WO1996009294A1 - Composes heteroaromatiques substitues et leur utilisation en medecine - Google Patents

Composes heteroaromatiques substitues et leur utilisation en medecine Download PDF

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Publication number
WO1996009294A1
WO1996009294A1 PCT/GB1995/002202 GB9502202W WO9609294A1 WO 1996009294 A1 WO1996009294 A1 WO 1996009294A1 GB 9502202 W GB9502202 W GB 9502202W WO 9609294 A1 WO9609294 A1 WO 9609294A1
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WIPO (PCT)
Prior art keywords
alkyl
mmol
alkoxy
hydrochloride
quinazoline
Prior art date
Application number
PCT/GB1995/002202
Other languages
English (en)
Inventor
Alan Thomas Hudson
Sadie Vile
Paul Barraclough
Karl Witold Franzmann
Stephen Carl Mc Keown
Martin John Page
Original Assignee
The Wellcome Foundation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB9418852A external-priority patent/GB9418852D0/en
Priority claimed from GBGB9507788.9A external-priority patent/GB9507788D0/en
Application filed by The Wellcome Foundation Limited filed Critical The Wellcome Foundation Limited
Priority to EP95931351A priority Critical patent/EP0782570A1/fr
Priority to AU34824/95A priority patent/AU3482495A/en
Priority to JP8509740A priority patent/JPH10505600A/ja
Publication of WO1996009294A1 publication Critical patent/WO1996009294A1/fr

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    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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 quinazoltne derivatives which exhibit protein tyrosine kinase inhibition.
  • Protein 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). Protein tyrosine kinases can be broadly classified as growth factor receptor (e.g. EGF-R, PDGF-R, FGF- R and c-erbB-2) or non-receptor (e.g. c-src bcr-abl) kinases. Inappropriate or uncontrolled activation of many of these kinases i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
  • growth factor receptor e.g. EGF-R, PDGF-R, FGF- R and c-erbB-2
  • non-receptor e.g. c-src bcr
  • Aberrant activity of protein tyrosine kinases such as c-erbB-2, c-src, p561ck, EGF-R, PDGF-R, and zap70 has been implicated in human malignancies.
  • aberrant EGF-R activity has 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.
  • European Patent Application 0520722A discloses a class of quinazoline derivatives having antitumour activity and having the formula (I)
  • R A is hydrogen, trifluoromethyl or nitro
  • n is 1
  • R B is halogeno, trifluoromethyl, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, N-(1- 4C)alkylamino, N,N-di-((1-4C)alkyl)amino, (1-4C)alkylthio, (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl.
  • These compounds are claimed to be inhibitors of the EGF tyrosine kinase receptor and other unspecified protein tyrosine kinases.
  • EP 0566 226A discloses quinazoline derivatives of the formula (2):
  • each R A includes hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C) alkoxycarbonyl, N(1-4C) alkylcarbamoyl, N,N-di[(1- 4C)alkyl]carbamoyl, hydroxyamino, (1-4C) alkylamino, (2-4C)alkanoyloxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy and (1-3C)alkenedioxy; 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 protein tyrosine kinases.
  • EP0602851 discloses quinazoline derivatives of the formula (3) :
  • each R A 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.
  • 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
  • R 2 includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C)alkoxy or (2-4C) alkanoylamino
  • n is 1, 2 or 3
  • R 3 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 3 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 preferential inhibition of the appropriate protein tyrosine kinase activity.
  • protein tyrosine kinases such as c-erbB-2, c-src, p561ck, EGF-R, PDGF-R, and zap70 protein tyrosine kinases.
  • 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, EGF-R. c-src, p561ck, PDGF, and zap 70 thereby allowing clinical management of particular diseased tissues.
  • protein tyrosine kinases such as c-erbB-2, EGF-R. c-src, p561ck, PDGF, and zap 70 thereby allowing clinical 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.
  • Y is a group W(CH 2 ), (CH 2 )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 1 -8 alkyl group;
  • R 1 , R 2 , R 3 and R 3' are the same or different and are each selected from the group comprising; amino, hydrogen, halogen, hydroxy, nitro, carboxy, trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkoxyl, C 4-8 alkylcyclo alkoxy, C 1-8 alkoxycarbonyl, N-C 1-4 alkylcarbamoyl, N,N-di-[C 1-4 alkyl]carbamoyl, hydroxyamino, C 1-4 alkoxyamino, C 2-4 alkanoyloxyamino, C 1-4 alkylamino, di[C 1-4 alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1- yl, 4-C 1 -4 alkylpiperazin-1-yl, C 1-8
  • R 5 is selected from the group comprising; hydrogen, halogen, trifluoromethyl, C 1 -4 alkyl and C 1 -4 alkoxy;
  • R 6 is a group ZR 7 wherein Z is joined to R 7 through a (CH 2 )p group in which p is 0, 1 or 2 and Z represents a group V(CH 2 ), V(CF 2 ), (CH 2 )V, (CF 2 )V, or V 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 b where R b is hydrogen or R b is C 1 -4 alkyl; and R 7 is an optionally substituted C 3-6 cycloalkyl; or an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety. or 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 heterocyclic moiety.
  • R 1 , R 2 and R 3 are each selected from amino, hydrogen, halogen, hydroxy, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkylsulphinyl, C 1-8 alkylsulphonyl, C 1 -4 alkylamino, or R 1 and R 2 or R 1 and R 3 together form an optionally substituted methylenedioxy or ethylenedioxy group;
  • R 3' is hydrogen;
  • R 4 is hydrogen, hydroxy, halogen, C 1 -4 alkyl, C 1 -4 alkoxy, di-[C 1 -4 alkyljamino, nitro or trifluoromethyl;
  • R 5 is hydrogen, C 1 -4 alkyl, C 1 -4 alkoxy or halogen
  • Z is oxygen, S or NR b wherein R b is hydrogen, or C 1 -4 alkyl, and
  • R 7 is 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; hydroxy, halogen, amino, C 1 -4 alkyl, C 1 -4 alkoxy or together form a methylenedioxy or ethylenedioxy group.
  • R 6 is in the para position with respect to Y.
  • X is N.
  • Y is NR b , NR b (CH 2 ), or (CH 2 )NR b , preferably Y is NR b .
  • Z is CH 2 , NR b , NR b (CH 2 ), (CH 2 )NR b ,O, O(CH 2 ), O(CF 2 ), (CH 2 )O, (CF 2 )O, S(CH 2 ), or carbonyl; preferably Z is CH 2 , NR b , O, O(CH 2 ) or O(CF 2 ).
  • X is nitrogen
  • Y is a group NR wherein R is hydrogen or methyl, preferably hydrogen.
  • Z is oxygen, O(CH 2 ) or CH 2 .
  • R 1 and R 2 are independently hydrogen; halogen; C 1 -4 alkyl, such as methyl; or C 1-4 alkoxy, such as methoxy.
  • R 3 and R 3' are independently hydrogen, halogen, methyl or methoxy.
  • R 4 is hydrogen, halogen or methyl, preferably R 4 is hydrogen.
  • R 5 is hydrogen or methyl.
  • R 6 is benzyl, phenoxy or benzyloxy.
  • R 6 is selected from benzyl, phenoxy or benzyloxy when X is N and Y is NH; or when X is CH and Y is oxygen, S(O)m or NR a , with R a preferably being H, wherein m and R a are as hereinbefore defined.
  • R 7 is thiophene or cyclohexane and p is 1 where Z is oxygen
  • 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, napthalene, tetralin, decalin, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the present invention provides a compound of the formula (Ia) : or a pharmaceutically acceptable salt thereof, wherein X is nitrogen or CH; Y is oxygen, S(O)m wherein m is 0, 1 or 2 or NR wherein R is hydrogen or a C 1 -4 alkyl group; R 1 and R 2 are the same or different and are each selected from hydrogen or C 1 -4 alkoxy; R 3 is a group ZR 6 wherein Z is oxygen, S or NR a wherein R a is hydrogen or C 1 -4 alkyl; R 4 is hydrogen, halo, C 1 -4 alkoxy or trifluoromethyl; and R 6 is phenyl or benzyl optionally substituted by one to three halo atoms.
  • Y is a group NR wherein R is hydrogen or methyl, preferably hydrogen.
  • Z is oxygen
  • R 1 and R 2 are both hydrogen or C 1 -4 alkoxy, such as methoxy.
  • R 3 is methoxy, phenoxy or benzyloxy, preferably benzyloxy.
  • R 4 is hydrogen, fluorine or trifluoromethyl, preferably R 4 is hydrogen.
  • R 3 is a subs tituent at the meta or para position of the phenyl ring.
  • R 3 is selected from phenoxy or benzyloxy when X is N and Y is NH.
  • Examples of compounds of the present invention include;
  • hydrochloride 4-(4-Benzoylanilino)-6,7-dimethoxyquinazoline hydrochloride; 4-(4-Benzoylaminoanilino)quinazoline hydrochloride; 4-(4-Benzoylaminoanilino)- 6,7-dimethoxyquinazoline hydrochloride; 4-(4-Anilinocarbonylanilino)quinazoline hydrochloride; 4-(4-Anilinocarbonylanilino)-6,7-dimethoxyquinazoline
  • hydrochloride 4-(4-Cyclohexyl)anilino-6,7-dimethoxyquinazoline hydrochloride; 4-[4- (Cyclohexylmethoxy)- anilino]quinazoline hydrochloride; 4-[4-(Cyclohexylmethoxy)- anilino]-6,7-dimethoxyquinazoline hydrochloride; 4-(4-methylmercapto- anilino)quinazoline hydrochloride; 4-(4-Methoxphenylthio)quinazoline; 6,7- Dimethoxy-4-(3-methylmercaptoanilino)quinazoline hydrochloride;
  • Preferred compounds of the present invention include:
  • Particularly preferred compounds of the present invention are:
  • halo is meant fluoro, chloro, bromo or iodo.
  • Alkyl groups containing three or more carbon atoms may be straight, branched or cyclised.
  • 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.
  • Optional substituents include, but are not limited to, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl carbonyl, carboxylate, C 1-4 alkoxy carbonyl, carboxamide, C 1-4 alkylamino carbonyl and di[C 1-4 alkyl]amino.
  • 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), or a pharmaceutically acceptable salt thereof, which process comprises the reaction of a compound of the formula (II).
  • L is a leaving group and 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 such as chloro and bromo; sulphonyloxy groups such as methanesulphonyloxy and toluene-p-sulphonyloxy; and alkoxy groups.
  • reaction is conveniently carried out in the presence of a suitable inert solvent, for example a C 1-4 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
  • a suitable inert solvent for example a C 1-4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone
  • suitable bases include an organic amine such as triethylamine, or an alkaline earth metal carbonate, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide.
  • 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 ®)
  • an organic peroxide eg benzoyl peroxide
  • 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.
  • the present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereinafter identified as the 'active compounds') 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, in the preparation of a medicament for the treatment of malignant tumours.
  • 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 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) together with one or more pharmaceutically acceptable carriers or excipients.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain for example 0.5mg to Ig, 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.
  • 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.
  • Pharmaceutical formulations 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 parenterai 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.
  • 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 physician 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 se.
  • Petrol refers to petroleum ether, either the fraction boiling at 40-60°C, or at 60-80°C.
  • Ether refers to diethylether.
  • THF refers to tetrahydrofuran
  • DMF refers to dimethylformamide
  • DCM refers to dichloromethane
  • DMSO dimethylsulphoxide
  • Hydrogen peroxide refers to the commercially available aqueous solution with a concentration of 30-35% by weight.
  • Procedure A First method for reaction of an amine and a 4-chloroquinazoline or quinoline:
  • the 4-chloroquinazoline or 4-chloroquinoline (optionally substituted) was suspended in 2-propanol and heated to ca 80°C.
  • the amine was added and the mixture was heated at reflux until judged complete (for example, by no 4-chloro starting material remaining by tlc), and then allowed to cool.
  • the resulting suspension may be diluted, e.g. with acetone, and the solid was collected by filtration, washed, and dried at 60°C in vacuo.
  • the 4-chloroquinazoline or 4-chloroquinoline (optionally substituted) and an amine were mixed in 2-propanol and heated to reflux. When the reaction was complete, the mixture was allowed to cool. The resulting suspension was diluted, e.g. with acetone, and the solid collected by filtration, washed, and dried at 60°C in vacuo.
  • 4-Ch]oro-6,7-dimethoxyquinoline was prepared by by the reaction of 6,7- dimethoxy-4-hydroxyquinoline (5.7g, 27.78 mmol) with phosphorous oxychloride (7.6 ml, 81.54 mmol) in toluene (45 ml) at reflux for 2 hours. The mixture was concentrated in vacuo at 50°C to give a solid, which was washed with sat. aq.
  • 4-Chloro-2-methylquinoline also known as 4-chloroquinaldine is commercially available.
  • 4-Chloroquinazoline was prepared from 4-hydroxyquinazoline (commercially available) according to the published method (J. Org. Chem, 27, 958 (1962)).
  • 4,5-Dimethyl-2-nitroaniline (commercially available) (25.0g, 150.4 mmol) was added to cone HCl (35 ml) and heated to reflux. The solution was cooled to 0°C and an aqueous solution of sodium nitrite (10.42g, 151 mmol in 37 ml) was added dropwise. After addition was complete, the slurry was stirred for 45 minutes at 0°C and then added over 30 min to a mixture of potassium cyanide (41.66g, 640 mmol) and copper sulphate (37.94g, 152 mmol) dissolved in water (190 ml) at reflux.
  • potassium cyanide 41.66g, 640 mmol
  • copper sulphate 37.94g, 152 mmol
  • 4,5-Dimethyl-2-nitrobenzonitrile (7.225g, 40.5 mmol) was dissolved in DMSO (35 ml) and cooled to 0°C. Potassium carbonate (0.85g, 6.15 mmol) was added, followed by hydrogen peroxide solution (5.1 ml), giving an exothermic reaction and forming a dark brown solid. The mixture was stirred at room temp, for 30 min, diluted with water to a total volume of 250 ml and filtered.
  • 4,5-Dimethyl-2-nitrobenzamide (7.0g, 36.0 mmol) was added to an aqueous solution of iron (II) sulphate heptahydrate (100g in 150 ml), and the suspension heated to reflux. Saturated aq. ammonia solution (50 ml) was added slowly, causing the mixture to turn black, and it was heated at reflux for 15 min and allowed to cool. The mixture was filtered, and the solid was treated with boiling ethanol to give an orange solution, which was concentrated to an orange solid. This was dissolved in ethyl acetate, filtered and concentrated to a solid. Trituration with ethyl acetate/petrol (1:1) gave a first batch of pale orange crystals.
  • 6-Acetoxy-4-chloroquinazoline was prepared according to the procedure described in European Patent Application 566226 A1 (Zeneca Limited).
  • Acetic anhydride (9ml, 88mmol) was added drop wise over 10 minutes to a stirred mixture of 4,7-dihydroxy quinazoline (prepared as described in Chim. Then, 2, (4), 231-
  • 1,3-Dinitrobenzene (commercially available) (25.0g, 148.7 mmol) was dissolved in methanol (375ml) and heated to 40°C. An aqueous solution of potassium cyanide (11.5g, 176.6 mmol in 20 ml) was added giving a dark solution, which was stirred at 40°C for 2 hours and then left to stand at room temperature for 2 days. The dark red mixture was filtered to yield a black solid. The filtrate was diluted with water (3000ml), left to stand overnight and filtered to yield further solid. The solids were combined and extracted with chloroform in a soxhlet apparatus for 1.5 hours. The extract was concentrated to a red solid.
  • 6-Methoxy-2-nitrobenzonitrile (3.6g, 20.2 mmol) was dissolved in DMSO (25 ml) and cooled to 0°C. Potassium carbonate (0.425g, 3.08 mmol) was added, followed by hydrogen peroxide solution (2.6 ml). The reaction was stirred at room temperature for 1 hour and further hydrogen peroxide (3 x 2.6 ml) added over the following hour to give an orange solution. The mixture was poured into water (200 ml), giving a white solid.
  • 6-Methoxy-2-nitrobenzamide (2.2g, 11.2 mmol) was added to an aqueous solution of iron (II) sulphate heptahydrate (31.5g in 50 ml), and the suspension heated to reflux. Saturated aq. ammonia solution (16 ml) was added slowly, causing the mixture to turn black, and it was heated at reflux for 10 min and allowed to cool. The mixture was filtered, and the solid was treated with boiling ethanol to give a solution, which was concentrated to a white solid.
  • 4-Chloro-6-fluoroquinazoline was prepared from 4-fluoroanthranilic acid as follows: 5-Fluoroanthranilic acid (Aldrich) (1.0g, 6.4mmol) and formamidine acetate (2g, 19mmol) were reacted in glacial acetic acid (10ml) at reflux for 1.5 hours. The reaction was concentrated under vacuum and water added, forming a precipitate. This was collected by filtration and dried at 60°c under vacuum to give 6-fluoro-4- hydroxyquinazoline as an off-white solid (0.770g, 73%). ⁇ H [ 2 H 6 ] -DMSO 12.20 (1H, br, OH), 8.09 (1H, s, 2-H), 7.83-7.62 (3H, m, 5-H, 7-H, 8-H).
  • 6-Fluoro-4-hydroxyquinazoline 0.580g, 3.5mmol
  • phosphorus oxychloride 2.6ml, 28mmol
  • triethylamine 1.4ml, 10mmol
  • the solid was re-extracted into boiling 60-80 petrol, filtered while hot and the filtrate concentrated under vacuum to give 4-chloro-6-fluoroquinazoline as a white solid (0.365g, 57%).
  • 6-Chloro-4-hydroxyquinazoline prepared according to J. Org. Chem., 141-148, 1951 (0.640g, 3.5mmol,), phosphorus oxychloride (2.6ml, 28mmol) and triethylamine (1.1ml, 7.9mmol) were reacted at reflux under nitrogen for 3.5 hours.
  • the excess reagents were removed at 70°C under vacuum and the reaction extracted with ethyl acetate (250ml).
  • Petrol 250ml was added to the extract and the solution decanted from the brown oil which separated.
  • 6-Bromo-4-hydroxyquinazoline (Maybridge Chemicals) (2.25 g; 10mmol) was added to a mixture of triethylamine (3 ml) and phosphoryl chloride (7 ml) at room temperature. After heating at reflux for 3 hours, the tan mixture was cooled to 50°C and evaporated to dryness under reduced pressure. The tan residue was dissolved in ethyl acetate (200 ml) and the solution washed with water (3 x 100 ml) and 5% aqueous potassium hydrogen carbonate solution (2 x 100 ml). After drying (Na 2 SO 4 ), the ethyl acetate solution was treated with charcoal (1 g), filtered and evaporated to dryness.
  • 2-Nitro-4-(trifluoromethyl)benzamide (0.900g, 3.8mmol) was added to a boiling solution of ferrous sulphate heptahydrate (7g) in water (100ml) and the solution heated to reflux for 30 minutes. .880 ammonia (15ml) was then added and the heating continued for 20 minutes. The cooled reaction was filtered and the residue extracted with hot ethanol.
  • Silver oxide suspension was prepared by treating a solution of silver nitrate (6.64 g; 40 mmol) in water (100 ml) with 10 M sodium hydroxide (6 ml; 60 mmol). To a well stirred suspension of silver oxide was added a hot (70°C) solution of 2-nitropiperonal (Aldrich) (4.0 g; 20 mmol) in ethanol (100 ml) over 30 minutes. When the addition was complete, the mixture was stirred vigorously for 3 hours at 40°C, and then at 90°C for 10 minutes. Metallic silver was removed by filtration and the tan filtrate was evaporated to two-thirds volume, cooled to 10°C and acidified (pH1) with 50% sulphuric acid.
  • 4-Benzyloxyaniline is available from Aldrich as the hydrochloride salt; this is treated with aqueous sodium hydrogen carbonate solution, and the mixture extracted with ethyl acetate; the organic solution is dried (MgSO 4 ) and concentrated to give the free base as a brown solid, used without further purification.
  • Bis(4-hydroxyphenyl)disulphide (containing tin impurity) (0.684g, ca. 0.57g of disulphide, 2.28 mmol) and potassium carbonate (0.691g, 5.00 mmol) were suspended in acetone under a nitrogen atmosphere, and stirred for 15 min at room temperature.
  • Benzyl bromide (0.6 ml, 0.86g, 5.04 mmol) was then added and the mixture was heated to reflux for 5 hours, by which point tlc showed no remaining starting material. After standing overnight at room temperature, the mixture was filtered to remove inorganics, washing with excess acetone. The combined filtrate and washings were concentrated to a cream solid.
  • Bis(4-benzyloxyphenyl)disulphide (0.129g, 0.30 mmol) was dissolved in freshly distilled THF (3 ml) with stirring under a nitrogen atmosphere.
  • Lithium tri-tert- butoxyaluminohydride (1.0 molar in THF, 0.6 ml, 0.6 mmol) was added via syringe and the mixture was stirred at room temperature for 24 hours. The sulphide could not be isolated due to atmospheric re-oxidation.
  • Tlc showed remaining disulphide and chloroquinazoline starting materials, so further lithium tri-tert-butoxyaluminohydride (1.0 molar in THF, 0.5 ml, 0.5 mmol) was added and the mixture stirred at room temperature for 1.5 hours. It was then heated to reflux for a further three hours, by which time tlc showed no remaining starting materials.
  • the mixture was partitioned between ethyl acetate and brine, and the aqueous extracted with further ethyl acetate (x 2). The combined organic extracts were dried (MgSO 4 ), and concentrated in vacuo to a white solid.
  • Lithium aluminium hydride (0.080g, 2.10 mmol) was added portionwise to dry ether (25 ml) with stirring under a nitrogen atmosphere.
  • the grey suspension was cooled using an ice-water bath and 4-phenoxybenzonitrile (Apin) (0.20g, 1.02 mmol) was added. Stirring was continued overnight, with the mixture being allowed to warm to room temperature. TLC indicated that the reduction had not occurred, so the mixture was heated to reflux for 2 hours, and then allowed to cool.
  • the mixture was diluted with ether, and allowed to settle. A yellow solution was decanted and carefully treated with water to give a yellow solid, which was collected by filtration.
  • 0.2H 2 O requires: C, 64.62; H, 5.28; N, 9.72%); ⁇ H [ 2 H 6 ]- DMSO 10.59 (1H, br t, J 5.5, NH), 8.78 (1H, s, 2-H), 8.16 (1H, s, 8-H), 7.45 (2H, d, J 9, 2'-H, 6'-H), 7.38 (2H, t, J 9, 3"-H, 5"-H), 7.32 (1H, s, 5-H), 7.12 (1H, t, J 8, 4"- H), 6.98 (4H, d, J 9, 3'-H, 5'-H, 2"-H, 6"-H), 4.91 (2H, d, J 7, QuinNHCH 2 ), 3.99 (6H, s, 2 x CH 3 O); m/z (%) 387 (100); v max (KBr disc)/cm -1 1634, 1591, 1578, 1508, 1489, 1244.
  • 6-Acetoxy-4-chloroquinazoline (0.600g, 2.7mmol) and 4-benzyloxyaniline (0.450g, 2.3mmol) were reacted in 2-propanol (25ml) according to Procedure B for 20 minutes, to give the product as a yellow solid (0.800g, 84%), with mp 206-209°C; (Found: C, 62.99; H, 5.06; N, 9.25.
  • 6-Acetoxy-4-(4-benzyloxyanilino)quinazoline hydrochloride (0.300g) was partitioned between ethyl acetate/triethylamine and water. The organic layer was separated, dried (MgSO 4 ) and concentrated under vacuum to give 6-acetoxy-4-(4- benzyloxyanilino)quinazoline as the free base (0.220g, 80%), which was used without further characterisation.
  • 6-Bromo-4-chloroquinazoline (0.150g, 0.62mmol) and 4-phenoxyaniline (0.150g, 0.81 mmol) were reacted in 2-propanol (6ml) for 2 minutes according to Procedure B.
  • the product was obtained as a yellow solid (0.130g, 49%); (Found: C, 54.85; H. 3.45; N, 9.58. C 20 H 14 N 3 O.HCl.0.5H 2 O requires C, 54.88; H.
  • 6-Amino-4-(4-benzyloxyanilino)quinazoline (0.170g, 0.50mmol) was dissolved in ethyl acetate (40ml) and added dropwise to a solution of triphosgene (0.150g, 0.51 mmol) in ethyl acetate (20ml). On completion of the addition, the reaction was stirred for 10 minutes then .880 ammonia (25ml) was added.
  • 6-Amino-4-(4-benzyloxyanilino)quinazoline (0.200g, 0.58mmol) was reacted with acetic anhydride (0.06ml, 0.58mmol) in dimethylacetamide (2ml) for 80 hours.
  • the solution was diluted with water and the precipitate collected by filtration, washed with water, and dried at 60°C to give the product as a beige solid (0.150g, 67%); with mp 225-228°C; (Found: C, 68.01; H, 5.55; N, 13.74. C 23 H 20 N 4 O 2 .
  • 1.2H 2 O requires C, 68.03; H, 5.56; N,13.80%); ⁇ H [ 2 H 6 ] -DMSO 10.14 (1H, b, NH), 9.58 (1H, b, NH), 8.59 (1H, s, 5-H), 8.41 (1H, s, 2-H), 7.80 (1H, d, 7-H), 7.70 (1H, d, 8-H), 7.64 (2H, d, 2'-H, 6' -H), 7.50-7.29 (5H, m, 5xPh-H), 7.03 (2H, d, 3'-H, 5'-H), 5.12 (2H, s. CH 2 ), 2.10 (3H, s, CH 3 ).
  • This material was converted to the free base by partitioning between ethyl acetate/triethylamine and water. The organic phase was washed with water, dried
  • 6-Nitro-4-(4-phenoxyanilino)quinazoline (0.250g, 0.70mmol) and 10% palladium on carbon (0.025g) were suspended in ethanol (15ml).
  • Ammonium formate (0.250g, 0.70mmol)
  • 0.25H 2 O requires C, 71.03; H, 5.31; N, 14.41%); ⁇ H [ 2 H 6 ] -DMSO 10.26 (1H, b, NH), 9.51 (1H, b, NH), 8.43 (1H, s, 2-H), 8.39 (1H, d, 5-H), 8.50 (1H, s, 8-H), 7.69 (3H, m, 6-H, 2'-H, 6' -H), 7.50-7.30 (5H, m, 5xPh-H), 7.03 (2H, d, 3'-H, 5'-H), 5.12 (2H, s, CH 2 ), 2.12 (3H, s, CH 3 ).
  • reaction mixture was partitioned between ethyl acetate and brine, and the aqueous was further extracted with ethyl acetate until no further yellow colour remained in the aqueous.
  • the combined organic extracts were dried (MgSO 4 ) and concentrated to a yellow solid.
  • the mixture was dissolved in hot THF , allowed to cool and treated with ethyl acetate. A yellow solid crystallised, which TLC indicated to be the sulphoxide.
  • the remaining solution was concentrated and purified by column chromatography on silica, eluting with methanol/ethyl acetate (gradient elution, 0% - 25%).
  • 6,7-Diacetoxyquinazol-4-(1H)-one hydrobromide (0.50 g, 1.5 mmol) was mixed with thionyl chloride (10 ml) and heated to reflux for 2 h. The thionyl chloride was removed in vacuo to leave a yellow gum. To a portion of this gum (0.065 g, 0.22 mmol if pure) was added 4-benzyloxyaniline (0.088 g, 0.44 mmol) followed by acetone (2 ml). A yellow precipitate formed almost immediately and the mixture was stirred for 10 min. The mixture was diluted with acetone and the precipitate collected by filtration to leave most of the unwanted impurities in the filtrate (as indicated by tlc).
  • 4-Benzamidoaniline was prepared from 4-nitroaniline (commercially available) according to the published method (D. L. Boger and H. Zarrinmayeh, J. Org. Chem.,
  • 6-Bromo-4-chloroquinazoline (0.122 g; 0.50 mmol) and 4-benzylaniline (0.092 g; 0.50 mmol) were reacted in 2-propanol (2.5 ml) for 30 minutes according to Procedure B.
  • the product was thus obtained as bright yellow prisms (0.194 g, 91%) with mp 264- 266°C; (Found C, 59.12; H, 4.04; N, 9.71.
  • 4-(4-Benzoylaminoanilino)-6,7-dimethoxyquinazoline hydrochloride 4-Chloro-6,7-dimethoxyquinazoline (0.102 g, 0.454 mmol) and 4-benzamidoaniline (Salor via Aldrich) (0.116 g, 0.546 mmol) were reacted in 2-propanol (15 ml) for 1 h according to Procedure B. The pale yellow solid thus obtained was 4-(4- benzoylaminoanilino)-6,7-dimethoxyquinazoline hydrochloride (0.1 10 g, 55%), mp 266-267°C; (Found: C, 62.82; H, 4.71; N, 12.48.
  • Bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.17 mmol) was added to a stirred solution of phenylacetylene (Aldrich) (1.3 g, 12.7 mmol) and 4-iodoaniline (Aldrich) (2.14 g, 9.8 mmol) in triethylamine (50 ml) at room temperature under nitrogen, followed immediately by copper iodide (0.04g, 0.21 mmol).
  • the reaction vessel was covered with aluminium foil to prevent exposure to light, and the mixture was stirred for 1 h.
  • HCl requires: C, 73.84; -H, 4.51; N, 1 1.74%); ⁇ H [ 2 H 6 ]-DMSO 11.60 (1H, br s, NH), 8.92 (1H, d. J 9, 8-H), 8.87 (1H, s, 2-H), 8.02 (1H, t, J 8, 7-H), 7.94 (1H, d, J 8, 5-H), 7.84 (2H, d, J 9, 3'-H, 5'-H), 7.77 (1H, t, J 8, 6-H), 7.60 (2H, d, J 9, 2'-H, 6'-H). 7.50 (2H, t.
  • Oxone® (2KHSO 5 .KHSO 4 .K 2 SO 4 ) (0.075 g, 0.12 mmol) was added to a stirred suspension of 6,7-dimethoxy-4-(4-phenylthioanilino)quinazoline hydrochloride (0.050 g, 0.12 mmol) in methanol (3 ml) and water (3 ml) at 0 °C and the mixture stirred for 2 h. The reaction mixture was then allowed to warm to room temperature and stirred for 10 h. The solvents were removed in vacuo and the residue treated with dichloromethane (2 ml) and methanol (1 ml) to give a white suspension.
  • the bright yellow solid thus obtained was 4-[4-(benzylthio)anilino]quinazoline hydrochloride (0.18 g, 80%), mp 215-216 °C; (Found: C, 66.64; H, 4.80; N, 10.93. C 21 H 17 N 3 S.HCl requires: C, 66.39; H, 4.78; N, 11.06%); ⁇ H [ 2 H 6 ]-DMSO 11.60 (1H, br s, NH), 8.90 (1H, d, J 9, 8-H), 8.88 (1H, s, 2-H), 8.09 (1H, t, J 8, 6-H), 7.98 (1H, d, J 8.
  • Oxone® (2KHSO 5 .KHSO 4 .K 2 SO 4 ) (0.11 g, 0.17 mmol) was added to a stirred suspension of 6,7-dimethoxy-4-[4-(phenylthiomethyl)anilino]quinazoline hydrochloride (0.050 g, 0.11 mmol) in methanol (5 ml) and water (5 ml) at 30 °C and the mixture stirred for 1 h. The reaction mixture was then gradually warmed to 60 °C over 5 h and stirred at that temperature for 2 h. Stirring was continued at room temperature for 10 h.
  • 6-Bromo-4-chloroquinazoline (0.139 g; 0.571 mmol) and 4-benzyloxy-3-chloroaniline (0.146 g; 0.628 mmol) were reacted in 2-propanol (8 ml) for 4.5 hours according to Procedure B.
  • the product was thus obtained as a bright yellow solid (0.255 g, 94%) with mp 256-258°C; (Found C, 52.78; H, 3.44; N, 8.66.
  • 6-Bromo-4-chloroquinazoline (0.122 g; 0.5 mmol) and 3,5-dibromo-4-benzyloxyaniline (0.214 g; 0.60 mmol) were reacted in 2-propanol (5 ml) for 6 hours according to procedure C.
  • the product was thus obtained as a cream solid (0.143 g, 51%) with mp 237 -239°C; (Found C, 44.20; H, 2.66; N, 7.13.
  • 6-Bromo-4-chloroquinazoline (0.244 g; 1.0 mmol) and 4-benzyloxy-3-methylaniline (0.270 g; 1.25 mmol) were reacted in 2-propanol (6 ml) for 90 minutes according to Procedure B.
  • the product was thus obtained as a bright yellow crystalline solid (0.403 g, 88%) with mp 250-251°C; (Found C, 57.08; H, 4.15; N, 8.99. C 22 H 18 BrN 3 O.
  • HCl.0.33 H 2 O requires C, 57.11; H, 4.28; N, 9.08); tlc (ethyl acetate) Rf 0.51; ⁇ H [ 2 H 6 ]-DMSO 11.50 (1H, br s, NH), 9.20 (1H, s, 5-H), 8.88 (1H, s, 2-H), 8.20 (1H, d, J 9, 7-H), 7.90 (1H, d, J 9, 8-H), 7.25-7.57 (7H, m, 2'-H, 6'-H, 5 x PhH), 7.11 (1H, d, J 9, 5'-H), 5.21 (2H, s, CH 2 ), 2.23 (3H, s, 3'-CH 3 ); m/z (%) 419, 421 (38, M + ), 328, 330 (100).
  • HCl.0.33H 2 O requires C, 61.67; H, 4.84; N, 9.38); tlc (ethyl acetate) Rf 0.15; ⁇ H [ 2 H 6 ]-DMSO 11.29 (1H, br s, PhH), 8.80 (1H, s, 2-H), 8.32 (1H, s, 8-H), 7.71 (1H, d, J 9, 6'-H), 7.30-7.52 (8H, m, 5-H, 2'-H. 5'-H, 5 x PhH), 5.29 (2H, s, CH 2 ), 4.05 and 4.00 (2 x 3H, 2 x s, 2 x OCH 3 ); m/z (%) 405 (100, M + ).
  • 6-Bromo-4-chloroquinazoline (0.223 g; 0.916 mmol) and 4-benzyloxy-3-fluoroaniline (0.220 g; 1.012 mmol) were reacted in 2-propanol (8 ml) for 2.5 hours according to Procedure B.
  • the product was thus obtained as a bright yellow solid (0.360 g, 85%) with mp 236-238°C; (Found C, 54.44; H, 3.42; N, 8.98.
  • 6-Bromo-4-chloroquinazoline (0.146 g; 0.60 mmol) and 4-benzyloxy-3-trifluoromethyl aniline (0.190 g; 0.78 mmol) were reacted in 2-propanol (4 ml) for 30 minutes according to Procedure B.
  • the product was thus obtained as pale lemon yellow prisms (0.295 g, 96%) with mp 243-245°C; (Found C, 52.48; H. 4.09; N, 7.37.
  • 6-Bromo-4-chloroquinazoline (0.146 g; 0.60 mmol) and 4-(2,4-dichlorophenoxy)aniline (0.190 g; 0.75 mmol) were reacted in 2-propanol (3 ml) for 2 hours according to Procedure B.
  • the product was thus obtained as a yellow solid (0.254 g; 85%) with mp 269-272°C; (Found C, 48.97; H, 2.58; N, 8.49.
  • C 1 1 H 9 NO 3 S requires: C, 56.16; H, 3.86; N, 5.95%); ⁇ H [ 2 H 6 ]-DMSO 8.25 (2H, d, J 10, 3'-H, 5'-H), 7.52- 7.65 (2H, m, 2-H, 5-H), 7.18-7.27 (3H, m, 4-H, 2'-H, 6'-H), 5.29 (2H, s, CH 2 ); m/z (%) 235 (3 , M + ), 97 (100).
  • 3-(4-Nitrophenoxymethyl)thiophene (0.50g, 2.13 mmol) was dissolved in ethanol (100 ml), treated with PtO 2 (50mg) and hydrogenated at atmospheric pressure for 16 hours. Further PtO 2 (25mg) was added and the hydrogenation continued for a further 20 hours, by which tlc showed no remaining starting material. The catalyst was removed by filtration through Hyflo, washing with excess ethanol, and the solution concentrated in vacuo.
  • HCl.0.2EtOAc requires: C, 67.75: H, 4.77; N, 11.97%); ⁇ H [ 2 H 6 ]- DMSO 9.99 (1H, br s, NH), 8.69-8.77 (2H, m, 8-H, 2-H), 7.97-8.09 (2H, m, 5-H, 7- H), 7.94 (2H, d, J 9, 2'-H, 6'-H), 7.75-7.89 (3H, m, 6-H, 2"-H, 5"-H), 7.43 (1H, d, J 6, 4"-H), 7.29 (2H, d, J 9, 3'-H, 5'-H), 5.35 (2H, s, CH 2 ); m/z (%) 333 (46, M+1 + ), 236 (100), 97 (62).

Abstract

On décrit des composés hétéroaromatiques substitués qui sont des inhibiteurs des tyrosines kinases, notamment des quinolines et quinazolines substituées. On décrit également des procédés de préparation de ces composés, des compositions pharmaceutiques comprenant de tels composés ainsi que l'utilisation de ceux-ci en médecine, par exemple dans le traitement du psoriasis, des fibroses, de l'athérosclérose, de la resténose, des maladies auto-immunes, des allergies, de l'asthme, du rejet de greffon, des inflammations, de la thrombose, des maladies du système nerveux et du cancer.
PCT/GB1995/002202 1994-09-19 1995-09-18 Composes heteroaromatiques substitues et leur utilisation en medecine WO1996009294A1 (fr)

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AU34824/95A AU3482495A (en) 1994-09-19 1995-09-18 Substituted heteroaromatic compounds and their use in medicine
JP8509740A JPH10505600A (ja) 1994-09-19 1995-09-18 置換複素環式化合物および薬剤におけるそれらの使用

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Cited By (229)

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WO1997022596A1 (fr) * 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
FR2750862A1 (fr) * 1996-07-12 1998-01-16 Dupin Jean Pierre Utilisation d'heterocycles diazotes fusionnes avec un systeme aromatique ou heteroaromatique pour le traitement des maladies thrombo-emboliques
WO1998002434A1 (fr) * 1996-07-13 1998-01-22 Glaxo Group Limited Composes heterocycliques condenses en tant qu'inhibiteurs de la proteine tyrosine kinase
WO1998010767A2 (fr) * 1996-09-13 1998-03-19 Sugen, Inc. Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs
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