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  • 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
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

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, Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303- 324).
• VEGF vascular endothelial growth factor
• VEGF vascular endothelial growth factor
• 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
• bFGF Basic FGF
• angiogenesis e.g. Hayek et al, 1987, Biochem. Biophys. Res. Commun. 147: 876-880
• raised levels of FGFs have been found in the serum (Fujimoto et al, 1991, Biochem. Biophys. Res. Commun. 180: 386-392) and urine (Nguyen et al, 1993, J. Natl. Cancer, hist.
• RTKs Receptor tyrosine kinases
• 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.
• RTK 5 subfamilies defined by amino acid sequence homology.
• One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Fit- 1 , the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Flt-4.
• KDR also referred to as Flk-1
• Flt-4 Flt-4
• Two of these related RTKs, Flt-1 and KDR have been shown to bind VEGF with high affinity (De Nries et al, 1992, Science 255: 989-991; Terman et al,
• the present invention is based on the discovery of compounds that inhibit the effects of NEGF, a property of value in the treatment of disease states associated with angiogenesis
• vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, 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 including macular degeneration.
• NEGF is a key stimulus for vasculogenesis and angiogenesis.
• This cytokine induces a vascular sprouting phenotype by inducing endothelial cell proliferation, protease expression and migration, and subsequent organisation of cells to form a capillary tube (Keck, P.J., Hauser, S.D., Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, D.T., Science (Washington DC), 246: 1309-1312, 1989; Lamoreaux, W.J., Fitzgerald, M.E., Reiner, A.,
• the compounds of WO 98/13354 and WO 01/32651 are generally more potent against KDR than against Flt-1 and generally they are more potent against VEGF RTK than against EGF RTK.
• a potential problem with some VEGF RTK inhibitors is that they have been found to act as potassium channel blockers and are positive in a hERG assay; such activity may give rise to ECG (electrocardiogram) changes in vivo.
• ECG electrocardiogram
• Q 2 (wherein Q 2 is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S andN, which heterocyclic group bears at least one substituent selected from C 2 -5alkenyl, C 2 - 5 alkynyl, -gfluoroalkyl, aminoC 2 - ⁇ alkanoyl, C 1 . alkylaminoC 2 -6alkanoyl, di(C 1 - 4 alkyl)aminoC . 6 alkanoyl, C 1 . 4 alkoxyC 1 . alkylaminoC 2 .
• alkanoyl di(C 1 - alkyl)aminoC 2 - 6 alkanoyl, C 1 . 4 alkoxyC 1 - 4 alkylaminoC 2 . 6 alkanoyl, d- 6 fluoroalkanoyl, carbamoyl, d ⁇ alkylcarbamoyl, di(d- 4 alkyl)carbamoyl, carbamoylC ⁇ - 6 alkyl, d ⁇ alkylcarbamoyld- ⁇ alkyl, di(C 1 . 4 alkyl)carbamoylC ⁇ - 6 alkyl, C !
• Q 13 cannot be hydrogen and one or both of Q 13 and Q 14 must be a 5-6-membered saturated or partially unsaturated heterocyclic group as defined hereinbefore which heterocyclic group bears at least one substituent selected from d-salkenyl, C 2 _5alkynyl, d- ⁇ fluoroalkyl, d- 6 alkanoyl, aminoC 2 . 6 alkanoyl, C ⁇ - 4 alkylaminoC 2 _ 6 alkanoyl, di(d- 4 alkyl)aminoC 2 .
• alkylQ 13 -C(O)-C 1 . 4 alkylQ 14n wherein Q 13 is as defined hereinbefore and is not hydrogen and Q 14n is a 5-6-membered saturated or partially unsaturated heterocyclic group containing at least one nitrogen atom and optionally containing a further heteroatom selected from N and O wherein Q 14n is linked to d- 6 alkyl via a nitrogen atom or a carbon atom and wherein Q I4n optionally bears 1, 2 or 3 substituents selected from C 2 - 5 alkenyl, C 2 - 5 alkynyl, d- 6 fluoroalkyl, d- 6 alkanoyl, aminoC 2 - 6 alkanoyl, C 1 - 4 alkylaminoC .
• alkanoyl di(C ⁇ _ 4 alkyl)aminoC 2 - 6 alkanoyl, C 1 - 4 alkoxyC 1 - alkylaminoC 2 . 6 alkanoyl, d- 6 fluoroa_kanoyl, carbamoyl, C M alkylcarbamoyl, di(C 1 . 4 alkyl)carbamoyl, carbamoyld- 6 alkyl, d- 4 alkylcarbamoyld- 6 alkyl, d.
• alkylsulphonyl d- ⁇ fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, d_ 4 cyanoalkyl, C ⁇ . alkyl, Ci- 4 hydroxyalkyl, C 1 - 4 alkoxy, d- 4 alkoxyd- 4 alkyl, d. 4 alkylsulphonylC ⁇ - 4 alkyl, d_
• R 2 is selected from group (ii) of the groups (i), (ii) and (iii) defined hereinbefore. According to one aspect of the present invention R 2 is selected from group (iii) of the groups (i), (ii) and (iii) defined hereinbefore. According to one aspect of the present invention R 2 is selected from: Q l X l - wherein X 1 is as defined hereinbefore and Q 1 is selected from one of the following ten groups: 1) Q 2 (wherein Q 2 is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears at least one substituent selected from C 2 .
• alkylamino di(C 1 - 4 alkyl)amino, di(C 1 - 4 alkyl)aminoC 1 - 4 alkyl, C ⁇ - 4 alkylaminod- alkoxy, and a group -(-O-)f(C .
• alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or more substituents selected from d- 4 alkyl), with the provisos that Q 13 cannot be hydrogen and one or both of Q 13 and Q 14 must be a 5-6-membered saturated or partially unsaturated heterocyclic group as defined hereinbefore which heterocyclic group bears at least one substituent selected from C 2 -5alkenyl, C 2 . 5 alkynyl, d ⁇ fluoroalkyl, Ci- 6 alkanoyl, aminoC 2 .
• alkanoyl C 1 . 4 alkylaminoC 2 . 6 alkanoyl, di(C 1 _ 4 alkyl)aminoC 2 - 6 alkanoyl, C 1 . 4 alkoxyC 1 . 4 alkylaminoC 2 - 6 alkanoyl, d- ⁇ fluoroalkanoyl, carbamoyl, C ⁇ . alkylcarbamoyl, di(C 1 - 4 alkyl)carbamoyl, carbamoyld.
• alkylaminoC 2 - 6 alkanoyl di(C 1 . 4 alkyl)aminoC - 6 alkanoyl, C 1 - alkoxyC ⁇ - 4 alkylaminoC 2 - 6 alkanoyl, C ⁇ - 6 fluoroalkanoyl, carbamoyl, d-
• R 2 is selected from: Q l X ⁇ - wherein X 1 is as defined hereinbefore and Q 1 is selected from one of the following ten groups: 1) Q 2 (wherein Q 2 is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears at least one substituent selected from C 2 -5alkenyl, C 2 -5alkynyl, aminoC 2 - 6 alkanoyl, d- alkylaminoC 2 - 6 alkanoyl, di(C ⁇ - 4 alkyl)aminoC 2 -6alkanoyl, 6 alkanoyl, d_ 6 fluoroalkanoyl, carbamoyld- 6 alkyl, d_ 4 alkylcarbamoyld- 6 alkyl, di(d_ 4 alkyl)carbamoylC 1 - 6 alkyl
• 6 alkanoyl d. 4 alkoxyd- 4 alkylaminoC 2 - 6 alkanoyl, d- 6 fluoroalkanoyl, carbamoyl, di(d_ alkyl)carbamoyl, carbamoylCi- ⁇ alkyl, d- 4 alkylcarbamoyld- 6 alkyl, di(d- 4 alkyl)carbamoylC 1 . 6 alkyl, d- 6 alkylsulphonyl and C ⁇ - 6 fluoroalkylsulphonyl and which heterocyclic group optionally bears 1 or 2 further substituents selected from those defined hereinbefore); and
• alkanoyl di(C 1 - 4 alkyl)aminoC 2 - 6 alkanoyl, C ⁇ - alkoxyC 1 - alkylaminoC 2 - 6 alkanoyl, Ci- ⁇ fluoroalkanoyl, carbamoyl, d- 4 alkylcarbamoyl, di(d- 4 alkyl)carbamoyl, carbamoylC ⁇ - 6 alkyl, d ⁇ alkylcarbamoyld- ⁇ alkyl, d ⁇ d ⁇ alky ⁇ carbamoyld-ealkyl, d- 6 alkylsulphonyl, d- ⁇ fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, d.
• alkylaminoC 1 - 4 alkoxy and a group -(-O-) f (C 1 - 4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or more substituents selected from d ⁇ alkyl) or Q 14 ⁇ bears a single substituent selected from methylenedioxy and ethylenedioxy).
• R 2 is selected from: Q l X l - wherein X 1 is as defined hereinbefore and Q 1 is selected from one of the following nine groups: 1) Q (wherem Q is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears at least one substituent selected from C 2 . 5 alkenyl, C 2 - 5 alkynyl, aminoC 2 - 6 alkanoyl, Ci- 4 alkylaminoC 2 - 6 alkanoyl, di(C 1 . 4 alkyl)aminoC 2 - 6 alkanoyl, C 1 . 4 alkoxyC 1 .
• alkyl)aminoC ⁇ - a_kyl d ⁇ alkylaminod- alkoxy, di(C 1 . 4 alkyl)aminoC 1 - alkoxy and a group -(-O-) f (C 1 - 4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or more substituents selected from d- 4 alkyl), with the provisos that Q cannot be hydrogen and one or both of Q 13 and Q 14 must be a 5-6-membered saturated or partially unsaturated heterocyclic group as defined hereinbefore which heterocyclic group bears at least one substituent selected from d-salkenyl, C 2 _5alkynyl, d- 6 alkanoyl, aminoC 2 .
• R is selected from:
• X 1 is as defined hereinbefore and Q 1 is selected from one of the following eight groups:
• Q 2 (wherein Q 2 is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears at least one substituent selected from C 2 . 5 alkenyl, C 2 - 5 alkynyl, aminoC 2 . 6 alkanoyl, C ⁇ 4 alkylaminoC 2 - 6 alkanoyl, di(C 1 - 4 alkyl)aminoC 2 - 6 alkanoyl, C ⁇ - 4 alkoxyC 1 .
• Q 2 (wherein Q 2 is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears at least one substituent selected from aminoC - 6 alkanoyl, C 1 - 4 alkylaminoC - 6 alkanoyl, di(d- 4 alkyl)aminoC 2 _ 6 alkanoyl, C 1 - 4 alkoxyC 1 - alkylaminoC 2 - 6 alkanoyl, carbamoyld.
• 6 alkanoyl di(d- 4 alkyl)aminoC 2 .
• 6 alkanoyl C ⁇ - 4 alkoxyC _ 4 alkylaminoC 2 - 6 alkanoyl, C ⁇ - ⁇ fluoroalkanoyl, carbamoyl, CMalkylcarbamoyl, di(C ⁇ - alkyl)carbamoyl, carbamoyld- 6 alkyl, d- 4 alkylcarbamoyld. 6 alkyl, di(C 1 .
• Q 13 is as defined hereinbefore and Q 14n is a 5-6- membered saturated or partially unsaturated heterocyclic group containing at least one nitrogen atom and optionally containing a further heteroatom selected from N and O wherein Q 14n is linked to d- ⁇ alkyl via a nitrogen atom or a carbon atom and wherein Q 14n optionally bears 1, 2 or 3 substituents selected from d-salkenyl, C 2 - 5 alkynyl, d- 6 fluoroalkyl, Ci- ealkanoyl, aminod- ⁇ alkanoyl, C 1 _ 4 alkylaminoC 2 .
• alkanoyl di(C 1 - 4 alkyl)aminoC 2 - 6 alkanoyl, C 1 - alkoxyC 1 - 4 alkylaminoC 2 - 6 alkanoyl, d- ⁇ fluoroalkanoyl, carbamoyl, d_ 4 alkylcarbamoyl, di(C 1 - 4 alkyl)carbamoyl, carbamoyld- 6 alkyl, di(d- 4 alkyl)carbamoyld- 6 alkyl, C ⁇ .
• alkylsulphonyl d- 6 fiuoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano, d. 4 cyanoalkyl, C ⁇ - 4 alkyl, d_ 4 hydroxyalkyl, d- 4 alkoxy, d ⁇ alkoxyd- 4 alkyl, C 1 - 4 alkylsulphonylC 1 - 4 alkyl, d ⁇ alkoxycarbonyl, d- 4 aminoalkyl, d- 4 alkylamino, di(d.
• Za is -NH-, -O- or -S-;
• R la represents bromo or chloro
• R 3a represents C ⁇ - 3 alkoxy or hydrogen
• X la represents -O-,-S- or -NR 4a - wherein R 4a is hydrogen, d- 3 alkyl or d- 3 alkoxyC 2 - 3 alkyl; R 2 is selected from one of the following groups:
• R 5a is a 5- or 6-membered heterocyclic ring selected from morpholine, pyrrolidine, piperidine and piperazine which heterocyclic ring bears at least one substituent selected from aminoC 2 _ 4 alkanoyl, C 1 _ 4 alkylaminoC 2 - 4 alkanoyl, di(d-
• C 1 - 5 alkylR 5a (wherein R 5a is a 5- or 6-membered heterocyclic ring selected from morpholine, pyrrolidine, piperidine and piperazine which heterocyclic ring bears at least one substituent selected from aminoC 2 . 4 alkanoyl, C 1 . 4 alkylaminoC 2 . 4 alkanoyl, di(d- 4 alkyl)aminoC 2 . 4 alkanoyl, C i - alkoxyC i _ 4 alkylaminoC 2 - 4 alkanoyl, methylenedioxy and ethylenedioxy);
• R 2a is selected from one of the following groups:
• d-salkylR 53 (wherein R 5a is a 5- or 6-membered heterocyclic ring selected from morpholine, pyrrolidine, piperidine and piperazine which heterocyclic ring bears at least one substituent selected from aminoC 2 . 4 alkanoyl, C 1 . 4 alkylaminoC 2 - 4 alkanoyl, di(d- 4 alkyl)aminoC 2 . 4 alkanoyl, C ⁇ . 4 alkoxyC 1 - 4 alkylaminoC 2 - 4 alkanoyl, methylenedioxy and ethylenedioxy);
• R a is selected from one of the following groups:
• R 5a is a 5- or 6-membered heterocyclic ring selected from morpholine, pyrrolidine, piperidine and piperazine which heterocyclic ring bears at least one substituent selected from aminoC 2 . 4 alkanoyl, C 1 - 4 alkylaminoC 2 - 4 alkanoyl, di(d- 4 alkyl)aminoC 2 . 4 alkanoyl, C ⁇ . 4 alkoxyC 1 . 4 alkylaminoC 2 - alkanoyl, methylenedioxy and ethylenedioxy);
• R 2a is d- 5 alkylR 5a (wherein R 5a is a 5- or 6-membered heterocyclic ring selected from morpholine, pyrrolidine, piperidine and piperazine which heterocyclic ring bears at least one substituent selected from aminoC 2 . 4 alkanoyl, C 1 - 4 alkylaminoC 2 - alkanoyl, di(C 1 .
• R 2a is C 1 - 5 alkylR 6a C(O)(CH ) ma R 7a (wherein ma is 1 or 2, R 6a is a 5- or 6-membered heterocyclic ring selected from morpholine, pyrrolidine, piperidine and piperazine which heterocyclic ring may bear one or two substituents selected from fluoro, hydroxy and methyl, and R 7a is a 5- or 6-membered heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine which heterocyclic ring is linked to (CH 2 ) ma via a nitrogen atom or a carbon atom and which heterocyclic ring may bear one or more substituents selected from hydroxy, halogeno, d-
• Za is -NH-.
• R 3a is methoxy.
• X la is -O-;
• 6 fluoroalkyl d. 6 alkanoyl, aminoC 2 - 6 alkanoyl, C ⁇ - 4 alkylaminoC 2 . 6 alkanoyl, di(d_ 4 alkyl)aminoC 2 - 6 alkanoyl, C 1 - 4 alkoxyC ⁇ - 4 alkylaminoC 2 - 6 alkanoyl, d- 6 fluoroalkanoyl, carbamoyl, d- 4 alkylcarbamoyl, di(C 1 .
• alkyl 3 alkyl, cyclopentyl, cyclohexyl and a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which d- 3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C ⁇ _ alkoxy and which cyclic group may bear 1, 2 or 3 substituents selected from C 2 - 5 alkenyl, C 2 - 5 alkynyl, d- 6 fluoroalkyl, d- 6 alkanoyl, aminoC 2 _ 6 alkanoyl, C 1 . alkylaminoC 2 .
• alkanoyl di(C 1 - 4 alkyl)aminoC 2 - 6 alkanoyl, C 1 - 4 alkoxyC ⁇ . 4 alkylaminoC 2 - 6 alkanoyl, d- 6 fluoroalkanoyl, carbamoyl, d_ alkylcarbamoyl, di(C 1 . 4 alkyl)carbamoyl, carbamoyld- 6 alkyl, C M alkylcarbamoyld-ealkyl, di(d- alkyl)carbamoylC ⁇ - 6 alkyl, C ⁇ .
• R 2b is selected from:
• Q is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group bears at least one substituent selected from C 2 - 5 alkenyl, C 2 . 5 alkynyl, aminod-ealkanoyl, d_ 4 alkylaminoC2- 6 alkanoyl, di(C ⁇ - 4 alkyl)aminoC2-ealkanoyl, C ⁇ - alkoxyC 1 .
• 4 alkyl)gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated or partially unsaturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from d- 4 alkyl), or Q bears a single substituent selected from methylenedioxy and ethylenedioxy); 1 h 1 with the proviso that if Q is Q and X is -O- then Q must bear at least one substituent selected from d-salkenyl, C 2 _ 5 alkynyl, C 1 - 4 alkoxyC ⁇ - 4 alkylaminoC 2 - 6 alkanoyl, carbamoyld- ealkyl, d- alkylcarbamoylCi-6alkyl, and di(d. 4 alkyl)carbamoylC 1 . 6 alkyl and optionally may bear
• alkylaminoC 2 - 6 alkanoyl di(C 1 - 4 alkyl)aminoC 2 . 6 alkanoyl, d. 4 alkoxyC_- 4 alkylaminoC2- 6 alkanoyl, d-efluoroalkanoyl, carbamoyl, d ⁇ alkylcarbamoyl, di(Ci. 4 alkyl)carbamoyl, carbamoyld- 6 alkyl, C ⁇ - 4 alkylcarbamoylCj- 6 alkyl, di(d. 4 alkyl)carbamoyld- 6 alkyl, d-ealkylsulphonyl, d.
• ealkanoyl C 1 - 4 alkoxyC ⁇ .alkylaminoC 2 -6alkanoyl, d-efluoroalkanoyl, carbamoyl, Ci- 4 alkylcarbamoyl, di(C ⁇ - 4 alkyl)carbamoyl, carbamoyld- 6 alkyl, d ⁇ alkylcarbamoyld-ealkyl, di(d- 4 alkyl)carbamoylCi- 6 alkyl, d-ealkylsulphonyl, C ⁇ _ 6 fluoroalkylsul ⁇ honyl, oxo, hydroxy, halogeno, cyano, d- 4 cyanoalkyl, d- alkyl, C ⁇ - 4 hydroxyalkyl, d.
• R is selected from: Q lb X ! - wherein X 1 is as defined hereinbefore and Q l is selected from one of the following eight groups:
• Q bears a single substituent selected from methylenedioxy and ethylenedioxy); with the proviso that if Q lb is Q 2b and X 1 is -O- then Q 2b must bear at least one substituent selected from C 2 . 5 alkenyl, C 2 - 5 alkynyl, C ⁇ alkoxyC ⁇ - 4 alkylaminoC 2 - 6 alkanoyl, carbamoyld- 6 alkyl, Ci- alkylcarbamoylCi. 6 alkyl, and di(C ⁇ - 4 alkyl)carbamoyld- 6 alkyl and optionally may bear a further 1 or 2 substituents as defined hereinbefore;
• R is selected from: Q lb X J - wherein X selected from one of the following ten groups:
• Q bears a single substituent selected from methylenedioxy and ethylenedioxy); with the proviso that if Q is Q and X is -O- then Q must bear at least one substituent selected from Ci- alkoxyC 1 - 4 alkylaminoC 2 - 6 alkanoyl, carbamoylC ⁇ - 6 alkyl, d- alkylcarbamoylC_- 6 alkyl, and di(d- 4 alkyl)carbamoylCi- 6 alkyl and optionally may bear a further 1 or 2 substituents as defined hereinbefore;
• Ci-salkylQ (wherein Q is as defined hereinbefore); 4) C 2 - 5 alkenylQ 2 (wherein Q 2 is as defined hereinbefore);
• Q 13b cannot be hydrogen and one or both of Q 13b and Q 14 must be a 5-6-membered saturated or partially imsaturated heterocyclic group as defined hereinbefore which heterocyclic group bears at least one substituent selected from aminoC 2 - 6 alkanoyl, C ⁇ - 4 alkylaminoC 2 - 6 alkanoyl, di(Ci- 4 alkyl)aminoC 2 - 6 alkanoyl, d- 4 alkoxyCi- 4 alkylaminoC2- 6 alkanoyl, carbamoylCi.
• Q 13b and Q 14 must be a 5-6-membered saturated or partially unsaturated heterocyclic group as defined hereinbefore which heterocyclic group bears at least one substituent selected from C 1 - 4 alkoxyC 1 - alkylaminoC 2 -ealkanoyl, d_ alkylcarbamoylC ⁇ -ealkyl and di(Ci_ 4 alkyl)carbamoylCi- 6 alkyl and which heterocyclic group optionally bears 1 or 2 further substituents selected from those defined hereinbefore); and
• Ci- 4 alkylQ 13b -C(O)-d- 4 alkylQ 14b (wherein Q 13b and Q 14 are as defined hereinbefore and with the provisos that Q 13b cannot be hydrogen and one or both of Q 13 and Q 14b must be a 5- 6-membered saturated or partially unsaturated heterocyclic group as defined hereinbefore which heterocyclic group bears at least one substituent selected from d- alkoxyCi- 4 aIkylaminoC 2 - 6 alkanoyl, Ci- 4 alkylcarbamoylCi.ealkyl and d ⁇ d ⁇ alky ⁇ carbamoyld-ealkyl and which heterocyclic group optionally bears 1 or 2 further substituents selected from those defined hereinbefore).
• 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 otherwise includes “alkyl”-O- groups in which "alkyl” is as hereinbefore defined.
• aryl as used herein unless stated otherwise includes reference to a C 6 - 10 aryl group which may, if desired, carry one or more substituents selected from halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (wherein alkyl and alkoxy are as hereinbefore defined).
• aryloxy as used herein unless otherwise stated includes “aryl"-O-groups in which "aryl” is as hereinbefore defined.
• sulphonyloxy refers to alkylsulphonyloxy and arylsulphonyloxy groups in which "alkyl” and “aryl” are as hereinbefore defined.
• Butanoyl refers to CH 3 -CH 2 -CH 2 -C(O)
• isobutyryl refers to (CH 3 ) 2 .CH-C(O).
• 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.
• haloalkyl refers to an alkyl group as defined hereinbefore which bears one or more halogeno groups, such as for example trifluoromethyl.
• a compound 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.
• the invention encompasses any tautomeric form which inhibits NEGF receptor tyrosine kinase activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
• 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, scalemic and racemic mixtures) as well as any tautomeric form which inhibits NEGF 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 NEGF receptor tyrosine kinase activity.
• X 1 represents - NR 4 - and R 4 is d- 3 alkoxyC 2 - 3 alkyl it is the C 2 - alkyl moiety which is linked to the nitrogen atom of X 1 and an analogous convention applies to other groups.
• Q 1 is, for example, a group of formula Ci. 4 alkylW 2 Ci- 4 alkylQ 2 , it is the terminal Ci.
• prodrugs include in vivo hydrolysable esters of a compound of the formula I.
• Various forms of prodrugs are known in the art. For examples of such prodrug derivatives see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Nol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H.
• An in vivo hydrolysable ester of a compound of formula I containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
• 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.
• pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
• 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, morpholine, N-methylmorpholine 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, 2-propanol or ethyl acetate, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, an ether such as tefrahydrofuran 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-methyl ⁇ yrrolidin-2-one or dimethylsulphoxide.
• an inert solvent or diluent for
• the reaction is conveniently effected at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 80°C.
• 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 1 wherein L 1 has the meaning defined hereinbefore.
• the salt may be treated with a base as defined hereinbefore using a conventional procedure.
• L 1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo or methanesulphonyloxy group.
• L 1 is a group O- + P(Y) 3 (wherein Y is butyl or phenyl) and in such cases the compound of formula N is conveniently formed in situ.
• P is a protecting group such as a carbamate (alkoxycarbonyl) (such as, for example, tert-butoxycarbonyl, tert- amyloxycarbonyl, cyclobutoxycarbonyl, propoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl). More preferably P 2 is tert- butoxycarbonyl.
• the reaction is preferably effected in the presence of an acid.
• an acid is, for example, an inorganic acid such as hydrogen chloride, hydrogen bromide or an organic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid.
• the reaction may be effected in the presence of an inert solvent such as methylene chloride, trichloromethane and in the presence of a trace of water.
• an inert solvent such as methylene chloride, trichloromethane and in the presence of a trace of water.
• the reaction is conveniently effected at a temperature in the range, for example, 10-100°C, preferably in the range 20-80°C.
• R 2 and R 3 are as hereinbefore defined, and A 1 is an hydroxy, alkoxy (preferably d- 4 alkoxy) or amino group) whereby to form a compound of formula X or salt thereof.
• the cyclisation may be effected by reacting a compound of the formula XII, where A 1 is an hydroxy or alkoxy group, with formamide or an equivalent thereof effective to cause cyclisation whereby a compound of formula X or salt thereof is obtained, such as [3- (dimethylamino)-2-azaprop-2-enylidene]dimethylammonium chloride.
• 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 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.
• One compound of fo ⁇ nula II may if desired be converted into another compound of formula II in which the moiety L 1 is different.
• a compound of formula II in which L 1 is other than halogeno for example optionally substituted phenoxy
• a compound of formula II in which L 1 is halogeno by hydrolysis of a compound of formula II (in which L 1 is other than halogeno) to yield a compound of formula X as hereinbefore defined, followed by mtroduction of halide to the compound of formula X, thus obtained as hereinbefore defined, to yield a compound of formula II in which L 1 represents halogeno.
• Compounds of the formula IV as hereinbefore defined and salts thereof may be made by deprotecting the compound of formula XVIII:
• VEGF and EGF receptor cytoplasmic domains which were obtained by expression of recombinant protein in insect cells, were found to display intrinsic tyrosine kinase activity, hi the case of the VEGF receptor Fit (Genbank accession number X51602), a lJkb 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.
• 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.
• a random copolymer containing tyrosine for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899)
• ABTS 2,2'- azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)
• 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. 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.
• FCS foetal calf serum
• a glass coverslip containing the cells was placed at the bottom of a Perspex chamber containing bath solution (see below) at ambient temperature ( ⁇ 20 °C). This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately after placing the coverslip in the chamber, bath solution was perfused into the chamber from a gravity- fed reservoir for 2 minutes at a rate of ⁇ 2 ml/min. After this time, perfusion was stopped. A patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus) using a P-97 micropipette puller (Sutter Instrument Co.) was filled with pipette solution (see hereinafter).
• the pipette was connected to the headstage of the patch clamp amplifier (Axopatch 200B, Axon firstnces) via a silver/silver chloride wire.
• the headstage ground was connected to the earth electrode.
• the cell was recorded in the whole cell configuration of the patch clamp technique. Following “break-in”, which was done at a holding potential of -80 mV (set by the amplifier), and appropriate adjustment of series resistance and capacitance controls, electrophysiology software (Clampex, Axon Instruments) was used to set a holding potential (-80 mV) and to deliver a voltage protocol.
• This protocol was applied every 15 seconds and consisted of a 1 s step to +40 mV followed by a 1 s step to -50 mV.
• the current response to each imposed voltage protocol was low pass filtered by the amplifier at 1 kHz.
• the filtered signal was then acquired, on line, by digitising this analogue signal from the amplifier with an analogue to digital converter.
• the digitised signal was then captured on a computer running Clampex software (Axon Instruments). During the holding potential and the step to + 40 mV the current was sampled at 1 kHz.
• the sampling rate was then set to 5 kHz for the remainder of the voltage protocol.
• the compositions, pH and osmolarity of the bath and pipette solution are tabulated below.
• Example 1 of the present application has IC 50 values of: 0.0114 ⁇ M with respect to VEGF and 0.1 with respect to EGF.
• Example 1 of the present application has an IC50 of 1.5 ⁇ M in the hERG assay (d).
• 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 tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder), for parenteral injection (for example as a sterile solution, suspension or emulsion for intravenous, subcutaneous, intramuscular, intravascular or infusion dosing), for topical administration (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), or for rectal administration (for example as a suppository).
• oral administration for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixi
• a compound of the formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of 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 0.1-50mg/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.
• immunotherapy approaches including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
• cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
• Particular antihypertensive agents are calcium channel blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists (A-II antagonists) and beta-adrenergic receptor blockers ( ⁇ -blockers), especially calcium channel blockers.
• ACE inhibitors angiotensin converting enzyme inhibitors
• A-II antagonists angiotensin II receptor antagonists
• ⁇ -blockers beta-adrenergic receptor blockers
• Such compounds 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. More particularly such compounds of the invention are expected to inhibit any form of cancer associated with VEGF including leukaemia, mulitple myeloma and lymphoma and also, for example, 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.
• reaction temperature was maintained at 5-10°C during the addition.
• the resultant reaction mixture was allowed to warm to ambient temperature overnight.
• the reaction mixture was washed successively with water, 0.1N aqueous hydrochloric acid solution, water, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated.

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