Classifications

• • 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
  • C07D239/88—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • 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
  • C07D239/93—Sulfur atoms
• • 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

Definitions

• the present invention relates to quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans.
• Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function.
• Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1 : 27-31).
• Alteration of vascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993.
• VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al. 1989, J. Biol. Chem. 264: 20017-20024).
• Antagonism of VEGF action by sequestration of VEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841 -844).
• Receptor tyrosine kinases are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.
• fms-like tyrosine kinase receptor Fit or Fltl .
• KDR kinase insert domain-containing receptor
• Flt4 Flt4
• Two of these related RTKs, Fit and KDR have been shown to bind VEGF with high affinity (De Vries et al, 1992. Science 255: 989-991 : Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
• European Patent Publication No. 0326330 discloses certain quinoline, quinazoline and cinnoline plant fungicides. Certain of these plant fungicides are also stated to possess insecticidal and miticidal activity. There is however no disclosure or any suggestion that any of the compounds disclosed may be used for any purpose in animals such as humans.
• the European Patent Publication contains no teaching whatsoever concerning angiogenesis and/or increased vascular permeability mediated by growth factors such as VEGF.
• the present invention is based on the discovery of compounds that surprisingly inhibit the effects of VEGF, a property of value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis. rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation.
• Compounds of the present invention possess higher potency against VEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase.
• compounds of the present invention possess substantially higher potency against VEGF receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF Rl receptor tyrosine kinase.
• compounds of the invention which have been tested possess activity against VEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit VEGF receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase or FGF Rl receptor tyrosine kinase.
• Z represents -O-, -NH- or -S-; m is an integer from 1 to 5 with the proviso that where Z is -NH- m is an integer from 3 to 5;
• R 1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C,. 3 alkyl,
• R 2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro
• R 3 represents hydroxy, halogeno, C,. 3 alkyl, C,., alkoxy, C,. 3 alkanoyloxy, trifluoromethyl, cyano. amino or nitro;
• X 1 represents -O-. -CH , -S-, -SO-, -SO r , -NR 7 -, -NR*CO-, -CONR 9 -, -SO 2 NR'°- or -
• R is selected from one of the following seven groups:
• R 17 represents hydrogen, C, .3 alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C,. 3 alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C M alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C alkyl, C, . 4 hydroxyalkyl and C alkoxy);
• R 23 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C alkyl, C hydroxyalkyl and C alkoxy);
• R 27 , R 28 and R 29 each independently represents hydrogen, C,. 3 alkyl or C alkoxyC 2 . 3 alkyl) and
• R 24 represents hydrogen or C,. 3 alkyl)]; and salts thereof.
• Z is advantageously -S-. preferably -0-. but especially -NH-.
• Z is -S- or -O- m is advantageously an integer from 2 to 5, preferably 2 or 3.
• R 1 is advantageously hydrogen, hydroxy, cyano, nitro, trifluoromethyl. C ⁇ alkyl, C, .3 alkoxy or amino. R 1 is preferably hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, more preferably hydrogen, cyano, nitro. trifluoromethyl, hydroxy, methyl or methoxy, but especially methoxy.
• R 1 is preferably hydrogen.
• R 2 is preferably hydrogen, fluoro, amino or nitro, but especially hydrogen.
• R 3 represents hydroxy, halogeno, C alkyl. C,. ,alkoxy. trifluoromethyl, cyano. amino or nitro. preferably hydroxy. halogeno or C, 2 alkyl, especially hydroxy or halogeno.
• one R 3 substituent is advantageously hydroxy, preferably meta-hydroxy, and the other one or more are each selected from halogeno, methyl and methoxy.
• phenyl group bearing (R ⁇ is preferably of the formula II:
• R a represents hydrogen, methyl, fluoro or chloro, preferably hydrogen, fluoro or chloro, especially fluoro;
• R b represents hydrogen, methyl, methoxy, bromo, fluoro or chloro
• R c represents hydrogen or hydroxy. especially hydroxy
• R d represents hydrogen, fluoro or chloro, especially hydrogen or fluoro.
• two R 1 substituents are halogeno, especially ortho,ortho'- difluoro, and the other one or more are each selected from halogeno. hydroxy and methyl, especially from halogeno and methyl.
• the phenyl group bearing (R 3 ), concerning is the 2-fluoro- 5-hydroxy-4-methylphenyl group, the 4-bromo-2,6-difluorophenyl group, the 4-chloro-2- fluoro-5-hydroxyphenyl group, the 4-chloro-2,6-difluorophenyl group or the 2,4-difluoro-5- hydroxyphenyl group or, where Z is O or S, the 4-chloro-2-fluorophenyl group.
• n is the 4-chloro-2-fluoro-5-hydroxyphenyl group or the 2-fluoro-5-hydroxy-4-methylphenyl group or, where Z is O or S. the 4-chloro-2- fluorophenyl group.
• the 4-chloro-2-fluoro-5-hydroxyphenyl group is an especially preferred value for the phenyl group bearing (R 3 ) m .
• X 1 represents -O-, -S-, -CH 2 -, -NR 8 CO-, -CONR 9 -, -NR n SO 2 - or -NR 7 - (wherein
• R 7 , R 8 , R 9 and R" each independently represents hydrogen, C,. 3 alkyl (especially C, ,alkyl) or C, .2 alkoxyethyl).
• X represents -O-, -S-, -NR 8 CO-, -NR"SO 2 - or -NR 7 - (wherein R 7 , R 8 and R" each independently represents hydrogen, C,. 2 alkyl or C,. 2 alkoxyethyl).
• X' represents -O-, -S-, -NR 8 CO-, -NR"SO 2 - (wherein R 8 and R" each independently represents hydrogen or C,. 2 alkyl) or NH. More preferably X 1 represents -O-, -S-, -NR 8 CO- (wherein R 8 represents hydrogen or methyl) or NH.
• X 1 represents -O- or -NHCO-, especially -O-.
• X 2 represents -O- or -NR ⁇ - (wherein R 13 represents hydrogen, C,.,alkyl or C,
• X 3 represents -O-, -S-. -SO-, -SO 2 -, -NR l8 CO-, -NR 21 SO 2 - or -NR 22 - (wherein
• R' 8 , R 21 and R 22 each independently represents hydrogen, C,. 2 alkyl or C, . ,alkoxyethyl).
• X 3 represents -O-, -S-, -SO-, -SO 2 - or -NR 22 - (wherein R 22 represents hydrogen, C,
• X 3 represents -O- or -NR 22 - (wherein R 22 represents hydrogen or C, .2 alkyl)
• X 4 and X 5 which may be the same or different each represents -0-. -S-, -SO-.
• R 29 represents hydrogen, C alkyl or C,. 2 alkoxyethyl.
• X 4 and X 5 which may be the same or different each represents -0-, -S- or -NR 29 -
• R 29 represents hydrogen, C,. 2 alkyl or C ⁇ alkoxyethyl.
• R 4 is selected from one of the following nine groups:
• R 4 is selected from one of the following nine groups:
• 3 alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C M alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C, . 2 alkyl. C,. 2 hydroxyalkyl and C,.
• C alkylR 3 ⁇ (wherein R 30 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3- dioxolan-2-yl, 1 ,3-dioxan-2-yl, l,3-dithiolan-2-yl and 1 ,3-dithian-2-yl, which group is linked to C,. 4 alkyl through a carbon atom and which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C,. 2 alkyl, C,.
• R 3 ' is a group selected from mo ⁇ holino, thiomo ⁇ holino, pyrrolidin-1 -yl, piperazin- 1 -yl and piperidino which group may carry one or two substituents selected from oxo. hydroxy, halogeno, C,. 2 alkyl, C,. 2 hydroxyalkyl and C,. 2 alkoxy);
• R 4 is selected from one of the following five groups: 1) C, .3 alkyl, C 2.3 hydroxyalkyl, C,. 3 fluoroalkyl, C 2 . 3 aminoalkyl;
• cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C M alkyl, C,. 2 hydroxyalkyl and C,. 2 alkoxy);
• R 30 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, l ,3-dioxolan-2-yl, l ,3-dioxan-2-yl, l ,3-dithiolan-2-yl and l ,3-dithian-2-yl, which group is linked to C,. 2 alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C,. 2 alkyl, C,. 2 hydroxy alkyl and C,.
• R 3 ' is a group selected from mo ⁇ holino, thiomo ⁇ holino, piperidino, piperazin- 1 -yl and pyrrolidin-1-yl which group may carry one substituent selected from oxo, hydroxy. halogeno. C, .2 alkyl. C,. 2 hydroxyalkyl and C,. 2 alkoxy); and
• R 24 (wherein X 4 and X 5 are as hereinbefore defined and R 24 represents hydrogen or C,. 2 alkyl). More preferably R' represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2- hydroxyethyl, 3 -hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl. 2-(methylsulphinyl)ethyl.
• 2-sulphamoylethyl 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimefhylamino)propyl, 2- mo ⁇ holinoethyl, 3-mo ⁇ holinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-l- yl)ethyl.
• R 4 represents 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3- methoxy propyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N- dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-mo ⁇ holinoethyl, 3- mo ⁇ holinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-l-yl)ethyl, 3-
• Preferred compounds are: 4-(4-bromo-2,6-difluoroanilino)-6,7-dimethoxyquinazoline,
• More preferred compounds are:
• 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. Unless otherwise stated the term “alkyl” advantageously refers to chains with 1 -6 carbon atoms, preferably 1-4 carbon atoms. In this specification the term “alkoxy” means an alkyl group as defined hereinbefore linked to an oxygen atom.
• aryl includes C 6.l0 aromatic groups which may, if desired, carry one or more substituents selected from halogeno, alkyl, alkoxy, cyano, nitro or trifluoromethyl (wherein alkyl and alkoxy are as hereinbefore defined).
• aryloxy means an aryl group as defined hereinbefore linked to an oxygen atom.
• sulphonyloxy includes alkylsulphonyloxy and arylsulphonyloxy wherein “alkyl” and "aryl” are as defined hereinbefore.
• alkenyl includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only.
• alkenyl advantageously refers to chains with 2-5 carbon atoms, preferably 3-4 carbon atoms.
• alkynyl includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as 2-butynyl are specific for the straight chain version only. Unless otherwise stated the term “alkynyl” advantageously refers to chains with 2-5 carbon atoms, preferably 3-4 carbon atoms.
• a quinazoline of the formula I or a salt thereof 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 inhibits VEGF receptor tyrosine kinase activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. It is also to be understood that certain quinazolines of the formula I and salts thereof 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 inhibit VEGF receptor tyrosine kinase activity.
• R 4 is, for example, a group of formula C,. 5 alkylR 23 , it is the terminal C, .5 alkyl moiety which is bound to X', similarly when R 4 is, for example, a group of formula C 2 _ 5 alkenylR 23 it is the C 2 . 5 alkenyl moiety which is bound to X 1 and an analogous convention applies to other groups.
• R 4 is a group l-R 23 prop-l-en-3-yl it is the first carbon to which the group R 23 is attached and it is the third carbon which is linked to X 1 and an analogous convention applies to other groups.
• the present invention relates to the compounds of formula I as hereinbefore defined as well as to the salts thereof.
• Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula 1 and their pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts of the invention may. for example, include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form such salts.
• Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid.
• salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, mo ⁇ holine or tris-(2-hydroxyethyl)amine.
• alkali metal salt such as a sodium or potassium salt
• alkaline earth metal salt such as a calcium or magnesium salt
• an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, mo ⁇ holine or tris-(2-hydroxyethyl)amine.
• a compound of the formula I, or salt thereof, and other compounds of the invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds.
• Such processes include, for example, those illustrated in European Patent Applications, Publication Nos. 0520722. 0566226, 0602851 and 0635498. Such processes, are provided as a further feature of the invention and are as described hereinafter.
• 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 convenient displaceable moiety L 1 is, for example, a halogeno, alkoxy (preferably C,. 4 alkoxy), aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-suIphonyloxy group.
• the reaction is advantageously effected in the presence of either an acid or a base.
• Such an acid is, for example, an anhydrous inorganic acid such as hydrogen chloride.
• a base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, mo ⁇ holine, N-methylmo ⁇ holine or diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
• such a base is, for example, an alkali metal hydride, for example sodium hydride, or an alkali metal or alkaline earth metal amide, for example sodium amide or sodium bis(trimethylsilyl)amide.
• the reaction is preferably effected in the presence of an 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, trichloromethane or carbon tetrachloride, an ether such as tetrahydrofuran or 1 ,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimefhylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.
• the reaction is conveniently effected at a temperature
• the compound of the invention 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-L' wherein L 1 has the meaning defined hereinbefore.
• the salt may be treated with a base as defined hereinbefore using a conventional procedure.
• phenolic hydroxy protecting group P is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that m-p 1 is equal to the number of R 3 substituents which are not protected hydroxy).
• the choice of phenolic hydroxy protecting group P is within the standard knowledge of an organic chemist, for example those included in standard texts such as "Protective Groups in Organic Synthesis" T.W. Greene and R.G.M.Wuts, 2nd Ed. Wiley
• ethers for example, methyl, methoxymethyl, allyl and benzyl
• silyl ethers for example, t-butyldiphenylsilyl and t-butyldimethylsilyl
• esters for example, acetate and benzoate
• carbonates for example, methyl and benzyl
• reaction conditions preferably being such that the hydroxy derivative is produced without unwanted reactions at other sites within the starting or product compounds.
• the protecting group P is acetate
• the transformation may conveniently be effected by treatment of the quinazoline derivative with a base as defined hereinbefore and including ammonia, and its mono and di-alkylated
• 25 derivatives preferably in the presence of a protic solvent or co-solvent such as water or an alcohol, for example methanol or ethanol.
• a protic solvent or co-solvent such as water or an alcohol, for example methanol or ethanol.
• Such a reaction can be effected in the presence of an additional inert solvent or diluent as defined hereinbefore and at a temperature in the range 0 to 50°C. conveniently at about 20°C.
• L' is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo or methanesulphonyloxy group.
• the reaction is preferably effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 50°C.
• reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 100°C.
• R 32 is selected from one of the following four groups: 1) X 6 C 1 3 alkyl (wherein X 6 represents -O-, -S-, -S0 2 -, -NR 33 CO- or -NR 3 SO 2 - (wherein R 33 and R 34 are each independently hydrogen, C,. 3 alkyl or C,. 3 alkoxyC 2 . 3 alkyl);
• R 35 and R 36 which may be the same or different are each hydrogen, C,. 3 alkyl or C,. 3 alkoxyC 2 . 3 alkyl);
• R (wherein R 31 is as defined hereinbefore);] may be prepared by reacting a compound of the formula X:
• reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), and at a temperature in the range, for example 0 to 150°C, conveniently at about 50°C.
• reaction is preferably effected in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)) and at a temperature in the range, for example, 10 to 100°C, conveniently at about ambient temperature.
• an inert solvent or diluent as defined hereinbefore in process (a)
• This process can also be used for preparing compounds in which R 4 -X' is an alkylamino or dialkylamino group.
• Convenient halogenating agents include inorganic acid halides, for example thionyl chloride. phosphorus(III)chloride, phosphorus(V)oxychloride and phosphorus(V)chloride.
• the halogenation reaction is conveniently effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene.
• an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene.
• the reaction is conveniently effected at a temperature in the range, for example 10 to 150°C, preferably in the range 40 to 100°C.
• the compounds of formula XII and salts thereof which constitute a further feature of the present invention may for example be prepared by reacting a compound of the formula XIII:
• reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150°C, conveniently at about 100°C.
• the compounds of formula XII and salts thereof may also be prepared by cyclising a compound of the formula XIV:
• R', R 2 , R 4 and X 1 are as hereinbefore defined, and A' is an hydroxy. alkoxy (preferably C alkoxy) or amino group) whereby to form a compound of formula XII or salt thereof.
• the cyclisation may be effected by reacting a compound of the formula XIV, where A' is an hydroxy or alkoxy group, with formamide or an equivalent thereof effective to cause cyclisation whereby a compound of formula XII or salt thereof is obtained, such as [3- (dimefhylamino)-2-azaprop-2-enylidene]dimethylammonium chloride.
• the cyclisation is conveniently effected in the presence of formamide as solvent or in the presence of an inert solvent or diluent such as an ether for example 1 ,4-dioxan.
• the cyclisation is conveniently effected at an elevated temperature, preferably in the range 80 to 200°C.
• the compounds of formula XII may also be prepared by cyclising a compound of the formula XIV, where A' is an amino group, with formic acid or an equivalent thereof effective to cause cyclisation whereby a compound of formula XII or salt thereof is obtained.
• Equivalents of formic acid effective to cause cyclisation include for example a tri-C alkoxymethane, for example triethoxymethane and trimethoxymethane.
• the cyclisation is conveniently effected in the presence of a catalytic amount of an anhydrous acid, such as a sulphonic acid for example p- toluenesulphonic acid, and in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, an ether such as diethylether or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene.
• the cyclisation is conveniently effected at a temperature in the range, for example 10 to 100°C, preferably in the range 20 to 50°C.
• the reduction of the nitro group may conveniently be effected by any of the procedures known for such a transformation.
• the reduction may be carried out. for example, by the hydrogenation of a solution of the nitro compound in the presence of an inert solvent or diluent as defined hereinbefore in the presence of a metal effective to catalyse hydrogenation reactions such as palladium or platinum.
• a further reducing agent is, for example, an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid).
• the reduction may be effected by heating the nitro compound and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range, for example 50 to 150°C, conveniently at about 70°C.
• a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol
• Compounds of the formula XV and salts thereof which constitute a further feature of the present invention may for example be prepared by the reaction of a compound of the formula XVI:
• a compound of formula XVIII is conveniently used in which L 2 represents a phenoxy group which may if desired carry up to 5 substituents, preferably up to 2 substituents, selected from halogeno, nitro and cyano.
• the reaction may be conveniently effected under conditions as described for process (c) hereinbefore.
• R', R 2 , P, X 1 and L 2 are as hereinbefore defined with the proviso that X 1 is not -CH 2 - ).
• Deprotection may be effected by techniques well known in the literature, for example where P represents a benzyl group deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid.
• One compound of formula III may if desired be converted into another compound of formula III in which the moiety L 1 is different.
• a compound of formula III in which L 1 is other than halogeno, for example optionally substituted phenoxy may be converted to a compound of formula III in which L 1 is halogeno by hydrolysis of a compound of formula III (in which L 1 is other than halogeno) to yield a compound of formula XII as hereinbefore defined, followed by introduction of halide to the compound of formula XII, thus obtained as hereinbefore defined, to yield a compound of formula III in which L 1 represents halogen.
• reaction may for example be effected as described for process (a) hereinbefore.
• the compounds of formula V and salts thereof may also be prepared by reacting a compound of formula XXI:
• Compounds of the formula XXV and salts thereof may be made by reacting compounds of the formulae XIX and IV as hereinbefore defined, under the conditions described in (a) hereinbefore, to give a compound of the formula XXV or salt thereof.
• Compounds of the formula VIII and salts thereof as hereinbefore defined may be made by reacting compounds of the formulae XXIII and IV as hereinbefore defined, the reaction for example being effected by a process as described in (a) above.
• a pharmaceutically acceptable salt of a compound of the formula I When a pharmaceutically acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with, for example, an acid using a conventional procedure, the acid having a pharmaceutically acceptable anion.
• an acid using a conventional procedure, the acid having a pharmaceutically acceptable anion.
• VEGF or epidermal growth factor (EGF) receptor cytoplasmic domains may be obtained by total gene synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. These may then be expressed in a suitable expression system to obtain polypeptide with tyrosine kinase activity.
• EGF and EGF receptor cytoplasmic domains which were obtained by expression of recombinant protein in insect cells, were found to display intrinsic tyrosine kinase activity.
• VEGF receptor Fit (Genbank accession number X51602), a 1.7kb DNA fragment encoding most of the cytoplasmic domain, commencing with methionine 783 and including the termination codon, described by Shibuya et al (Oncogene, 1990, 5: 519-524), was isolated from cDNA and cloned into a baculovirus transplacement vector (for example pAcYMl (see The Baculovirus Expression System: A Laboratory Guide. L.A. King and R. D. Possee. Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from Invitrogen Co ⁇ oration)).
• pAcYMl see The Baculovirus Expression System: A Laboratory Guide. L.A. King and R. D. Possee. Chapman and Hall, 1992
• pAc360 or pBlueBacHis available from Invitrogen Co ⁇ oration
• This recombinant construct was co-transfected into insect cells (for example Spodoptera frugiperda 21(Sf21 )) with viral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.
• insect cells for example Spodoptera frugiperda 21(Sf21 )
• viral DNA eg Pharmingen BaculoGold
• cytoplasmic fragments starting from methionine 806 (KDR, Genbank accession number L04947) and methionine 668 (EGF receptor, Genbank accession number X00588) may be cloned and expressed in a similar manner.
• a stock of substrate solution was prepared from a random copolymer containing tyrosine. for example Poly (Glu. Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at -20°C and diluted 1 in 500 with PBS for plate coating.
• Poly (Glu. Ala, Tyr) 6:3:1 Sigma P3899
• Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 ⁇ l of diluted compound was transferred to wells in the washed assay plates. "Total" control wells contained 10% DMSO instead of compound. Twenty five microlitres of 40mM manganese(II)chloride containing 8 ⁇ M adenosine-5' -triphosphate (ATP) was added to all test wells except "blank" control wells which contained manganese(II)chloride without ATP. To start the reactions 50 ⁇ l of freshly diluted enzyme was added to each well and the plates were incubated at room temperature for 20 minutes. The liquid was then discarded and the wells were washed twice with PBST.
• DMSO dimethylsulphoxide
• mice IgG anti-phosphotyrosine antibody Upstate Biotechnology Inc. product 05-321
• PBST bovine serum albumin
• HRP horse radish peroxidase
• ABTS 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)
• This assay determines the ability of a test compound to inhibit the growth factor- stimulated proliferation of human umbilical vein endothelial cells (HUVEC).
• HUVEC human umbilical vein endothelial cells
• HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7.5% v/v foetal calf 0 serum (FCS) and were plated out (at passage 2 to 8), in MCDB 131 + 2% v/v FCS + 3 ⁇ g/ml heparin + 1 ⁇ g/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours they were dosed with the appropriate growth factor (i.e. VEGF 3ng/ml. EGF 3ng/ml or b-FGF 0.3ng/ml) and compound. The cultures were then incubated for 4 days at 37°C with 7.5% carbon dioxide. On day 4 the cultures were pulsed with the appropriate growth factor (i.e. VEGF 3ng/ml. EGF 3ng/ml or b-FGF 0.3ng/ml) and compound. The cultures were then incubated for 4 days at 37°C with 7.5% carbon dioxide. On day 4 the
• oestradiol benzoate (2.5 ⁇ g/rat) in a solvent, or solvent only. The latter served as unstimulated controls.
• Test compounds were orally administered at various times prior to the administration of oestradiol benzoate. Five hours after the administration of oestradiol benzoate the rats were humanely sacrificed and their uteri were dissected, blotted and weighed. The increase in uterine weight in groups treated with test compound and oestradiol benzoate and with oestradiol benzoate alone was compared using a Student T test. Inhibition of the effect of oestradiol benzoate was considered significant when p ⁇ 0.05.
• a pharmaceutical composition which comprises a compound of the formula I as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.
• the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository.
• parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
• a sterile solution, suspension or emulsion for topical administration for example as an ointment or cream or for rectal administration for example as a suppository.
• the above compositions may be prepared in a conventional manner using conventional excipients.
• compositions of the present invention are advantageously presented in unit dosage form.
• the compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000mg per square metre body area of the animal, i.e. approximately O.l-lOOmg/kg.
• a unit dose in the range, for example, 1-lOOmg/kg, preferably l-50mg/kg is envisaged and this normally provides a therapeutically-effective dose.
• a unit dose form such as a tablet or capsule will usually contain, for example l -250mg of active ingredient.
• a compound of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
• compounds of the present invention inhibit VEGF receptor tyrosine kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability.
• a further feature of the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament, conveniently a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.
• a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore.
• the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated. the route of administration and the severity of the illness being treated.
• a daily dose in the range of l-50mg/kg is employed.
• the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
• the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
• the other component(s) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy.
• Such chemotherapy may cover three main categories of therapeutic agent:
• antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function, angiostatin. razoxin. thalidomide); (ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifenc, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5 ⁇ - dihydroreductase (for example finasteride), anti
• antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin.
• antimetabolites for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside
• antitumour antibiotics for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C,
• alkylating agents for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa
• antimitotic agents for example vinca alkaloids like vincrisitine and taxoids like taxol, taxotere
• topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine. topotecan).
• the compounds defined in the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects.
• Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation.
• diseases of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
• Such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with VEGF, especially those tumours which are significantly dependent on VEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin.
• the compounds of formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of VEGF receptor tyrosine kinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
• NMR nuclear magnetic resonance
• mass spectral techniques proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet;
• Isopropanolic hydrogen chloride (0.1ml of a 5M solution) was added to a solution of 4-chloro-6,7-dimethoxyquinazoline (202mg, 0.9mmol) and 4-bromo-2-fluoro-5- hydroxy aniline (as described in EP 61741 A2) (206mg, lmmol) in 2-butanol (8ml). The mixture was heated at reflux for 45 minutes, then allowed to cool.
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• Example 3 As part of the procedure described in Example 2 a second compound was extracted during the abso ⁇ tion HPLC by eluting with trichloromethane/acetonitrile (75/25) to give 6,7- dimethoxy-4-(5-hydroxy-2-methylphenoxy)quinazoline (123mg, 36%). m.p. 231 -239°C
• the starting material was prepared as follows: A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med. Chem. 1977, vol 20, 146-149, l Og, 0.04mol) and Gold's reagent (7.4g. 0.05mol) in dioxane (100ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02g, 0.037mol) and acetic acid (1.65ml, 0.029mol) were added to the reaction mixture and it was heated for a further 3 hours. The mixture was evaporated, water was added to the residue, the solid was filtered off, washed with water and dried. Recrystallisation from acetic acid gave 7-benzyloxy-6-methoxy-3,4- dihydroquinazolin-4-one (8.7g, 84%).
• the starting material was prepared as follows: Boron tribromide (1.4ml, 14mmol) was added to a solution of 3- methoxybenzenethiol (lg, 7.1 mmol) in methylene chloride (10ml) at 0°C. The mixture was allowed to warm to ambient temperature and stirred for a further 60 minutes. The reaction mixture was diluted with ethyl acetate and water and basified with aqueous 2M sodium hydroxide solution to pH9. The mixture was then extracted with ethyl acetate, the combined extract washed with brine, dried (MgSO 4 ) and the solvent removed by evaporation.
• the starting material was prepared as follows:
• Example 7 A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.1g, 8mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2-fluoro-5-hydroxyaniline (1.43g, 8.9mmol), (as described in EP 61741 A2), in isopropanol (150ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4- chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoIine hydrochloride (1.45g, 47%). m.p. >250°C
• Example 8 A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.5g, 9.6mmol),
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (9.5g, 37mmol) was added portionwise to stirred concentrated nitric acid (75ml) at 0°C. The mixture was allowed to warm to ambient temperature and stirred for a further 90 minutes. The mixture was diluted with water and extracted with methylene chloride, dried (MgSO 4 ) and the solvent removed by evaporation. The residue was triturated with hexane to give ethyl 5-methoxy-4-(2- methoxyethoxy)-2-nitrobenzoate (10.6g, 95%) as an orange solid, m.p. 68-69°C
• the starting material was prepared as follows:
• Methyl chloroformate (16.35ml, 0.173mol) was added to a solution of 2,4- difluorophenol (25g, 0.192mol) and sodium hydroxide (8.1g, 0.203mol) in water (140ml). The mixture was stirred at ambient temperature for 2 hours and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4 ) and the volatiles removed by evaporation to give 2,4-difluoro- 1 -methoxycarbonyloxybenzene (32g, 89%).
• 6-Methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (200mg, 0.8mmol), (prepared as described for the starting material in Example 9), and DMF (0.1ml) in thionyl chloride (20ml) were heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was dissolved in isopropranol (15ml), 2,4-difluoro-5-hydroxyaniline (128mg, 0.88mmol), (prepared as described for the starting material in Example 1 1 ), added, and the mixture heated at reflux for 2 hours.
• the starting material was prepared as follows: A mixture of 4-fluoro-2-methyl-5-nitrophenol (4.69g, 27mmol), (prepared as described for the starting material in Example 8), benzyl bromide (3.59ml, 30mmol) and potassium carbonate (7.58g, 55mmol) in DMF (100ml) was heated at 80 °C for 4 hours. The reaction mixture was allowed to cool and diluted with water and stirred for 15 minutes. The precipitated product was collected by filtration, washed with water and dried to give 5- benzyloxy-2-fluoro-4-methyl- 1 -nitrobenzene (6.4g. 89%).
• Acetic anhydride (55ml, 0.58mmol) was added to a mixture of 4-(5-benzyloxy-2- fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (233mg, 0.52mmol), triethylamine (80ml, 0.57mmol) and 4-(N,N-dimethylamino)pyridine (5mg) in ethyl acetate (50ml). The mixture was stirred for 2 hours at ambient temperature, water was added, the organic layer separated, washed with water and brine and dried (MgSO 4 ). Most of the solvent was removed by evaporation and hexane added. The precipitated product was collected by filtration to give 7-(2-acetoxyethoxy)-4-(5-benzyloxy-2-fluoro-4-methylanilino)-6- methoxyquinazoline (1 lOmg, 43%).
• Example 14 A mixture of 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6- methoxyquinazoline (150mg, 0.33mmol), (prepared as described for the starting material in Example 13), and 10% palladium-on-charcoal catalyst (20mg) in ethyl acetate (8ml) was stirred under 1 atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and most of the solvent removed by evaporation and hexane added to the residue. The resulting precipitate was collected by filtration and dried to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-hydroxyethoxy)-6- methoxyquinazoline (50mg, 41%).
• the starting material was prepared as follows:
• a solution of sodium nitrite (220mg, 3.18mmol) in concentrated sulphuric acid (2ml) was added over 15 minutes to a suspension of 4-amino-2,6-difluorobenzoic acid (550mg. 3.18mmol) in acetic acid (6ml) at 15°C.
• the mixture was stirred at 15°C for 1 hour then heated to 90°C and poured into a solution of copper(I)chloride (800mg) in concentrated hydrochloric acid (1 1ml) at 95°C.
• the mixture was heated at 95°C for 45 minutes and then allowed to cool.
• the starting material was prepared as follows: Sodium hydride (400mg of an 80%o suspension in paraffin oil. 13.3mmol) was added to a solution of phenol (1.26g, 13.3mmol) in dry 1 -methyl-2-pyrrolidinone (20ml) and the mixture stirred for 10 minutes. 7-Benzyloxy-4-chloro-6-methoxyquinazoline (1.6g, 5.3mmol), (prepared as described for the starting material in Example 4 but with an aqueous work up), was then added and the reaction mixture heated at 1 10°C for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3 x
• the starting material was prepared as follows: 2-Chloroethyl methyl sulphide (1.2g, 10.9mmol) was added to 7-hydroxy-6- methoxy-4-phenoxyquinazoline (2.25g, 8.4mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (6.0g, 43.4mmol) in DMF (70ml). The mixture was heated at 1 10°C for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4) to give 6-methoxy- 7-(2-methylthioethoxy)-4-phenoxyquinazoline (1.55g, 54%).
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• Example 24 A mixture of 6-methoxy-7-(2-piperidinoethoxy )-3 ,4-dihydroquinazolin-4-one (440mg, 1.45mmol), thionyl chloride (15ml) and DMF (3 drops) was heated at reflux for 3 hours then allowed to cool. The excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene to give a crude 4-chloro-6-methoxy-7-(2- piperidinoethoxy)quinazoline hydrochloride (640mg).
• the starting material was prepared as follows:
• the suspension was diluted with acetone, and the precipitate collected by filtration.
• the crude product was dissolved in methylene chloride/methanol/ammonia (100/8/1, 2ml), the insoluble material removed by filtration and the solvent removed from the filtrate by evaporation.
• the residue was dissolved in acetone, IM ethereal hydrogen chloride (1ml, lmmol) added and the resultant precipitate collected by filtration and dried to give 4-(4-chloro-2-fluoro-5- hydroxyanilino)-7-(2-cyclopentyloxyethoxy)-6-methoxyquinazoline hydrochloride (50mg, 12%).
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• 1,3-Dicyclohexylcarbodiimide (343mg, 1.6mmol) was added to a suspension of 3- mo ⁇ holinopropionic acid (325mg, l . ⁇ mmol) in pyridine (12ml) and the mixture stirred for 10 minutes.
• 7-Amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (370mg, 0.97mmol), (prepared as described for the starting material in Example 29), was added and the mixture stirred for 32 hours.
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• Methoxyacetyl chloride (62 ⁇ l, 0.68mmol) was added dropwise to a solution of 7- amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (215mg, 0.52mmol) in methylene chloride (5ml) and pyridine (1.5ml) at 0°C and the mixture stirred for 2 hours at 0°C. Further methoxyacetyl chloride (14 ⁇ l, 0.15mmol) was added and the mixture stirred for 20 minutes at 0°C.
• reaction mixture was partitioned between ethyl acetate and water and the aqueous layer adjusted to pH9 with saturated aqueous sodium hydrogen carbonate solution.
• the organic layer was separated, washed with brine, dried (MgSO 4 ) and the solvent removed by evaporation.
• the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/38/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7- methoxyacetamidoquinazoline (175mg, 75%>) as a white solid.
• reaction mixture was diluted with acetone and the precipitated product collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoro-5- hydroxyanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline hydrochloride hemihydrate (480mg. 88%) as beige powder.
• the starting material was prepared as follows:
• 1,2-Dibromoethane (19.2ml, 286mmol) was added to 7-hydroxy-6-methoxy-4- phenoxyquinazoline (6.0g, 22mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (14.4g, 107mmol) in DMF. The mixture was stirred at
• the starting material was prepared as follows:
• 6-methoxy-7-(2-(2- methoxyethylamino)ethoxy)-3,4-dihydroquinazolin-4-one 600mg, 99%>
• a mixture of 6-methoxy-7-(2-(2-mefhoxyethylamino)efhoxy)-3,4- dihydroquinazolin-4-one 300mg, lmmol
• thionyl chloride 5ml
• DMF 0.1ml
• the starting material was prepared as follows: Diethyl azodicarboxylate (2.67ml, 17mmol) was added dropwise to a solution of 3- mo ⁇ holinopropan-1-ol (1.54g, lOmmol), 7-hydroxy-3,4-dihydro-6-methoxy-3- ((pivaloyloxy)methyl)quinazolin-4-one (2.6g, 8.5mmol) and triphenylphosphine (4.45g, 17mmol) in methylene chloride (40ml). After stirring for 2 hours at ambient temperature, the volatiles were removed by evaporation.
• Maize starch paste (5% w/v paste) 2.25
• 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.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Cardiology (AREA)
• Immunology (AREA)
• Heart & Thoracic Surgery (AREA)
• Diabetes (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Rheumatology (AREA)
• Emergency Medicine (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Ophthalmology & Optometry (AREA)
• Pain & Pain Management (AREA)
• Endocrinology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Dermatology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (17)

Applications Claiming Priority (6)

Publications (1)

Family

ID=27237827

Family Applications (1)

Country Status (24)

Cited By (422)

Families Citing this family (35)

Citations (7)

Family Cites Families (81)

• 1997
  • 1997-02-10 KR KR1019980706196A patent/KR19990082463A/ko not_active Ceased
  • 1997-02-10 AU AU17290/97A patent/AU719434B2/en not_active Ceased
  • 1997-02-10 PT PT97904512T patent/PT880508E/pt unknown
  • 1997-02-10 TR TR1998/01530T patent/TR199801530T2/xx unknown
  • 1997-02-10 SI SI9730539T patent/SI0880508T1/xx unknown
  • 1997-02-10 NZ NZ330868A patent/NZ330868A/xx not_active IP Right Cessation
  • 1997-02-10 HU HU9901155A patent/HUP9901155A3/hu unknown
  • 1997-02-10 PL PL97328310A patent/PL194689B1/pl not_active IP Right Cessation
  • 1997-02-10 ES ES97904512T patent/ES2194181T3/es not_active Expired - Lifetime
  • 1997-02-10 JP JP52907897A patent/JP4471404B2/ja not_active Expired - Lifetime
  • 1997-02-10 US US09/125,271 patent/US6184225B1/en not_active Expired - Lifetime
  • 1997-02-10 BR BR9707495A patent/BR9707495A/pt not_active Application Discontinuation
  • 1997-02-10 CA CA002242425A patent/CA2242425C/en not_active Expired - Fee Related
  • 1997-02-10 DK DK97904512T patent/DK0880508T3/da active
  • 1997-02-10 CZ CZ19982535A patent/CZ291386B6/cs not_active IP Right Cessation
  • 1997-02-10 AT AT97904512T patent/ATE237596T1/de active
  • 1997-02-10 IL IL12568697A patent/IL125686A/en not_active IP Right Cessation
  • 1997-02-10 DE DE69720965T patent/DE69720965T2/de not_active Expired - Lifetime
  • 1997-02-10 EP EP97904512A patent/EP0880508B1/en not_active Expired - Lifetime
  • 1997-02-10 WO PCT/GB1997/000365 patent/WO1997030035A1/en not_active Ceased
  • 1997-02-10 CN CN97192221A patent/CN1125817C/zh not_active Expired - Fee Related
  • 1997-02-10 SK SK1087-98A patent/SK285141B6/sk not_active IP Right Cessation
  • 1997-02-12 TW TW086101670A patent/TW581765B/zh not_active IP Right Cessation
• 1998
  • 1998-08-12 NO NO19983687A patent/NO311359B1/no not_active IP Right Cessation
• 2008
  • 2008-09-11 JP JP2008234068A patent/JP2009013181A/ja not_active Withdrawn