOUNDS OF 4- (1H-INDAZOL-5-IL-AMINO) -CHINAZOLINE AS INHIBITORS OF THE ERBB RECEIVER OF THYROSINE KINASE FOR THE TREATMENT OF CANCER.
AU2006201635A1 (en) * 2005-10-20 2007-05-10 Ludwig Institute For Cancer Research Novel inhibitors and methods for their preparation
US8404697B2 (en) 2005-11-11 2013-03-26 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
EP2022498A3 (en) 2005-11-21 2012-08-15 Novartis AG Neuroendocrine tumour treatment
BRPI0620462A2 (en) * 2005-12-22 2011-11-16 Astrazeneca Ab compound, process for preparing a compound, pharmaceutical composition, use of a compound, and methods for producing a b-raf inhibitory effect and an anti-cancer effect in a warm-blooded animal, and for treating a disease.
CN101003514A (en) 2006-01-20 2007-07-25 上海艾力斯医药科技有限公司 Derivative of quinazoline, preparation method and usage
JO2660B1 (en) 2006-01-20 2012-06-17 نوفارتيس ايه جي PI-3 Kinase inhibitors and methods of their use
UA95945C2 (en) 2006-02-03 2011-09-26 Имклоун Ллк Method for the treatment of prostate cancer comprosing androgen deprivation therapy in combination with imc-a12 administration
PE20070978A1 (en) * 2006-02-14 2007-11-15 Novartis Ag HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks)
TWI404709B (en) * 2006-02-21 2013-08-11 Eisai R&D Man Co Ltd 4-(3-benzamidophenyl) -6,7-dimethoxy-2-methylamine quinazoline derivatives
US20090076075A1 (en) * 2006-03-02 2009-03-19 Frederic Henri Jung Quinoline derivatives
UY30183A1 (en) 2006-03-02 2007-10-31 Astrazeneca Ab QUINOLINE DERIVATIVES
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
US20070231298A1 (en) * 2006-03-31 2007-10-04 Cell Genesys, Inc. Cytokine-expressing cancer immunotherapy combinations
JP2009532503A (en) 2006-04-05 2009-09-10 ノバルティス アクチエンゲゼルシャフト Combination of therapeutic agents for treating cancer
KR20080109068A (en) 2006-04-05 2008-12-16 노파르티스 아게 Combination comprising RC-AL / C-VIT / PDV-R TV inhibitors to treat cancer
TW200808739A (en) * 2006-04-06 2008-02-16 Novartis Vaccines & Diagnostic Quinazolines for PDK1 inhibition
AU2007240496A1 (en) 2006-04-19 2007-11-01 Novartis Ag Indazole compounds and methods for inhibition of CDC7
WO2007128820A1 (en) 2006-05-09 2007-11-15 Novartis Ag Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
UA91129C2 (en) 2006-05-09 2010-06-25 Пфайзер Продактс Инк. Cycloalkylamino acid derivatives and pharmaceutical compositions thereof
CA2655997A1 (en) 2006-06-30 2008-01-10 Schering Corporation Igfbp2 biomarker
CN101100466B (en) 2006-07-05 2013-12-25 天津和美生物技术有限公司 Non-reversible protein tyrosine phosphorus acylase inhibitor and its preparation and application
EP2061469B8 (en) * 2006-09-11 2014-02-26 Curis, Inc. Quinazoline based egfr inhibitors
SG174774A1 (en) 2006-09-11 2011-10-28 Curis Inc Quinazoline based egfr inhibitors containing a zinc binding moiety
EP2061772A4 (en) * 2006-09-11 2011-06-29 Curis Inc Multi-functional small molecules as anti-proliferative agents
US7547781B2 (en) * 2006-09-11 2009-06-16 Curis, Inc. Quinazoline based EGFR inhibitors containing a zinc binding moiety
US20100008910A1 (en) 2006-09-12 2010-01-14 John Chant Methods and compositions for the diagnosis and treatment of cancer
CA2663599A1 (en) 2006-09-18 2008-03-27 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
BRPI0719509A2 (en) * 2006-09-28 2013-12-31 Follica Inc METHODS, KITS AND COMPOSITIONS FOR GENERATING NEW HAIR FOLICULES AND HAIR GROWTH
DE602007013441D1 (en) 2006-09-29 2011-05-05 Novartis Ag PYRAZOLOPYRIMIDINE AS PI3K LIPID KINASE INHIBITOR
JO3598B1 (en) * 2006-10-10 2020-07-05 Infinity Discovery Inc Boronic acids and esters as inhibitors of fatty acid amide hydrolase
BRPI0717753B1 (en) 2006-10-27 2022-04-12 Bioresponse, Llc Use of a composition comprising 50-250 mg of one or more dim-related indoles and one or more anti-protozoal agents, and, composition
EP1921070A1 (en) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation
CN104013956B (en) 2007-01-25 2018-12-18 达娜-法勃肿瘤研究所公司 Purposes of the anti-egfr antibodies in the mutant mediated disease for the treatment of EGFR
AU2008212999A1 (en) 2007-02-06 2008-08-14 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
CN101245050A (en) 2007-02-14 2008-08-20 上海艾力斯医药科技有限公司 4-aniline quinazoline derivative salt
MX2009008584A (en) 2007-02-15 2009-08-18 Novartis Ag Combinations of therapeutic agents for treating cancer.
AU2008227123B2 (en) 2007-03-15 2014-03-27 Ludwig Institute For Cancer Research Ltd. Treatment method using EGFR antibodies and src inhibitors and related formulations
SI2154967T1 (en) 2007-04-16 2014-06-30 Hutchison Medipharma Enterprises Limited Offshore Group Chambers Pyrimidine derivatives
JP4782239B2 (en) 2007-04-18 2011-09-28 ファイザー・プロダクツ・インク Sulfonylamide derivatives for the treatment of abnormal cell proliferation
CA2687611A1 (en) * 2007-05-24 2008-11-27 Bayer Schering Pharma Aktiengesellschaft Novel sulphoximine-substituted quinoline and quinazoline derivatives as kinase inhibitors
JP5532486B2 (en) * 2007-08-14 2014-06-25 ルードヴィッヒ インスティテュート フォー キャンサー リサーチ Monoclonal antibody 175 targeting EGF receptor and derivatives and uses thereof
US8119616B2 (en) * 2007-09-10 2012-02-21 Curis, Inc. Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
CA2698944C (en) * 2007-09-10 2015-06-16 Curis, Inc. Tartrate salts or complexes of quinazoline based egfr inhibitors containing a zinc binding moiety
KR20100099128A (en) * 2007-10-19 2010-09-10 파르마 마르 에스.에이. Improved antitumoral treatments
CN101918579A (en) * 2007-10-22 2010-12-15 先灵公司 Fully human anti-VEGF antibodies and methods of use
KR20100087185A (en) * 2007-10-29 2010-08-03 낫코 파마 리미티드 Novel 4-(tetrazol-5-yl)-quinazoline derivatives as anti cancer agents
US8969313B2 (en) 2007-11-02 2015-03-03 Agency For Science, Technology And Research Methods and compounds for preventing and treating a tumour
EP2060565A1 (en) 2007-11-16 2009-05-20 4Sc Ag Novel bifunctional compounds which inhibit protein kinases and histone deacetylases
US20110053991A1 (en) * 2007-11-19 2011-03-03 Gore Lia Treatment of Histone Deacetylase Mediated Disorders
WO2009067242A2 (en) * 2007-11-20 2009-05-28 Imclone Llc Co-crystal of antibody 11f8 fab fragment and egfr extracellular domain and uses thereof
AR069393A1 (en) * 2007-11-21 2010-01-20 Imclone Systems Inc INHIBITION OF THE RECEIVER FOR MACROFAGO STIMULATING PROTEIN (RON) AND METHODS FOR THE TREATMENT OF THE SAME
EP2072502A1 (en) * 2007-12-20 2009-06-24 Bayer Schering Pharma Aktiengesellschaft Sulfoximide substituted chinolin and chinazolin derivatives as kinase inhibitors
WO2009080694A1 (en) 2007-12-20 2009-07-02 Novartis Ag Thiazole derivatives used as pi 3 kinase inhibitors
CA2711737C (en) 2008-01-18 2015-03-31 Natco Pharma Limited 6,7-dialkoxy quinazoline derivatives useful for treatment of cancer related disorders
US20100323021A1 (en) * 2008-01-30 2010-12-23 Pharma Mar, S.A. Antitumoral treatments
TWI472339B (en) 2008-01-30 2015-02-11 Genentech Inc Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof
MX2010008621A (en) 2008-02-07 2010-09-24 Boehringer Ingelheim Int Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production.
DE102008009609A1 (en) 2008-02-18 2009-08-20 Freie Universität Berlin Substituted 4- (indol-3-yl) quinazolines and their use and preparation
PL2259800T3 (en) * 2008-03-05 2014-09-30 Novartis Ag Use of 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine for the treatment of non small cell lung carcinoma with acquired resistance to epidermal growth factor receptor (EGFR) modulators.
JP2011513370A (en) * 2008-03-07 2011-04-28 ファルマ・マール・ソシエダード・アノニマ Improved anti-tumor treatment
EP2268612B1 (en) 2008-03-24 2014-08-20 Novartis AG Arylsulfonamide-based matrix metalloprotease inhibitors
MY150437A (en) 2008-03-26 2014-01-30 Novartis Ag Hydroxamate-based inhibitors of deacetylases b
CA2721060A1 (en) * 2008-04-09 2009-10-15 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US7829574B2 (en) 2008-05-09 2010-11-09 Hutchison Medipharma Enterprises Limited Substituted quinazoline compounds and their use in treating angiogenesis-related diseases
MX2010012442A (en) 2008-05-13 2011-10-11 Astrazeneca Ab Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxy}quinazoline.
CN101584696A (en) * 2008-05-21 2009-11-25 上海艾力斯医药科技有限公司 Composition containing quinazoline derivatives, preparation method and use
US8426430B2 (en) * 2008-06-30 2013-04-23 Hutchison Medipharma Enterprises Limited Quinazoline derivatives
EP2313397B1 (en) 2008-08-08 2016-04-20 Boehringer Ingelheim International GmbH Cyclohexyloxy substituted heterocycles, medicine containing these connections, their application and production method
TW201008933A (en) * 2008-08-29 2010-03-01 Hutchison Medipharma Entpr Ltd Pyrimidine compounds
US20110223241A1 (en) 2008-10-16 2011-09-15 Celator Pharmaceuticals, Inc. Combination methods and compositions
MX2011004824A (en) 2008-11-07 2012-01-12 Triact Therapeutics Inc Use of catecholic butane derivatives in cancer therapy.
US20100222371A1 (en) * 2008-11-20 2010-09-02 Children's Medical Center Corporation Prevention of surgical adhesions
PT2379497E (en) 2008-12-18 2013-11-29 Novartis Ag Hemifumarate salt of 1- ã¿4- ã¿1- ( 4 -cyclohexyl-3 -trifluoromethyl-benzyloxyimino ) -ethylâ¿-2 -ethyl-benzylâ¿-a zetidine-3-carboxylic acid
CN102256941A (en) 2008-12-18 2011-11-23 诺瓦提斯公司 New salts
RU2011129230A (en) 2008-12-18 2013-01-27 Новартис Аг NEW POLYMORPHIC FORM 1- [4- [1- (4-Cyclohexyl-3-trifluoromethylbenzyloxylimino) Ethyl] -2-Ethylbenzyl] Azetidine-3-Carboxylic Acid
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
PT2391366E (en) 2009-01-29 2013-02-05 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
JP2012518657A (en) 2009-02-25 2012-08-16 オーエスアイ・ファーマシューティカルズ，エルエルシー Combined anticancer treatment
JP2012519170A (en) 2009-02-26 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー INSITU method for monitoring EMT status of tumor cells in vivo
JP2012519282A (en) 2009-02-27 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー Methods for identifying mesenchymal tumor cells or agents that inhibit their production
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
EP2401614A1 (en) 2009-02-27 2012-01-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
WO2010107968A1 (en) 2009-03-18 2010-09-23 Osi Pharmaceuticals, Inc. Combination cancer therapy comprising administration of an egfr inhibitor and an igf-1r inhibitor
CN104447995A (en) 2009-03-20 2015-03-25 霍夫曼-拉罗奇有限公司 Bispecific anti-HER antibodies
AU2010234445A1 (en) * 2009-04-07 2011-11-03 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
JP2012523425A (en) 2009-04-07 2012-10-04 インフイニトイ プハルマセウトイカルス インコーポレイテッド Inhibitors of fatty acid amide hydrolase
SI2445903T1 (en) 2009-06-26 2014-07-31 Novartis Ag 1,3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
LT2451445T (en) 2009-07-06 2019-06-25 Boehringer Ingelheim International Gmbh Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US9050341B2 (en) 2009-07-14 2015-06-09 Natco Pharma Limited Methods of treating drug resistant and other tumors by administering 6,7-dialkoxy quinazoline derivatives
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
EP2464649A1 (en) 2009-08-12 2012-06-20 Novartis AG Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
KR101721280B1 (en) 2009-08-17 2017-03-29 인텔리카인, 엘엘씨 Heterocyclic compounds and uses thereof
KR20120089463A (en) 2009-08-20 2012-08-10 노파르티스 아게 Heterocyclic oxime compounds
IN2012DN01693A (en) 2009-08-26 2015-06-05 Novartis Ag
CA2772194A1 (en) 2009-09-01 2011-03-10 Pfizer Inc. Benzimidazole derivatives
MY160243A (en) 2009-09-03 2017-02-28 Bristol Myers Squibb Co Quinazolines as potassium ion channel inhibitors
KR20120093867A (en) 2009-09-10 2012-08-23 아이알엠 엘엘씨 Ether derivatives of bicyclic heteroaryls
US20110076232A1 (en) 2009-09-29 2011-03-31 Ludwig Institute For Cancer Research Specific binding proteins and uses thereof
JP5581390B2 (en) 2009-10-23 2014-08-27 イーライ リリー アンド カンパニー AKT inhibitor
US20120220594A1 (en) 2009-10-30 2012-08-30 Bristol-Meyers Squibb Company Methods for treating cancer in patients having igf-1r inhibitor resistance
PE20121471A1 (en) 2009-11-04 2012-11-01 Novartis Ag HELPFUL HETEROCYCLIC SULFONAMIDE DERIVATIVES AS MEK INHIBITORS
KR20120103587A (en) 2009-11-12 2012-09-19 제넨테크, 인크. A method of promoting dendritic spine density
CA2780875A1 (en) 2009-11-13 2011-05-19 Pangaea Biotech, S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
US20110130711A1 (en) * 2009-11-19 2011-06-02 Follica, Inc. Hair growth treatment
EA201200617A1 (en) 2009-11-23 2012-11-30 Серулин Фарма Инк. POLYMERS ON THE BASIS OF CYCLODEXTRINE FOR DELIVERY OF MEDICINES
CN102712648A (en) 2009-11-25 2012-10-03 诺瓦提斯公司 Benzene-fused 6-membered oxygen-containing heterocyclic derivatives of bicyclic heteroaryls
PE20121384A1 (en) 2009-12-08 2012-10-13 Novartis Ag HETEROCYCLIC SULFONAMIDE DERIVATIVES
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
CU24130B1 (en) 2009-12-22 2015-09-29 Novartis Ag ISOQUINOLINONES AND REPLACED QUINAZOLINONES
CA2781578A1 (en) 2010-01-12 2011-07-21 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof
US20110178287A1 (en) 2010-01-19 2011-07-21 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
CA2788587C (en) 2010-02-03 2020-03-10 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
AU2011218125A1 (en) 2010-02-18 2012-07-19 Genentech, Inc. Neuregulin antagonists and use thereof in treating cancer
WO2011113512A1 (en) 2010-03-16 2011-09-22 Merck Patent Gmbh Morpholinylquinazolines
US20130096104A1 (en) 2010-03-17 2013-04-18 Genentech, Inc. Imidazopyridine compounds, compositions and methods of use
WO2011119995A2 (en) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations and methods of use
TWI406853B (en) * 2010-04-07 2013-09-01 Dev Center Biotechnology Dual inhibitors of egfr and vegfr-2 and uses and production processes thereof
CA2793892A1 (en) 2010-04-16 2011-10-20 Elizabeth Punnoose Foxo3a as predictive biomarker for pi3k/akt kinase pathway inhibitor efficacy
US20130085161A1 (en) 2010-06-17 2013-04-04 Novartis Ag Piperidinyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives
EP2582680A1 (en) 2010-06-17 2013-04-24 Novartis AG Biphenyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives
UA112517C2 (en) 2010-07-06 2016-09-26 Новартіс Аг TETRAHYDROPYRIDOPYRIMIDINE DERIVATIVES
AR082418A1 (en) 2010-08-02 2012-12-05 Novartis Ag CRYSTAL FORMS OF 1- (4-METHYL-5- [2- (2,2,2-TRIFLUORO-1,1-DIMETHYL-Ethyl) -PIRIDIN-4-IL] -TIAZOL-2-IL) -AMIDE OF 2 -AMIDA OF THE ACID (S) -PIRROLIDIN-1,2-DICARBOXILICO
EP2612151B1 (en) 2010-08-31 2017-08-09 Genentech, Inc. Biomarkers and methods of treatment
RU2013114352A (en) 2010-09-15 2014-10-20 Ф. Хоффманн-Ля Рош Аг AZABENZENESIAZOLES, COMPOSITIONS AND METHODS OF APPLICATION
US8946260B2 (en) 2010-09-16 2015-02-03 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
WO2012052948A1 (en) 2010-10-20 2012-04-26 Pfizer Inc. Pyridine- 2- derivatives as smoothened receptor modulators
JP2013542966A (en) 2010-11-19 2013-11-28 エフ．ホフマン−ラ ロシュ アーゲー Pyrazolopyridines and their use as TYK2 inhibitors and their use
BR112013015449A2 (en) 2010-12-21 2016-09-20 Novartis Ag biheteroaryl compounds as vps23 inhibitors
EP2468883A1 (en) 2010-12-22 2012-06-27 Pangaea Biotech S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
WO2012085176A1 (en) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Tricyclic pyrazinone compounds, compositions and methods of use thereof as janus kinase inhibitors
US9134297B2 (en) 2011-01-11 2015-09-15 Icahn School Of Medicine At Mount Sinai Method and compositions for treating cancer and related methods
WO2012104776A1 (en) 2011-01-31 2012-08-09 Novartis Ag Novel heterocyclic derivatives
WO2012107500A1 (en) 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
EP2678016B1 (en) 2011-02-23 2016-08-10 Intellikine, LLC Heterocyclic compounds and uses thereof
EP2492688A1 (en) 2011-02-23 2012-08-29 Pangaea Biotech, S.A. Molecular biomarkers for predicting response to antitumor treatment in lung cancer
EP2680844B1 (en) 2011-03-04 2016-10-19 GlaxoSmithKline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
AU2012225693A1 (en) 2011-03-04 2013-09-19 Newgen Therapeutics, Inc. Alkyne substituted quinazoline compound and methods of use
CN103492390A (en) 2011-03-08 2014-01-01 诺瓦提斯公司 Fluorophenyl bicyclic heteroaryl compounds
US9321759B2 (en) 2011-03-17 2016-04-26 The Trustees Of The University Of Pennsylvania Methods and use of bifunctional enzyme-building clamp-shaped molecules
US9295676B2 (en) 2011-03-17 2016-03-29 The Trustees Of The University Of Pennsylvania Mutation mimicking compounds that bind to the kinase domain of EGFR
WO2012129145A1 (en) 2011-03-18 2012-09-27 OSI Pharmaceuticals, LLC Nscle combination therapy
US9896730B2 (en) 2011-04-25 2018-02-20 OSI Pharmaceuticals, LLC Use of EMT gene signatures in cancer drug discovery, diagnostics, and treatment
GB201106870D0 (en) 2011-04-26 2011-06-01 Univ Belfast Marker
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
CN102918029B (en) 2011-05-17 2015-06-17 江苏康缘药业股份有限公司 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof
IN2014DN00123A (en) 2011-06-09 2015-05-22 Novartis Ag
EP2721008B1 (en) 2011-06-20 2015-04-29 Novartis AG Hydroxy substituted isoquinolinone derivatives as p53 (mdm2 or mdm4) inhibitors
US8859586B2 (en) 2011-06-20 2014-10-14 Novartis Ag Cyclohexyl isoquinolinone compounds
AU2012277391A1 (en) 2011-06-27 2013-12-19 Novartis Ag Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives
WO2013007768A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors
WO2013007765A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
BR112014003237A2 (en) 2011-08-12 2017-04-25 Hoffmann La Roche indazole compounds, compositions and methods of use
CA2863679A1 (en) 2011-08-17 2014-05-30 Dennis Brown Compositions and methods to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dibromodulcitol
EP2744824A1 (en) 2011-08-17 2014-06-25 F.Hoffmann-La Roche Ag Neuregulin antibodies and uses thereof
TWI547494B (en) 2011-08-18 2016-09-01 葛蘭素史克智慧財產發展有限公司 Aminoquinazolines as kinase inhibitors
EP2751285B2 (en) 2011-08-31 2020-04-01 Genentech, Inc. Method for sensitivity testing of a tumour for a egfr kinase inhibitor
UY34329A (en) 2011-09-15 2013-04-30 Novartis Ag TRIAZOLOPIRIDINE COMPOUNDS
JP2014526538A (en) 2011-09-20 2014-10-06 エフ．ホフマン−ラ ロシュ アーゲー Imidazopyridine compounds, compositions and methods of use
AP2014007475A0 (en) 2011-09-22 2014-02-28 Pfizer Pyrrolopyrimidine and purine derivates
US20130084287A1 (en) 2011-09-30 2013-04-04 Genentech, Inc. Diagnostic markers
EP2766497A1 (en) 2011-10-13 2014-08-20 Bristol-Myers Squibb Company Methods for selecting and treating cancer in patients with igf-1r/ir inhibitors
WO2013061305A1 (en) 2011-10-28 2013-05-02 Novartis Ag Novel purine derivatives and their use in the treatment of disease
WO2013080141A1 (en) 2011-11-29 2013-06-06 Novartis Ag Pyrazolopyrrolidine compounds
CN104271761B (en) 2011-11-30 2017-03-15 霍夫曼-拉罗奇有限公司 Erbb3 mutation in cancer
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
CN103172641B (en) 2011-12-20 2014-06-11 钱卫 Heterocyclic amino and alkoxy-replaced quinazoline derivative and application thereof
CR20200286A (en) 2011-12-22 2020-09-23 Novartis Ag Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives
US20150148377A1 (en) 2011-12-22 2015-05-28 Novartis Ag Quinoline Derivatives
CN104125953A (en) 2011-12-23 2014-10-29 诺华股份有限公司 Compounds for inhibiting interaction of bcl2 with binding partners
JP2015503516A (en) 2011-12-23 2015-02-02 ノバルティス アーゲー Compound for inhibiting interaction between BCL2 and binding partner
US20130178520A1 (en) 2011-12-23 2013-07-11 Duke University Methods of treatment using arylcyclopropylamine compounds
CA2859862A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
MX2014007732A (en) 2011-12-23 2015-01-12 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners.
EA201491264A1 (en) 2011-12-23 2014-11-28 Новартис Аг COMPOUNDS FOR INHIBITING THE INTERACTION OF BCL-2 WITH PARTNERS ON BINDING
JO3357B1 (en) 2012-01-26 2019-03-13 Novartis Ag Imidazopyrrolidinone compounds
EP2752413B1 (en) 2012-03-26 2016-03-23 Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences Quinazoline derivative and application thereof
CN104220457A (en) 2012-03-27 2014-12-17 霍夫曼-拉罗奇有限公司 Diagnosis and treatments relating to her3 inhibitors
RU2660354C2 (en) 2012-04-03 2018-07-05 Новартис Аг Combined products containing tyrosine kinase inhibitors and their use
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
CN103373966A (en) * 2012-04-17 2013-10-30 南京大学 4-anilino quinazoline amido derivatives as well as preparation methods and applications thereof
JP6381523B2 (en) 2012-05-16 2018-08-29 ノバルティス アーゲー Administration regimen of PI-3 kinase inhibitor
EP2855483B1 (en) 2012-05-24 2017-10-25 Novartis AG Pyrrolopyrrolidinone compounds
AU2013274101B2 (en) 2012-06-15 2017-09-07 The Brigham And Women's Hospital, Inc. Compositions for treating cancer and methods for making the same
WO2013190089A1 (en) 2012-06-21 2013-12-27 Pangaea Biotech, S.L. Molecular biomarkers for predicting outcome in lung cancer
WO2014025395A1 (en) 2012-08-06 2014-02-13 Duke University Compounds and methods for targeting hsp90
WO2014033281A1 (en) 2012-08-31 2014-03-06 Westfaelische Wilhelms-Universitaet Muenster Methods and peptides for preventing and treating a bcr-abl and a c-abl associated disease
AR092530A1 (en) 2012-09-13 2015-04-22 Glaxosmithkline Llc AMINO-QUINOLINE COMPOSITE, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND USE OF THIS COMPOUND FOR THE PREPARATION OF A MEDICINAL PRODUCT
AR092529A1 (en) 2012-09-13 2015-04-22 Glaxosmithkline Llc AMINOQUINAZOLINE COMPOUND, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND USE OF THIS COMPOSITE FOR THE PREPARATION OF A MEDICINAL PRODUCT
EP2914278B1 (en) 2012-11-05 2021-06-02 Dana-Farber Cancer Institute, Inc. Xbp1, cd138, and cs1 peptides, pharmaceutical compositions that include the peptides, and methods of using such peptides and compositions
TW201422625A (en) 2012-11-26 2014-06-16 Novartis Ag Solid form of dihydro-pyrido-oxazine derivative
EP2948453B1 (en) 2013-01-22 2017-08-02 Novartis AG Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
EP2948451B1 (en) 2013-01-22 2017-07-12 Novartis AG Substituted purinone compounds
RU2721418C2 (en) 2013-02-01 2020-05-19 Веллстат Терапьютикс Корпорейшн Amine compounds having anti-inflammatory, antifungal, anti-parasitic and anticancer activity
CN105358576B (en) 2013-02-20 2020-05-05 诺华股份有限公司 Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptors
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
JP6301374B2 (en) 2013-02-21 2018-03-28 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Quinazolines as kinase inhibitors
BR112015018418A2 (en) 2013-02-22 2017-07-18 Hoffmann La Roche methods for treating cancer, for increasing the effectiveness of a treatment, for postponing and / or preventing cancer development, for increasing sensitivity to a targeted therapy, to extending the sensitivity period, to extending the response duration to a targeted therapy. and pharmaceutical
JP6255038B2 (en) 2013-02-26 2017-12-27 トリアクト セラピューティクス，インク． Cancer treatment
US9468681B2 (en) 2013-03-01 2016-10-18 California Institute Of Technology Targeted nanoparticles
CA2902263A1 (en) 2013-03-06 2014-09-12 Genentech, Inc. Methods of treating and preventing cancer drug resistance
EP3342770B1 (en) 2013-03-06 2022-03-30 AstraZeneca AB Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
US10035801B2 (en) 2013-03-13 2018-07-31 Genentech, Inc. Pyrazolo compounds and uses thereof
CA2903480A1 (en) 2013-03-14 2014-09-25 Genentech, Inc. Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use
CA2905070A1 (en) 2013-03-14 2014-09-25 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
HK1219421A1 (en) 2013-03-15 2017-04-07 因特利凯有限责任公司 Combination of kinase inhibitors and uses thereof
EP2968537A1 (en) 2013-03-15 2016-01-20 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
US20160051556A1 (en) 2013-03-21 2016-02-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Method and Pharmaceutical Composition for use in the Treatment of Chronic Liver Diseases Associated with a Low Hepcidin Expression
WO2014147631A1 (en) 2013-03-22 2014-09-25 Natco Pharma Limited Formulation comprising gefitinib as oral suspension
WO2014155268A2 (en) 2013-03-25 2014-10-02 Novartis Ag Fgf-r tyrosine kinase activity inhibitors - use in diseases associated with lack of or reduced snf5 activity
BR112015024971B1 (en) 2013-04-04 2022-09-20 Janssen Pharmaceutica Nv N-(2,3-DIHYDRO-1H-PYROLO[2,3-B]PYRIDIN-5-IL)-4-QUINAZOLINAMINE AND N-(2,3-DIHYDRO-1HINDOL-5-IL) DERIVATIVES )-4-QUINAZOLINAMINE AS PERK INHIBITORS AND PHARMACEUTICAL COMPOSITION COMPRISING THEM
CN103275019B (en) * 2013-04-26 2016-05-18 浙江工业大学 The chloro-4-substituted anilinic of 4-[3-]-6-methoxyl group displacement formamido group quinazoline compounds and preparation and application
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
CN103304491A (en) * 2013-06-17 2013-09-18 连云港盛和生物科技有限公司 Preparation method of gefitinib
UY35675A (en) 2013-07-24 2015-02-27 Novartis Ag SUBSTITUTED DERIVATIVES OF QUINAZOLIN-4-ONA
WO2015022663A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
WO2015022664A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
WO2015035062A1 (en) 2013-09-05 2015-03-12 Genentech, Inc. Antiproliferative compounds
WO2015035410A1 (en) 2013-09-09 2015-03-12 Triact Therapeutic, Inc. Cancer therapy
SG11201600707QA (en) 2013-09-22 2016-02-26 Calitor Sciences Llc Substituted aminopyrimidine compounds and methods of use
CN103483276B (en) * 2013-09-22 2018-04-17 南京恒道医药科技有限公司 Preparation method of vandetanib impurity
AR097894A1 (en) 2013-10-03 2016-04-20 Hoffmann La Roche CDK8 THERAPEUTIC INHIBITORS OR USE OF THE SAME
EP3057615B1 (en) 2013-10-18 2021-02-24 F.Hoffmann-La Roche Ag Anti-rspo antibodies and methods of use
UA115388C2 (en) 2013-11-21 2017-10-25 Пфайзер Інк. 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders
WO2015084804A1 (en) 2013-12-03 2015-06-11 Novartis Ag Combination of mdm2 inhibitor and braf inhibitor and their use
CN105979947A (en) 2013-12-06 2016-09-28 诺华股份有限公司 Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor
AU2014364601A1 (en) 2013-12-17 2016-07-07 Genentech, Inc. Methods of treating HER2-positive cancers using PD-1 axis binding antagonists and anti-HER2 antibodies
JP2017501167A (en) 2013-12-17 2017-01-12 ジェネンテック， インコーポレイテッド Combination therapy comprising OX40 binding agonist and PD-1 axis binding antagonist
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
WO2015148531A1 (en) 2014-03-24 2015-10-01 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with hgf expression
US10000469B2 (en) 2014-03-25 2018-06-19 Duke University Heat shock protein 70 (hsp-70) receptor ligands
RS61536B1 (en) 2014-03-26 2021-04-29 Astex Therapeutics Ltd Combinations of fgfr- and cmet-inhibitors for the treatment of cancer
WO2015145388A2 (en) 2014-03-27 2015-10-01 Novartis Ag Methods of treating colorectal cancers harboring upstream wnt pathway mutations
JP6538148B2 (en) 2014-03-28 2019-07-03 キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーＣａｌｉｔｏｒ Ｓｃｉｅｎｃｅｓ， Ｌｌｃ Substituted heteroaryl compounds and methods of use
CR20160500A (en) 2014-03-31 2016-12-14 Genentech Inc ANTI-OX40 ANTIBODIES AND METHODS OF USE
AU2015241038A1 (en) 2014-03-31 2016-10-13 Genentech, Inc. Combination therapy comprising anti-angiogenesis agents and OX40 binding agonists
RU2016140160A (en) 2014-04-03 2018-05-07 Инвиктус Онколоджи Пвт. Лтд. SUPRAMOLECULAR COMBINATOR MEDICINES
WO2015156674A2 (en) 2014-04-10 2015-10-15 Stichting Het Nederlands Kanker Instituut Method for treating cancer
WO2015155624A1 (en) 2014-04-10 2015-10-15 Pfizer Inc. Dihydropyrrolopyrimidine derivatives
KR20160149256A (en) 2014-04-30 2016-12-27 화이자 인코포레이티드 Cycloalkyl-linked diheterocycle derivatives
US9388239B2 (en) 2014-05-01 2016-07-12 Consejo Nacional De Investigation Cientifica Anti-human VEGF antibodies with unusually strong binding affinity to human VEGF-A and cross reactivity to human VEGF-B
WO2016001789A1 (en) 2014-06-30 2016-01-07 Pfizer Inc. Pyrimidine derivatives as pi3k inhibitors for use in the treatment of cancer
WO2016011658A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
RU2695230C2 (en) 2014-07-31 2019-07-22 Новартис Аг Combined therapy
JP6814730B2 (en) 2014-09-05 2021-01-20 ジェネンテック， インコーポレイテッド Therapeutic compounds and their use
JP2017529358A (en) 2014-09-19 2017-10-05 ジェネンテック， インコーポレイテッド Use of CBP / EP300 inhibitors and BET inhibitors for the treatment of cancer
WO2016057924A1 (en) 2014-10-10 2016-04-14 Genentech, Inc. Pyrrolidine amide compounds as histone demethylase inhibitors
US20160161485A1 (en) 2014-11-03 2016-06-09 Genentech, Inc. Assays for detecting t cell immune subsets and methods of use thereof
WO2016073380A1 (en) 2014-11-03 2016-05-12 Genentech, Inc. Method and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment
CN107073126A (en) 2014-11-06 2017-08-18 豪夫迈·罗氏有限公司 Combination treatment comprising OX40 combinations activator and TIGIT inhibitor
CN107108613B (en) 2014-11-10 2020-02-25 基因泰克公司 Bromo domain inhibitors and their uses
MA40943A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
MA40940A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
US20160166685A1 (en) 2014-11-17 2016-06-16 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
US9763922B2 (en) 2014-11-27 2017-09-19 Genentech, Inc. Therapeutic compounds and uses thereof
KR20170094165A (en) 2014-12-23 2017-08-17 제넨테크, 인크. Compositions and methods for treating and diagnosing chemotherapy-resistant cancers
EP3237638B1 (en) 2014-12-24 2020-01-15 F.Hoffmann-La Roche Ag Therapeutic, diagnostic and prognostic methods for cancer of the bladder
CN107208138A (en) 2014-12-30 2017-09-26 豪夫迈·罗氏有限公司 For cancer prognosis and the method and composition for the treatment of
JP6855379B2 (en) 2015-01-09 2021-04-07 ジェネンテック， インコーポレイテッド (Piperidin-3-yl) (naphthalene-2-yl) metanone derivatives and related compounds as inhibitors of histone demethylase KDM2B for the treatment of cancer
EP3242874B1 (en) 2015-01-09 2018-10-31 Genentech, Inc. Pyridazinone derivatives and their use in the treatment of cancer
JP6889661B2 (en) 2015-01-09 2021-06-18 ジェネンテック， インコーポレイテッド 4,5-Dihydroimidazole derivative and its use as a histone dimethylase (KDM2B) inhibitor
CN107531692B (en) 2015-01-29 2020-12-25 基因泰克公司 Therapeutic compounds and uses thereof
EP3250552B1 (en) 2015-01-30 2019-03-27 Genentech, Inc. Therapeutic compounds and uses thereof
JOP20200201A1 (en) 2015-02-10 2017-06-16 Astex Therapeutics Ltd Pharmaceutical compositions comprising n-(3,5-dimethoxyphenyl)-n'-(1-methylethyl)-n-[3-(1-methyl-1h-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine
MA41598A (en) 2015-02-25 2018-01-02 Constellation Pharmaceuticals Inc PYRIDAZINE THERAPEUTIC COMPOUNDS AND THEIR USES
KR20180002653A (en) 2015-04-07 2018-01-08 제넨테크, 인크. Antigen binding complexes having an agonistic activity activity and methods of use
JP7048319B2 (en) 2015-05-12 2022-04-05 ジェネンテック， インコーポレイテッド Treatment and diagnosis methods for cancer
ES2789500T5 (en) 2015-05-29 2023-09-20 Hoffmann La Roche Therapeutic and diagnostic procedures for cancer
HK1252272A1 (en) 2015-06-08 2019-05-24 豪夫迈‧罗氏有限公司 Methods of treating cancer using anti-ox40 antibodies
WO2016200835A1 (en) 2015-06-08 2016-12-15 Genentech, Inc. Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
CA2986263A1 (en) 2015-06-17 2016-12-22 Genentech, Inc. Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes
WO2017003668A1 (en) 2015-07-01 2017-01-05 California Institute Of Technology Cationic mucic acid polymer-based delivery systems
WO2017009751A1 (en) 2015-07-15 2017-01-19 Pfizer Inc. Pyrimidine derivatives
CN105001167B (en) * 2015-07-16 2018-01-05 西安交通大学 1 substituted-phenyl 3（The quinazolyl of 4 substituted-phenyl amino 6）Carbamide compounds and preparation method and purposes
ES2862727T3 (en) 2015-08-26 2021-10-07 Fundacion Del Sector Publico Estatal Centro Nac De Investigaciones Oncologicas Carlos Iii F S P Cnio Fused tricyclic compounds as protein kinase inhibitors
WO2017044434A1 (en) 2015-09-11 2017-03-16 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
CA2994858C (en) 2015-09-25 2024-01-23 Genentech, Inc. Anti-tigit antibodies and methods of use
KR20180086187A (en) 2015-10-05 2018-07-30 더 트러스티이스 오브 콜롬비아 유니버시티 인 더 시티 오브 뉴욕 Clearance of protein aggregates including phospholipase D and tau, and treatment of protein diseases
ES2893100T3 (en) 2015-10-12 2022-02-08 Advanced Cell Diagnostics Inc In situ detection of nucleotide variants in samples with a high level of noise, and related compositions and methods
EP3370719A1 (en) 2015-11-02 2018-09-12 Novartis AG Dosage regimen for a phosphatidylinositol 3-kinase inhibitor
SG11201804204QA (en) 2015-12-16 2018-06-28 Genentech Inc Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer
EP3397618B1 (en) 2015-12-30 2020-11-18 Synthon B.V. Process for making crystalline form a of gefitinib
AR107303A1 (en) 2016-01-08 2018-04-18 Hoffmann La Roche METHODS OF TREATMENT OF POSITIVE CANCER FOR ACE USING ANTAGONISTS OF AXISION TO AXIS PD-1 AND ANTI-ACE / ANTI-CD3, USE, COMPOSITION, KIT
US10710968B2 (en) 2016-01-13 2020-07-14 Hadasit Medical Research Services And Development Ltd. Radiolabeled erlotinib analogs and uses thereof
EP4155415A1 (en) 2016-02-29 2023-03-29 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2017180864A1 (en) 2016-04-14 2017-10-19 Genentech, Inc. Anti-rspo3 antibodies and methods of use
WO2017180581A1 (en) 2016-04-15 2017-10-19 Genentech, Inc. Diagnostic and therapeutic methods for cancer
ES2850428T3 (en) 2016-04-15 2021-08-30 Hoffmann La Roche Cancer monitoring and treatment procedures
EP3443120A2 (en) 2016-04-15 2019-02-20 H. Hoffnabb-La Roche Ag Methods for monitoring and treating cancer
WO2017184956A1 (en) 2016-04-22 2017-10-26 Duke University Compounds and methods for targeting hsp90
CN115028617A (en) 2016-05-24 2022-09-09 基因泰克公司 Heterocyclic inhibitors of CBP/EP300 and their use in the treatment of cancer
CN109476663B (en) 2016-05-24 2021-11-09 基因泰克公司 Pyrazolopyridine derivatives for the treatment of cancer
CN109312407A (en) 2016-06-08 2019-02-05 豪夫迈·罗氏有限公司 Diagnosis and treatment methods for cancer
US11046776B2 (en) 2016-08-05 2021-06-29 Genentech, Inc. Multivalent and multiepitopic antibodies having agonistic activity and methods of use
JP7250674B2 (en) 2016-08-08 2023-04-03 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト CANCER TREATMENT AND DIAGNOSTIC METHOD
US20190209669A1 (en) 2016-08-23 2019-07-11 Oncopep, Inc. Peptide vaccines and durvalumab for treating breast cancer
WO2018039203A1 (en) 2016-08-23 2018-03-01 Oncopep, Inc. Peptide vaccines and durvalumab for treating multiple myeloma
WO2018060833A1 (en) 2016-09-27 2018-04-05 Novartis Ag Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib
RU2019112860A (en) 2016-09-27 2020-10-30 Серо Терапьютикс, Инк. CHIMERIC INTERNALIZING RECEPTOR MOLECULES
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
US10207998B2 (en) 2016-09-29 2019-02-19 Duke University Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof
MX2019003934A (en) 2016-10-06 2019-07-10 Genentech Inc THERAPEUTIC AND DIAGNOSTIC METHODS FOR CANCER.
WO2018078143A1 (en) 2016-10-28 2018-05-03 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Means and methods for determining efficacy of anti-egfr inhibitors in colorectal cancer (crc) therapy
JP2019535250A (en) 2016-10-29 2019-12-12 ジェネンテック， インコーポレイテッド Anti-MIC antibody and method of use
AU2017379074C9 (en) 2016-12-22 2023-06-08 Amgen Inc. Benzisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as KRAS G12C inhibitors for treating lung, pancreatic or colorectal cancer
JP7053665B2 (en) * 2016-12-30 2022-04-12 南京明徳新薬研発有限公司 Quinazoline compounds as EGFR inhibition
KR20190134631A (en) 2017-03-01 2019-12-04 제넨테크, 인크. How to diagnose and treat cancer
MX2019012187A (en) 2017-04-13 2019-11-25 Hoffmann La Roche An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer.
JOP20190272A1 (en) 2017-05-22 2019-11-21 Amgen Inc Kras g12c inhibitors and methods of using the same
JP7296954B2 (en) 2017-06-22 2023-06-23 キュラデブ・ファーマ・リミテッド Small Molecule Regulators of Human STING
EP3655034A1 (en) 2017-07-21 2020-05-27 Genentech, Inc. Therapeutic and diagnostic methods for cancer
CA3070297A1 (en) 2017-08-11 2019-02-14 Genentech, Inc. Anti-cd8 antibodies and uses thereof
CA3073073A1 (en) 2017-09-08 2019-03-14 F. Hoffmann-La Roche Ag Diagnostic and therapeutic methods for cancer
TWI731264B (en) 2017-09-08 2021-06-21 美商安進公司 Inhibitors of kras g12c and methods of using the same
JP7286658B2 (en) 2017-09-26 2023-06-05 セロ・セラピューティクス・インコーポレイテッド Chimeric engulfment receptor molecules and methods of use
AU2018353984A1 (en) 2017-10-24 2020-05-07 Oncopep, Inc. Peptide vaccines and pembrolizumab for treating breast cancer
WO2019083960A1 (en) 2017-10-24 2019-05-02 Oncopep, Inc. Peptide vaccines and hdac inhibitors for treating multiple myeloma
US11369608B2 (en) 2017-10-27 2022-06-28 University Of Virginia Patent Foundation Compounds and methods for regulating, limiting, or inhibiting AVIL expression
PL3707510T3 (en) 2017-11-06 2024-09-30 F. Hoffmann-La Roche Ag Diagnostic and therapeutic methods for cancer
WO2019099311A1 (en) 2017-11-19 2019-05-23 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
US11708335B2 (en) 2017-12-18 2023-07-25 Sterngreene, Inc. Pyrimidine compounds useful as tyrosine kinase inhibitors
AU2017444054B2 (en) 2017-12-21 2021-10-07 Hefei Institutes Of Physical Science, Chinese Academy Of Sciences Class of pyrimidine derivative kinase inhibitors
SG11202006441SA (en) 2018-01-15 2020-08-28 Epiaxis Therapeutics Pty Ltd Agents and methods for predicting response to therapy
KR102737185B1 (en) 2018-01-20 2024-12-05 선샤인 레이크 파르마 컴퍼니 리미티드 Substituted aminopyrimidine compounds and methods of use thereof
CN111836831A (en) 2018-02-26 2020-10-27 豪夫迈·罗氏有限公司 Administration for Anti-TIGIT Antagonist Antibody and Anti-PD-L1 Antagonist Antibody Therapy
US20210024607A1 (en) 2018-03-28 2021-01-28 Cero Therapeutics, Inc. Expression vectors for chimeric engulfment receptors, genetically modified host cells, and uses thereof
WO2019191334A1 (en) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
MX2020010241A (en) 2018-03-28 2020-10-16 Cero Therapeutics Inc Cellular immunotherapy compositions and uses thereof.
US11045484B2 (en) 2018-05-04 2021-06-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
EP3788038B1 (en) 2018-05-04 2023-10-11 Amgen Inc. Kras g12c inhibitors and methods of using the same
EP3790886B1 (en) 2018-05-10 2024-06-26 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
EP3797173A2 (en) 2018-05-21 2021-03-31 Nanostring Technologies, Inc. Molecular gene signatures and methods of using same
MA52765A (en) 2018-06-01 2021-04-14 Amgen Inc KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE
MA52780A (en) 2018-06-11 2021-04-14 Amgen Inc KRAS G12C INHIBITORS FOR CANCER TREATMENT
JP7369719B2 (en) 2018-06-12 2023-10-26 アムジエン・インコーポレーテツド KRas G12C inhibitors and methods of using the same
JP7483193B2 (en) 2018-06-13 2024-05-15 カリフォルニア・インスティテュート・オブ・テクノロジー Nanoparticles for crossing the blood-brain barrier and their therapeutic applications
MX2020014091A (en) 2018-06-23 2021-05-27 Genentech Inc Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor.
CN112839644A (en) 2018-07-18 2021-05-25 豪夫迈·罗氏有限公司 Methods of treating lung cancer with PD-1 axis binding antagonists, antimetabolites and platinum agents
US12220423B2 (en) 2018-07-24 2025-02-11 Hygia Pharmaceuticals, Llc Compounds, derivatives, and analogs for cancer
JP7535500B2 (en) 2018-09-03 2024-08-16 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Carboxamide and Sulfonamide Derivatives Useful as TEAD Modulators
WO2020055504A1 (en) * 2018-09-13 2020-03-19 University Of Southern California Novel inhibitors of guanosine monophosphate synthetase as therapeutic agents
EP3853611A1 (en) 2018-09-19 2021-07-28 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for bladder cancer
EP3857230B1 (en) 2018-09-21 2023-06-07 F. Hoffmann-La Roche AG Diagnostic methods for triple-negative breast cancer
AU2019352741A1 (en) 2018-10-04 2021-05-06 Assistance Publique-Hôpitaux De Paris (Aphp) EGFR inhibitors for treating keratodermas
JP2022512744A (en) 2018-10-18 2022-02-07 ジェネンテック， インコーポレイテッド Diagnosis and treatment for sarcomatoid kidney cancer
JP7516029B2 (en) 2018-11-16 2024-07-16 アムジエン・インコーポレーテツド Improved synthesis of key intermediates for KRAS G12C inhibitor compounds
JP7377679B2 (en) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド Combination therapy comprising a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancer
WO2020106640A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020131674A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer
US12180207B2 (en) 2018-12-19 2024-12-31 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of FGFR tyrosine kinases
CA3123227A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
IL283639B2 (en) 2018-12-20 2024-06-01 Amgen Inc KIF18A inhibitors
JP7676308B2 (en) 2018-12-20 2025-05-14 アムジエン・インコーポレーテツド Heteroaryl amides useful as KIF18A inhibitors - Patents.com
MX2021007104A (en) 2018-12-20 2021-08-11 Amgen Inc Kif18a inhibitors.
CN113396230A (en) 2019-02-08 2021-09-14 豪夫迈·罗氏有限公司 Methods of diagnosis and treatment of cancer
KR20210133237A (en) 2019-02-27 2021-11-05 제넨테크, 인크. Dosing for treatment with anti-TIGIT and anti-CD20 or anti-CD38 antibodies
US20220146495A1 (en) 2019-02-27 2022-05-12 Epiaxis Therapeutics Pty Ltd Methods and agents for assessing t-cell function and predicting response to therapy
WO2020180770A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
CA3130080A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
CN109796415B (en) * 2019-03-29 2020-10-30 武汉德诺美生物医药股份有限公司 EGFR inhibitor and application thereof
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
CN114269376A (en) 2019-05-03 2022-04-01 豪夫迈·罗氏有限公司 Methods of treating cancer with anti-PD-L1 antibodies
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
CN118834208A (en) 2019-05-21 2024-10-25 美国安进公司 Solid state form
CN112300279A (en) 2019-07-26 2021-02-02 上海复宏汉霖生物技术股份有限公司 Methods and compositions directed to anti-CD 73 antibodies and variants
CN114269731A (en) 2019-08-02 2022-04-01 美国安进公司 KIF18A inhibitor
EP4007752A1 (en) 2019-08-02 2022-06-08 Amgen Inc. Kif18a inhibitors
CA3147272A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
CA3147276A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
EP4025608A1 (en) 2019-09-04 2022-07-13 F. Hoffmann-La Roche AG Cd8 binding agents and uses thereof
PE20221110A1 (en) 2019-09-27 2022-07-11 Genentech Inc DOSE ADMINISTRATION FOR TREATMENT WITH ANTI-TIGIT AND ANTI-PD-L1 ANTAGONIST ANTIBODIES
WO2021067875A1 (en) 2019-10-03 2021-04-08 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
AU2020369569A1 (en) 2019-10-24 2022-04-14 Amgen Inc. Pyridopyrimidine derivatives useful as KRAS G12C and KRAS G12D inhibitors in the treatment of cancer
WO2021083949A1 (en) 2019-10-29 2021-05-06 F. Hoffmann-La Roche Ag Bifunctional compounds for the treatment of cancer
TW202132314A (en) 2019-11-04 2021-09-01 美商銳新醫藥公司 Ras inhibitors
AU2020379734A1 (en) 2019-11-04 2022-05-05 Revolution Medicines, Inc. Ras inhibitors
WO2021091967A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
CN115066613A (en) 2019-11-06 2022-09-16 基因泰克公司 Diagnostic and therapeutic methods for treating hematologic cancers
TW202128688A (en) 2019-11-08 2021-08-01 美商銳新醫藥公司 Bicyclic heteroaryl compounds and uses thereof
AU2020381458A1 (en) 2019-11-13 2022-05-12 Genentech, Inc. Therapeutic compounds and methods of use
BR112022009390A2 (en) 2019-11-14 2022-08-09 Amgen Inc IMPROVED SYNTHESIS OF KRAS INHIBITOR COMPOUND G12C
CA3161156A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
US20220395553A1 (en) 2019-11-14 2022-12-15 Cohbar, Inc. Cxcr4 antagonist peptides
EP4065231A1 (en) 2019-11-27 2022-10-05 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
CR20230210A (en) 2019-12-13 2023-06-14 Genentech Inc Anti-ly6g6d antibodies and methods of use
TW202136276A (en) 2019-12-20 2021-10-01 美商艾瑞斯卡公司 Tricyclic pyridones and pyrimidones
MX2022008305A (en) 2020-01-07 2022-08-08 Revolution Medicines Inc Shp2 inhibitor dosing and methods of treating cancer.
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
EP4096646A1 (en) 2020-01-27 2022-12-07 Genentech, Inc. Methods for treatment of cancer with an anti-tigit antagonist antibody
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
WO2021233534A1 (en) 2020-05-20 2021-11-25 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
WO2021185844A1 (en) 2020-03-16 2021-09-23 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
WO2021202959A1 (en) 2020-04-03 2021-10-07 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2021222167A1 (en) 2020-04-28 2021-11-04 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
CN111499583B (en) * 2020-05-22 2022-02-15 沈阳工业大学 Quinazoline derivative and application thereof as antitumor drug
CA3181820A1 (en) 2020-06-16 2021-12-23 Genentech, Inc. Methods and compositions for treating triple-negative breast cancer
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
JP2023531200A (en) 2020-06-18 2023-07-21 ジェネンテック， インコーポレイテッド Treatment with anti-TIGIT antibody and PD-1 axis binding antagonist
US11787775B2 (en) 2020-07-24 2023-10-17 Genentech, Inc. Therapeutic compounds and methods of use
WO2022031749A1 (en) 2020-08-03 2022-02-10 Genentech, Inc. Diagnostic and therapeutic methods for lymphoma
EP4192509A1 (en) 2020-08-05 2023-06-14 Ellipses Pharma Ltd Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor
WO2022036146A1 (en) 2020-08-12 2022-02-17 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2022036285A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Compositions and methods for treating cancer with chimeric tim receptors in combination with inhibitors of poly (adp-ribose) polymerase
WO2022036287A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Anti-cd72 chimeric receptors and uses thereof
WO2022036265A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Chimeric tim receptors and uses thereof
US11999964B2 (en) 2020-08-28 2024-06-04 California Institute Of Technology Synthetic mammalian signaling circuits for robust cell population control
JP2023541236A (en) 2020-09-03 2023-09-29 レボリューション メディシンズ インコーポレイテッド Use of SOS1 inhibitors to treat malignant tumors with SHP2 mutations
CA3194067A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Ras inhibitors
AU2021347232A1 (en) 2020-09-23 2023-04-27 Erasca, Inc. Tricyclic pyridones and pyrimidones
IL301547A (en) 2020-10-05 2023-05-01 Genentech Inc Dosage for treatment with bispecific anti-FCRH5/anti-CD3 antibodies
TW202237638A (en) 2020-12-09 2022-10-01 日商武田藥品工業股份有限公司 Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
US20230107642A1 (en) 2020-12-18 2023-04-06 Erasca, Inc. Tricyclic pyridones and pyrimidones
AU2021409816A1 (en) 2020-12-22 2023-07-06 Qilu Regor Therapeutics Inc. Sos1 inhibitors and uses thereof
PE20231505A1 (en) 2021-02-12 2023-09-26 Hoffmann La Roche BICYCLIC TETRAHYDROAZEPINE DERIVATIVES FOR THE TREATMENT OF CANCER
IL305411A (en) 2021-02-26 2023-10-01 Kelonia Therapeutics Inc Lymphocyte-targeted lentiviral vectors
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
AU2022268962A1 (en) 2021-05-05 2023-12-14 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
AU2022280025A1 (en) 2021-05-25 2023-12-07 Erasca, Inc. Sulfur-containing heteroaromatic tricyclic kras inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023010097A1 (en) 2021-07-28 2023-02-02 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
EP4384522A1 (en) 2021-08-10 2024-06-19 Erasca, Inc. Selective kras inhibitors
AR127308A1 (en) 2021-10-08 2024-01-10 Revolution Medicines Inc RAS INHIBITORS
EP4436957A1 (en) 2021-11-24 2024-10-02 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
WO2023097194A2 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic compounds and methods of use
CN119212994A (en) 2021-12-17 2024-12-27 建新公司 Pyrazolopyrazine compounds as SHP2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
EP4504780A1 (en) 2022-04-01 2025-02-12 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
CN119856056A (en) 2022-06-07 2025-04-18 基因泰克公司 Methods for determining the efficacy of lung cancer treatment comprising anti-PD-L1 antagonists and anti-TIGHT antagonist antibodies
IL317476A (en) 2022-06-10 2025-02-01 Revolution Medicines Inc Macrocyclic ras inhibitors
EP4554978A1 (en) 2022-07-13 2025-05-21 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
AU2023309556A1 (en) 2022-07-19 2025-01-23 F. Hoffmann-La Roche Ag Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
CN119816589A (en) 2022-08-02 2025-04-11 国立大学法人北海道大学 Methods to improve cell therapy using organelle complexes
AU2023322637A1 (en) 2022-08-11 2024-11-14 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
PE20250876A1 (en) 2022-08-11 2025-03-28 Hoffmann La Roche Bicyclic derivatives of tetrahydrothiazepine
AR130167A1 (en) 2022-08-11 2024-11-13 Hoffmann La Roche BICYCLIC TETRAHYDROAZEPINE DERIVATIVES
AR130169A1 (en) 2022-08-11 2024-11-13 Hoffmann La Roche BICYCLIC TETRAHYDROTHIAZEPINE DERIVATIVES
IL320217A (en) 2022-10-14 2025-06-01 Black Diamond Therapeutics Inc Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
WO2024085242A2 (en) 2022-10-21 2024-04-25 Kawasaki Institute Of Industrial Promotion Non-fouling or super stealth vesicle
CN120112796A (en) 2022-10-25 2025-06-06 基因泰克公司 Methods for the treatment and diagnosis of multiple myeloma
TW202434206A (en) 2023-02-17 2024-09-01 美商伊瑞斯卡公司 Kras inhibitors
TW202504611A (en) 2023-03-30 2025-02-01 美商銳新醫藥公司 Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
AR132338A1 (en) 2023-04-07 2025-06-18 Revolution Medicines Inc RAS INHIBITORS
WO2024216016A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of a ras inhibitor
WO2024216048A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2024233341A1 (en) 2023-05-05 2024-11-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024254455A1 (en) 2023-06-08 2024-12-12 Genentech, Inc. Macrophage signatures for diagnostic and therapeutic methods for lymphoma
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
TW202515614A (en) 2023-08-25 2025-04-16 美商建南德克公司 Methods and compositions for treating non-small cell lung cancer
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025137507A1 (en) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Sos1 inhibitors and uses thereof

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US398749A (en) * 1889-02-26 Harvey d
US3985742A (en) * 1971-12-01 1976-10-12 Merck & Co., Inc. Process for preparing 3-hydroxymethyl cephalosporins
US3985749A (en) * 1975-12-22 1976-10-12 Eastman Kodak Company Process for preparation of 4-aminoquinazoline
JPS5538325A (en) * 1978-09-11 1980-03-17 Sankyo Co Ltd 4-anilinoquinazoline derivative and its preparation
JPS5620577A (en) * 1979-07-27 1981-02-26 Sankyo Co Ltd 4- n-alkylanilino quinazoline derivative and its preparation
US4510307A (en) * 1980-08-20 1985-04-09 Asahi Kasei Kogyo Kabushiki Kaisha 6-Quinazolinesulfonyl derivatives and process for preparation thereof
JPS57143266A (en) * 1981-02-27 1982-09-04 Shin Kobe Electric Mach Co Ltd Plate for lead acid battery
JPS57143296A (en) * 1981-02-28 1982-09-04 Matsushita Electric Works Ltd Switching unit
JPS5913765A (en) * 1982-07-15 1984-01-24 Kyorin Pharmaceut Co Ltd 2-(4-quinazolyl)aminobenzoic acid derivative
GB2160201B (en) * 1984-06-14 1988-05-11 Wyeth John & Brother Ltd Quinazoline and cinnoline derivatives
GB8424979D0 (en) * 1984-10-03 1984-11-07 Wyeth John & Brother Ltd Benzenesulphonamide derivatives
HU207287B (en) * 1989-01-17 1993-03-29 Biosignal Kutato Fejlesztoe Kf Polyene fatty acid derivatives of tyrozine-quinaze inhibiting activity and pharmaceutical composition containing them as active component
DE69202243T2 (en) * 1991-02-20 1995-08-31 Pfizer 2,4-diaminoquinazoline derivatives to increase the anti-tumor effect.
DK0584222T3 (en) * 1991-05-10 1998-02-23 Rhone Poulenc Rorer Int Bis-mono and bicyclic aryl and heteroaryl compounds that inhibit EGF and / or PDGF receptor tyrosine kinase
NZ243082A (en) * 1991-06-28 1995-02-24 Ici Plc 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof
PT100905A (en) * 1991-09-30 1994-02-28 Eisai Co Ltd BICYCLE HYGIENEOUS HETEROCYCLIC COMPOUNDS CONTAINING BENZENE, CYCLOHEXAN OR PYRIDINE AND PYRIMIDINE, PYRIDINE OR IMIDAZOLE SUBSTITUTES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE41065E1 (en) 1995-06-06 2009-12-29 Pfizer, Inc. Alkynl and azido-substituted 4-anilinoquinazolines
CN103382182A (en) * 2013-05-17 2013-11-06 河北医科大学 Phenylurea coupling quinazoline compound, and preparation method, pharmaceutical composition and pharmaceutical use thereof
CN103382182B (en) * 2013-05-17 2016-08-10 河北医科大学 Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage

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