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  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/14—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 three or more hetero rings
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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 vascular endothelial growth factor
• 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).
• Basic FGF (bFGF) is a potent stimulator of angiogenesis (e.g. Hayek et al, 1987, Biochem. Biophys. Res.
• 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
• the kinase insert domain-containing receptor KDR (also referred to as Flk-1)
• Flt4 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).
• 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, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
• 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, excessive scar formation and adhesions, endometriosis, dysfunctional uter
• Compounds ofthe present invention generally possess higher potency against VEGF receptor tyrosine kinase than against epidermal growth factor (EGF) receptor tyrosine kinase.
• Compounds ofthe 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.
• Compounds ofthe present invention generally possess higher potency against VEGF receptor tyrosine kinase than against FGF Rl receptor tyrosine kinase.
• ring C is a 5-6-membered heterocyclic moiety which may be saturated or unsaturated, which may be aromatic or non-aromatic, and which contains 1 -3 heteroatoms selected independently from O, N and S;
• Z is -O-, -NH-, -S- or -CH 2 -;
• R 1 represents hydrogen, C alkyl, C alkoxymethyl, di(C alkoxy)methyl, C, . 4 alkanoyl, trifluoromethyl, cyano, amino, C 2 . 5 alkenyl, C 2 . 5 alkynyl, a phenyl group, a benzyl group or a 5-6-membered heterocyclic group with 1-3 heteroatoms, selected independently from O, S and N, which heterocyclic group may be aromatic or non-aromatic and may be saturated (linked via a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), and which phenyl, benzyl or heterocyclic group may bear on one or more ring carbon atoms up to 5 substituents selected from hydroxy, halogeno, C M alkyl, C ⁇ alkoxy, C,.
• alkanoyloxy trifluoromethyl, cyano, amino, nitro, C 2 . 4 alkanoyl, C M alkanoylamino, C,. 4 alkoxycarbonyl, C alkylsulphanyl, C,. 4 alkylsulphinyl, C,. 4 alkylsulphonyl, carbamoyl, N-C,_ 4 alkylcarbamoyl, N,N-di(C,. 4 alkyl)carbamoyl, aminosulphonyl, N-C alkylaminosulphonyl, N,N-di(C alkyl)aminosulphonyl, C,.
• alkylsulphonylamino and a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl, which saturated heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,. 3 alkyl, C,. 3 alkoxy, C,. 3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C alkoxycarbonyl, and additionally substituents on the phenyl, benzyl or heterocyclic group may be selected from C alkylamino, C,.
• R' may represent carboxy, C 3 . 7 cycloalkyl, C 7 cycloalkylC alkyl, or phenylC 2 . 4 alkyl wherein the phenyl moiety may bear up to 5 substituents selected from the list hereinbefore defined for a phenyl ring which is directly linked to ring C; n is an integer from 0 to 5; m is an integer from 0 to 3;
• R 2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C,. 3 alkyl, C,. 3 alkoxy, C,. 3 alkylsulphanyl, -NR 3 R 4 (wherein R 1 and R 4 , which may be the same or different, each represents hydrogen or C alkyl), or R'X 1 - (wherein X 1 represents a direct bond, -O-, - CH 2 -, -OCO-, carbonyl, -S-.
• R 6 , R 7 , R s , R 9 and R'° each independently represents hydrogen, C alkyl or C, . 3 alkoxyC 2 3 alkyl
• R 3 is selected from one ofthe following seventeen groups:
• R 17 , R 18 , R 19 , R 20 and R 2 ' each independently represents hydrogen, C,_ 3 alkyl or C,. 3 alkoxyC 2.3 alkyl
• R 16 represents hydrogen, C,. 3 alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C,.
• 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C M alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C alkyl, C,. 4 hydroxyalkyl and C alkoxy, and additional possible substituents for the cyclic group are C,_ 4 cyanoalkyl and C M alkoxy carbonyl);
• R 2 ⁇ R 2 ⁇ R 23 , R 26 and R 27 each independently represents hydrogen, C,. 3 alkyl or C,. 3 alkoxyC 2 . alkyl
• R 22 represents hydrogen or C M alkyl, or R 22 represents C l . 3 alkoxyC 2 . .. alkyl
• R 2S (wherein R 28 is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 -2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C, . 4 alkyl, C __ydroxyalkyl, C alkoxy, C l . 4 alkoxyC l _ 4 alkyl and C,_ 4 alkylsulphonylC alkyl, and an additional possible substituent is C alkoxycarbonyl);
• R 29 represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents on an available carbon atom selected from hydroxy, halogeno, amino, C alkyl, C
• R 3 alkylR 29 (wherein X 9 represents -0-, -S-, -SO-, -S0 2 -, -NR 49 CO-, - CONR 50 -, -S0 2 NR 51 -, -NR 52 S0 2 - or -NR 53 - (wherein R 49 , R 50 , R s ⁇ , R 52 and R 53 each independently represents hydrogen, C M alkyl or C,_ 3 alkoxyC 2 . 3 alkyl) and R 29 is as defined hereinbefore); and 17) C ⁇ alkylX' ⁇ C ⁇ alkylR 28 (wherein X 9 and R 28 are as defined hereinbefore); and additionally R 3 may be selected from a group:
• 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C alkyl, C hydiOxyalkyl, C alkoxy, C, .4 cyanoalkyl and C, . 4 alkoxycarbonyl), with the proviso that R 34 cannot be hydrogen; and additionally wherein any C,. 5 alkyl, C 2 . 5 alkenyl or C 2 .
• R'X 1 - may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
• ring C is a 5-6-membered heteroaromatic moiety which contains 1-3 heteroatoms selected independently from O, N and S.
• ring C is a 5-membered heteroaromatic moiety which contains 1-3 heteroatoms selected independently from O, N and S.
• ring C is pyrazolyl.
• Particularly ring C is pyrazolyl wherein the substituent at the 4-position ofthe pyrazolyl ring is hydrogen.
• Z is -O- or -S-, especially -0-.
• Z is -O- or -NH-.
• R 1 represents a phenyl group, a benzyl group or a 5-6-membered heteroaromatic group with 1-3 heteroatoms, selected independently from O, S and N, (linked via a ring carbon atom), which phenyl, benzyl or heteroaromatic group may be substituted as defined hereinbefore.
• Preferred 5-6-membered heteroaromatic groups contain one or two N atoms (for example, pyrrole, pyridine, pyrazole, imidazole, pyrimidine, pyrazine and pyridazine), two N atoms and one S atom (for example 1 ,2,5- and 1 ,3,4-thiadiazole), one N and one O atom (for example oxazole, isoxazole and oxazine), one N and one S atom (for example thiazole and isothiazole) and one O or one S atom (furan and thiophene). More preferably R' is a phenyl group or a 5-6-membered heteroaromatic group with 1-
• heteroatoms selected independently from O, S and N, (linked via a ring carbon atom), which phenyl or heteroaromatic group is optionally substituted as hereinbefore defined.
• R 1 is phenyl optionally substituted as hereinbefore defined.
• R 1 is a phenyl, thienyl or a furyl group which phenyl, thienyl or furyl group is optionally substituted as hereinbefore defined.
• R 1 is a phenyl or a furyl group which phenyl or furyl group is optionally substituted as hereinbefore defined.
• the substituents on an available ring carbon atom in R 1 are selected independently from halogeno, C,. 2 alkyl, C,. 2 alkoxy, trifluoromethyl, cyano, nitro, C 2. 3 alkanoyl, C
• alkyl)carbamoyl aminosulphonyl, N-C alkylaminosulphonyl, N,N-di(C alkyl)aminosulphonyl, C,. 3 alkylsulphonylamino, and a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidin- 1 -yl, piperazin- 1 -yl, piperazin-4-yl, and piperidino which saturated heterocyclic group may be substituted as hereinbefore defined.
• the substituents on an available ring carbon atom in R 1 are selected independently from halogeno, trifluoromethyl, cyano, nitro, C 2 . 3 alkanoyl, C, .3 alkoxycarbonyl, C
• alkylaminosulphonyl N,N-di(C,_ 3 alkyl)aminosulphonyl
• a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1 -yl, piperazin-4-yl, and piperidino which saturated heterocyclic group is unsubstituted.
• the substituents on an available ring carbon atom in R 1 are selected independently from C,. 2 alkyl, C,. 2 alkoxy, halogeno, trifluoromethyl, cyano, nitro, C 2 . 3 alkanoyl, C,. 3 alkoxycarbonyl, C,. 3 alkylsulphinyl, C, .3 alkylsulphonyl, carbamoyl, N-C,_ 3 a_kylcarbamoyl, N,N-di(C,. 3 alkyl)carbamoyl, aminosulphonyl, N-C,. 3 alkylaminosulphonyl, N,N-di(C,.
• n is 1.
• m is an integer from 0 to 2, more preferably 1 or 2, most preferably 2.
• X 1 represents -O-, -S-, -NR 6 CO-, -NR 9 SO 2 - or -NR 10 - (wherein R 6 , R 9 and R 10 each independently represents hydrogen, C, .2 alkyl or C, .2 alkoxyethyl).
• X 1 represents -O-, -S-, -NR 6 CO-, -NR 9 S0 2 - (wherein R 6 and R 9 each independently represents hydrogen or C,. 2 alkyl) or NH. More preferably X 1 represents -O-, -S-, -NR 6 CO- (wherein R 6 represents hydrogen or
• X 1 represents -O- or -NR 6 CO- (wherein R 6 represents hydrogen or C, . 2 alkyl), more particularly -O- or -NHCO-, especially -0-.
• X 2 represents -O- or NR 12 (wherein R 12 represents hydrogen, C, .3 alkyl or C, .2 alkoxyethyl).
• X 3 represents -0-, -S-, -SO-, -S0 2 -, -NR l7 CO-, -NR 20 SO 2 - or -NR 21 - (wherein R 17 , R 20 and R 21 each independently represents hydrogen, C,. 2 alkyl or C,. 2 alkoxy ethyl).
• X 3 represents -O-, -S-, -SO-, -S0 2 - or -NR 21 - (wherein R 21 represents hydrogen, C,_ 2 alkyl or C
• X 3 represents -O- or -NR 21 - (wherein R 21 represents hydrogen or C,. 2 alkyl).
• X 4 and X 5 which may be the same or different each represents -O-, -S- , -SO-, -SO 2 - or -NR 27 - (wherein R 27 represents hydrogen, C,. 3 alkyl or C ⁇ alkoxyethyl).
• R 27 represents hydrogen, C,. 3 alkyl or C ⁇ alkoxyethyl.
• X 4 and X 5 which may be the same or different each represents -O-, -S- or -
• NR 27 - (wherein R 27 represents hydrogen, C,. 2 alkyl or C,. 2 alkoxy ethyl).
• X 4 and X 5 which may be the same or different each represents -O- or - NH-.
• X 6 represents -O-, -S- or -NR 38 - (wherein R 38 represents hydrogen, C,_ 2 alkyl or C,. 2 alkoxy ethyl).
• X 6 represents -O- or -NR 38 - (wherein R 38 represents hydrogen or C,. 2 alkyl).
• X 7 represents -0-, -S- or -NR 43 - (wherein R 43 represents hydrogen, C,_ alkyl or C
• X 7 represents -O- or -NR 43 - (wherein R 43 represents hydrogen or C, .2 alkyl).
• X s represents -0-, -S- or -NR 48 - (wherein R 48 represents hydrogen, C,_ 2 alkyl or C,. 2 alkoxyethyl).
• X 8 represents -O- or -NR 48 - (wherein R 48 represents hydrogen or C, .2 alkyl).
• X 9 represents -O-, -S- or -NR' 3 - (wherein R 53 represents hydrogen, C, . 2 alkyl or C,. 2 alkoxyethyl).
• X 9 represents -O- or -NR 53 - (wherein R 33 represents hydrogen or C, .2 alkyl).
• R 28 is pyrrolidinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino
• R 29 represents a pyridone group or a 5-6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which pyridone group or heterocyclic group may be substituted as hereinbefore defined.
• R 29 is a 5-6-membered aromatic heterocyclic group, it preferably has 1 or 2 heteroatoms, selected from O, N and S, of which more preferably one is N, and may be substituted as hereinbefore defined.
• R 29 is particularly a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group which group may be substituted as hereinbefore defined, more particularly a pyridone, pyridyl, imidazolyl, thiazolyl or triazolyl group, especially a pyridone, pyridyl, imidazolyl or triazolyl group which group may be substituted as hereinbefore defined.
• R 29 represents a pyridone, phenyl or 5- 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which group may preferably carry up to 2 substituents, more preferably up to one substituent, selected from the group of substituents as hereinbefore defined.
• R 29 conveniently substituents are selected from halogeno, C,_ 4 alkyl, C alkoxy and cyano, more conveniently substituents are selected from chloro, fluoro, methyl and ethyl.
• R 3'1 is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is optionally substituted as hereinbefore defined.
• R 34 is a 6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is optionally substituted as hereinbefore defined.
• R 54 is piperidinyl, pyrrolidinyl or piperazinyl, which group is optionally substituted as hereinbefore defined.
• R 51 is C,. 3 alkyl or a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is optionally substituted as hereinbefore defined.
• R" is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is optionally substituted as hereinbefore defined.
• R 5D is a group selected from morpholino, pyrrolidin-l-yl, piperidino, piperazin-1-yl and thiomorpholino which group is optionally substituted as hereinbefore defined.
• R 2 represents hydroxy, halogeno, nitro, trifluoromethyl, C, .3 alkyl, cyano, amino or R 3 X'- [wherein X 1 is as hereinbefore defined and R 3 is selected from one of the following seventeen groups:
• C,_ 5 a_kyl which may be unsubstituted or substituted with one or more fluorine atoms, or C 2 .
• 5 alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
• C 2 _ 4 alkylX 3 R 16 (wherein X 3 is as hereinbefore defined and R 16 represents hydrogen, C alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C,. 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C,. 3 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,_ 4 alkyl, C M hydroxyalkyl and C,. 4 alkoxy); 4) C 2 . 3 alkylX 4 C 2 . 3 alkylX 3 R 22 (wherein X 4 and X 3 are as hereinbefore defined and R 22 represents hydrogen or C,. 3 alkyl);
• C,_ 5 alkylR 16 (wherein R 36 is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C
• R 37 is a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to C 2 . 5 alkyl through a nitrogen atom and which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C alkyl, C hydroxyalkyl, C,. 4 alkoxy, C l . alkoxyC,. 4 alkyl and C,_ alkylsulphonylC alkyl);
• R 5 may be selected from a group:
• R 2 represents hydroxy, halogeno, nitro, trifluoromethyl, C alkyl, cyano, amino or R'X 1 - [wherein X 1 is as hereinbefore defined and R 3 is selected from one of the following seventeen groups: 1) C,. 4 alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C 2 . 4 alkyl which may be unsubstituted or substituted with 1 or 2 groups selected from hydroxy and amino;
• R I 3 ,R 14 and R b which may be the same or different are each C,. 2 alkyl or C,. 2 alkoxy ethyl
• R >9 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 alkyl through a carbon atom and which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,. 3 alkyl, C M hydroxyalkyl, C,. 3 alkoxy, C,. 2 alkoxyC
• R 60 is a group selected from morpholino, thiomorpholino, pyrrolidin-l-yl, piperazin-1-yl and piperidino which group ma)' carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,. 3 alkyl, C
• R' may be selected from a group:
• R 2 represents hydroxy, halogeno, nitro, trifluoromethyl, C, .3 alkyl, cyano, amino or R 5 X'- [wherein X 1 is as hereinbefore defined and R 5 is selected from one ofthe following fifteen groups:
• R 16 (wherein X 3 is as defined hereinbefore and R 16 is a group selected from C
• R 29 (wherein R 29 is as defined hereinbefore); 7) C,_ 4 alkylR 29 (wherein R 29 is as defined hereinbefore);
• R 3 may be selected from a group: 16) ethyl R 5 thylX 9 R 55 (wherein X 9 , R 54 and R 55 are as defined hereinbefore): and additionally wherein any C,. 5 alkyl, C 2 .,alkenyl or C 2 .,alkynyl group in R'X 1 - may bear one or more substituents selected from hydroxy, halogeno and amino].
• R 2 represents C,. 3 alkyl, amino or R 3 X'- [wherein X 1 is as hereinbefore defined and R 3 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-
• R 2 represents methoxy, 2-methoxyethoxy, 2-(2- methoxyethoxy)ethoxy, 3-methoxypropoxy.
• R 2 represents 2-methoxyethoxy, 2-(2-methoxyethoxy)ethoxy, 3- methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(tetrahydropyran- 4-yloxy)ethoxy, 3-(tetrahydropyran-4-yloxy)propoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4- methylpiperazin- 1 -yl)propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(imidazol- 1 - yl)ethoxy, 3-(imidazol-l -yl)propoxy 2-(l ,l-dioxothiomorpholino)ethoxy, 3-(l ,l- dioxothiomorpholino)propoxy, 2-(l ,2,3-triazol-l-yl)ethoxy, 3-(l,2.3-triazol-l-yl)
• R 3 X'- the substituent R'X 1 - is preferably at the 6- or 7-position of the quinazoline ring, more preferably at the 7-position of the quinazoline ring.
• R 2 substituents When one of the R 2 substituents is at the 6-position ofthe quinazoline ring it is preferably halogeno, C,. 3 alkyl. C M alkoxy, C
• R 2 substituents When one of the R 2 substituents is at the 6-position of the quinazoline ring it is more preferably C,. 3 alkoxy, especially methoxy.
• R 2 '' represents halogeno, C,. 3 alkyl, C,. 3 alkoxy, C,. 3 alkylthio, -NR 3a R 4a (wherein R 3 and R 4 '', which may be the same or different, each represents hydrogen or C,. 3 alkyl), or R 5 ''(CH 2 ) z .
• X ld (wherein R 3 ' 1 is a 5- or 6-membered saturated heterocyclic group with 1-2 heleroatoms, selected independently from O, S and N. which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,. 4 alkyl, C hydroxyalkyl and C, .
• za is an integer from 0 to 4 and X la represents a direct bond, -O-, -CH 2 -, -S-, -SO-, - SO 2 -, -NR 6a CO-, -CONR 7a -, -SO 2 NR 8a -, -NR 9a S0 2 - or -NR IOa - (wherein R 6 , R 7a , R 8a . R 9a and R 10 each independently represents hydrogen, C,.
• R 2a represents hydrogen
• salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
• X la represents -0-, -S-, -NR 6a CO-, -NR 9a S0 2 - or -NR 10a - (wherein R 6a , R 9a and R 10a each independently represents hydrogen, C, .2 alkyl or C, .2 alkoxyethyl).
• X l a represents -0-, -S-, -NR 6a CO-, -NR 9a S0 2 - (wherein R fa and R 9a each independently represents hydrogen or C,. 2 alkyl) or NH. More preferably X la represents -0-, -S-, -NR 6a CO- (wherein R 6a represents hydrogen or
• X l represents -O- or -NR 6a CO- (wherein R 6a represents hydrogen or C, . 2 alkyl). More particularly -O- or -NHCO-, especially -0-.
• za is an integer from 1 to 3.
• R 3 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholino which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,. 2 alkyl, C M hydroxyalkyl and C,. 2 alkoxy.
• R a represents C,. 3 alkyl, C,. 3 alkoxy, amino or R 5a (CH 2 ) z .X''' (wherein R 3a , X i a and za are as defined hereinbefore).
• R 2a is hydrogen.
• R 2 is methyl, ethyl, methoxy, ethoxy or R 5a (CH 2 )_ a X ia (wherein R 5a , X la and za are as defined hereinbefore).
• Another preferred value of R 2a is hydrogen.
• R 2a is methyl, ethyl, methoxy, ethoxy or R :,a (CH 2 )_ : ,X l
• R 5a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholino which group may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno, C,. 2 alkyl, C, .2 hydroxyalkyl and C,.
• R 2 alkoxy X la is -0-, -S-, -NR 6a CO-, -NR a S0 2 - (wherein R 6a and R 9a each independently represents hydrogen or C,_ 2 alkyl) or NH, and za is an integer from 1 to 3).
• R 6a and R 9a each independently represents hydrogen or C,_ 2 alkyl) or NH
• za is an integer from 1 to 3).
• R 2a is hydrogen.
• R 2a represents methyl, methoxy or R ⁇ CH ⁇ X 1 " (wherein R 5a . X l and za are as defined hereinbefore).
• R 2a represents methoxy
• ring C, R 1 , R 2 , R 2a and n are as defined hereinbefore with the proviso that R 2 is not hydrogen;
• Zb is -O- or -S-; and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
• Zb is -O-.
• ring C, R 1 , R 2 , R 2a , Zb and n are as defined hereinbefore with the proviso that R 2 does not have any of the following values: hydrogen, substituted or unsubstituted C alkyl. halogeno, C, .5 alkoxy, phenoxy or phenylC alkoxy; and salts thereof, and prodrugs thereof for example esters, amides and sulphides, preferably esters and amides.
• Preferred compounds of the present invention include
• More preferred compounds of the present invention include 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(l-methylpiperidin-4- ylmethoxy)quinazoline, 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-l- yl)propoxy)quinazoline, 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline.
• Especially preferred compounds of the present invention include
• Another more preferred group of compounds of the present invention includes 7-(2-methoxyethoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline, 4-(5-(2-lluorophenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline, 6-methoxy-7-(3-morpholinopiOpoxy)-4-(5-(3-nitiOphenyl)pyrazol-3-yloxy)quinazoline, 6-methoxy-7-(3-morpholinopropoxy)-4-(5-(4-nitiOphenyl)pyrazol-3-yloxy)quinazoline, 6-methoxy-7-(3-morpholinopropoxy)-4-(5-(4-pyridyl)pyrazol-3-yloxy)quinazoline, 4-(5-(4-fluorophenyl)pyrazol-3-yloxy)-6-methoxy-7-(3
• Another preferred group of compounds of the present invention includes 4-(5-benzylpyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline, 4-(5-butylpyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline, 6-methoxy-7-(3-morpholinopropoxy)-4-(5-propylpyrazol-3-yloxy)quinazoline,
• 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.
• alkoxy' as used herein, unless stated otherw ise includes “alkyP'-O- groups in which "alkyl' " is as hereinbefore defined.
• aryl as used herein unless stated otherwise includes reference to a C 6. , 0 aryl group which may.
• alkyl and alkoxy are as hereinbefore defined.
• aryloxy as used herein unless otherwise stated includes “aryP'-O-groups in which "aryl” is as hereinbefore defined.
• sulphonyloxy ' as used herein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which "alkyl” and “aryl” are as hereinbefore defined.
• 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. Unless otherwise stated the term “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.
• R 2 has a value of substituted or unsubstituted C,. 5 alkyl, it has been selected from C alkyl or from R 5 X'- wherein R ⁇ has been selected from group 1) as defined hereinbefore and wherein X 1 has the value -CII 2 - or is a direct bond.
• a compound ofthe 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.
• the formulae drawings within this specification can represent only one o the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms ofthe compounds drawn not just those forms which it has been possible to show graphically herein.
• compounds of the formula I or a salt thereof may possess an asymmetric carbon atom.
• Such an asymmetric carbon atom is also involved in the tautomerism described above, and it is to be understood that the present invention encompasses any chiral form (including both pure enantiomers and racemic mixtures) as well as any tautomeric form which inhibits VEGF receptor tyrosine kinase activity, and is not to be limited merely to any one tautomeric form or chiral form utilised within the formulae drawings. It is to be understood that the invention encompasses all optical and diastereomers which inhibit VEGF receptor tyrosine kinase activity.
• R 3 is. for example, a group of formula C
• R is, for example, a group of formula C 2 . 5 alkenylR 28 it is the C 2 . 5 alkenyl moiety which is linked to X 1 and an analogous convention applies to other groups.
• R 5 is a group l-R 29 prop-l-en-3-yl it is the first carbon to which the group R 29 is attached and it is the third carbon which is linked to X 1 and an analogous convention applies to other groups.
• R 29 carries a C,_
• aminoalkyl substituent it is the C,. alkyl moiety which is attached to R 29 whereas when R 29 carries a C,. 4 alkylamino substituent it is the amino moiety which is attached to R 29 and an analogous convention applies to other groups.
• R 28 carries a C,_ 4 alkoxyC alkyl substituent it is the C,_ 4 alkyl moiety which is attached to R 28 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 ofthe compounds of formula I and their pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts ofthe 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 methyl am ine, dimethyla ine, trimethylamine, piperidine, morpholine 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
• a compound o 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 and in International Patent Applications Publication Nos. WO 97/22596, WO 97/30035, WO 97/32856, ⁇ 'O 97/42187 and WO 98/13354. Such processes also include, for example, solid phase synthesis. 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 M alkoxy), aryloxy, alkylsulphanyl, arylsulphanyl. alkoxyalkylsulphanyl or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methylsulphanyl, 2- methoxyethylsulphanyl, methanesulphonyloxy or toluene-4-sulphonyloxy group.
• the reaction is advantageously effected in the presence of a base.
• Such a base is, for example, an organic amine base such as, for example, pyridine. 2.6-lutidine. collidine. 4-dimethylaminopyridine, triethylamine, morpholine, N-n .ethyl morpholine or diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine 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, sodium bis(trimethylsilyl)amide, potassium amide or potassium bis(trimethylsilyl)amide.
• the reaction is preferably effected in the presence of an inert solvent or diluent, for example 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-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulphoxide.
• the reaction is conveniently effected at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 90°C.
• the free base may be treated with an acid such as a hydrogen halide, for example hydrogen chloride, sulphuric acid, a sulphonic acid, for example methane sulphonic acid, or a carboxylic acid, for example acetic or citric acid, using a conventional procedure.
• an acid such as a hydrogen halide, for example hydrogen chloride, sulphuric acid, a sulphonic acid, for example methane sulphonic acid, or a carboxylic acid, for example acetic or citric acid, using a conventional procedure.
• L 1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group, or L 1 may be generated in situ from an alcohol under standard Mitsunobu conditions ("Organic Reactions", John Wiley & Sons Inc, 1992, vol 42, chapter 2, David L Hughes).
• 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.
• a base as defined hereinbefore in process (a)
• an inert solvent or diluent as defined hereinbefore in process (a)
• a temperature in the range for example 10 to 150°C, conveniently at about 50°C.
• R 10 represents hydrogen, C,. 3 alkyl or C alkoxyC
• X'°C alkyl (wherein X 10 represents -0-, -S-, -S0 2 -, -NR 6 CO- or -NR 64 SO 2 -
• R 63 and R 64 which may be the same or different are each hydrogen, C,. 3 alkyl or C,_ 3 alkoxyC 2 . 3 alkyl);
• R ( ' 6 wherein R 63 and R 66 which may be the same or different are each hydrogen, C, .3 alkyl or C,_ 3 alkoxyC 2 . 3 alkyl);
• X I2 R 29 (wherein X 12 represents -0-, -S-, -SO 2 -, -NR 70 CO-, -NR 71 SO 2 -, or -NR 72 -
• R 70 , R 71 , and R 72 which may be the same or different are each hydrogen, C,. 3 alkyl or C, .3 alkoxyC 2 . alkyl) and R 29 is as defined hereinbefore); _>/
• X 1 C,. 5 alkylR 29 preferably X 13 C alkylR 29 , (wherein X 13 represents -0-, -S-, -S0 2 -, NR 7 CO-, -NR 74 S0 2 - or -NR 75 - (wherein R", R 74 and R 75 each independently represents hydrogen, C, .3 alkyl or C
• R 54 C,. : ,alkylX 9 R 55 (wherein R 54 , R 55 and X 9 are as defined hereinbefore); may be prepared by reacting a compound of the formula IX:
• 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.
• Process (a) is preferred over processes (b), (c) and (d).
• (e) The production of those compounds of the formula I and salts thereof wherein one or more of the substituents (R 2 ) m is represented by -NR 79 R 80 , where one (and the other is hydrogen) or both of R 79 and R 80 are C,. 3 alkyl, may be effected by the reaction of compounds - _>_) - of formula I wherein the substituent (R 2 ) m is an amino group and an alkylating agent, preferably in the presence of a base as defined hereinbefore. Such alkylating agents are C,.
• 3 alkyl moieties bearing a displaceable moiety as defined hereinbefore such as C M alkyl halides for example C, 3 alkyl chloride, bromide or iodide.
• the 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.
• the production of compounds of formula I and salts thereof wherein one or more ofthe substituents R 2 is an amino group may be effected by the reduction of a corresponding compound of formula 1 wherein the substituent(s) at the corresponding position(s) of the quinazoline group is/are a nitro group(s).
• the reduction may conveniently be effected as described in process (i) hereinafter.
• the production of a compound of formula I and salts thereof wherein the substituent(s) at the corresponding position(s) of the quinazoline group is/are a nitro group(s) may be effected by the processes described hereinbefore and hereinafter in processes (a-d) and (i-v) using a compound selected from the compounds of the formulae (I-XXII) in which the substituent(s) at the corresponding position(s) of the quinazoline group is/are a nitro group(s).
• Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphorus(III)chloride, phosphorus(V)oxychloride and phosphorus(V)chloride.
• Thc halogenation reaction may be effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon letrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene, or the reaction ma)' be effected without the presence of a solvent.
• 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 XI and salts thereof may, for example, be prepared by reacting a compound of the formula XII:
• 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 2 and m. are as hereinbefore defined, and A 1 is an hydroxy, alkoxy (preferably C,. 4 alkoxy) or amino group) whereby to form a compound of formula XI 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 XI or salt thereof is obtained, such as [3- (dimethylamino)-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 XI may also be prepared by cyclising a compound ofthe formula XIV, where A 1 is an amino group, with formic acid or an equivalent thereof effective to cause cyclisation whereby a compound of formula XI or salt thereof is obtained.
• Equivalents of formic acid effective to cause cyclisation include for example a tri-C,. 4 alkoxymethane, for example triethoxymethane and triiuethoxymethane.
• 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 diethyl ether or tetrahydroturan, 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 ofthe 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 stirring a solution ofthe nitro compound under hydrogen at 1 to 4 atmospheres pressure 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 under hydrogen at 2 atmospheres pressure in the presence ofthe activated metal and a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, at 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, at a temperature in the range, for example 50 to 150°C, conveniently at about 70°C.
• the compounds of formula III and salts thereof wherein at least one R 2 is R'X 1 and wherein X 1 is -CH-,- may be prepared for example as described above from a compound ofthe formula XV (in which R 2 is -CH 3 ) or XIII (in which FIX 1 - is -CH 3 ). by radical bromination or chlorination to give a -CH 2 Br or -CH 2 C1 group which may then be reacted with a compound of the formula R'-FI under standard conditions for such substitution reactions.
• the compounds of formula III and salts thereof wherein at least one R 2 is R'X 1 and wherein X 1 is a direct bond may be prepared for example as described above from a compound of the formula XI, wherein the R group is already present in the intermediate compounds (for example in a compound of the formula XV) used to prepare the compound of formula XI.
• the compounds of formula III and salts thereof wherein at least one R 2 is R'X 1 and wherein X 1 is -NR 6 CO- or -NR 9 SO 2 - may be prepared for example from a compound ofthe formula XIII in which ITX 1 - is an -NHR 6 - or -NHR 9 - group (prepared for example from an amino group (later functionalised if necessary) by reduction of a nitro group) which is reacted with an acid chloride or sul onyl chloride compound of the formula R 5 COCl or R 3 S0 2 C1.
• R 2 is R'X 1 and wherein X 1 is -0-. -S-. -SO,-, -OCO-. -CONR 7 -, -S0 2 NR 8 - or -NR 10 - (wherein R 7 , R 8 and R 10 each independently represents hydrogen, C,. 3 alkyl or C,_ 3 alkoxyC 2 _,alkyl), may also be prepared for example by reacting a compound of the formula XVIII:
• 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 (b) hereinbefore.
• the compounds of formula XVIII and salts thereof may for example be prepared by deprotecting a compound of the formula XIX:
• protecting group P 1 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 1991 , including N-sulphonyl derivatives (for example, p-toluenesulphonyl), carbamates (for example, t-butyl carbonyl), N-alkyl derivatives (for example, 2-chloroethyl.
• benzyl and amino acetal derivatives (for example benzyloxymethyl).
• the removal of such a protecting group may be effected by any of the procedures known for such a transformation, including those reaction conditions indicated in standard texts such as that indicated hereinbefore, or by a related procedure.
• Deprotection may be effected by techniques well known in the literature, for example where P 1 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 XI as hereinbefore defined, followed by introduction of halide to the compound of formula XI, thus obtained as hereinbefore defined, to yield a compound of formula III in which L 1 represents halogen.
• This assay determines the ability of a test compound to inhibit tyrosine kinase activity.
• DNA encoding VEGF, FGF or 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 activit) .
• VEGF FGF 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 Corporation)).
• 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 Corporation
• 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), methionine 668 (EGF receptor, Genbank accession number X00588) and methionine 399 (FGF Rl receptor, Genbank accession number X51803) 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.
• Test compounds were diluted with 10% dimcthylsulphoxide (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 dimcthylsulphoxide
• mice IgG anti-phosphotyrosine antibody Upstate Biotechnology Inc. product 05-321
• PBST bovine serum albumin
• HRP horse radish peroxidase
• SSA bovine serum albumin
• 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 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.
• FCS foetal calf serum
• VEGF 3ng/ml. EGF 3ng/ml or b-FGF 0.3ng/ml the appropriate growth factor
• the cultures were then incubated for 4 days at 37°C with 7.5%) CO 2 .
• the cultures were pulsed with l ⁇ Ci/well of tritiated-thymidine (Amersham product TRA 61) and incubated for 4 hours.
• the cells were harvested using a 96-well plate harvester (Tomtek) and then assayed for incorporation of tritium with a Beta plate counter. Incorporation of radioactivity into cells, expressed as cpm, was used to measure inhibition of growth factor-stimulated cell proliferation by compounds.
• oestradiol benzoate Groups of 20 to 22-day old rats were treated with a single subcutaneous dose of 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 parentcral 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.
• parentcral 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.
• topical administration for example as an ointment or cream
• 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 ofthe animal, i.e. approximately 0.1-1 OOmg/kg.
• a unit dose in the range, for example, 1-lOOmg/kg, preferably l-50mg/kg is envisaged and this normally provides a therapeutical ly-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 ofthe 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.
• Flowever 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 field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer.
• the other component(s) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be: surgery. radiotherap ⁇ or chemotherapy.
• Such chemotherapy may cover three main categories of therapeutic agent:
• cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfenc), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane).
• antioestrogens for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfenc
• progestogens for example megestrol acetate
• aromatase inhibitors for example anastrozole, letrazole, vorazole, exemestane
• antiprogestogens for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5 ⁇ - dihydroreductase (for example fmasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example platelet derived growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors); and
• 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, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); topoisomerase
• antimetabolites
• the compounds defined in the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects.
• Such compounds ofthe 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, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding 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 pharmaceutical!' 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 ofthe search for new therapeutic agents.
• the starting material was prepared as follows: A mixture of 4,5-dimethoxyanthranilic acid (19.7g) and formamide (10ml) was stirred and heated at 190°C for 5 hours. The mixture was allowed to cool to approximately 80°C and water (50ml) was added. The mixture was then allowed to stand at ambient temperature for 3 hours. The precipitate was collected by filtration, washed with water and dried to give 6,7- dimethoxy-3,4-dihydroquinazolin-4-one (3.65g).
• the starting material was prepared as follows:
• 6-methoxy-7-(3- morpholinopropoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline as the free base.
• the free base was dissolved in a mixture of methylene chloride/methanol (1/1 ) and 3M hydrochloric acid in methanol was added. The volatiles were removed by evaporation to give 6-methoxy-7-(3- morpholinopropoxy)-4-(5-pheny_pyrazol-3-y_oxy)quinazoI_ne hydrochloride (1 15mg, 43%.).
• the starting material was prepared as follows: A mixture of ethyl 4-hydroxy-3-methoxybenzoate (9.8g, 50mmol). 2-bromoethyl methyl ether (8.46ml. 90mmol) and potassium carbonate (12.42g, 90mmol) in acetone (60ml) was heated at reflux for 30 hours. The mixture was allowed to cool and the solids removed by filtration. The volatiles were removed from the filtrate by evaporation and the residue triturated with hexane to give ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (1 1.3g, 89%o) as a white solid, m.p. 57-60°C
• Example 5 3-(4-Fluorophenyl)-4,5-dihydro-lH-pyrazol-5-one (222mg, 1.25mmol) was added in portions over 10 minutes to a suspension of sodium hydride (50mg, 1.25mmol, prewashed with hexane) in DMF (3ml) under nitrogen. After stirring for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-n.orpholinopropoxy)quinazoline (169mg, O.Smmol), (prepared as described for the starting material in Example 2), was added and the mixture was heated at 60°C for 1 hour. After cooling, the mixture was diluted with aqueous ammonium chloride solution and ether was added.
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• Example 7 Using an analogous procedure to that described for Example 6, 4-chloro-6-methoxy-7-
• the starting material was prepared as follows:
• Diethyl azodicarboxylate (435mg, 2.5mmol) was added dropwise to a suspension of 7- hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (612mg. 2mmol), 2-(imidazol-l-yl)ethanol (280mg, 2.5mmol), (J. Med. Chem. 1993, 25, 4052-4060), and triphenylphosphine (655mg, 2.5mmol) in methylene chloride (10ml) at 5°C. The mixture was stirred for 10 minutes at 5°C and then 1 hour at ambient temperature.
• Example 8 Using an analogous procedure to that described for Example 6, 4-chloro-6-methoxy-7-
• the starting material was prepared as follows:
• Diethyl azodicarboxylate (864 ⁇ l, 5.5mmol) was added dropwise to a mixture of 7- hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.2g, 3.9mmol) (prepared as described for the starting material in Example 7), triphenylphosphine (1.44g, 5.5mmol) and 2-(2-methoxyethoxy)ethanol (653 ⁇ l, 5.5mmol) in methylene chloride (70ml) cooled at 0°C. The mixture was stirred for 1.5 hours at ambient temperature and the solvent was removed by evaporation.
• the starting material was prepared as follows:
• the starting material was prepared using an analogous procedure to that described in
• the starting material was prepared as follows: l -Bromo-3-chloropiOpane (0.97ml, 9.8mmol) was added to a solution of 7-hydroxy-6- methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.5g, 8.17mmol), (prepared as described for the starting material in Example 7), in DMF (40ml) containing potassium carbonate (2.8g, 20mmol). The mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water.
• Example 17 ⁇ NMR Spectrum: (DMSOd ⁇ , CD 3 COOD) 1.55-1.7(m, 2FI), 2.05(d, 2H), 2.15-2.25(m, IH),
• the starting material was prepared as follows:
• Example 24 4-ChloiO-6-methoxy-7-(3-morpholinopiOpoxy)quinazoline was reacted with 3-(2- iluoiOphei yl)-4.5-dihydro- l H-pyrazol-5-one (95mg) to give Example 24.
• the starting material was prepared as follows: Using an analogous procedure to that described for the preparation of the starting material in Example 9, ethyl 2-fluorobenzoyl acetate was reacted with hydrazine to give 3-(2- fiuoiOphenyl)-4,5-dihydiO- l H-pyrazol-5-one (975mg, 48%>).
• the starting material was prepared as follows: Using an analogous procedure to that described for the preparation of the starting material in Example 9. ethyl 3-nitrobenzoyl acetate was reacted with hydrazine to give 3-(3- nitrophenyl)-4.5-dihydiO-l H-pyrazol-5-one (765mg. 72%>).
• the starting material was prepared as follows: Using an analogous procedure to that described for the preparation of the starting material in Example 9. ethyl 4-nitiObenzoyl acetate was reacted with hydrazine to give 3-(4- nitrophenyl)-4.5-dihydiO-l b/-pyrazol-5-one (630mg. 60%>).
• the starting material was prepared as follows:
• the starting material was prepared as follows:
• Example 32 Using a procedure analogous to that described in Example 15, 4-chloiO-6-methoxy-7-
• the starting material was prepared as follows: Triphenylphosphine (2.82g, 10.7mmol) was added to a solution of 2-(l ,2,3-iriazol-l - yljcthanol (609mg. 5.4n ⁇ n ⁇ ol). (J. Antib. 1993, 46. 177), and 7-hydroxy-6-methoxy-3- ((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (l .lg, 3.6mmol), (prepared as described for the starting material in Example 7). in methylene chloride (70ml). diethyl azodicarboxylate (600 ⁇ l, l ⁇ .7mmol) was then added.
• the starting material was prepared as follows:
• Example 36 A suspension of 4-chloro-6-niethoxy-7-(3-morpholinopiOpoxy)quinazoline (150mg,
• the starting material was prepared as follows:
• Example 39 Using a procedure analogous to that described in Example 34. 4-chloro-6-mcthoxy-7- (3-methylsulphonylpropoxy)quinazoline (150mg. 0.45mol) was reacted with 3-(4- methoxyphenyl)-4.5-dihydro-lH-pyrazol-5-one (105mg, 0.54mol). (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6- methoxy-7-(3-methylsulphonylpropoxy)quinazoline (220mg, 91%). MS - ESI: 485 [M ⁇ ] +
• the starting material was prepared as follows:
• Triphenylphosphine (8.9g, 35.2mmol) was added to a suspension of 7-hydroxy-6- methoxy-3-((pivaloyioxy)methyl)-3,4-dihydroquinazolin-4-one (6g, 19.6mmol), (prepared as described for the starting material in Example 7), in methylene chloride (150ml). This was followed by the addition of 3-n ⁇ ethylsulphonylpropanol (3.5g, 25.4mmol) and diethylazodicarboxylate (5.55ml, 35.2mn ⁇ ol) in portions. The reaction was complete once the reaction became homogeneous. Silica was added and the volatiles were removed by evaporation. The free flowing powder was placed on the top of a flash chromatography column pre-equilibrated with ethyl acetate (100%). Elution was done using ethyl acetate
• 6-Methoxy-7-(3-methylsulphonylpiOpoxy)-3-((pivaloyloxy)methyl)-3,4- dihydiOquinazolin-4-one 7g, 17mmol was suspended in methanol and 2M sodium hydroxide (3.3ml. 6.6mmol) was added with continuous stirring. The reaction mixture became homogeneous after 15 minutes. After a further 45 minutes water was added (7ml) and the reaction mixture was adjusted to pHIO with 2M hydrochloric acid.
• 6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydiOquinazolin-4-one (3.6g, 1 1.5mmol) was suspended in thionyl chloride (40ml). DMF (1.8ml) was added under argon and the mixture was heated at reflux for 1.5 hours. The thionyl chloride was eliminated by several azeotropic distillations using toluene. The solid residue was suspended in ice/water and a saturated solution of sodium hydrogen carbonate was added to adjust the mixture to pH7.
• Maize starch paste (5% w/v paste) 2.25
• Maize starch 15.0 Polyvinylpyrrolidone (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 coaling of cellulose acetate phthalate.

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