Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—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
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• the present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine.
• the invention relates to quinoline and quinazoline derivatives which exhibit protein tyrosine kinase inhibition.
• Protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A.F.Wilks, Progress in Growth Factor Research, 1990 (2), 97-111).
• Tyrosine kinases can be broadly classified as growth factor receptor (e.g. EGF-R, PDGF-R, FGF-R and erbB-2) or non-receptor (e.g. src, bcr-abl) kinases. Inappropriate or uncontrolled activation of many of these kinases i.e. aberrant tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
• Aberrant activity of protein tyrosine kinases such as c-erbB-2, c-src, p56lck, EGF- R, PDGF-R, and zap70 have been implicated in human malignancies.
• Aberrant EGF-R activity has, for example, been implicated in cancers of the head and neck, and aberrant c-erbB-2 activity in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers.
• Inhibitors of protein tyrosine kinase should therefore provide a treatment for tumours such as those outlined above.
• thrombosis (Salari et al, FEBS; 1990, 263f1V 104-108) and nervous system diseases (Ohmichi et al, Biochemistry, 1992, 3 . , 4034-4039).
• Inhibitors of the specific tyrosine kinases involved in these diseases eg PDGF-r in restenosis and EGF-r in psoriasis, should lead to novel therapies for such disorders.
• P56lck and zap 70 are indicated in disease conditions in which T cells are hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection.
• EP0602851 discloses quinazoline derivatives of the formula (1) :
• each RA includes hydroxy, amino, ureido, hydroxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C) alkoxy and (1-3C) alkenedioxy; and Q is a 9 or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms and optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur, or Q is a 9 or 10-membered bicyclic aryl moiety, the heterocyclic or aryl moiety optionally bearing one or two substituents selected from halogeno, hydroxy, oxo, amino, nitro, carbamoyl, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino, di-[(1-4C) alkyljamino and (2-4C) alkanoylamino.
• the compounds are claimed to be inhibitors of the EGF tyrosine kinase receptor
• European Patent Application 0520722A discloses a class of quinazoline derivatives having antitumour activity and having the formula (2)
• RA is hydrogen, trifluoromethyl or nitro
• n is 1 and R ⁇ is halogeno, trifluoromethyl, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, N-(1- 4C)alkylamino, , -di-((1-4C)alkyl)amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulph- onyl.
• These compounds are claimed to be inhibitors of the EGF tyrosine kinase receptor and other unspecified tyrosine kinases.
• EP 0566226A discloses quinazoline derivatives of the formula (3):
• n is 1 or 2 and each R B includes; hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano and (1-4C) alkyl.
• the compounds are claimed to be inhibitors of the EGF tyrosine kinase receptor and other unspecified tyrosine kinases.
• EP0635498 discloses quinazolines of the formula (4)
• R 1 includes hydroxy, amino, hydroxyamino, (1-4C)alkoxy, (1-4C) alkylamino and di-[(1-4C)alkyl]amino
• R2 includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C)alkoxy or (2-4C) alkanoylamino
• n is 1, 2 or 3
• R ⁇ is halogeno.
• EP0635507 discloses tricyclic derivatives of the formula (5) :
• R 1 and R 2 together form specified optionally substituted groups containing at least one heteroatom so as to form a 5 or 6 membered ring
• R ⁇ includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C) alkoxy di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino.
• the present invention envisages that other disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity
• protein tyrosine kinases such as c-erbB-2, c-erbB-4, c-src, p56lck, EGF-R, fyn, cdk2, PDGF-R, and zap70 protein tyrosine kinases.
• the present invention envisages that disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity in a preferential manner.
• a further object of the present invention is to provide compounds useful in the treatment of protein tyrosine kinase related diseases which minimise undesirable side-effects in the recipient.
• the present invention relates to certain quinoline and quinazoline derivatives which may be used to treat disorders mediated by protein tyrosine kinases and in particular have anti-cancer properties. More particularly, the compounds of the present invention are potent inhibitors of protein tyrosine kinases such as c-erbB- 2, c-erbB-4, EGF-R, c-src, p56lck, fyn, cdk2, PDGF, and zap 70 thereby allowing chemical management of particular diseased tissues.
• the present invention envisages, in particular, the treatment of human malignancies, for example breast, stomach, ovary, colon, lung and pancreatic tumours, especially those driven by c-erbB-2, using the compounds of the present invention.
• the invention includes compounds which are highly active against the c-erbB-2 protein tyrosine kinase in preference to the EGF receptor kinase hence allowing treatment of c-erbB-2 driven tumours.
• the present invention envisages that disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity in a relatively selective manner, thereby minimising potential side effects.
• Certain compounds of the present invention for example 4-(1-benzyl-5- indolylamino)-6,7-dimethoxyquinazoline and 4-(1-benzyl-5-indolylamino)- quinazoline have the unexpected advantage of being highly selective for c-erbB-2 over EGF, in contrast to compounds of the prior art which show little activity towards c-erbB-2 and no selectivity towards this tyrosine kinase.
• the 4-(5-indolylamino)-6,7-dimethoxyquinazoline inhibits EGF to a much greater extent than it inhibits c-erbB-2, and the c-erbB-2 activity is relatively poor.
• Y is a group W(CH2), (CH2)W or W in which W is O, S(O) m wherein m is 0, 1 or 2, or NR a wherein R a is hydrogen or a C ⁇
• U represents a 5 to 10-membered mono or bicyclic ring system in which one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S, wherein the ring system is substituted by at least one independently selected R ⁇ group and is optionally substituted by at least one independently selected R 4 group;
• R1 , R2, R3 and R ⁇ ' are the same or different and are each selected from amino, hydrogen, halogen, hydroxy, nitro, carboxy, trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, C ⁇ .Q alkyl, C-j.8 alkoxy, C3.8 cycloalkoxyl, C4.8 alkylcyclo alkoxy, C-j_8 alkoxycarbonyl, N-C ⁇
• alkylamino di[C-
• _4 alkoxy ,N-di-[C-
• _4 alkylamino N,N-di-[C ⁇ _ alkyl]carbamoyl-C ⁇ _4 alkylamino, amino-C2-4 alkylamino, C-j_4 alkylamino-C2-4 alkylamino, di-[C-j ⁇ alkylamino-C2_4 alkylamino, phenyl-C-j ⁇ alkylamino, phenoxy-C2_4 alkylamino, anilino-C2_4 alkylamino, phenylthio-C2-4 alkylamino, C2-4 alkanoylamino, C-j_4 alkoxycarbonylamino, C-
• each R 6 is independently a group ZR 7 wherein Z is joined to R 7 through a (CH2)p group in which p is 0, 1 or 2 and Z represents a group V(CH2), V(CF2), (CH2)V, (CF2)V, V(CRR ' ), V(CHR) or V where R and R ' are each C ⁇ alkyl and in which V is a hydrocarbyl group containing 0,1 or 2 carbon atoms, carbonyl, CH(OH), sulphonamide, amide, O, S(O) m or NR D where R D is hydrogen or R D is C-
• R 6 is a group ZR 7 in which Z is NR b , and NR b and R 7 together form an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety.
• R 1 , R 2 and R 3 are each selected from amino, hydrogen, halogen, hydroxy, nitro, C-
• R1 and R 2 or R1 and R 3 together form an optionally substituted methylenedioxy or ethylenedioxy group;
• R 3 ' is hydrogen;
• R 4 is hydrogen, hydroxy, halogen, C-
• R 5 is hydrogen, C ⁇
• Z is absent or represents CH 2 , oxygen, S(O) m , wherein m is 0, 1 or 2, or NR D wherein R D is hydrogen or R D is C-
• R 7 is an optionally substituted phenyl, benzyl, pyridyl, dioxolanyl, phenoxy, benzyloxy, phenylamino, benzylamino, phenymercapto or benzylmercapto group, preferably a phenyl, fluorophenyl, pyridyl, 1 ,3-dioxolanyl or benzyl group.
• R 6 R 7 .
• R 1 , R 2 and R 3 are each selected from hydroxy, C- ⁇ _4 alkyl, C ⁇
• R ⁇ is in the ring which is remote from Y when U represents a bicyclic group.
• X is N.
• Y is NRb, NRb(CH2), or (CH2)NR b , preferably Y is NR b .
• Heterocyclic groups comprise one or more rings which may be saturated, unsaturated or aromatic and which may independently contain one or more heteroatoms in each ring.
• Carbocyclic groups comprise one or more rings which may be independently saturated, unsaturated or aromatic and which contain only carbon and hydrogen.
• X is nitrogen
• Y is a group NR wherein R is hydrogen or methyl, preferably hydrogen.
• R " * and R 2 are independently hydrogen; C ⁇ _4 alkyl, such as methyl; or
• R 3 and R 3 ' are independently hydrogen, methyl or methoxy.
• R 4 is hydrogen, halogen or methyl, preferably R 4 is hydrogen.
• R5 is hydrogen or methyl.
• R 6 is phenyl, fluorophenyl, phenethyl, benzyl, pyridyl, phenylsulphonyl, benzylsulphonyl, phenoxy, benzyloxy or 1 ,3-dioxolanyl.
• One or both of the rings comprising the mono or bicyclic ring system may be aromatic or non-aromatic.
• the R 4 and R ⁇ groups may be bound to the ring system by either a carbon atom or a heteroatom of the ring system.
• the ring system itself may be bound to the bridging group Y which is linked to the 4- position of the quinoline or quinazoline skeleton by a carbon atom or a heteroatom.
• the R 4 and R ⁇ groups may be bound to either ring when U represents a bicyclic ring system, but these groups are preferably bound to the ring which is not bound to the bridging group Y in such a case.
• Suitable mono or bicyclic groups U which are ultimately linked to the 4-position of the quinoline or quinazoline include: isoindenyl, indenyl, indanyl, naphthyl, 1,2-dihydronaphthyl or 1,2,3,4-tetrahydronaphthyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, 2H-pyranyl, thiophenyl, 1H-azepinyl, oxepinyl, thiepinyl, azocinyl, 2H-oxocinyl, thieno[2,3-b] furanyl, thianaphthenyl, indolyl, indolinyl, isioindolyl, isoindolinyl, indolizinyl, 1H-benzimidazolyl, 2,3- dihydro
• U represents an indolyl, isoindolyl, indolinyl, isoindolinyl, IJH-indazolyl, 2,3- dihydro-IJd-indazolyl, IH-benzimidazolyl, 2,3-dihydro-IH-benzimidazolyl or IM- benzotriazolyl group.
• the 5, 6, 7, 8, 9 or 10-membered heterocyclic moiety is selected from the group comprising: furan, dioxolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazoline, oxazolidine, thiazole, thiadiazole, benzofuran, indole, isoindole, quinazoline, quinoline and isoquinoline.
• the 5, 6, 7, 8, 9 or 10-membered carbocyclic moiety is selected from the group comprising: phenyl, benzyl, indene, naphthalene, tetralin, decalin, cyclopentyl, cyclohexyl and cycloheptyl.
• halo is meant fluoro, chloro, bromo or iodo.
• Alkyl groups containing three or more carbon atoms may be straight, branched or cyclised.
• the optional substitutents for the carbocyclic or heterocyclic moiety, which may be present at any available position of said moiety are selected from the group comprising:
• R 8 and R 9 are independently selected from the group comprising hydrogen, C ⁇ alkyl, C ⁇ cycloalkyl, aryl, a 5- or 6-membered saturated or unsaturated heterocyclic ring which may be the same or different and which contains one or more heteroatoms which are selected from N, O or S, with the proviso that the heterocyclic ring does not contain two adjacent O or S atoms.
• the optional substitutents for the carbocyclic or heterocyclic moiety are selected from the group comprising morpholine, piperazine, piperidine, pyrrolidine, tetrahydrofuran, dioxolane, oxothiolane and oxides thereof, dithiolane and oxides thereof, dioxane, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiofuran, pyrrole, triazine, imidazole, triazole, tetrazole, pyrazole, oxazole, oxadiazole and thiadiazole.
• optional substituents for the carbocyclic or heterocyclic moiety and also for other optionally substituted groups include, but are not limited to, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, C-
• Preferred compounds of the present invention include:
• Particularly preferred compounds of the present invention include:
• Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula (I).
• the therapeutic activity resides in the moiety derived from the compound of the invention as defined herein and the identity of the other component is of less importance although for therapeutic and prophylactic purposes it is, preferably, pharmaceutically acceptable to the patient.
• Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p_- toluenesulphonic, acids.
• mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
• organic acids such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p_- toluenesulphonic, acids.
• the present invention provides a process for the preparation of a compound of the formula (I), which process comprises the reaction of a compound of the formula (II).
• L is a leaving group and U, X, Y and R 1 to R 6 are as hereinbefore defined.
• Suitable leaving groups will be well known to those skilled in the art and include, for example, halo and sulphonyloxy groups such as chloro, bromo, methanesulphonyloxy and toluene-p-sulphonyloxy.
• the reaction is conveniently carried out in the presence of a suitable inert solvent, for example a C ⁇ _4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent, such as acetone, at a non-extreme temperature, for example from 0 to 150°, suitably 10 to 100°C, preferably 50 to 100°C.
• a suitable inert solvent for example a C ⁇ _4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent, such as acetone
• the reaction is carried out in the presence of a base, for example an organic amine such as triethylamine, or an alkaline earth metal carbonate, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide.
• a base for example an organic amine such as triethylamine, or an alkaline earth metal carbonate, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide.
• the compound of the formula (I) may be obtained from this process in the form of a salt with the acid HL, wherein L is as hereinbefore defined, or as the free base by treating the salt with a base as hereinbefore defined.
• one compound of formula (I) may be converted to another compound of formula (I) by chemical transformation of the appropriate substituent or substituents using appropriate chemical methods (see, for example, J. March “Advanced Organic Chemistry", Edition III, Wiley Interscience, 1985).
• a compound containing an alkyl or aryl mercapto group may be oxidised to the corresponding sulphinyl or sulphonyl compound by use of an organic peroxide (eg benzoyl peroxide) or suitable inorganic oxidant (eg OXONE
• a compound containing a nitro substituent may be reduced to the corresponding amino-compound, eg by use of hydrogen and an appropriate catalyst (if there are no other susceptible groups) or by use of Raney Nickel and hydrazine hydrate.
• Amino or hydroxy substituents may be acylated by use of an acid chloride or an anhydride under appropriate conditions. Equally an acetate or amide group may be cleaved to the hydroxy or amino compound respectively by treatment with, for example dilute aqueous base.
• amino substituent may also be converted to a dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride.
• the present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereinafter identified as the 'active ingredients') for use in medical therapy, and particularly in the treatment of disorders mediated by aberrant protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above.
• the compounds are especially useful for the treatment of disorders caused by aberrant c-erbB-2 activity such as breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers.
• a further aspect of the invention provides a method of treatment of the human or animal body suffering from a disorder mediated by aberrant protein tyrosine kinase activity which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the human or animal patient.
• a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
• a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of malignant tumours.
• a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of atherosclerosis, restenosis or thrombosis.
• a further aspect of the present invention provides a pharmaceutical formulation comprising one or more compounds of formula (I), or pharmaceutically acceptable salt(s) thereof, together with one or more pharmaceutically acceptable carriers.
• the compounds or salts of the present invention Whilst it is possible for the compounds or salts of the present invention to be administered as the new chemical, it is preferred to present them in the form of a pharmaceutical formulation.
• compositions comprising at least one compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
• compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
• a unit may contain for example O. ⁇ mg to 1g, preferably 5mg to 100mg of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
• compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
• Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
• compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.
• compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
• the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
• compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
• the formulations are preferably applied as a topical ointment or cream.
• the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
• the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
• compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
• compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
• compositions adapted for rectal administration may be presented as suppositories or as enemas.
• compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
• Fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
• compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti- oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
• Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
• the compounds and salts of the formula (I) have anticancer activity as demonstrated hereinafter by their inhibition of the protein tyrosine kinase c-erbB-2 enzyme. It has thus been established that compounds of the present invention are of use in medicine and, in particular in the treatment of certain human malignancies, for example breast, ovarian non-small cell lung, pancreatic, gastric and colon cancers. Accordingly, the present invention provides a method for the treatment of susceptible malignancies in an animal, e.g. a human, which comprises administering to the animal a therapeutically effective amount of a compound or salt of the present invention. In the alternative, there is also provided a compound or salt of the present invention for use in medicine and, in particular, for use in the treatment of cancers.
• the present invention also provides the use of a compound of formula (I) or a salt thereof for the manufacture of a medicament for treatment of malignant tumours.
• the animal requiring treatment with a compound or salt of the present invention is usually a mammal, such as a human being.
• a therapeutically effective amount of a compound or salt of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant phsician or veterinarian.
• an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
• the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
• An effective amount of a salt of the present invention may be determined as a proportion of the effective amount of the compound per ££.
• IR spectra were recorded on a Perkin-Elmer 257 grating spectrophotometer or a
• Petrol refers to petroleum ether, either the fraction boiling at 40-60°C, or at 60-
• Ether refers to diethyl ether.
• THF refers to tetrahydrofuran
• DMF refers to dimethylformamide
• DCM refers to dichloromethane
• DMSO dimethylsulphoxide
• 4-Chloroquinazoline was prepared from 4-hydroxyquinazoline (commercially available) according to the published method (J. Org. Chem, 27, 958 (1962)). 4-Chloro-6.7-dimethoxyquinazoline was prepared in an analogous manner according to the proceedure described in European Patent Application 566 226 A1 (Zeneca Limited).
• 5-Amino-2-(2-pyridyl)-benzimidazole was prepared according to the published method (J. Med. Chem., 22, 1113-8, (1979)).
• 5-Amino-2-benzylbenzimidazole was prepared according to the published method (J. Het. Chem., 23, 1109-13, (1986)).
• 5-Amino-1 -benzylbenzimidazole was prepared according to the published method (Khim. Geterotsikl. Soedin, 7, 1136-8, (1971)).
• 5-Amino-1-benzylindazole was prepared according to the published method (FR 5600 68.01.08).
• 5-Amino-2-phenylbenzimidazole was prepared according to the published method (J. Org. Chem., 60, 5678-82, (1995).
• 5-Amino-1-phenylsulphonylindole was prepared according to the published method (J. Org. Chem., 55, 1379-90, (1990)).
• 5-Nitro-3-benzylbenzimidazole and 6-nitro-3-benzvl-benzimidazole 5-nitrobenzimidazole (1 g, 6.13 mmol) in acetone (20 ml) containing potassium hydroxide pellets (1 g, 18.39 mmol) was stirred and treated with benzyl bromide (0.73 ml, 6.13 mmol). After 1h the mixture was acidified to ea pH 7, diluted with water, and extracted with ethyl acetate. The dried extracts were evaporated giving a cream solid (1.56g, 100%); m/z (M + 1) + 254.
• uinazoline hydrochloride 4-Chloroquinazoline (0.10 g, 0.61 mmol) and 5-amino-1 -benzylindole (0.16 g, 0.73 mmol) were reacted in 2-propanol (10 ml) for 30 minutes according to the General Procedure. The bright yellow solid thus obtained was 4-(1-benzyl-5- indoylamino)quinazoline hydrochloride (0.22 g, 92%), m.p. 265-266 °C; (Found: C, 70.64; H, 4.83, N, 14.11.
• 4-(1-Benzyl-5-indolylaminoV6.7-dimethoxyquinazoline hydrochloride 4-Chloro-6,7-dimethoxyquinazoline (0.10 g, 0.45 mmol) and 5-amino-1- be ⁇ zylindole (0.37 g, 0.63 mmol) were reacted in 2-propanol (15 ml) for 4 h according to the General Procedure. The pale yellow solid thus obtained was 4-(1-benzyl-5-indoylamino)-6,7-dimethoxyquinazoline hydrochloride (0.16 g, 78%), m.p.
• the isomers were assigned by means of the nuclear Overhauser effect.
• the desired product was obtained by filtration as a yellow solid (0.264 g, 84%); m/z (M+1 + ) 413; ⁇ H (d 6 -DMSO) 8.75 (IH,s), 8.20 (IH.s), 7.20-7.40 (8H,m), 6.65 (IH,d), 4.35 (2H,s), 3.97 (6H,s), 3.34 (2H,t), 2.97 (2H,t).
• 4-M-Benzyl-6-indolylaminoV6.7-dimethoxyquinazoline hydrochloride 4-Chloro-6,7-dimethoxyquinazoline (0.031 g, 0.19 mmol) and 6-amino-1- benzylindole (0.05 g, 0.23 mmol) were reacted in 2-propanol (6.5 ml) for 30 min according to the General procedure, the light orange solid thus obtained was 4- (1-benzyl-6-indolylamino)-6,7-dimethoxyquinazoline hydrochloride (0.045 g, 62%); M.pt.
• 4-(3-Benzyl-5-benzimidazolylaminoVquinazoline hydrochloride 4-Chloroquinazoline (0.053 g, 0.322 mmol) and 5-amino-3-benzylbenzimidazole (0.72 g, 0.322 mmol) were reacted in 2-propanol (5 ml) according to the General Procedure.
• the desired compound was obtained by filtration as a pale yellow solid (0.05 g, 40%); m/z (M + 1 + ) 352; ⁇ H (d 6 DMSO) 9.35 (IH, s), 8.9 (2H, m), 7.5- 8.2 (6H,m), 7.3-7.5 ( 5H,m), 5.65 (2H,s).
• the major isomer was assigned as 4-f 1 -benzyl -5-benzotriazolylamino)- 6.7-dimethoxyquinazoline and the minor isomer was assigned as 4-(3-benzyl-5- benzotriazolylamino -6.7-dimethoxvquinazoline.
• the isomers were assigned by means of the nuclear Overhauser effect.
• Example 20 4-(2-Phenethyl-5-indazolylaminoV6.7-dimethoxyquinazoline 4-Chloro-6,7-dimethoxyquinazoline (0.189 g, 0.842 mmol) and an isomeric mixture of 1- and 2- ⁇ henethyl-5-aminoindazole (0.200 g, 0.842 mmol) were reacted in acetonitrile (15 ml) according the General Procedure. On cooling a pale yellow precipitate was formed which was collected by filtration. This material was chromatographed on silica gel (Merck 9385, 45 g).
• the desired product was obtained by filtration as a yellow solid (0.072 g, 50%); m/z (M + 1 + ) 339; ⁇ H (d 6 -DMSO) 8.93 (IH.s), 8.88 (IH.d), 8.78 (IH.d), 8.38 (IH,d), 7.86-8.15 (5H,m), 7.75 (IH,d), 7.55-7.64 (2H,m).
• Biological Data Compounds of the present invention were tested for protein tyrosine kinase inhibitory activity in a substrate phosphorylation assay and a cell proliferation assay.
• the substrate phosphorylation assay uses a baculovirus expressed, recombinant construct of the intracellular domain of c-erbB-2 that is constitutively active.
• the method measures the ability of the isolated enzyme to catalyse the transfer of 33p.
• the enzyme is incubated for 1 hour, at room temperature, with 100 ⁇ M ATP, 10mM MnC-2, 1mg/ml PolyGluAlaTyr (6:3:1) and test compound (diluted from a 5mM stock in DMSO, final DMSO concentration is 2%) in 40mM HEPES buffer, pH 7.4.
• the cell proliferation assay uses an immortalised human breast epithelial cell line (HB4a) which has been transformed by over-expression of c-erbB-2. Growth of these cells in low serum is dependent upon the c-erbB-2 tyrosine kinase activity. The specificity of the effect of the test compounds on tyrosine kinase dependent growth over general toxicity is assessed by comparison to an HB4a cell line which has been transfected with ras. Cells are plated at 3000/well in 96-well plates in 0.1 ml medium and allowed to attach overnight, test compound is added in 0.1 ml medium, with a final concentration of 0.5% DMSO, and the plates incubated for 4 days at 37°C. The cells are then examined microscopically for evidence of morphological detransformation and cell mass is estimated by staining with methylene blue and measuring the absorbance at 620nm. The results are shown in Table 2 below as the IC50 values in ⁇ M.

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