CA2086968C - Quinazoline derivatives - Google Patents
Quinazoline derivativesInfo
- 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
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkoxy
- amino
- quinazoline
- alkylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Cosmetics (AREA)
- Treatments For Attaching Organic Compounds To Fibrous Goods (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.
(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
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.
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,
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.
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.
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.
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.
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.
(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.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9201095.8 | 1992-01-20 | ||
| GB929201095A GB9201095D0 (en) | 1992-01-20 | 1992-01-20 | Quinazoline derivatives |
| GB9213572.2 | 1992-06-26 | ||
| GB929213572A GB9213572D0 (en) | 1992-06-26 | 1992-06-26 | Quinazoline derivatives |
| GB9223735.3 | 1992-11-12 | ||
| GB929223735A GB9223735D0 (en) | 1992-11-12 | 1992-11-12 | Quinazoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2086968A1 CA2086968A1 (en) | 1993-07-21 |
| CA2086968C true CA2086968C (en) | 1998-06-23 |
Family
ID=27266013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002086968A Expired - Lifetime CA2086968C (en) | 1992-01-20 | 1993-01-08 | Quinazoline derivatives |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US5457105A (en) |
| EP (1) | EP0566226B1 (en) |
| KR (1) | KR100229294B1 (en) |
| AT (1) | ATE130000T1 (en) |
| AU (1) | AU661533B2 (en) |
| CA (1) | CA2086968C (en) |
| CZ (1) | CZ282038B6 (en) |
| DE (1) | DE69300754T2 (en) |
| DK (1) | DK0566226T3 (en) |
| ES (1) | ES2078798T3 (en) |
| FI (1) | FI111631B (en) |
| GB (1) | GB9300059D0 (en) |
| GR (1) | GR3018143T3 (en) |
| HK (1) | HK36497A (en) |
| HU (2) | HU221622B1 (en) |
| IL (1) | IL104479A (en) |
| NO (1) | NO301541B1 (en) |
| NZ (1) | NZ245662A (en) |
| RU (1) | RU2127263C1 (en) |
| SK (1) | SK281551B6 (en) |
| TW (1) | TW283146B (en) |
| UA (1) | UA34426C2 (en) |
Cited By (2)
| 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 (715)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6645969B1 (en) * | 1991-05-10 | 2003-11-11 | Aventis 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 |
| 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 |
| 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 |
| 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 |
| US7772432B2 (en) | 1991-09-19 | 2010-08-10 | Astrazeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
| 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 |
| US5763441A (en) * | 1992-11-13 | 1998-06-09 | Sugen, Inc. | 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 |
| US5712395A (en) * | 1992-11-13 | 1998-01-27 | Yissum Research Development Corp. | Compounds for the treatment of disorders related to vasculogenesis and/or angiogenesis |
| 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 |
| AU686843B2 (en) * | 1994-02-23 | 1998-02-12 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
| AU2096895A (en) * | 1994-03-07 | 1995-09-25 | Sugen, Incorporated | Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof |
| EP0682027B1 (en) * | 1994-05-03 | 1997-10-15 | Novartis AG | Pyrrolopyrimidine derivatives with antiproliferative action |
| DK0783505T3 (en) * | 1994-09-29 | 2001-07-02 | 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 |
| DE69522717T2 (en) | 1995-03-30 | 2002-02-14 | Pfizer Inc., New York | quinazoline derivatives |
| AU711592B2 (en) * | 1995-04-03 | 1999-10-14 | Novartis Ag | Pyrazole derivatives and processes for the preparation thereof |
| US5721277A (en) * | 1995-04-21 | 1998-02-24 | Sugen, Inc. | Compounds and methods for inhibiting hyper-proliferative cell growth |
| EP0824525B1 (en) * | 1995-04-27 | 2001-06-13 | AstraZeneca AB | Quinazoline derivatives |
| GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| GB9508535D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivative |
| GB9508537D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| GB9508565D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
| 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 |
| 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 |
| 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 |
| US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| 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 |
| US7119174B2 (en) | 1995-12-18 | 2006-10-10 | 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 |
| 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 |
| JP4471404B2 (en) * | 1996-02-13 | 2010-06-02 | アストラゼネカ ユーケイ リミテッド | Quinazoline derivatives as VEGF inhibitors |
| GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
| GB9603097D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline compounds |
| ATE211134T1 (en) * | 1996-03-05 | 2002-01-15 | 4-ANILINOQUINAZOLINE DERIVATIVES | |
| HU228446B1 (en) | 1996-04-12 | 2013-03-28 | Warner Lambert Co | Kinazoline derivatives as irreversible inhibitors of protein-kinase, pharmaceutical compositions containing these compounds and use thereof |
| GB9607729D0 (en) * | 1996-04-13 | 1996-06-19 | Zeneca Ltd | Quinazoline derivatives |
| JP4386967B2 (en) * | 1996-07-13 | 2009-12-16 | グラクソ、グループ、リミテッド | Condensed heterocyclic compounds as protein tyrosine kinase inhibitors |
| EA003188B1 (en) * | 1996-08-06 | 2003-02-27 | Пфайзер Инк | Substituted pyrido- or pyrimido- containing 6,6- or 6,7- bicyclic derivatives |
| RU2196137C2 (en) * | 1996-08-08 | 2003-01-10 | Зенека Лимитед | Quinazoline derivatives and their use as inhibitors of vessel endothelium growth factor |
| WO1998010767A2 (en) * | 1996-09-13 | 1998-03-19 | Sugen, Inc. | Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders |
| US6004967A (en) * | 1996-09-13 | 1999-12-21 | Sugen, Inc. | Psoriasis treatment with quinazoline compounds |
| 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 |
| CN1237177A (en) * | 1996-11-27 | 1999-12-01 | 辉瑞大药厂 | 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 |
| US6316429B1 (en) | 1997-05-07 | 2001-11-13 | Sugen, Inc. | Bicyclic protein kinase inhibitors |
| US6486185B1 (en) | 1997-05-07 | 2002-11-26 | Sugen, Inc. | 3-heteroarylidene-2-indolinone 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 |
| 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 |
| US6313158B1 (en) | 1997-06-20 | 2001-11-06 | Sugen, Inc. | Bioavailability of 3-heteroarylidenyl-2-indolinones active as 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 |
| WO1999008668A2 (en) * | 1997-08-15 | 1999-02-25 | Cephalon, Inc. | Combination of tyrosine kinase inhibitor and chemical castration to treat prostate cancer |
| ATE368665T1 (en) | 1997-08-22 | 2007-08-15 | Astrazeneca Ab | OXINDOLYLQUINAZOLINE DERIVATIVES AS ANGIOGENESIS INHIBITORS |
| US6093728A (en) * | 1997-09-26 | 2000-07-25 | Asta Medica Aktiengesellschaft | Methods of modulating serine/threonine protein kinase function with azabenzimidazole-based compounds |
| 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 |
| US6531502B1 (en) | 1998-01-21 | 2003-03-11 | Sugen, Inc. | 3-Methylidenyl-2-indolinone modulators of protein kinase |
| AU2237899A (en) | 1998-01-21 | 1999-08-09 | Sugen, Inc. | Human orthologues of wart |
| US6943191B1 (en) | 1998-02-27 | 2005-09-13 | The United States Of America As Represented By The Department Of Health And Human Services | Disubstituted lavendustin A analogs and pharmaceutical composition comprising the 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 |
| ATE302269T1 (en) | 1998-04-14 | 2005-09-15 | Sugen Inc | STE20-RELATED PROTEIN KINASES |
| 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. |
| MXPA00011773A (en) * | 1998-05-28 | 2002-06-04 | Parker Hughes Inst | Quinazolines for treating brain tumor. |
| IL139934A (en) | 1998-05-29 | 2007-10-31 | Sugen Inc | Pyrrole substituted 2-indolinone derivatives and pharmaceutical compositions containing the same |
| 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 |
| JP2002523455A (en) | 1998-08-31 | 2002-07-30 | スージェン・インコーポレーテッド | 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 |
| US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| BRPI9914164B8 (en) | 1998-09-29 | 2021-05-25 | American Cyanamid Co | 3-cyano quinoline compounds |
| DK1117653T3 (en) | 1998-10-01 | 2003-05-26 | Astrazeneca Ab | Quinoline and quinazoline derivatives and their use as inhibitors of cycokin-mediated diseases |
| 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 |
| NZ514195A (en) | 1999-03-17 | 2004-05-28 | Astrazeneca Ab | Amide derivatives |
| US6258820B1 (en) | 1999-03-19 | 2001-07-10 | Parker Hughes Institute | Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines |
| US7064114B2 (en) * | 1999-03-19 | 2006-06-20 | Parker Hughes Institute | Gel-microemulsion formulations |
| RS49836B (en) * | 1999-03-31 | 2008-08-07 | Pfizer Products Inc., | PROCEDURES AND INTERMEDIATES FOR OBTAINING ANTI-CANCIN UNITS |
| IT1312310B1 (en) * | 1999-05-07 | 2002-04-15 | Recordati Ind Chimica E Farma | USE OF SELECTIVE 1B ADRENERGIC RECEPTOR ANTAGONISTS TO IMPROVE SEXUAL DYSFUNCTION |
| HK1047236A1 (en) * | 1999-05-14 | 2003-02-14 | Imclone Llc | 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 |
| US6933299B1 (en) | 1999-07-09 | 2005-08-23 | Smithkline Beecham Corporation | Anilinoquinazolines as protein tyrosine kinase inhibitors |
| JP2003504363A (en) | 1999-07-09 | 2003-02-04 | グラクソ グループ リミテッド | 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 |
| CN1391562A (en) * | 1999-09-21 | 2003-01-15 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives used as medicines |
| CZ20021010A3 (en) * | 1999-09-21 | 2002-06-12 | Astrazeneca Ab | Novel quinazoline compounds and pharmaceutical preparations in which they are comprised |
| WO2001025218A1 (en) * | 1999-10-01 | 2001-04-12 | Japan Energy Corporation | Novel 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 |
| PL203782B1 (en) * | 1999-11-05 | 2009-11-30 | 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 |
| JP2003521543A (en) | 2000-02-07 | 2003-07-15 | アボット ゲーエムベーハー ウント カンパニー カーゲー | 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 |
| DE122008000002I1 (en) | 2000-02-15 | 2008-04-17 | Sugen Inc | PYRROL SUBSTITUTED INDOLIN-2-ON PROTEIN KINASE INHIBITORS |
| AU779695B2 (en) | 2000-04-07 | 2005-02-10 | Astrazeneca Ab | Quinazoline compounds |
| UA73993C2 (en) * | 2000-06-06 | 2005-10-17 | Астразенека Аб | Quinazoline derivatives for the treatment of tumours and a pharmaceutical composition |
| RU2276151C2 (en) * | 2000-06-06 | 2006-05-10 | Астразенека Аб | Quinazoline derivatives for tumor treatment |
| EE200200715A (en) * | 2000-06-28 | 2004-08-16 | Astrazeneca Ab | Substituted quinazoline derivatives and their use as inhibitors |
| JP2004527456A (en) * | 2000-08-09 | 2004-09-09 | イムクローン システムズ インコーポレイティド | Treatment of hyperproliferative diseases with EGF receptor antagonists |
| AU2001278609B2 (en) | 2000-08-21 | 2005-04-14 | Astrazeneca Ab | Quinazoline derivatives |
| DE10042059A1 (en) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
| US6617329B2 (en) | 2000-08-26 | 2003-09-09 | Boehringer Ingelheim Pharma Kg | Aminoquinazolines and their use as medicaments |
| 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 |
| EP3342411B1 (en) | 2001-02-19 | 2019-08-21 | Novartis Pharma AG | Rapamycin derivative for treating pancreas 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. |
| CA2443144A1 (en) * | 2001-04-02 | 2002-10-10 | Merck & Co., Inc. | In vivo methods of determining activity of receptor-type kinase inhibitors |
| EP1381384B1 (en) | 2001-04-24 | 2011-05-25 | Merck Patent GmbH | COMBINATION THERAPY USING ANTI-ANGIOGENIC AGENTS AND TNFalpha |
| US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
| DE60234094D1 (en) | 2001-05-11 | 2009-12-03 | Ludwig Inst For Cancer Res Ltd | SPECIFIC TIE PROTEINS AND ITS USE |
| US20110313230A1 (en) | 2001-05-11 | 2011-12-22 | Terrance Grant Johns | Specific binding proteins and uses thereof |
| WO2002092577A1 (en) * | 2001-05-14 | 2002-11-21 | Astrazeneca Ab | Quinazoline derivatives |
| KR20080091866A (en) | 2001-05-16 | 2008-10-14 | 노파르티스 아게 | Ν- ｛5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl｝ -4- (3-pyridyl) -2-pyrimidin-amine and chemotherapeutic agent Formulated to |
| 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 |
| EP1434774A1 (en) | 2001-10-10 | 2004-07-07 | Sugen, Inc. | 3-(4-substituted heterocyclyl)-pyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors |
| GB0126433D0 (en) * | 2001-11-03 | 2002-01-02 | Astrazeneca Ab | Compounds |
| ES2333702T3 (en) * | 2001-12-24 | 2010-02-26 | Astrazeneca Ab | SUBSTITUTED QUINAZOLINE DERIVATIVES ACTING AS AURORA CINASE UNHIBITORS. |
| RS63204A (en) * | 2002-01-17 | 2006-10-27 | Neurogen Corporation | Substituted quinazolin-4-ylamine analogues as modulators of capsaicin |
| DK1474420T3 (en) | 2002-02-01 | 2012-05-21 | Astrazeneca Ab | quinazoline |
| GB0204392D0 (en) * | 2002-02-26 | 2002-04-10 | Astrazeneca Ab | Pharmaceutical compound |
| MY135609A (en) * | 2002-02-26 | 2008-05-30 | Astrazeneca Ab | Pharmaceutical formulation of iressa comprising a water-soluble cellulose derivative |
| EP1480650B1 (en) * | 2002-02-26 | 2010-04-28 | AstraZeneca AB | Novel crystalline forms of the anti-cancer compound zd1839 |
| GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
| US7078409B2 (en) | 2002-03-28 | 2006-07-18 | Beta Pharma, Inc. | Fused quinazoline derivatives useful as tyrosine kinase inhibitors |
| TW200813014A (en) * | 2002-03-28 | 2008-03-16 | Astrazeneca Ab | Quinazoline derivatives |
| 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 |
| CN100352441C (en) * | 2002-04-16 | 2007-12-05 | 阿斯特拉曾尼卡有限公司 | 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 |
| NZ560662A (en) | 2002-05-16 | 2009-09-25 | Novartis Ag | Use of EDG receptor binding agents in cancer |
| WO2003103581A2 (en) | 2002-06-05 | 2003-12-18 | Genentech, Inc. | 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 |
| NZ539408A (en) * | 2002-11-04 | 2007-09-28 | Astrazeneca Ab | Quinazoline derivatives as SRC tyrosine kinase inhibitors for treating solid tumours |
| AR042461A1 (en) * | 2002-12-13 | 2005-06-22 | Neurogen Corp | ANALOGS 2-SUBSTITUTED FOR QUINAZOLIN-4-IL - AMINA. PHARMACEUTICAL COMPOSITIONS |
| CA2529611C (en) | 2002-12-20 | 2009-12-15 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| JP2006515871A (en) * | 2003-01-23 | 2006-06-08 | ティー．ケイ． シグナル リミテッド | Irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and use 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 |
| MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
| WO2005000833A1 (en) | 2003-05-19 | 2005-01-06 | Irm, Llc | Immunosuppressant compounds and compositions |
| MXPA05012939A (en) | 2003-05-30 | 2006-05-17 | Astrazeneca Uk Ltd | Process. |
| CN1972712A (en) | 2003-06-09 | 2007-05-30 | 塞缪尔·瓦克萨尔 | Methods of inhibiting receptor tyrosine kinases using extracellular and intracellular antagonists |
| CA2527832A1 (en) | 2003-06-10 | 2004-12-23 | F. Hoffmann-La Roche Ag | 1.3.4-triaza-phenalene and 1,3,4,6-tetraazaphenalene derivatives |
| GB0317663D0 (en) * | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Pharmaceutical composition |
| JP2007500177A (en) * | 2003-07-29 | 2007-01-11 | アストラゼネカ アクチボラグ | Piperidylquinazoline derivatives as tyrosine kinase inhibitors |
| GB0317665D0 (en) | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
| KR20060065662A (en) | 2003-07-31 | 2006-06-14 | 사노피-아벤티스 | Aminoquinoline Derivatives and Their Uses as Adenosine A3 Ligands |
| JP2007501229A (en) | 2003-08-06 | 2007-01-25 | スゲン，インコーポレイティド | Geometrically constrained 3-cyclopentylidene-1,3-dihydroindol-2-ones as potent protein kinase inhibitors |
| GB0318422D0 (en) | 2003-08-06 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
| 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 |
| MXPA06002964A (en) * | 2003-09-16 | 2006-06-14 | Astrazeneca Ab | Quinazoline derivatives as tyrosine kinase inhibitors. |
| ATE353888T1 (en) * | 2003-09-19 | 2007-03-15 | Astrazeneca Ab | CHINAZOLINE DERIVATIVES |
| US8318752B2 (en) * | 2003-09-19 | 2012-11-27 | Astrazeneca Ab | 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl-methyl)piperidin-4-yl]oxy}quinazoline, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same |
| GB0322409D0 (en) | 2003-09-25 | 2003-10-29 | Astrazeneca Ab | Quinazoline derivatives |
| EP1670786A1 (en) * | 2003-09-25 | 2006-06-21 | Astrazeneca AB | Quinazoline derivatives |
| 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 |
| WO2005032481A2 (en) * | 2003-09-30 | 2005-04-14 | Scios Inc. | Quinazoline derivatives as medicaments |
| 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 |
| GB0326459D0 (en) | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
| CA2545711A1 (en) * | 2003-11-13 | 2005-06-02 | Ambit Biosciences Corporation | Urea derivatives as kinase modulators |
| CA2552658A1 (en) * | 2004-01-07 | 2005-07-28 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to epidermal growth factor receptor modulators |
| DE602005010824D1 (en) | 2004-02-03 | 2008-12-18 | Astrazeneca Ab | quinazoline derivatives |
| BRPI0400869B8 (en) * | 2004-03-02 | 2021-05-25 | Univ Estadual Campinas Unicamp | new compounds derived from 4-anilinoquinazolines with adenosine kinase inhibiting property |
| ES2554330T3 (en) * | 2004-02-19 | 2015-12-18 | Rexahn Pharmaceuticals, Inc. | Quinazoline derivatives and therapeutic use thereof |
| PT1735348E (en) * | 2004-03-19 | 2012-07-24 | Imclone Llc | Human anti-epidermal growth factor receptor antibody |
| PT1733056E (en) | 2004-03-31 | 2013-08-29 | Gen Hospital Corp | METHOD FOR DETERMINING CANCER RESPONSIVENESS TO TREATMENTS VISITING THE EPIDERIC GROWTH FACTOR RECEIVER |
| RS52545B (en) | 2004-04-07 | 2013-04-30 | Novartis Ag | INHIBITORI PROTEIN APOPTOZE (IAP) |
| NZ550796A (en) | 2004-05-06 | 2010-07-30 | Warner Lambert Co | 4-phenylamino-quinazolin-6-yl-amides |
| CA2565721C (en) | 2004-05-06 | 2015-10-06 | Bioresponse, L.L.C. | Diindolymethane formulations for the treatment of leiomyomas |
| WO2005120557A2 (en) * | 2004-05-13 | 2005-12-22 | Imclone Systems Incorporated | Inhibition of macrophage-stimulating protein receptor (ron) |
| WO2006002422A2 (en) | 2004-06-24 | 2006-01-05 | Novartis Vaccines And Diagnostics Inc. | Compounds for immunopotentiation |
| GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
| AU2005293336B2 (en) | 2004-10-12 | 2009-05-28 | Astrazeneca Ab | Quinazoline derivatives |
| WO2006064196A1 (en) | 2004-12-14 | 2006-06-22 | Astrazeneca Ab | Pyrazolopyrimidine compounds as antitumor agents |
| DE602005026328D1 (en) | 2004-12-30 | 2011-03-24 | Bioresponse Llc | USE OF DIINDOLYLMETHAN-RELATED INDOLAS FOR THE TREATMENT AND PREVENTION OF DISEASES RELATED TO THE RESPIRATORY SYNCYTIAL VIRUS |
| US20090155247A1 (en) * | 2005-02-18 | 2009-06-18 | Ashkenazi Avi J | Methods of Using Death Receptor Agonists and EGFR Inhibitors |
| US20060188498A1 (en) * | 2005-02-18 | 2006-08-24 | Genentech, Inc. | Methods of using death receptor agonists and EGFR inhibitors |
| DK1854789T3 (en) | 2005-02-23 | 2013-10-21 | Shionogi & Co | QUINAZOLINE DERIVATIVES WITH TYROSIN-KINASE INHIBITORIC ACTIVITY |
| ATE521603T1 (en) | 2005-02-26 | 2011-09-15 | Astrazeneca Ab | QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS |
| ES2319462T3 (en) * | 2005-03-28 | 2009-05-07 | Bristol-Myers Squibb Company | COMPETITIVE INHIBITORS OF ATP CINASAS. |
| BRPI0607537A2 (en) * | 2005-04-12 | 2009-09-15 | Elan Pharma Int Ltd | nanoparticulate quinazoline derivative formulations |
| GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
| CN101287761A (en) | 2005-06-15 | 2008-10-15 | 先灵公司 | Anti-IGF1R Antibody Preparations |
| PT2100618E (en) | 2005-06-17 | 2014-04-07 | Philadelphia Health & Educatio | AN ANTI-PDGFR-ALPHA ANTIBODY FOR THE TREATMENT OF METASTATIC BONE CANCER |
| JP2009505658A (en) * | 2005-08-24 | 2009-02-12 | 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 |
| 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 |
| US7820683B2 (en) | 2005-09-20 | 2010-10-26 | Astrazeneca Ab | 4-(1H-indazol-5-yl-amino)-quinazoline compounds as erbB receptor tyrosine kinase inhibitors 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 |
| JP5688877B2 (en) | 2005-11-11 | 2015-03-25 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Quinazoline derivatives for the treatment of cancer diseases |
| NO20220050A1 (en) | 2005-11-21 | 2008-08-12 | Novartis Ag | Neuroendocrine tumor treatment |
| CA2632929A1 (en) * | 2005-12-22 | 2007-06-28 | Astrazeneca Ab | Quinazoline derivatives, process for their preparation and their use as anti-cancer agents |
| JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | PI-3 Kinase inhibitors and methods of their use |
| 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 |
| AU2007212447B2 (en) | 2006-02-03 | 2013-02-21 | Imclone Llc | IGF-IR antagonists as adjuvants for treatment of prostate cancer |
| 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 |
| EP1994024A2 (en) * | 2006-03-02 | 2008-11-26 | AstraZeneca AB | 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 |
| CN102861338A (en) | 2006-04-05 | 2013-01-09 | 诺瓦提斯公司 | Combinations of comprising a bcr-abl, c-kit and pdgf-r tyrosine kinase inhibitor used for treating cancer |
| WO2007124252A2 (en) | 2006-04-05 | 2007-11-01 | Novartis Ag | Combinations of therapeutic agents for treating cancer |
| AR060358A1 (en) * | 2006-04-06 | 2008-06-11 | Novartis Vaccines & Diagnostic | QUINAZOLINS FOR THE INHIBITION OF PDK 1 |
| EP2010521A1 (en) | 2006-04-19 | 2009-01-07 | Novartis Ag | Indazole compounds and methods for inhibition of cdc7 |
| KR20090007635A (en) | 2006-05-09 | 2009-01-19 | 노파르티스 아게 | Combinations comprising iron chelators and anti-neoplastic agents and uses thereof |
| EA200802058A1 (en) | 2006-05-09 | 2009-06-30 | Пфайзер Продактс Инк. | DERIVATIVES OF CYCLO-ALKYLAMINO ACIDS AND THEIR PHARMACEUTICAL COMPOSITIONS |
| JP5399900B2 (en) | 2006-06-30 | 2014-01-29 | メルク・シャープ・アンド・ドーム・コーポレーション | IGFBP2 inhibitor |
| 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 |
| US7547781B2 (en) | 2006-09-11 | 2009-06-16 | Curis, Inc. | Quinazoline based EGFR inhibitors containing a zinc binding moiety |
| CA2662937A1 (en) * | 2006-09-11 | 2008-03-20 | Curis, Inc. | Multi-functional small molecules as anti-proliferative agents |
| EP2061469B8 (en) * | 2006-09-11 | 2014-02-26 | Curis, Inc. | Quinazoline based egfr inhibitors |
| JP5580592B2 (en) * | 2006-09-11 | 2014-08-27 | キュリス，インコーポレイテッド | Quinazoline-based EGFR inhibitors containing zinc binding moieties |
| WO2008033782A2 (en) | 2006-09-12 | 2008-03-20 | Genentech, Inc. | Methods and compositions for the diagnosis and treatment of lung cancer using pdgfra, kit or kdr gene as genetic marker |
| DK2068880T3 (en) | 2006-09-18 | 2012-07-23 | Boehringer Ingelheim Int | Method of treating cancer harboring EGFR mutations |
| EP2077819A4 (en) * | 2006-09-28 | 2011-05-25 | Follica Inc | METHODS, MATERIALS, AND COMPOSITIONS FOR GENERATING NEW CELLULAR FOLLICLES AND PUSHING HAIR |
| RU2009115954A (en) | 2006-09-29 | 2010-11-10 | Новартис АГ (CH) | Pyrazolopyrimidines as P13K Lipid Kinase Inhibitors |
| JO3598B1 (en) * | 2006-10-10 | 2020-07-05 | Infinity Discovery Inc | Boronic acids and esters as inhibitors of fatty acid amide hydrolase |
| US8586621B2 (en) | 2006-10-27 | 2013-11-19 | Michael A. Zeligs | Anti-parasitic methods and compositions utilizing diindolylmethane-related indoles |
| 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 |
| CA2676244C (en) | 2007-01-25 | 2017-01-17 | Kwok-Kin Wong | Use of anti-egfr antibodies in treatment of egfr mutant mediated disease |
| EA200901041A1 (en) | 2007-02-06 | 2010-02-26 | Бёрингер Ингельхайм Интернациональ Гмбх | BICYCLIC HETEROCYCLES CONTAINING THESE COMPOUNDS MEDICINES, THEIR APPLICATION AND METHOD OF OBTAINING THEM |
| 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 |
| US20100069458A1 (en) | 2007-02-15 | 2010-03-18 | Peter Wisdom Atadja | Combination of lbh589 with other therapeutic agents for treating cancer |
| CN101688229B (en) | 2007-03-15 | 2013-06-12 | 路德维格癌症研究所 | Compositions comprising EGFR antibodies and SRC inhibitors and their use in the preparation of medicaments for treating cancer in mammals |
| NZ580671A (en) * | 2007-04-16 | 2012-03-30 | Hutchison Medipharma Entpr Ltd | Pyrimidine derivatives |
| DK2146779T3 (en) | 2007-04-18 | 2016-11-28 | Pfizer Prod Inc | Sulfonylamid derivatives to treat abnormal cell growth. |
| CA2687611A1 (en) * | 2007-05-24 | 2008-11-27 | Bayer Schering Pharma Aktiengesellschaft | Novel sulphoximine-substituted quinoline and quinazoline derivatives as kinase inhibitors |
| CA2696360C (en) * | 2007-08-14 | 2018-11-20 | Ludwig Institute For Cancer Research | Monoclonal antibody targeting the egfr receptor and uses thereof |
| ES2526718T3 (en) * | 2007-09-10 | 2015-01-14 | Curis, Inc. | EGFR inhibitors based on tartrate salts or quinazoline complexes containing a moiety that binds zinc |
| US8119616B2 (en) * | 2007-09-10 | 2012-02-21 | Curis, Inc. | Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety |
| JP2011500723A (en) * | 2007-10-19 | 2011-01-06 | ファルマ・マール・ソシエダード・アノニマ | Improved anti-tumor treatment |
| WO2009055343A2 (en) * | 2007-10-22 | 2009-04-30 | Schering Corporation | Fully human anti-vegf antibodies and methods of using |
| KR20100087185A (en) * | 2007-10-29 | 2010-08-03 | 낫코 파마 리미티드 | Novel 4-(tetrazol-5-yl)-quinazoline derivatives as anti cancer agents |
| CN101909630A (en) | 2007-11-02 | 2010-12-08 | 新加坡科技研究局 | Methods and compounds for the prevention and treatment of tumors |
| EP2060565A1 (en) | 2007-11-16 | 2009-05-20 | 4Sc Ag | Novel bifunctional compounds which inhibit protein kinases and histone deacetylases |
| WO2009067543A2 (en) * | 2007-11-19 | 2009-05-28 | The Regents Of The University Of Colorado | 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 |
| UY31478A1 (en) * | 2007-11-21 | 2009-07-17 | RECEIVER INHIBITION FOR MACROFAGO STIMULATING PROTEIN (RON) AND METHODS FOR TREATMENT OF THE SAME | |
| BRPI0820722A2 (en) | 2007-12-20 | 2015-06-16 | Novartis Ag | Thiazole derivatives used as inhibitors of pi 3 kinases |
| EP2072502A1 (en) * | 2007-12-20 | 2009-06-24 | Bayer Schering Pharma Aktiengesellschaft | Sulfoximide substituted chinolin and chinazolin derivatives as kinase inhibitors |
| KR101762306B1 (en) | 2008-01-18 | 2017-07-27 | 낫코 파마 리미티드 | 6,7-dialkoxy quinazoline derivatives useful for treatment of cancer related disorders |
| TWI472339B (en) | 2008-01-30 | 2015-02-11 | Genentech Inc | Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof |
| AU2009209541A1 (en) * | 2008-01-30 | 2009-08-06 | Pharma Mar, S.A. | Improved antitumoral treatments |
| JP5336516B2 (en) | 2008-02-07 | 2013-11-06 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Spirocyclic heterocyclic compounds, pharmaceuticals containing the compounds, uses thereof and methods for producing the same |
| DE102008009609A1 (en) | 2008-02-18 | 2009-08-20 | Freie Universität Berlin | Substituted 4- (indol-3-yl) quinazolines and their use and preparation |
| EP2259800B1 (en) * | 2008-03-05 | 2014-05-07 | 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 |
| KR101673621B1 (en) | 2008-03-24 | 2016-11-07 | 노파르티스 아게 | Arylsulfonamide-based matrix metalloprotease inhibitors |
| PT2260020E (en) | 2008-03-26 | 2014-10-28 | Novartis Ag | Hydroxamate-based inhibitors of deacetylases b |
| CN102046179B (en) * | 2008-04-09 | 2015-01-14 | 英菲尼提制药公司 | 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 |
| BRPI0912170A2 (en) | 2008-05-13 | 2015-10-13 | Astrazeneca Ab | compound, form, process for preparation thereof, pharmaceutical composition, use of a compound, and method for treating cancer in a warm-blooded animal |
| 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 |
| CA2733153C (en) | 2008-08-08 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them |
| US7737157B2 (en) * | 2008-08-29 | 2010-06-15 | Hutchison Medipharma Enterprises Limited | 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 CATHOLIC BUTANE DERIVATIVES IN THERAPY AGAINST CANCER. |
| US20100222371A1 (en) * | 2008-11-20 | 2010-09-02 | Children's Medical Center Corporation | Prevention of surgical adhesions |
| MX2011006610A (en) | 2008-12-18 | 2011-06-30 | Novartis Ag | New polymorphic form of 1-(4-{l-[(e)-4-cyclohexyl--3-triflu oromethyl-benzyloxyimino]-ethyl)-2-ethyl-benzy l)-azetidine -3-carboxylic. |
| ES2478842T3 (en) | 2008-12-18 | 2014-07-23 | Novartis Ag | Salt 1- (4- (1 - ((E) -4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -ethyl) -2-ethyl-benzyl) -azetidine-3-carboxylic acid |
| KR20160064245A (en) | 2008-12-18 | 2016-06-07 | 노파르티스 아게 | Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid |
| WO2010083617A1 (en) | 2009-01-21 | 2010-07-29 | Oncalis Ag | Pyrazolopyrimidines as protein kinase inhibitors |
| HRP20121006T1 (en) | 2009-01-29 | 2013-01-31 | Novartis Ag | BENZIMIDAZOLES SUBSTITUTED FOR ASTROCYTOMA TREATMENT |
| EP2400985A2 (en) | 2009-02-25 | 2012-01-04 | OSI Pharmaceuticals, LLC | Combination of an either an anti-igf-1r antibody or an igf binding protein and a small molecule igf-1r kinase inhibitor |
| 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 |
| 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 |
| 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 |
| EP2408479A1 (en) | 2009-03-18 | 2012-01-25 | OSI Pharmaceuticals, LLC | Combination cancer therapy comprising administration of an egfr inhibitor and an igf-1r inhibitor |
| NZ594665A (en) | 2009-03-20 | 2013-08-30 | Genentech Inc | Bispecific anti-her antibodies |
| US8546564B2 (en) | 2009-04-07 | 2013-10-01 | Infinity Pharmaceuticals, Inc. | Inhibitors of fatty acid amide hydrolase |
| AU2010234449A1 (en) | 2009-04-07 | 2011-11-03 | Infinity Pharmaceuticals, Inc. | Inhibitors of fatty acid amide hydrolase |
| UY32730A (en) | 2009-06-26 | 2011-01-31 | Novartis Ag | CYP17 INHIBITORS |
| US8293753B2 (en) | 2009-07-02 | 2012-10-23 | Novartis Ag | Substituted 2-carboxamide cycloamino ureas |
| HUE044629T2 (en) | 2009-07-06 | 2019-11-28 | Boehringer Ingelheim Int | 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 |
| CA2770873A1 (en) | 2009-08-12 | 2011-02-17 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
| GEP201706639B (en) | 2009-08-17 | 2017-03-27 | Intellikine Llc | Heterocyclic compounds and uses thereof |
| CA2771432A1 (en) | 2009-08-20 | 2011-02-24 | Novartis Ag | Heterocyclic oxime compounds |
| IN2012DN01693A (en) | 2009-08-26 | 2015-06-05 | Novartis Ag | |
| JP2013503846A (en) | 2009-09-01 | 2013-02-04 | ファイザー・インク | Benzimidazole derivatives |
| EP3575288B1 (en) | 2009-09-03 | 2021-10-27 | Bristol-Myers Squibb Company | Quinazolines as potassium ion channel inhibitors |
| WO2011029915A1 (en) | 2009-09-10 | 2011-03-17 | Novartis Ag | Ether derivatives of bicyclic heteroaryls |
| US20110076232A1 (en) | 2009-09-29 | 2011-03-31 | Ludwig Institute For Cancer Research | Specific binding proteins and uses thereof |
| EA020151B1 (en) | 2009-10-23 | 2014-09-30 | Эли Лилли Энд Компани | Akt inhibitors and pharmaceutical compositions comprising them |
| WO2011053779A2 (en) | 2009-10-30 | 2011-05-05 | Bristol-Myers Squibb Company | Methods for treating cancer in patients having igf-1r inhibitor resistance |
| EA201200651A1 (en) | 2009-11-04 | 2012-12-28 | Новартис Аг | HETEROCYCLIC SULPHONAMIDE DERIVATIVES APPLICABLE AS MEK INHIBITORS |
| CN102612374A (en) | 2009-11-12 | 2012-07-25 | 霍夫曼-拉罗奇有限公司 | A method of promoting dendritic spine density |
| JP2013510564A (en) | 2009-11-13 | 2013-03-28 | パンガエア ビオテック、ソシエダッド、リミターダ | 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 |
| CN102781237A (en) | 2009-11-23 | 2012-11-14 | 天蓝制药公司 | Cyclodextrin-based polymers for delivery of therapeutic agents |
| US20120289501A1 (en) | 2009-11-25 | 2012-11-15 | Novartis Ag | Benzene-fused 6-membered oxygen-containing heterocyclic derivatives of bicyclic heteroaryls |
| ES2484171T3 (en) | 2009-12-08 | 2014-08-11 | Novartis Ag | Heterocyclic sulfonamide derivatives |
| CU24130B1 (en) | 2009-12-22 | 2015-09-29 | Novartis Ag | ISOQUINOLINONES AND REPLACED QUINAZOLINONES |
| US8440693B2 (en) | 2009-12-22 | 2013-05-14 | Novartis Ag | Substituted isoquinolinones and quinazolinones |
| US8461328B2 (en) | 2010-01-12 | 2013-06-11 | Genentech, Inc. | Tricyclic heterocyclic compounds, compositions and methods of use thereof |
| WO2011090940A1 (en) | 2010-01-19 | 2011-07-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
| JP2013518886A (en) | 2010-02-03 | 2013-05-23 | 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 | Fatty acid amide hydrolase inhibitor |
| MX2012008958A (en) | 2010-02-18 | 2012-08-23 | Genentech Inc | Neuregulin antagonists and use thereof in treating cancer. |
| SG183855A1 (en) * | 2010-03-16 | 2012-10-30 | 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 |
| CN103038643A (en) | 2010-04-16 | 2013-04-10 | 基因泰克公司 | FOXO3A as a predictive biomarker of PI3K/AKT kinase pathway inhibitor potency |
| EP2582681A1 (en) | 2010-06-17 | 2013-04-24 | 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 |
| CA2808236A1 (en) | 2010-08-31 | 2012-03-08 | 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 |
| EP2627648A1 (en) | 2010-09-16 | 2013-08-21 | Novartis AG | 17aHYDROXYLASE/C17,20-LYASE INHIBITORS |
| WO2012052948A1 (en) | 2010-10-20 | 2012-04-26 | Pfizer Inc. | Pyridine- 2- derivatives as smoothened receptor modulators |
| CA2817785A1 (en) | 2010-11-19 | 2012-05-24 | Toby Blench | Pyrazolopyridines and pyrazolopyridines and their use as tyk2 inhibitors |
| WO2012085815A1 (en) | 2010-12-21 | 2012-06-28 | Novartis Ag | Bi-heteroaryl compounds as vps34 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 |
| MX343706B (en) | 2011-01-31 | 2016-11-18 | Novartis Ag | Novel heterocyclic derivatives. |
| JP2014505088A (en) | 2011-02-10 | 2014-02-27 | ノバルティス アーゲー | [1,2,4] Triazolo [4,3-b] pyridazine compounds as C-MET tyrosine kinase inhibitors |
| JP5808826B2 (en) | 2011-02-23 | 2015-11-10 | インテリカイン， エルエルシー | 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 |
| AU2012225693A1 (en) | 2011-03-04 | 2013-09-19 | Newgen Therapeutics, Inc. | Alkyne substituted quinazoline compound and methods of use |
| KR101940340B1 (en) | 2011-03-04 | 2019-01-18 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | Amino-quinolines as kinase inhibitors |
| US20130338152A1 (en) | 2011-03-08 | 2013-12-19 | Irm Llc | Fluorophenyl bicyclic heteroaryl compounds |
| EP2685980B1 (en) | 2011-03-17 | 2017-12-06 | The Trustees Of The University Of Pennsylvania | Methods and use of bifunctional enzyme-building clamp-shaped molecules |
| WO2012125904A1 (en) | 2011-03-17 | 2012-09-20 | 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 |
| MX359399B (en) | 2011-04-28 | 2018-09-27 | Novartis Ag | 17a-HYDROXYLASE/C17,20-LYASE INHIBITORS. |
| WO2012155339A1 (en) | 2011-05-17 | 2012-11-22 | 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 |
| KR20140034898A (en) | 2011-06-09 | 2014-03-20 | 노파르티스 아게 | Heterocyclic sulfonamide derivatives |
| US8859535B2 (en) | 2011-06-20 | 2014-10-14 | Novartis Ag | Hydroxy substituted isoquinolinone derivatives |
| WO2012175487A1 (en) | 2011-06-20 | 2012-12-27 | Novartis Ag | Cyclohexyl isoquinolinone compounds |
| AU2012277391A1 (en) | 2011-06-27 | 2013-12-19 | Novartis Ag | Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives |
| WO2013007765A1 (en) | 2011-07-13 | 2013-01-17 | F. Hoffmann-La Roche Ag | Fused tricyclic compounds for use as inhibitors of janus kinases |
| 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 |
| WO2013024011A1 (en) | 2011-08-12 | 2013-02-21 | F. Hoffmann-La Roche Ag | Indazole compounds, compositions and methods of use |
| WO2014081405A2 (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 |
| KR20140057326A (en) | 2011-08-17 | 2014-05-12 | 제넨테크, 인크. | 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 |
| WO2013033380A1 (en) | 2011-08-31 | 2013-03-07 | Genentech, Inc. | Diagnostic markers |
| AU2012310168B2 (en) | 2011-09-15 | 2015-07-16 | Novartis Ag | 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase |
| MX2014002949A (en) | 2011-09-20 | 2014-04-30 | Hoffmann La Roche | Imidazopyridine compounds, compositions and methods of use. |
| MD20140023A2 (en) | 2011-09-22 | 2014-06-30 | Pfizer Inc. | Pyrrolopyrimidine and purine derivatives |
| US20130084287A1 (en) | 2011-09-30 | 2013-04-04 | Genentech, Inc. | Diagnostic markers |
| US20140309229A1 (en) | 2011-10-13 | 2014-10-16 | Bristol-Myers Squibb Company | Methods for selecting and treating cancer in patients with igf-1r/ir inhibitors |
| BR112014009890A2 (en) | 2011-10-28 | 2020-10-27 | Novartis Ag | purine derivatives and their use in the treatment of disease |
| WO2013080141A1 (en) | 2011-11-29 | 2013-06-06 | Novartis Ag | Pyrazolopyrrolidine compounds |
| RU2019103083A (en) | 2011-11-30 | 2019-03-22 | Дженентек, Инк. | Mutations of ErbB3 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 |
| US20150148377A1 (en) | 2011-12-22 | 2015-05-28 | Novartis Ag | Quinoline Derivatives |
| IN2014CN04174A (en) | 2011-12-22 | 2015-09-04 | Novartis Ag | |
| CA2859873A1 (en) | 2011-12-23 | 2013-06-27 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners |
| CN104125955A (en) | 2011-12-23 | 2014-10-29 | 诺华股份有限公司 | Compounds for inhibiting interaction of bcl2 with binding partners |
| BR112014015322A8 (en) | 2011-12-23 | 2017-06-13 | Novartis Ag | compounds and compositions for inhibiting bcl2 interaction with binding partners |
| MX2014007731A (en) | 2011-12-23 | 2015-01-12 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners. |
| WO2013096055A1 (en) | 2011-12-23 | 2013-06-27 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners |
| US20130178520A1 (en) | 2011-12-23 | 2013-07-11 | Duke University | Methods of treatment using arylcyclopropylamine compounds |
| US8815926B2 (en) | 2012-01-26 | 2014-08-26 | Novartis Ag | Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases |
| WO2013143057A1 (en) | 2012-03-26 | 2013-10-03 | 中国科学院福建物质结构研究所 | Quinazoline derivative and application thereof |
| WO2013148315A1 (en) | 2012-03-27 | 2013-10-03 | Genentech, Inc. | Diagnosis and treatments relating to her3 inhibitors |
| EP3964513A1 (en) | 2012-04-03 | 2022-03-09 | Novartis AG | Combination products with 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 |
| BR112014028420A2 (en) | 2012-05-16 | 2017-09-19 | Novartis Ag | Dosage regimen for a pi-3 kinase inhibitor |
| CN104321325B (en) | 2012-05-24 | 2016-11-16 | 诺华股份有限公司 | Pyrrolopyrrole alkanone compound |
| BR112014031421A2 (en) | 2012-06-15 | 2017-06-27 | Brigham & Womens Hospital Inc | cancer treatment compositions and methods for producing them |
| WO2013190089A1 (en) | 2012-06-21 | 2013-12-27 | Pangaea Biotech, S.L. | Molecular biomarkers for predicting outcome in lung cancer |
| EP2879675B1 (en) | 2012-08-06 | 2019-11-13 | Duke University | Compounds and methods for targeting hsp90 |
| US9637523B2 (en) | 2012-08-31 | 2017-05-02 | 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 |
| AU2013337247B2 (en) | 2012-11-05 | 2018-08-09 | 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 |
| WO2014115077A1 (en) | 2013-01-22 | 2014-07-31 | Novartis Ag | Substituted purinone compounds |
| WO2014115080A1 (en) | 2013-01-22 | 2014-07-31 | Novartis Ag | Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction |
| DK2950649T3 (en) | 2013-02-01 | 2020-05-04 | Wellstat Therapeutics Corp | AMINE COMPOUNDS WITH ANTI-INFLAMMATION, ANTI-FUNGI, ANTIPARASITY AND ANTICANCER ACTIVITY |
| PL2958943T3 (en) | 2013-02-20 | 2020-04-30 | The Trustees Of The University Of Pennsylvania | Treatment of malignant neoplasm with a humanized chimeric anti-egfrviii antigen receptor |
| WO2014128612A1 (en) | 2013-02-20 | 2014-08-28 | Novartis Ag | Quinazolin-4-one derivatives |
| BR112015019624A2 (en) | 2013-02-21 | 2017-07-18 | Glaxosmithkline Ip Dev Ltd | quinazolines as kinase inhibitors |
| EP2958592A1 (en) | 2013-02-22 | 2015-12-30 | F. Hoffmann-La Roche AG | Methods of treating cancer and preventing drug resistance |
| US9834575B2 (en) | 2013-02-26 | 2017-12-05 | Triact Therapeutics, Inc. | Cancer therapy |
| US9468681B2 (en) | 2013-03-01 | 2016-10-18 | California Institute Of Technology | Targeted nanoparticles |
| DK2964638T3 (en) | 2013-03-06 | 2017-10-30 | Astrazeneca Ab | QUINAZOLIN INHIBITORS TO ACTIVATE MUTANEOUS FORMS OF EPIDERMAL GROWTH FACTOR RECEPTOR |
| RU2015137610A (en) | 2013-03-06 | 2017-04-10 | Дженентек, Инк. | METHODS FOR TREATMENT AND PREVENTION OF DRUG RESISTANCE OF MALIGNANT TUMORS |
| EP2970307B1 (en) | 2013-03-13 | 2020-03-11 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
| BR112015022576A2 (en) | 2013-03-14 | 2017-10-24 | Genentech Inc | pharmaceutical product and its use, kit and method for treating hyperproliferative dysfunction |
| HK1220916A1 (en) | 2013-03-14 | 2017-05-19 | 基因泰克公司 | Methods of treating cancer and preventing cancer drug resistance |
| CN105339001A (en) | 2013-03-15 | 2016-02-17 | 基因泰克公司 | Ways to treat cancer and prevent cancer resistance |
| WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
| WO2014147246A1 (en) | 2013-03-21 | 2014-09-25 | 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 |
| EP2989091B1 (en) | 2013-04-04 | 2017-05-10 | Janssen Pharmaceutica NV | Novel n-(2,3-dihydro-1h-pyrrolo[2,3-b]pyridin-5-yl)-4- quinazolinamine and n-(2,3-dihydro-1h-indol-5-yl)-4- quinazolinamine derivatives as perk inhibitors |
| 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 |
| WO2015022664A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
| 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 |
| US9505767B2 (en) | 2013-09-05 | 2016-11-29 | Genentech, Inc. | Pyrazolo[1,5-A]pyrimidin-7(4H)-onehistone demethylase inhibitors |
| CA2923667A1 (en) | 2013-09-09 | 2015-03-12 | Triact Therapeutics, Inc. | Cancer therapy |
| KR20160060100A (en) | 2013-09-22 | 2016-05-27 | 칼리토르 사이언시즈, 엘엘씨 | 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 |
| TW201605857A (en) | 2013-10-03 | 2016-02-16 | 赫孚孟拉羅股份公司 | Therapeutic inhibitors of CDK8 and uses thereof |
| CN105744954B (en) | 2013-10-18 | 2021-03-05 | 豪夫迈·罗氏有限公司 | anti-RSPO 2 and/or anti-RSPO 3 antibodies and uses thereof |
| UA115388C2 (en) | 2013-11-21 | 2017-10-25 | Пфайзер Інк. | 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders |
| TW201605450A (en) | 2013-12-03 | 2016-02-16 | 諾華公司 | Combination of Mdm2 inhibitor and BRAF inhibitor and their use |
| PL3076969T3 (en) | 2013-12-06 | 2022-01-17 | Novartis Ag | Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor |
| NZ760065A (en) | 2013-12-17 | 2022-12-23 | Genentech Inc | Methods of treating cancers using pd-1 axis binding antagonists and taxanes |
| CA2934028A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
| 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 |
| BR112016021383A2 (en) | 2014-03-24 | 2017-10-03 | Genentech Inc | METHOD TO IDENTIFY A PATIENT WITH CANCER WHO IS LIKE OR LESS LIKELY TO RESPOND TO TREATMENT WITH A CMET ANTAGONIST, METHOD TO IDENTIFY A PATIENT WITH PREVIOUSLY TREATED CANCER, METHOD TO DETERMINE THE EXPRESSION OF THE HGF BIOMARKER, ANTI-C-MET ANTAGONIST AND ITS USE, DIAGNOSTIC KIT AND ITS PREPARATION METHOD |
| US10000469B2 (en) | 2014-03-25 | 2018-06-19 | Duke University | Heat shock protein 70 (hsp-70) receptor ligands |
| HUE053654T2 (en) | 2014-03-26 | 2021-07-28 | 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 |
| WO2015148868A1 (en) | 2014-03-28 | 2015-10-01 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| HRP20192285T1 (en) | 2014-03-31 | 2020-03-06 | F. Hoffmann - La Roche Ag | ANTI-OX40 ANTIBODIES AND METHODS OF ADMINISTRATION |
| RU2016142476A (en) | 2014-03-31 | 2018-05-07 | Дженентек, Инк. | COMBINED THERAPY, INCLUDING ANTI-ANGIOGENESIS AGENTS AND AGONISTS BINDING OX40 |
| MX2016012893A (en) | 2014-04-03 | 2017-05-12 | Invictus Oncology Pvt Ltd | SUPRAMOLECULAR COMBINED THERAPEUTIC SUBSTANCES. |
| WO2015155624A1 (en) | 2014-04-10 | 2015-10-15 | Pfizer Inc. | Dihydropyrrolopyrimidine derivatives |
| WO2015156674A2 (en) | 2014-04-10 | 2015-10-15 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
| WO2015166373A1 (en) | 2014-04-30 | 2015-11-05 | Pfizer Inc. | 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 |
| BR112017001695A2 (en) | 2014-07-31 | 2017-11-21 | Novartis Ag | combination 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 |
| CN107073125A (en) | 2014-09-19 | 2017-08-18 | 基因泰克公司 | CBP/EP300 and BET inhibitor is used for the purposes for the treatment of cancer |
| CN107912040B (en) | 2014-10-10 | 2021-04-06 | 基因泰克公司 | Pyrrolidinamide compounds as histone demethylase inhibitors |
| CN107109484B (en) | 2014-11-03 | 2021-12-14 | 豪夫迈·罗氏有限公司 | Methods and biomarkers for efficacy prediction and assessment of OX40 agonist therapy |
| AU2015343337A1 (en) | 2014-11-03 | 2017-06-15 | Genentech, Inc. | Assays for detecting T cell immune subsets and methods of use thereof |
| KR20170072343A (en) | 2014-11-06 | 2017-06-26 | 제넨테크, 인크. | Combination therapy comprising ox40 binding agonists and tigit inhibitors |
| WO2016077375A1 (en) | 2014-11-10 | 2016-05-19 | Genentech, Inc. | Bromodomain inhibitors and uses thereof |
| 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 |
| MX2017006320A (en) | 2014-11-17 | 2017-08-10 | Genentech Inc | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists. |
| CN107531690B (en) | 2014-11-27 | 2020-11-06 | 基因泰克公司 | 4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-amine compounds useful as CBP and/or EP300 inhibitors |
| MX2017006864A (en) | 2014-12-23 | 2017-08-28 | Genentech Inc | COMPOSITIONS AND METHODS FOR TREATMENT AND DIAGNOSIS OF CHEMOTHERAPY-RESISTANT CANCER. |
| EP3237638B1 (en) | 2014-12-24 | 2020-01-15 | F.Hoffmann-La Roche Ag | Therapeutic, diagnostic and prognostic methods for cancer of the bladder |
| EP3240908A2 (en) | 2014-12-30 | 2017-11-08 | F. Hoffmann-La Roche AG | Methods and compositions for prognosis and treatment of cancers |
| EP3242874B1 (en) | 2015-01-09 | 2018-10-31 | Genentech, Inc. | Pyridazinone derivatives and their use in the treatment of cancer |
| CN107406414B (en) | 2015-01-09 | 2022-04-19 | 基因泰克公司 | (piperidin-3-yl) (naphthalen-2-yl) methanone derivatives as inhibitors of histone demethylase KDM2B for 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 |
| CN107438593B (en) | 2015-01-30 | 2020-10-30 | 基因泰克公司 | Therapeutic compounds and their uses |
| 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 |
| MX2017012805A (en) | 2015-04-07 | 2018-04-11 | Genentech Inc | Antigen binding complex having agonistic activity and methods of use. |
| EP3294770B2 (en) | 2015-05-12 | 2024-03-20 | F. Hoffmann-La Roche AG | Therapeutic and diagnostic methods for cancer |
| KR20250151554A (en) | 2015-05-29 | 2025-10-21 | 제넨테크, 인크. | Therapeutic and diagnostic methods for cancer |
| US20170000885A1 (en) | 2015-06-08 | 2017-01-05 | Genentech, Inc. | Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists |
| EP3303399A1 (en) | 2015-06-08 | 2018-04-11 | H. Hoffnabb-La Roche Ag | Methods of treating cancer using anti-ox40 antibodies |
| IL256080B2 (en) | 2015-06-17 | 2025-06-01 | Genentech Inc | Methods for treating locally advanced or metastatic breast cancer using PD-1 axis-binding antagonists and taxanes |
| JP6914860B2 (en) | 2015-07-01 | 2021-08-04 | カリフォルニア インスティチュート オブ テクノロジー | Cationic mucic acid polymer delivery system |
| 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 |
| WO2017033019A1 (en) | 2015-08-26 | 2017-03-02 | Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) | Condensed tricyclic compounds as protein kinase inhibitors |
| US9938257B2 (en) | 2015-09-11 | 2018-04-10 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| KR20250021613A (en) | 2015-09-25 | 2025-02-13 | 제넨테크, 인크. | Anti-tigit antibodies and methods of use |
| WO2017062500A2 (en) | 2015-10-05 | 2017-04-13 | The Trustees Of Columbia University In The City Of New York | Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies |
| EP3362462B1 (en) | 2015-10-12 | 2021-07-21 | Advanced Cell Diagnostics, Inc. | In situ detection of nucleotide variants in high noise samples, and compositions and methods related thereto |
| MX2018005298A (en) | 2015-11-02 | 2018-06-22 | Novartis Ag | Dosage regimen for a phosphatidylinositol 3-kinase inhibitor. |
| DK3389662T3 (en) | 2015-12-16 | 2022-02-28 | Genentech Inc | Process for the preparation of tricyclic PI3K inhibitor compounds and methods for their use in 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 |
| EP3402536A4 (en) | 2016-01-13 | 2019-07-03 | Hadasit Medical Research Services And Development Limited | RADIOMARKETED ANALOGUES OF ERLOTINIB AND USES THEREOF |
| KR102500659B1 (en) | 2016-02-29 | 2023-02-16 | 제넨테크, 인크. | Therapeutic and diagnostic methods for cancer |
| EP3443004A1 (en) | 2016-04-14 | 2019-02-20 | H. Hoffnabb-La Roche Ag | Anti-rspo3 antibodies and methods of use |
| CA3019921A1 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
| EP3443120A2 (en) | 2016-04-15 | 2019-02-20 | H. Hoffnabb-La Roche Ag | Methods for monitoring and treating cancer |
| CN109072311A (en) | 2016-04-15 | 2018-12-21 | 豪夫迈·罗氏有限公司 | Diagnostic and therapeutic method for cancer |
| US11261187B2 (en) | 2016-04-22 | 2022-03-01 | Duke University | Compounds and methods for targeting HSP90 |
| JP7160688B2 (en) | 2016-05-24 | 2022-10-25 | ジェネンテック， インコーポレイテッド | Heterocyclic inhibitors of CBP/EP300 and their use in treating 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 |
| EP3494139B1 (en) | 2016-08-05 | 2022-01-12 | F. Hoffmann-La Roche AG | Multivalent and multiepitopic anitibodies having agonistic activity and methods of use |
| CN109476748B (en) | 2016-08-08 | 2023-05-23 | 豪夫迈·罗氏有限公司 | Methods for the treatment and diagnosis of cancer |
| WO2018039203A1 (en) | 2016-08-23 | 2018-03-01 | Oncopep, Inc. | Peptide vaccines and durvalumab for treating multiple myeloma |
| EP3503914A1 (en) | 2016-08-23 | 2019-07-03 | Oncopep, Inc. | Peptide vaccines and durvalumab for treating breast cancer |
| WO2018060833A1 (en) | 2016-09-27 | 2018-04-05 | Novartis Ag | Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib |
| CA3035080A1 (en) | 2016-09-27 | 2018-04-05 | Cero Therapeutics, Inc. | Chimeric engulfment receptor molecules |
| 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 |
| US10927083B2 (en) | 2016-09-29 | 2021-02-23 | Duke University | Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase |
| IL265759B2 (en) | 2016-10-06 | 2025-10-01 | 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 |
| NZ754994A (en) | 2016-12-22 | 2022-12-23 | 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 |
| US11040984B2 (en) | 2016-12-30 | 2021-06-22 | Medshine Discovery Inc. | Quinazoline compound for EGFR inhibition |
| PL3589754T3 (en) | 2017-03-01 | 2023-10-09 | F. Hoffmann-La Roche Ag | Diagnostic and therapeutic methods for cancer |
| JP2020516638A (en) | 2017-04-13 | 2020-06-11 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Interleukin 2 immunoconjugates, CD40 agonists, and optional PD-1 axis binding antagonists for use in a method of treating cancer |
| JOP20190272A1 (en) | 2017-05-22 | 2019-11-21 | Amgen Inc | Kras g12c inhibitors and methods of using the same |
| CN111132972B (en) | 2017-06-22 | 2024-07-12 | 克拉德夫制药有限公司 | Small molecule modulators of human STING |
| CN111492245A (en) | 2017-07-21 | 2020-08-04 | 基因泰克公司 | Methods of treatment and diagnosis of cancer |
| CN111295394B (en) | 2017-08-11 | 2024-06-11 | 豪夫迈·罗氏有限公司 | Anti-CD8 antibodies and uses thereof |
| ES2928576T3 (en) | 2017-09-08 | 2022-11-21 | Amgen Inc | KRAS G12C inhibitors and methods of use thereof |
| KR102811888B1 (en) | 2017-09-08 | 2025-05-27 | 에프. 호프만-라 로슈 아게 | Diagnosis and treatment of cancer |
| 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 |
| WO2019083960A1 (en) | 2017-10-24 | 2019-05-02 | Oncopep, Inc. | Peptide vaccines and hdac inhibitors for treating multiple myeloma |
| EP3700575A1 (en) | 2017-10-24 | 2020-09-02 | Oncopep, Inc. | Peptide vaccines and pembrolizumab for treating breast cancer |
| WO2019084395A1 (en) | 2017-10-27 | 2019-05-02 | University Of Virginia Patent Foundation | Compounds and methods for regulating, limiting, or inhibiting avil expression |
| WO2019090263A1 (en) | 2017-11-06 | 2019-05-09 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
| US10683297B2 (en) | 2017-11-19 | 2020-06-16 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| EP3727387A4 (en) | 2017-12-18 | 2021-12-15 | 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 |
| EP3740756A4 (en) | 2018-01-15 | 2021-10-27 | Epiaxis Therapeutics Pty Ltd | AGENTS AND METHODS FOR PREDICTING THE THERAPEUTIC RESPONSE |
| CA3083040A1 (en) | 2018-01-20 | 2019-07-25 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
| MX2020008882A (en) | 2018-02-26 | 2021-01-08 | Genentech Inc | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies. |
| AU2019243154A1 (en) | 2018-03-28 | 2020-10-01 | Cero Therapeutics, Inc. | Cellular immunotherapy compositions and uses thereof |
| WO2019191339A1 (en) | 2018-03-28 | 2019-10-03 | Cero Therapeutics, Inc. | Expression vectors for chimeric engulfment receptors, genetically modified host cells, and uses thereof |
| EP3774906A1 (en) | 2018-03-28 | 2021-02-17 | Cero Therapeutics, Inc. | Chimeric tim4 receptors and uses thereof |
| CA3099118A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| MA52501A (en) | 2018-05-04 | 2021-03-10 | Amgen Inc | KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE |
| EP3790886B1 (en) | 2018-05-10 | 2024-06-26 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
| US20210363590A1 (en) | 2018-05-21 | 2021-11-25 | Nanostring Technologies, Inc. | Molecular gene signatures and methods of using same |
| EP3802535B1 (en) | 2018-06-01 | 2022-12-14 | Amgen, Inc | Kras g12c inhibitors and methods of using the same |
| CA3099799A1 (en) | 2018-06-11 | 2019-12-19 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
| MA51848A (en) | 2018-06-12 | 2021-04-21 | Amgen Inc | KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE |
| EP3806887A4 (en) | 2018-06-13 | 2022-04-06 | California Institute of Technology | BLOOD-BRAIN BARRIER CROSSING NANOPARTICLES AND METHODS OF TREATMENT THEREOF |
| AU2019288728A1 (en) | 2018-06-23 | 2021-01-14 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor |
| BR112021000673A2 (en) | 2018-07-18 | 2021-04-20 | Genentech, Inc. | methods for treating an individual with lung cancer, kits, anti-pd-l1 antibody and compositions |
| US12220423B2 (en) | 2018-07-24 | 2025-02-11 | Hygia Pharmaceuticals, Llc | Compounds, derivatives, and analogs for cancer |
| TW202024023A (en) | 2018-09-03 | 2020-07-01 | 瑞士商赫孚孟拉羅股份公司 | Therapeutic compounds and methods of use |
| WO2020055504A1 (en) * | 2018-09-13 | 2020-03-19 | University Of Southern California | Novel inhibitors of guanosine monophosphate synthetase as therapeutic agents |
| CN112955747A (en) | 2018-09-19 | 2021-06-11 | 豪夫迈·罗氏有限公司 | Methods for treatment and diagnosis of bladder cancer |
| MX2021003213A (en) | 2018-09-21 | 2021-05-12 | Genentech Inc | 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 |
| US12404540B2 (en) | 2018-10-17 | 2025-09-02 | The University Of Queensland | Epigenetic biomarker and uses therefor |
| EP3867646A1 (en) | 2018-10-18 | 2021-08-25 | F. Hoffmann-La Roche AG | Diagnostic and therapeutic methods 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 |
| US11053226B2 (en) | 2018-11-19 | 2021-07-06 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| 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 |
| JP2022515198A (en) | 2018-12-19 | 2022-02-17 | アレイ バイオファーマ インコーポレイテッド | Substituted pyrazolo [1,5-a] pyridine compound as an inhibitor of FGFR tyrosine kinase |
| CN113474337A (en) | 2018-12-19 | 2021-10-01 | 奥瑞生物药品公司 | 7- ((3, 5-dimethoxyphenyl) amino) quinoxaline derivatives as FGFR inhibitors for the treatment of cancer |
| AU2019401495B2 (en) | 2018-12-20 | 2025-06-26 | Amgen Inc. | Heteroaryl amides useful as KIF18A inhibitors |
| MA54546A (en) | 2018-12-20 | 2022-03-30 | Amgen Inc | HETEROARYL AMIDES USEFUL AS KIF18A INHIBITORS |
| EA202191730A1 (en) | 2018-12-20 | 2021-08-24 | Эмджен Инк. | KIF18A INHIBITORS |
| MA54550A (en) | 2018-12-20 | 2022-03-30 | Amgen Inc | KIF18A INHIBITORS |
| EP3921443A1 (en) | 2019-02-08 | 2021-12-15 | F. Hoffmann-La Roche AG | Diagnostic and therapeutic methods for cancer |
| WO2020172712A1 (en) | 2019-02-27 | 2020-09-03 | Epiaxis Therapeutics Pty Ltd | Methods and agents for assessing t-cell function and predicting response to therapy |
| BR112021016923A2 (en) | 2019-02-27 | 2021-11-03 | Genentech Inc | Methods for treating a patient with hematologic cancer, methods for treating a patient with relapsed or refractory mm, methods for treating a patient having a relapsed or refractory lnh, and kits |
| CN113727758A (en) | 2019-03-01 | 2021-11-30 | 锐新医药公司 | Bicyclic heterocyclic compounds and use thereof |
| KR20210146287A (en) | 2019-03-01 | 2021-12-03 | 레볼루션 메디슨즈, 인크. | 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 |
| TWI879768B (en) | 2019-05-03 | 2025-04-11 | 美商建南德克公司 | Methods of treating cancer with an anti-pd-l1 antibody |
| EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
| EP3972973A1 (en) | 2019-05-21 | 2022-03-30 | Amgen Inc. | Solid state forms |
| 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 |
| WO2021026098A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| CN114391012B (en) | 2019-08-02 | 2025-10-31 | 美国安进公司 | Pyridine derivatives as KIF18A inhibitors |
| ES3051918T3 (en) | 2019-08-02 | 2025-12-30 | Amgen Inc | Kif18a inhibitors |
| JP7640521B2 (en) | 2019-08-02 | 2025-03-05 | アムジエン・インコーポレーテツド | Heteroaryl amides useful as KIF18A inhibitors - Patents.com |
| KR20220057563A (en) | 2019-09-04 | 2022-05-09 | 제넨테크, 인크. | CD8 binders and uses thereof |
| TW202126690A (en) | 2019-09-27 | 2021-07-16 | 美商建南德克公司 | Dosing 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 |
| EP4048671B1 (en) | 2019-10-24 | 2026-03-18 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
| JP2023511472A (en) | 2019-10-29 | 2023-03-20 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | Bifunctional compounds for the treatment of cancer |
| EP4054719B1 (en) | 2019-11-04 | 2026-02-11 | Revolution Medicines, Inc. | Ras inhibitors |
| KR20220109407A (en) | 2019-11-04 | 2022-08-04 | 레볼루션 메디슨즈, 인크. | RAS inhibitors |
| JP7823816B2 (en) | 2019-11-04 | 2026-03-04 | レヴォリューション・メディスンズ，インコーポレイテッド | RAS inhibitors |
| CN115066613A (en) | 2019-11-06 | 2022-09-16 | 基因泰克公司 | Diagnostic and therapeutic methods for treating hematologic cancers |
| BR112022008858A2 (en) | 2019-11-08 | 2022-09-06 | Revolution Medicines Inc | COMPOUND, PHARMACEUTICAL COMPOSITION AND METHODS FOR INHIBITING SOS1 IN A SUBJECT, FOR INHIBITING THE INTERACTION OF SOS1 AND A PROTEIN, TO TREAT OR PREVENT A DISEASE AND TO TREAT OR PREVENT CANCER |
| EP4058435A1 (en) | 2019-11-13 | 2022-09-21 | Genentech, Inc. | Therapeutic compounds and methods of use |
| JP2023501528A (en) | 2019-11-14 | 2023-01-18 | アムジエン・インコーポレーテツド | Improved Synthesis of KRAS G12C Inhibitor Compounds |
| US20220395553A1 (en) | 2019-11-14 | 2022-12-15 | Cohbar, Inc. | Cxcr4 antagonist peptides |
| WO2021097207A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
| WO2021108683A1 (en) | 2019-11-27 | 2021-06-03 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| PE20221511A1 (en) | 2019-12-13 | 2022-10-04 | Genentech Inc | ANTI-LY6G6D ANTIBODIES AND METHODS OF USE |
| AU2020408562A1 (en) | 2019-12-20 | 2022-06-23 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
| CN114929279A (en) | 2020-01-07 | 2022-08-19 | 锐新医药公司 | Methods of administering SHP2 inhibitors and treating cancer |
| WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
| JP2023511595A (en) | 2020-01-27 | 2023-03-20 | ジェネンテック， インコーポレイテッド | Methods for treating cancer using anti-TIGIT antagonist antibodies |
| 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 |
| EP4127724A1 (en) | 2020-04-03 | 2023-02-08 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
| EP4136228A4 (en) | 2020-04-15 | 2024-09-11 | California Institute of Technology | THERMAL CONTROL OF T-CELL IMMUNOTHERAPY BY MOLECULAR AND PHYSICAL ACTIVATION |
| JP2023523450A (en) | 2020-04-28 | 2023-06-05 | ジェネンテック， インコーポレイテッド | 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 |
| CA3183032A1 (en) | 2020-06-18 | 2021-12-23 | Mallika Singh | Methods for delaying, preventing, and treating acquired resistance to ras inhibitors |
| IL298946A (en) | 2020-06-18 | 2023-02-01 | Genentech Inc | Treatment with anti-TIGIT antibodies and PD-1 spindle-binding antagonists |
| US11787775B2 (en) | 2020-07-24 | 2023-10-17 | Genentech, Inc. | Therapeutic compounds and methods of use |
| JP2023536602A (en) | 2020-08-03 | 2023-08-28 | ジェネンテック， インコーポレイテッド | 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 |
| EP4196612A1 (en) | 2020-08-12 | 2023-06-21 | 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 |
| WO2022036265A1 (en) | 2020-08-14 | 2022-02-17 | Cero Therapeutics, Inc. | Chimeric tim receptors and uses thereof |
| WO2022036287A1 (en) | 2020-08-14 | 2022-02-17 | Cero Therapeutics, Inc. | Anti-cd72 chimeric receptors and uses thereof |
| WO2022047259A1 (en) | 2020-08-28 | 2022-03-03 | California Institute Of Technology | Synthetic mammalian signaling circuits for robust cell population control |
| MX2023002248A (en) | 2020-09-03 | 2023-05-16 | Revolution Medicines Inc | Use of sos1 inhibitors to treat malignancies with shp2 mutations. |
| CR20230165A (en) | 2020-09-15 | 2023-06-02 | Revolution Medicines Inc | Indole derivatives as ras inhibitors in the treatment of cancer |
| US12162893B2 (en) | 2020-09-23 | 2024-12-10 | 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 |
| WO2022133345A1 (en) | 2020-12-18 | 2022-06-23 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
| CN117396472A (en) | 2020-12-22 | 2024-01-12 | 上海齐鲁锐格医药研发有限公司 | SOS1 inhibitors and their uses |
| 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 |
| IL308193A (en) | 2021-05-05 | 2024-01-01 | Revolution Medicines Inc | Ras inhibitors |
| CR20230558A (en) | 2021-05-05 | 2024-01-24 | Revolution Medicines Inc | RAS INHIBITORS FOR CANCER TREATMENT |
| EP4347603A1 (en) | 2021-05-25 | 2024-04-10 | Erasca, Inc. | Sulfur-containing heteroaromatic tricyclic kras inhibitors |
| WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
| US20250127896A1 (en) | 2021-07-28 | 2025-04-24 | Cero Therapeutics Holdings, Inc. | Chimeric tim4 receptors and uses thereof |
| WO2023018699A1 (en) | 2021-08-10 | 2023-02-16 | Erasca, Inc. | Selective kras inhibitors |
| AR127308A1 (en) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | RAS INHIBITORS |
| JP2024541508A (en) | 2021-11-24 | 2024-11-08 | ジェネンテック， インコーポレイテッド | Therapeutic indazole compounds and methods of use in the treatment of cancer - Patents.com |
| US12275745B2 (en) | 2021-11-24 | 2025-04-15 | Genentech, Inc. | Therapeutic compounds and methods of use |
| JP2025500878A (en) | 2021-12-17 | 2025-01-15 | ジェンザイム・コーポレーション | PYRAZOLO-PYRAZINE COMPOUNDS AS SHP2 INHIBITORS |
| EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| IL314883A (en) | 2022-03-07 | 2024-10-01 | Amgen Inc | Process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile |
| CN119136806A (en) | 2022-03-08 | 2024-12-13 | 锐新医药公司 | Methods for treating immune-refractory lung cancer |
| KR20240169042A (en) | 2022-04-01 | 2024-12-02 | 제넨테크, 인크. | Dosage regimen for treatment with anti-FCRH5/anti-CD3 bispecific antibodies |
| AU2022458320A1 (en) | 2022-05-11 | 2024-11-28 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
| IL317449A (en) | 2022-06-07 | 2025-02-01 | Genentech Inc | Method for determining the efficacy of a lung cancer treatment comprising an anti-pd-l1 antagonist and an anti-tigit antagonist antibody |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | 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 |
| IL318252A (en) | 2022-07-19 | 2025-03-01 | Genentech Inc | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
| IL318710A (en) | 2022-08-02 | 2025-03-01 | Univ Hokkaido Nat Univ Corp | Methods of improving cellular therapy with organelle complexes |
| PE20251399A1 (en) | 2022-08-11 | 2025-05-22 | Hoffmann La Roche | Bicyclic tetrahydrothiazepine derivatives |
| CN119677732A (en) | 2022-08-11 | 2025-03-21 | 豪夫迈·罗氏有限公司 | Bicyclic tetrahydroazepine derivatives |
| CR20250043A (en) | 2022-08-11 | 2025-03-25 | Hoffmann La Roche | Bicyclic tetrahydrothiazepine derivatives |
| JP2025526683A (en) | 2022-08-11 | 2025-08-15 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | Bicyclic tetrahydrothiazepine derivatives |
| PE20251879A1 (en) | 2022-10-14 | 2025-07-22 | Black Diamond Therapeutics Inc | Cancer treatment methods using isoquinoline or 6-azaquinoline derivatives |
| JP2025538859A (en) | 2022-10-21 | 2025-12-02 | 公益財団法人川崎市産業振興財団 | Non-adsorbing or super stealth vesicles |
| TW202426505A (en) | 2022-10-25 | 2024-07-01 | 美商建南德克公司 | Therapeutic and diagnostic methods for cancer |
| TW202434206A (en) | 2023-02-17 | 2024-09-01 | 美商伊瑞斯卡公司 | Kras inhibitors |
| AU2024241633A1 (en) | 2023-03-30 | 2025-11-06 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024211663A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| PE20260039A1 (en) | 2023-04-07 | 2026-01-09 | Revolution Medicines Inc | MACROCYCLIC RAS INHIBITORS |
| CN121100123A (en) | 2023-04-14 | 2025-12-09 | 锐新医药公司 | Crystalline forms of Ras inhibitors |
| TW202448897A (en) | 2023-04-14 | 2024-12-16 | 美商銳新醫藥公司 | 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 |
| TW202448949A (en) | 2023-05-05 | 2024-12-16 | 美商建南德克公司 | 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 |
| US20250049810A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025049277A1 (en) | 2023-08-25 | 2025-03-06 | Genentech, Inc. | Methods and compositions for treating non-small cell lung cancer comprising an anti-tigit antagonist antibody and a pd-1 axis binding antagonist |
| TW202530228A (en) | 2023-10-12 | 2025-08-01 | 美商銳新醫藥公司 | Ras inhibitors |
| TW202542151A (en) | 2023-12-22 | 2025-11-01 | 美商銳格醫藥有限公司 | Sos1 inhibitors and uses thereof |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| TW202547461A (en) | 2024-05-17 | 2025-12-16 | 美商銳新醫藥公司 | Ras inhibitors |
| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025265060A1 (en) | 2024-06-21 | 2025-12-26 | Revolution Medicines, Inc. | Therapeutic compositions and methods for managing treatment-related effects |
| WO2026006747A1 (en) | 2024-06-28 | 2026-01-02 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015790A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015801A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015825A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Use of ras inhibitor for treating pancreatic cancer |
| WO2026030464A1 (en) | 2024-07-30 | 2026-02-05 | Genentech, Inc. | Dosage regimen for reducing cytokine release syndrome (crs) with anti-fcrh5/anti-cd3 bispecific antibodies in multiple myeloma therapy |
| WO2026030476A1 (en) | 2024-07-30 | 2026-02-05 | Genentech, Inc. | Precision medicine for optimal dosage of combined therapies systems and methods of use thereof |
| WO2026050446A1 (en) | 2024-08-29 | 2026-03-05 | Revolution Medicines, Inc. | Ras inhibitors |
Family Cites Families (16)
| 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-quinazolinyl)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 |
| JPH06500117A (en) * | 1991-02-20 | 1994-01-06 | フアイザー・インコーポレイテツド | 2,4-diaminoquinazoline derivatives that enhance antitumor activity |
| AU658646B2 (en) * | 1991-05-10 | 1995-04-27 | Rhone-Poulenc Rorer International (Holdings) Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which 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 |
-
1993
- 1993-01-04 AU AU31010/93A patent/AU661533B2/en not_active Expired
- 1993-01-04 GB GB939300059A patent/GB9300059D0/en active Pending
- 1993-01-08 CA CA002086968A patent/CA2086968C/en not_active Expired - Lifetime
- 1993-01-12 NZ NZ245662A patent/NZ245662A/en not_active IP Right Cessation
- 1993-01-15 AT AT93300270T patent/ATE130000T1/en active
- 1993-01-15 HU HU9300094A patent/HU221622B1/en unknown
- 1993-01-15 ES ES93300270T patent/ES2078798T3/en not_active Expired - Lifetime
- 1993-01-15 DE DE69300754T patent/DE69300754T2/en not_active Expired - Lifetime
- 1993-01-15 DK DK93300270.1T patent/DK0566226T3/en active
- 1993-01-15 EP EP93300270A patent/EP0566226B1/en not_active Expired - Lifetime
- 1993-01-18 CZ CZ9343A patent/CZ282038B6/en not_active IP Right Cessation
- 1993-01-18 TW TW082100292A patent/TW283146B/zh not_active IP Right Cessation
- 1993-01-19 SK SK16-93A patent/SK281551B6/en not_active IP Right Cessation
- 1993-01-19 RU RU93004423/04A patent/RU2127263C1/en active
- 1993-01-19 FI FI930208A patent/FI111631B/en not_active IP Right Cessation
- 1993-01-19 NO NO930178A patent/NO301541B1/en not_active IP Right Cessation
- 1993-01-20 KR KR1019930000645A patent/KR100229294B1/en not_active Expired - Lifetime
- 1993-01-21 IL IL10447993A patent/IL104479A/en not_active IP Right Cessation
- 1993-04-22 UA UA93002840A patent/UA34426C2/en unknown
-
1994
- 1994-08-02 US US08/284,293 patent/US5457105A/en not_active Expired - Lifetime
-
1995
- 1995-06-12 HU HU95P/P00185P patent/HU211311A9/en unknown
- 1995-06-15 US US08/490,666 patent/US5616582A/en not_active Expired - Lifetime
- 1995-11-21 GR GR950403262T patent/GR3018143T3/en unknown
-
1997
- 1997-03-27 HK HK36497A patent/HK36497A/en not_active IP Right Cessation
Cited By (3)
| 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 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2086968C (en) | Quinazoline derivatives | |
| US5475001A (en) | Quinazoline derivatives | |
| US5580870A (en) | Quinazoline derivatives | |
| US5880130A (en) | 4,6-dianilino-pyrimidine derivatives, their preparation and their use as tyrosine kinase inhibitors | |
| US6015814A (en) | Quinazoline derivative | |
| CA2215732C (en) | Quinazoline derivatives | |
| EP0520722B1 (en) | Therapeutic preparations containing quinazoline derivatives | |
| US5932574A (en) | Quinazoline derivatives | |
| US5942514A (en) | Quinazoline derivatives | |
| JP2994165B2 (en) | Quinazoline derivative, method for producing the same, and pharmaceutical preparation containing the quinazoline derivative for obtaining anticancer activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20130108 |