HRP960316A2 - Heterocyclic compounds - Google Patents

Description

This invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical preparations containing them and their use in medicine. In particular, this invention relates to quinolines and quinazolines that exhibit protein tyrosine kinase inhibition.

Protein tyrosine kinases catalyze the phosphorylation of specific residues in various proteins involved in 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 (eg, EGF-R, PDGF-R, FGF-R, and erbB-2) or non-receptor (eg, src, bcr-abl) kinases. Inappropriate or uncontrolled activity of many of these kinases e.g. aberrant tyrosine kinase activity, for example by over-expression or mutation, results in uncontrolled cell growth.

Aberrant activity of protein tyrosine kinases such as c-erbB-2, c-src, p561ck, EGF-R, PDGF-R, and zap70 is involved in human malignancies. Aberrant EGF-R activity, for example, has been implicated in head and neck cancers, and aberrant c-erbB-2 activity in breast, ovarian, non-small cell lung, pancreatic, stomach, and colon cancers. Protein tyrosine kinase inhibitors should therefore provide treatment for tumors such as those listed above.

Aberrant protein tyrosine kinase activity is also involved in various other disorders: psoriasis, (Dvir et al, J. Cell Biol.; 1991, 113, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al, Proc . Natl. Acad. Sci. USA; 1991, 92, 2258-2262), autoimmune diseases, allergies, asthma, transplant rejection reactions (Klausner and Samelson, Cell; 1991, 64, 875-878), inflammatory reactions (Berkois, Blood ; 1992, 79(9), 2446-2454), thrombosis (Salari et al., FEBS; 1990, 263(1), 104-108) and diseases of the central nervous system (Ohmichi et al, Biochemistry, 1992, 31, 4034 -4039). Inhibitors of specific tyrosine kinases involved in these diseases, e.g. F'DGF-r in restenosis and EGF-r in psoriasis should lead to new therapies for such disorders. P56lck and zap 70 are shown in disease states in which T cells are hyperactive, e.g. rheumatoid arthritis, autoimmune diseases, allergies, asthma and graft rejection.

Published European Patent numbers 0520722, 0566226, 0602851, 0635498 and 0635507 disclose quinazoline derivatives and their preparation for use in the treatment of cancer. The above citations indicate that receptor tyrosine kinases in general, which are important in the transmission of biochemical signals that initiate cell replication, are often present in common human cancers such as breast cancer (Sainsbury et al, Brit. J. Cancer 1988, 58, 458). . These citations also claim that tyrosine kinase activity is rarely detected in normal cells and suggest that receptor tyrosine kinase inhibitors should have value as inhibitors of mammalian carcinoma cell growth (Yaish et al. Science, 1988, 242, 933). Above, quotes. therefore, they have a common goal to provide quinazoline derivatives that inhibit tyrosine kinases and believe that quinazoline derivatives should possess anti-cancer activity directed against a wide range of cancers.

Such broad-spectrum tyrosine kinase inhibitors may not provide optimal tumor treatment, and may in some cases even harm the individual because tyrosine kinases play a fundamental role in the normal regulation of cell growth.

EP0602851 discloses quinazoline derivatives having the formula (1):

[image]

wherein m is 1, 2 or 3 and each R 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 contains a further heteroatom selected from nitrogen, oxygen or sulfur, or Q is a 9- or 10-membered bicyclic aryl moiety, the heterocyclic or aryl moiety optionally carrying one or two substituents selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino, di-[(1-4C)alkyl ]amino and (2-4 C)alkanoylamino. These compounds are claimed to inhibit EGF receptor tyrosine kinases and other unspecified tyrosine kinases.

European Patent Application 0520722A discloses a class of quinazoline derivatives having antitumor activity and having the formula (2)

[image]

characterized in that, for example, RA is hydrogen, trifluoromethyl or nitro, n is 1 and RB is halogen, trifluoromethyl, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, N-(1- 4C)alkylamino, N,N-di-((1-4C)alkylthio), (1-4C)alkylsulfinyl or (1-4C)alkylsulfonyl. These compounds are claimed to inhibit EGF receptor tyrosine kinases and other unspecified kinases and other unspecified.

EP 0566 226A discloses quinazoline derivatives having the formula (3):

[image]

wherein m is 1, 2 or 3 each RA 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 RB includes: hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano and (1-4C)alkyl. The compounds are claimed to be inhibitors of the EGF receptor tyrosine kinase and other unspecified tyrosine kinases.

EP0635498 discloses quinazolines that have formula (4),

[image]

characterized in that R 1 includes hydroxy, amino, hydroxyamino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; R 2 includes independently hydrogen, hydroxy, halogen, (1-4C)alkyl, (1-4C)alkyloxy or (2-4C)alkanoylamino; n is 1, 2 or 3; and R 3 is halogen.

EP0635507 discloses tricyclic derivatives having the formula (5):

[image]

characterized in that R1 and R2 together form the indicated optionally substituted groups containing at least one heteroatom to form a 5- or 6-membered ring, and R3 includes independently hydrogen, hydroxy, halogen, (1-4C)alkyl, (1-4C)alkoxy , di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino.

Selective inhibition of the EGF receptor, however, was discovered by Fry et al (Science, 265, 1093 (1994)). This quotation reveals that the compound whose formula is:

[image]

highly selective inhibitor of EGF receptor tyrosine kinase in picomolar concentrations, while it inhibits other tyrosine kinases only in micromolar or higher concentrations. However, no compounds have been discovered that selectively inhibit tyrosine kinases other than EGF.

Therefore, it is a general object of the present invention to provide compounds that are suitable for the treatment of disorders mediated by the action of protein tyrosine kinase, and in particular for the treatment of the aforementioned disorders. In addition to the treatment of tumors, the present invention demonstrates that other disorders mediated by protein tyrosine kinase activity can be effectively treated by inhibiting the activity of the corresponding protein tyrosine kinase.

Another object of this invention is to provide compounds that preferably inhibit protein tyrosine kinases, such as c-erbB-2, c-erbB-4, c-src, p561ck, EGF-R, fyn, cdk2, PDGF-R, and zap 70 protein tyrosine kinase. In other words, this invention demonstrates that disorders mediated by protein tyrosine kinase activity can be effectively treated by inhibiting the activity of the corresponding protein tyrosine kinase in a desirable manner.

Another object of this invention is to provide compounds that are useful in the treatment of diseases associated with the action of protein tyrosine kinase that minimize undesirable side effects in the recipient.

This invention relates to certain quinoline and quinazoline derivatives which can be used in the treatment of disorders mediated by protein tyrosine kinase and which in particular have anti-carcinogenic properties, moreover, the compounds of this invention are potent inhibitors of protein tyrosine kinases such as c-erbB -2, c-erbB-4, EGF.R, c-src, p561ck, fyn, ckd2, PDGF, and zap 70 thus enabling chemical management of certain diseased tissues.

This invention particularly contemplates the treatment of human malignancies, for example breast, gastric, ovarian, colon, lung and pancreatic tumors, particularly those generated by c-erbB-2, using the compounds of this invention. For example, the present invention includes compounds that are highly active against c-erbB-2 protein tyrosine kinase rather than against EGF receptor kinase and thus enable the treatment of c-erbB-2 generated tumors.

Moreover, this invention demonstrates that disorders mediated by protein tyrosine kinase activity can be effectively treated by inhibiting the activity of the respective protein tyrosine kinases in a relatively selective manner, thereby minimizing possible side effects.

Some compounds of this 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 via EGF, in contrast to compounds in earlier works that show little activity towards c-erbB-2 and are not selective towards this tyrosine kinase. In the above case, 4-(5-indolylamino)-6,7-dimethoxyquinazoline inhibits EGF to a much greater extent than it inhibits c-erbB-2, and the activity of c-erbB-2 is relatively weak. It has been found that by appropriate substitution of the mono- or bicyclic ring system, compounds of the present invention can be synthesized which exhibit the exact opposite tyrosine kinase selectivity to that expected from earlier works, with the activity of the compounds of the present invention providing further advantages. For this reason, it is expected that such compounds will find application in the treatment of numerous disorders, and in particular tumors formed by c-erbB-2 as mentioned above.

Accordingly, the present invention provides a compound of formula (I);

[image]

or its pharmaceutically acceptable salts, characterized in that;

X is N or CH;

Y is the group W(CH 2 ), (CH 2 )W or W where W is O, S(O)m where m is 0, 1 or 2, or NRa where Ra is hydrogen or a C 1-8 alkyl group;

U represents a 5- to 10-membered mono- or bicyclic ring system in which one or more carbon atoms is optionally substituted by a heteroatom independently selected from N, O, and S, characterized in that the ring system is substituted by at least one independently selected R6 group and is optionally substituted by at least one independently selected R 4 group;

R 1 , R 2 , R 3 and R 4 are the same or different and are each selected from amino, hydrogen, halogen, hydroxy, nitro, carboxy, trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 4- 8AlkylcycloAlkoxy, C1-8Alkoxycarbonyl, N-C1-4Alkylcarbamoyl, N,N-Di-[C1-4Alkyl]Carbamoyl, Hydroxyamino, C1-4Alkoxyamino, C2-4Alkanoyloxyamino, C1-4Alkylamino, Di[C1-4Alkyl]amino, Pyrrolidine-1 -yl, piperidin, morpholine, piperazin-1-yl, 4-C1-4alkylpiperazin-1-yl, C1-4alkylthio, arylthio, C1-4alkylsulfinyl, C1-4alkylsulfonyl, arylsulfonyl, halo-C1-4alkyl, hydroxy-C1-4alkyl . ,N-di-[C1-4alkyl]carbamoyl-C1-4alkyl, amino-C1-4alkyl, C1-4alkylamino-C1-4alkyl, di-[C1-4alkyl]amino-C1-4alkyl, piperidine-C1-4alkyl, morpholine -C1-4alkyl, Piperazin-1-yl-C1-4alkyl, 4-C1-4alkylpiperazin-1-yl-C1-4alkyl, Hydroxy-C2-4Alkoxy-C1-4alkyl, C1 -4Alkoxy-C2-4Alkoxy-C1-4Alkyl, Hydroxy-C2-4Alkylamino-C1-4Alkyl, C1-4Alkoxy-C2-4Alkylamino-C1-4Alkyl, C1-4Alkylthio-C1-4Alkyl, Hydroxy-C2-4Alkylthio-C1-4Alkyl , C1-4Alkoxy-C2-4alkylthio-C1-4alkyl, Phenoxy-C1-4alkyl, Aniline-C1-4alkyl, Phenylthio-C1-4alkyl, Cyano-C1-4alkyl, Halogen-C2-4Alkoxy, Hydroxy-C2-4Alkoxy, C2 -4alkanoyloxy-C2-4Alkoxy, C1-4Alkoxy-C2-4Alkoxy, Carboxy-C1-4Alkoxy., C1-4Alkoxycarbonyl-C1-4Alkoxy, Carbamoyl-C1-4Alkoxy, N-C1-4Alkylcarbamoyl-C1-4Alkoxy, N,N- di[C1-4alkyl]carbamoyl-C1-4Alkoxy, Amino-C2-4Alkoxy, C1-4Alkylamino-C2-4Alkoxy, Di-[C1-4Alkyl]Amino-C2-4Alkoxy, C1-4Alkanoyloxy, Hydroxy-C2-4alkanoyloxy, C1-4 -4Alkoxy-C2-4Alkanoyloxy, Pheny1-C1-4Alkoxy, Phenoxy-C2-4Alkoxy, Aniline-C2-4Alkoxy, Phenylthio-C2-4Alkoxy, Piperidine-C2-4Alkoxy, Morpholine-C2-4Alkoxy, Piperazin-1-yl-C2 -4Alkoxy, 4-C1-4alkylpiperazin-1-yl-C2-4Alkoxy, Halogen-C2-4Alkylamino, Hydroxy-C2-4Alkylamino, C2-4alkanoyloxy-C2-4Alkylamino, C1-4Alkoxy-C2-4Alkylamino, Carboxy-C1-4alk ylamino, C1-4alkoxycarbonyl-C1-4alkylamino, carbamoyl-C1-4alkylamino, N-C1-4alkylcarbamoyl-C1-4alkylamino, N, N-di-[C1-4alkyl]carbamoyl-C1-4alkylamino, amino-C2-4alkylamino, C1 -4alkylamino-C2-4alkylamino, di-[C1-4alkyl]amino-C2-4alkylamino, phenyl-C1-4alkylamino, phenoxy-C2-4alkylamino, aniline-C2-4alkylamino, phenylthio-C2-4alkylamino, C2-4alkanoylamino, C1- 4Alkoxycarbonylamino, C1-4alkylsulfonylamino, benzamido, benzenesulfonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, Halogen-C2-4alkanoylamino, hydroxy-C2-4alkanoylamino, C1-4alkoxy-C2- 4alkanoylamino, Carboxy-C2-4alkanoylamino, C1-4Alkoxycarbonyl-C2-4alkanoylamino, Carbamoyl-C2-4alkanoylamino, N-C1-4alkylcarbamoyl-C2-4alkanoylamino, N,N-di-[C1-4alkyl]carbamoyl-C2-4alkanoylamino, amino -C2-4alkanoylamino, C1-4alkylamino-C2-4alkanoylamino or di-[C1-4alkyl]amino-C2-4alkanoylamino, and indicated that said benzamido or benzenesulfonamido substituent or any aniline, phenoxy or phenyl group on R1 subst ituent can optionally carry one or more halogen, C1-4alkyl or C1-4 alkoxy substituents;

or any adjacent pair of R1, R2, R3 and R3' together form an optionally substituted methylenedioxy or ethylenedioxy group;

each R4 is independently hydrogen, hydroxy, halogen, C1-4alkyl, C1-4alkoxy, C1-4alkylamino, di-[C1-4alkyl]amino, C1-4alkylthio, C1-4alkylsulfinyl, C1-4alkylsulfonyl, C1-4alkylcarbonyl, C1-4alkylcarbamoyl , di-[C 1-4 alkyl]carbamoyl, carbamyl, C 1-4 alkoxycarbonyl, cyano, nitro or trifluoromethyl;

R 5 is hydrogen, halogen, trifluoromethyl, C 1-4 alkyl or C 1-4 alkoxy;

each R6 is independently a group ZR7 indicated by Z being attached to R7 through a (CH2)p group where 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 C1-4 alkyl and where V is a hydrocarbyl xupine containing 0, 1 or 2 carbon atoms, carbonyl, CH(OH), sulfonamide, amide , O, S(O)m or NRb where Rb is hydrogen or Rb is C1-4alkyl; and

R 7 is optionally substituted C 3-6 cycloalkyl;

or an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety;

or R6 is a group ZR7 in which Z is NRb, and NRb and R7 together form an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety.

In one compound, R 1 , R 2 and R 3 are each selected from amino, hydrogen, halogen, hydroxy, nitro, C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkylthio, C 1-4 alkylamino, or R 1 and R 2 or R 1 and R 2 together form an optionally substituted methylenedioxy or ethylenedioxy group; R3' is hydrogen; R 4 is hydrogen, hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, di-[C 1-4 alkyl]amino, nitro or trifluoromethyl;

R 5 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy;

Z is absent or represents CH 2 , oxygen, S(O) m , where m is 0, 1 or 2, or NR b , where R b is hydrogen or R b is C 1-4 alkyl, and

R7 is an optionally substituted phenyl, benzyl, pyridyl, dioxolanyl, phenoxy, benzyloxy, phenylamino, benzylamino, phenylmercapto or benzylmercapto group, preferably a phenyl, fluorophenyl, pyridyl, 1,3-dioxolanyl or benzyl group.

When group Z is absent, R6= R7.

In the following compound, R 1 , R 2 and R 3 are each selected from hydroxy, C 1-4 alkyl, C 1-4 alkoxy or an adjacent pair and together form a methylenedioxy or ethylenedioxy group; and R 3 is hydrogen.

In a further compound, R 6 is a ring remote from V when U represents a bicyclic group.

In the following compound, X is N.

In the further compound, Y is NRb, NRb(CH2), or (CH2)NRb, preferably Y is NRb.

Heterocyclic groups contain 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 contain one or more rings which may be independently saturated, unsaturated or aromatic and contain only carbon or hydrogen.

Suitably X is nitrogen.

Suitably Y is a group NR indicated by R being hydrogen or methyl, preferably hydrogen.

Suitably R1 and R2 are independently hydrogen; C 1-4 alkyl, such as methyl; or C1-4 alkoxy, such as methoxy.

Suitably R3 and R3' are independently hydrogen, methyl or methoxy.

Suitably R4 is hydrogen, halogen or methyl, preferably R4 is hydrogen.

Suitably R5 is hydrogen or methyl.

Suitably R 6 is phenyl, fluorophenyl, phenethyl, benzyl, pyridyl, phenylsulfonyl, benzylsulfonyl, phenoxy, benzyloxy or 1,3-dioxolanyl.

One or both rings containing a mono- or bicyclic ring system may be aromatic or non-aromatic. R4 and R6 groups can be attached to the ring system either via carbon atoms or heteroatoms from the ring system. The ring system itself may be attached to a Y bridging group attached at the -4 position of the quinoline or quinazoline skeleton by a carbon atom or a heteroatom. The R 4 and R 6 groups can be attached to the ring when U represents a bicyclic ring system, but these groups in such a case prefer to be attached to a ring that is not connected to the bridging group Y.

Examples of suitable mono or bicyclic groups U initially attached at the -4 position of 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-oxycinyl, thieno[2,3-b]furanyl, tianaphtenyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indolizinyl, 1H- benzimidazoles1, 2,3-dihydro-1H-benzimidazoles1, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzo[c]zoxazolyl, benzo[d]isoxazolyl, 2,3- dihydrobenzo[d]isoxazolyl, benzothiazolyl, 2,3-dihydrobenzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 1H-benzotriazolyl, benzo[c]furanyl, benzo[c]isothiazolyl [1,2,3]thiadiazolyl, benzo[d][1,2,3]oxadiazolyl, benzo[d][1,2,3]diadiazolyl, quinolyl, 1,2-dihydroquinolinyl, 1,2,3,4 -tetrahydroquinolinyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolinyl, quino linyl, quinazolinyl, quinoxalinyl, phthalazinyl, 4H-1,4-benzoxazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl or 2,3-dihydro-4H-1,4- benzothiazinyl.

Suitable U represents indolyl, isoindolyl, indolinyl, isoindolyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group.

A suitably 5, 6, 7, 8, 9 or 10-membered heterocyclic moiety is selected from the group consisting of: furan, dioxolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazoline, oxazolidine, thiazole , thiadiazole, benzofuran, indole, isoindole, quinazoline, quinoline and isoquinoline.

A suitably 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 means fluorine, chlorine, bromine or iodine.

Alkyl groups containing three or more carbon atoms can be straight, branched or cyclic.

In one compound, optional substituents for the carbocyclic or heterocyclic moiety, which may be present at any accessible position of said moiety, are selected from the group consisting of;

(CH2)qS(O)m-C1-4alkyl, (CH2)qS(O)m-C3-6cycloalkyl, and (CH2)qSO2NR8R9, (CH2)qNR8R9, (CH2)qCO2R8, (CH2)qOR8, (CH2) qOR8, (CH2)qCONR8R9, (CH2)qNR8COR9, (CH2)qCOR8, (CH2)qR8, NR8SO2R9 and S(O)mR8.

wherein q is an integer from 0 to 4 inclusive; m is 0, 1 or 2;

R 8 and R 9 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 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 selected from N, O or S, provided that the heterocyclic ring does not contain two adjacent O or S atoms.

In the further compound, optional substituents for the carbocyclic or heterocyclic part are selected from the group comprising morpholine, piperazine, piperidine, pyrrolidine, tetrahydrofuran, dioxolane, oxothiolane and its oxides, dithiolane and its oxides, dioxane, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiofuran, pyrrole, triazine, imidazole, triazole, tetrazole, pyrazole, oxazole, oxadiazole and thiadiazole.

Other 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, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, carboxylate and C1 -4Alkoxy carboxyl.

Preferred compounds of this invention include;

4-(1-benzyl-5-indolylamino)quinazoline

4-(1-benzyl-5-indolylamino)-6,7-dimethoxyquinazoline;

4-(2-benzyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline;

4-(2-benzyl-5-benzimidazolylamino)-quinazoline;

4-(2-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline;

4-(1-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline;

4-(1-benzyl-5-indazolylamino)-quinazoline;

4-(1-phenylsulfonyl-5-indolylamino)-6,7-dimethoxyquinazoline;

4-(1-benzyl-2,3-dihydroindolyl-5-amino)-6,7-dimethoxyquinazoline;

4-[3-(4-fluorophenyl)-6-indazolylamino]-6,7-dimethoxyquinazoline;

4-(1-benzyl-5-indolylamino)-6,7-diethoxyquinazoline;

4-[1-[2-(1,3-dioxolan-2-yl)-ethyl]-5-indazolylamino]-6,7-dimethoxyquinazoline;

4-(1-benzyl-6-indolylamino)-6,7-dimethoxyquinazoline;

4-(2-phenyl-5-benzimidazolylamino)-6,7-dimethoxyquinazonine;

4-(1-benzyl-5-indolylamino)-6,7-methylenedioxyquinazoline;

4-(3-benzyl-5-benzimidazolylamino)-quinazoline;

4-(1-benzyl-5-benzimidazolylamino)-quinazoline;

4-(2-benzyl-5-benzotyrazolylamino)-6,7-dimethoxyquinazoline;

4-(1-benzyl-5-benzotriazolylamino)-6,7-dimethoxyquinazoline;

4-(3-benzyl-5-benzotriazolylamino)-6,7-dimethoxyquinazoline;

4-(2-phenethyl-5-indazolylamino)-6,7-dimethoxyquinazoline;

4-(1-phenethyl-5-indazolylamino)-6,7-dimethoxyquinazoline;

4-(2-(2-pyridyl)-benzimidazolylamino)-quinazoline;

4-(2-benzylsulfonyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline;

and their salts, especially pharmaceutically acceptable salts.

Particularly acceptable compounds of this invention include:

4-(2-benzyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline;

4-(2-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline;

4-(1-benzyl-5-indazolylamino)-quinazoline;

4-(1-phenylsulfonyl-5-indolylamino)-6,7-dimethoxyquinazoline;

and their salts, especially pharmaceutically acceptable salts.

Certain compounds of formula (I) contain asymmetric carbon atoms and can therefore exist in the form of optical isomers. Individual isomers and mixtures thereof are included within the scope of this invention. It is equally understood that compounds of formula (I) may exist in other tautomeric forms than those shown in the formula.

The salts of the compounds of this invention may contain salts with an acidic addition obtained from the nitrogen in the compound of formula (I). The therapeutic activity is found in the part obtained from the compound of this invention as defined herein and the identity of the second component is of minor importance although for therapeutic and prophylactic reasons it is preferably pharmaceutically acceptable to the patient. Examples of pharmaceutically acceptable acid addition salts include those obtained from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinyl and methanesulfonic and arylsulfonic, for example q-toluenesulfonic acids.

In a further aspect, the present invention provides a process for preparing a compound of formula (I), which process comprises the reaction of a compound of formula (II).

[image]

with the compound of formula (III):

UYH (III)

wherein L is a residue and U, X, Y and R1 to R6 are as previously defined herein. Suitable remaining groups will be well known to those skilled in the art and include, for example, halo and sulfonyloxy groups such as chloro, bromo, methanesulfonyloxy and toluene-p-sulfonyloxy.

The reaction is conveniently carried out in the presence of a suitable inert solvent, for example a C1-4 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.

Optionally, 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 compound of formula (I) can be obtained from this process in the form of a salt with an acid HL, where L is as previously defined herein, or in the form of a free base by treatment of the salt with a base as hereinbefore defined.

The preparation of compounds (II) and (III) is well known to those skilled in the art.

In addition to the above, one compound of formula (I) can be converted into 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).

For example, a compound containing an alkyl or aryl mercapto group can be oxidized to the corresponding sulfinyl or sulfonyl compound using an organic peroxide (eg, benzoyl peroxide) or a suitable inorganic oxidant (eg, OXONE®).

A compound containing a nitro substituent can be reduced to the corresponding amino compound, e.g. by using hydrogen and a suitable catalyst (if there are no other sensitive groups) or by using Raney Nickel and hydrazine hydrate.

Amino and hydroxy substituents can be acylated using an acid chloride or anhydride under appropriate conditions. Equally, an acetate or amide group can be cleaved to a hydroxy or amino compound by treatment with, for example, a dilute aqueous base.

In addition, the reaction of the amino substituent with triphosgene and another amine (eg aqueous ammonia, dimethylamine) gives a urea substituted product.

The amino substituent can also be converted to the dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride.

The present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereafter identified as "active ingredients") for use in medical treatment, and in particular in the treatment of disorders mediated by protein tyrosine kinase activity such as human malignancies and other disorders. which are mentioned above. The compounds are particularly useful for the treatment of disorders caused by aberrant c-erbB-2 activity such as breast, ovarian, lung, pancreatic, gastric and colon cancers.

A further aspect of the present invention provides a method of treating a human or animal organism suffering from disorders mediated by aberrant protein tyrosine kinase activity comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the diseased human or animal.

A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in treatment.

A further aspect of the present invention relates to 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 tumors.

In a further aspect of this invention, 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 is shown.

A further aspect of the present invention provides pharmaceutical compositions comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.

While it is possible for the compounds and salts of this invention to be used as novel chemicals, it is preferable to present them in the form of pharmaceutical preparations.

In accordance with the following feature of the present invention we provide pharmaceutical compositions comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more acceptable carriers, diluents or excipients.

Pharmaceutical preparations can be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such units may contain, for example, 0.5 mg to 1 g, preferably 5 mg to 100 mg of the compound of formula (I) depending on the condition being treated, the method of administration and the age, body weight and condition of the patient.

The pharmaceutical compositions may be adapted for administration by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes . Such compositions may be prepared by any method known in the pharmaceutical art, for example by combining the active ingredient with a carrier(s) or excipient(s).

Pharmaceutically, preparations suitable for oral administration may be presented in the form of discrete units such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or braids; or liquid oil-in-water emulsions or water-in-oil emulsions.

Pharmaceutical preparations adapted for transdermal administration can be presented in the form of discrete patches that remain in close contact with the epidermis of the recipient for a long period of time. For example, the active ingredient can be released from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical preparations suitable for topical application may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, for example the mouth or the skin, the compositions are preferably applied as topical ointments or creams. When they are prepared in the form of an ointment, the active ingredient can be used either with paraffin or with an oily base which. can be mixed with water. Alternatively, the active ingredient can be prepared in the form of a cream with an oil-in-water or water-in-oil cream base.

Pharmaceutical preparations adapted for topical application to the eye include eye drops where the active substance is dissolved or suspended in a suitable vehicle, especially an aqueous solvent.

Pharmaceutical preparations adapted for topical use in the mouth include lozenges, lozenges and mouthwashes.

Pharmaceutical preparations adapted for rectal administration can be presented in the form of suppositories or enemas.

Pharmaceutical preparations adapted for nasal administration where the carrier is a solid include a regular powder having a particle size for example in the range of 20 to 500 microns and which is administered by snorting, e.g. by rapid inhalation through the nasal passages from a container of powder held very close to the nose. Suitable preparations where the carrier is a liquid, for administration in the form of a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.

Pharmaceutical preparations adapted for administration by inhalation include fine particles of dust or mist that can be obtained. by means of various types of certain pressurized doses such as aerosols, nebulizers or insufflators.

Pharmaceutical preparations adapted for vaginal use can. be presented in the form of pessaries, tampons, creams, gels, pastes, foams or sprays.

Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatic and soluble substances that keep the preparation isotonic with the recipient's blood; and aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents. The compositions may be presented in unit dose or multi-dose form, for example sealed ampoules and vials, and may be stored in a lyophilized state thus requiring only the addition of a sterile liquid vehicle, for example water for injections, immediately before use. Improvised injectable solutions and suspensions can be prepared from sterile powders, granules and tablets.

Preferred dosage units of the compositions are those containing a daily dose or sub-dose, as set forth hereinabove, or some appropriate portion thereof, of the active ingredient.

It should be understood that in addition to the ingredients specifically mentioned above, the preparations may include other substances common in the art depending on the type of preparation in question, for example those which are. suitable for oral administration may contain substances to improve taste.

Compounds and salts of formula (I) have anticancer activity as shown later herein, via inhibition of the protein tyrosine kinase c-erbB-2 enzyme. The compounds of this invention have been found to be useful in medicine, particularly in the treatment of certain malignant diseases in humans, for example breast, ovarian, lung, pancreatic, stomach, and colon cancers. Accordingly, the present invention provides a method of treating susceptible malignancies in an animal, comprising administration to the animal. effective amounts of a compound or salt of the present invention. Alternatively, 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 cancer.

This invention also provides the use of a compound of formula (I) or a salt thereof for the production of a medicament for the treatment of malignant tumors.

An animal in need of treatment with a compound or salt of the present invention is typically a mammal, such as a human.

The therapeutically effective amount of a compound or salt of the present invention will depend on a number of factors, including, for example, the age and body weight of the animal, the exact condition requiring treatment and the severity, condition, nature of the preparation, and the route of administration, and ultimately will be decided by the physician. or a veterinarian. However, an effective amount of a compound of the present invention for the treatment of a neoplastic growth, for example breast or colon cancer will generally be in the range of 0.1 to 100 mg/kg body weight of the recipient (mammal) per day or more usually in the range of 1 to 10 mg/ kg of body weight per day. Thus, for an adult mammal of 70 kg, the daily amount will usually be from 70 to 700 mg and this amount can be given in one dose per day or more usually in several sub-doses (two, three, four, five or six) at day so that the total amount of the daily dose is the same. The effective amount of a salt of the present invention can be determined as a proportion of the effective amount of the compound per se.

Certain compounds of the present invention will now be illustrated by way of example. The physical data given for the compounds from the examples are in accordance with the given structure of these compounds.

IR spectra were obtained on a Perkin-Elmer 257 grating spectrophotometer or a Bruker FS66 spectrophotometer.

1H NMR spectra were obtained on a Bruker WM 360-NMR spectrophorometer at 360 MHz, or on a Bruker AC200 spectrophotometer at 200 MHz, J values are given in Hz. Mass spectra were obtained on Varian CH5D (El), Kratos Concept (El) or Kratos Ms50 (FAB) machines.

Analytical thin layer chromatography (TLC) is used to confirm the purity of some intermediates that could not be isolated for full characterization, and to follow the progress of reactions. Unless otherwise specified, do is performed using silica gel (Merck Silica Gel 60 F254).

Unless otherwise specified, column chromatography for the purification of certain compounds uses Merck Silica gel 60 (Art. 1.09385, 230-400 mesh), and the specified pressurized solvent system.

Gasoline refers to petroleum ether, or the part that boils at 40-60°C, or at 60-80°C.

Ether refers to diethyl ether.

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

DCM refers to dichloromethane.

DMSO refers to dimethylsulfoxide.

Preparation of intermediate products

4-Chloroquinazoline was prepared from 4-hydroxyquinazoline (commercially available) according to a published method (J. Org. Chem. 27, 958 (1962)).

4-Chloro-6,7-dimethoxyquinazoline is prepared in an analogous manner according to the procedure described in European Patent Application 566 226 A1 (Zeneca Limited).

5-Amino-1-benzyl-2,3-dihydroindole was prepared according to a published method (Chem. Ber., 102, 1084-5, (1969)).

5-Amino-2-(2-pyridyl)-benzimidazole was prepared according to a published method (J. Med. Chem., 22, 1113-8, (1979)).

5-Amino-2-benzylbenzimidazole was prepared according to a published method (J. Het. Chem., 23, 1109-13, (1986)).

5-Amino-1-benzylbenzimidazole was prepared according to a published method (Khim. Geterotsikl. Soedin., 7, 1136-8, (1971)).

5-Amino-1-benzylindazole is prepared according to the published method (FR 5600 68.01.08).

5-Amino-2-phenylbenzimidazole was prepared according to a published method (3. Org, Chem., 60, 5678-82, (1995)).

5-Amino-1-phenylsulfonylindole was prepared according to with a published method (J. Org. Chem,, 55, 1379-90, (1990)).

2-Fluoro-4-nitrobenzoyl chloride was prepared according to a published method (J. Med. Chem., 37, 2361-70, (1994)).

1-Benzyl-5-nitroindole

Dry dimethyl sulfoxide (20 mL) was added to potassium hydroxide (4.2 g, 0.074 mol) (crushed particles) and the mixture was stirred under nitrogen for 5 minutes. Then 5-nitroindole (commercially available) (3.0 g, 0.019 mol) was added and the red mixture was stirred for 30 minutes at room temperature. The mixture was then cooled to -10°C, benzyl bromide (4.4 ml, 0.037 mol) was slowly added and the mixture was stirred and allowed to warm to room temperature over a period of 40 minutes. Water (50 ml) was then added and the mixture was extracted with diethyl ether (2 x 200 ml). The extracts were washed with water (450 ml), dried over sodium sulfate and evaporated to give an oily solid. Excess benzyl bromide is removed by dissolving all in diethyl ether (50 ml), this solution is diluted with 40-60 benzine (50 ml) and then the diethyl ether is gradually removed in vacuo to give a yellow solid suspended in benzine. The solid was filtered, washed with copious amounts of 40-60 benzine and dried to give 1-benzi1-5-nitroindole (2.4 g, 5.17;) as a yellow solid, m.p. 102-104°C: δ H [2H6] DMSO 8.53 (1H, s, 4H), 8.00 (1H, d, J 9, 6-H), 7.78 (1H, s, 2-H), 7.68 (1H, d, J 9, 7-H), 7.36-7.20 (5H, m, 2'-H, 3'-H, 4'-H, 5'-H, 6'-H), 6.81 (1H, s, 3-H), 5.52 (2H, s, CH2).

5-Amino-1-benzylindole

A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture of ethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10% palladium on charcoal (45 mg). The resulting suspension is stirred at room temperature under one atmosphere of hydrogen. Upon completion of the reaction (observed by tlc or calculated hydrogen consumption), the suspension was filtered and the filtrate evaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as an off-white solid, m.p. 66-68°C. : S H [2H6] DMSO 7.30-7.12 (6H, m, 2-H, 2''-H, 3''-H, 4''-H, 5''-H, 6''-H) , 7.08 (1H, d, J 8, 7-H), 6.70 (1H, s, 4-H), 6.49 (1H, d, J 8, 6-H)„ 6.18 (1H, s, 3- H), 5.28 (2H, s, CH2), 4.38 (2H, br s, NH2)

5-Nitro-3-benzylbenzimidazole and 6-nitro-3-benzyl-benzimidazole 5-nitrobenzimidazole (1 g, 6.13 mmol) in acetone (20 ml) containing potassium hydroxide particles (1 g, 18.39 mmol) was stirred and treated with with benzyl bromide (0.73 ml, 6.13 mmol). After 1 hour, the mixture is acidified to ca pH 7, diluted with water, and extracted with ethyl acetate. The dried extracts were evaporated to give a cream-colored solid (1.56 g, 100%); m/z (M + 1)+ 254.

5-Amino-3-benzylbenzimidazole

A mixture of 5-nitro-3-benzi1benzimidazole and 6-nitro-3-benzylbenzimidazole (0.25 g, 0.987 mmol) in ethyl acetate was hydrogenated over a palladium catalyst (50% w/w H2O, 10% in carbon, 0.1 g) at room temperature. and pressure. (Hydrogen uptake = 81 ml, theoretical = 71 ml). The mixture is filtered through Celite and the filtrate is evaporated. The residue is chromatographed on silica gel (Merck 9385, 30 g). Elution with CH2Cl2:EtOH:NH3 100:8:1 gives the desired isomer (determined by nuclear Overhauser effect nmr) as a solid (0.083 g, 38%); m/z (M + 1+) 224.

1-Benzyl-5-nitroindazole and 2-benzyl-5-nitroindazole

5-Nitroindazole (0.5 g, 3.065 mmol) in acetone (10 mL) containing potassium hydroxide particles (0.51 g, 0.090 mmol) was stirred and treated dropwise with benzyl bromide (0.37 mL, 3.065 mmol). The mixture was stirred for 3 h and then acidified with 2N HCl and extracted with ethyl acetate. The dried organic phase was evaporated to give a brown solid (0.78 g, 100 7); nmr shows an isomeric mixture; m/z (M + 1)+ 254.

5-Amino-1-benzylindazole and 5-Amino-2-benzylindazole

An isomeric mixture of nitroindazole (0.4 g, 1.579 mmol) is hydrogenated in ethanol (35 ml) over a palladium catalyst (10% on carbon, 0.1 g) at room temperature and pressure. Hydrogen intake = 120 ml (theory = 114 ml), reaction time 45 minutes. The catalyst was removed by filtration through Celite and the solvent was evaporated to give a yellow solid (0.32 g, 91%); m/z (M + 1)+ 224.

A mixture of 1-, 2- and 3-benzi1-5-aminobenzotriazole

An isomeric mixture of 1-, 2- and 3-benzi1-5-nitrobenzotriazole (0.518 g, 2.037 mmol) in THF (15 ml) is hydrogenated over a palladium catalyst (5% on carbon, 0.1 g) at room temperature and pressure. Hydrogen uptake = 145 ml (theoretical = 147 ml); reaction time = 4 h. The catalyst was removed by filtration through Celite and the solvent was then evaporated to give a pale yellow oil (0.456 g, 100%); m/z (M + 1)+ 225.

A mixture of 1-, 2- and 3-benzi1-5-nitrobenzotriazole

5-Nitrobenztriazole (0.750 g, 4.569 mmol) and benzyl bromide (0.54 ml, 4.569 mmol) in acetone (30 ml) containing potassium carbonate (1.89 g, 13.675 mmol) were stirred and heated to reflux. through 2 h. After this time, the solvent is evaporated, and then the residue is partitioned between water and ethyl acetate. The dried extracts were evaporated to give an orange oil which solidified on standing (1.ls g, 100%); m/z (M + H)+ 255

2,4'-Difluoro-4-nitrobenzophenone

A stirred solution of 2-fluoro-4-nitrobenzoyl chloride (2.91 g, 12.97 mmol) in fluorobenzene (10 ml) was treated with aluminum chloride anhydride (1.73 g, 12.97 mmol). After 2 h, the mixture is poured into cold (0°C) 2N hydrochloric acid, and the product is extracted with ethyl acetate. The combined extracts were washed with water, dried, and evaporated to give a pale brown oil which crystallized on standing (3.35 g, 98%); δ H (CDCl3) 8.17 (1H, dd ), 8.07 (1H, dd), 7.85 (2H, m), 7.71 (1H, dd), 7.19 (2H, m).

6-Amino-3-(4-fluorophenyl)-indazole

A mixture of 2,4'-difluoro-4-nitrobenzophenone (0.263 g, 1 mmol) and hydrazine hydrate (0.2 ml, 4 mmol) in ethanol (8 ml) was heated to reflux for 4 days. The solvent is then evaporated and the residue is chromatographed on silica gel (Merck 9385, 30 g). Elution with CH2Cl2 : EtOH:NH3 200:8:1 gives a colorless solid (0.075 g, 337.); m/z (M + 1)+ 228.

1-[2-(1,3-Dioxolan-2-yl)-ethyl]-5-nitroindazole

5-nitroindazole (0.5 g, 3.065 mmol) potassium carbonate (1.06 g, 7.66 mmol) and bromomethyl dioxolane (0.33 ml, 3.218 mmol) in acetonitrile (20 ml) were stirred and heated to reflux for 18 hours. The cooled mixture was partitioned between water and ethyl acetate. The dried extracts were evaporated to give a yellow solid. This material is chromatographed on silica gel (Merck. 9385, 40 g). Elution with ethyl acetate:cyclohexane 1:1 gave a colorless solid (0.41.1 g, 57%): m/z (M+1)+ 250.

5-Amino-1-[2-(1,3-dioxolan-2-yl)-ethyl]-indazole

1-[(1,3-Dioxolan-2-yl)-ethyl]-5-nitroindazole (0.405 g, 1.625 mmol) in THF (15 mL) was pyrogenated over palladium (5% on carbon, 0.05 g) at room temperature and pressure. Hydrogen uptake = 140 ml, theoretical = 117 ml. Reaction time = 1.5 H. The catalyst was removed by filtration through Celite and the filtrate was evaporated to give pale yellow k.rutin (0.355 g, 100%); m/z (M + 1)+ 220.

A mixture of 1- and 2-phenethyl-5-nitroindazole

A mixture of 5-nitroindazole (0.5000 g, 3.065 mmol), phenethyl bromide (0.42 ml, 3.065 mmol) and potassium carbonate (1.06 g, 7.670 mmol) in acetonitrile (20 ml) was stirred and heated to reflux for 18 h. The cooled mixture was partitioned between water and ethyl acetate. The dried extracts were evaporated to give a yellow solid (0.810 g, 99%); m/z (M + 1)+ 268.

A mixture of 1- and 2-phenethyl-5-aminoindazole

An isomeric mixture of 1- and 2-phenethyl-5-nitroindazole (0.800 g, 2.993 mmol) in THF (25 ml) is hydrogenated over palladium (50% v/1, H2O, 10% on carbon, 0.2 g) at room temperature. temperature and pressure. Hydrogen was taken = 232 ml; theoretical = 2.15 ml. The catalyst was removed by filtration through Celite and then the filtrate was evaporated to give a yellow-green oil (0.690 g, 97%): m/z (M + 1)+ 238.

2-Benzylthio-5-nitro benzimidazole

2-Mercapto-5-nitrobenzimidazole (0.25 g, 1.280 mmol), benzyl bromide (0.15 ml, 1.280 mmol) and potassium carbonate (0.531 g, 3.840 mmol) in acetone (1.0 ml) were heated to reflux for 2 h. The cooled mixture was partitioned between water and ethyl acetate. The dried extracts were evaporated to give a pale yellow solid (0.365 g, 1007.); m/z (M + 1)+ 286.

2-Benzylsulfonyl-5-nitrobenzimidazole

1-Benzylthio-5-nitrobenzimidazole (0.36 g, 1.261 mmol) and oxone (2.32 g, 3.783 mmol) in aqueous methanol (1:3; 20 ml) were stirred at 20°C for 18 h. The methanol is then evaporated and the residue partitioned between water and dichloromethane. The dried extracts were then evaporated to give a yellow foam (0.384 g, 96%); m/z (M + 1)+ 318.

5-Amino-2-benzylsulfonylbenzimidazole

2-Benzylsulfonyl-5-nitrobenzimidazole (0.165 g, 0.520 mmol) in ethanol (10 ml) was hydrogenated over a palladium catalyst (507. w/v 10% carbon, 0.1 g) at room temperature and pressure. Hydrogen uptake = 57 ml, theoretical = 57 ml; reaction time = 3 h. The catalyst was removed by filtration through Celite and the filtrate was evaporated to give a colorless oil (0.146 mg, 987.); m/z (M + 1)+ 288.

General procedure

An optionally substituted quinazoline or quinoline and the specified amine are mixed in a suitable solvent and heated to reflux. Upon completion of the reaction (assessed by TLC), the reaction mixture was allowed to cool. The resulting suspension is diluted with acetone and the solid is collected by filtration, washed with excess acetone, and dried at 60°C in vacuo.

Example 1

4-1-benzyl-5-indolylamino)quinazoline 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 light yellow solid thus obtained is 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. C23H18N4HCl 0.2H2O required; C, 70.75; H, 5.01; N, 14.35%); δ H [2H6] DMSO 11.70 (1H, br b, NH), 8.90 (1H, d, J 9, 8-H), 8.80 (1H, s, 2-H), 8.10 (1H, t, J 8, 6-H), 7.98 (1H, d, J 8, 5-H), 7.87 (1H, s, 4'-H), 7.83 (1H, t, J 8, 7-H), 7.60 (1H, s , 2'-H)„ 7.55 (1H, d, J 9, 6'-H), 7.40-7.20 (6H, m, 7'-H, 2''-H, 3''-H, 4'' -H, 5''-H, 6''-H), 6.57 (1H, s, 3'-H), 5.48 (2H, s, CH2); m/z (%) 351 (100, M + 1)+; Vmax (KBr disc)/cm-1 2592, 1626, 1610, 1566, 1485, 1423, 1371.

Example 2

4-(1-benzyl-5-indolylamino)-6,7-dimethoxy quinazoline hydrochloride

4-Chloro-6,7-dimethoxyquinazoline (0.10 g, 0.45 mmol) and 5-amino-1-benzylindole (0.37 g, 0.63 mmol) were reacted in 2-propanol in (15 ml) for 4 h according to the general procedure . The pale yellow solid thus obtained is 4-(1-benzyl-5-indoylamino)-6,7-dimethoxyquinazoline hydrochloride (0.16 g, 78%), m.p. 244-245°C; (Found; C, 66.66; H, 4.97; N, 12.40.

C25H22N4O2.HCl. 0.22 H2O requires: C, 66.64; H, 5.24; N, .12.43%); δ H [2H6]-DMSO 11.42 (1H, br s, NH), 8.68 (1H, s, 2-H), 8.32 (1H, s, 8-H), 7.80 (1H, s, 4'-H) , 7.59 (2H, s, 2'-H), 7.53 (1H, d, J 9, 6'-H), 7.40-7.20 (7H, m, 5-H, 7'-H, 2''-H , 3''-H, 4''-H, 5''-H, 6''-H), 6.53 (1H, s, 3'-H), 5.48 (2H, s, CH2), 4.00 (6H, 2 s, 2 × OCH3) ; m/z (%) 411 (100, M + 1+); Vmax (KBr disc)/cm-1 2837, 1632, 1576, 1568, 1512, 1454, 1437,1365, 1281 .

Comparative

4-(5-Indolylamino)quinazoline hydrochloride

This is synthesized for comparative purposes in an analogous manner to Example 1 using 5-aminoindole.

Comparative example 4

4-(5-Indolylamino)-6,7-dimethoxyquinazoline hydrochloride

This is synthesized for comparative purposes in an analogous manner to Example 2 using 5-aminoindole.

Example 5

4-(2-benzyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline hydrochloride

4-Chloro-6,7-dimethoxyquinazoline (0.112 g, 0.5 mmol) and 5-amino-2-benzylbenzimidazole (0.111 g, 0.5 mmol) were reacted in acetonitrile (10 ml) according to the general procedure, the desired the compound was collected by filtration as a cream-colored solid (0.114 g, 65%); m/z (M+1)+ 412; δ H (d6-DMSO) 8.48 (1H, s), 8.51 (1H, s), 8.19 (1H, s), 7.85 (2H, s), 7.35-7.52 (6H, m), 4.54 (2H, s) , 4.02 (6H, 2 × s).

Example 6

4-(2-benzyl-5-benzimidazolylamino)-quinazoline hydrochloride

4-Chloroquinazoline (0.147 g, 0.895 mmol) and 5-amino-2-benzylbenzimidazole (0.200 g, 0.895 mmol) are reacted together in 2-propanol (10 ml) according to the general procedure, the desired material is collected by filtration in the form of a pale yellow solid (0.241 g, 69%); m/z (H+1+) 352; δ H (d6-DMSO) 8.9-9.1 (2H, s + d), 8.2 (1H, s), 7.7-8.15 (5H, m), 7.3-7.5 (5H, m), 4.6 (2H, s).

Example 7

4-(2-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline

4-Chloro-6,7-dimethoxyquinazoline (0.206 g, 0.918 mmol) and an isomeric mixture of 5-amino-2-benzylindazole and 5-amino-1-benzylindazole (0.205 g, 0.918 mmol) were reacted in acetonitrile (10 ml ) in accordance with the general procedure. When cooled, a yellow precipitate forms, which is collected by filtration. This material is chromatographed on silica gel (Merck 9385, 35 g). Elution with CH2Cl2:EtOH:NH3 200:8:1 gives a beige crystalline solid (0.104 g, 27%); m/z (M+1)+ 412; δ H (d6-DMSO) 8.65 (1H, s), 8.09 (1H, d), 7.89 (1H, s), 7„76 (1H, d), 7.24-7.40 (7H, m), 7.06 (1H, s), 5.60 (2H, s), 4.02 (6H, 2 × s).

4-(1-benzyl-5-imidazolylamino)-6,7-dimethoxyquinazoline (0.072 g, 19%) was also isolated from this chromatographic column as a colorless solid; LC/MS - one isomer (M + 1)+ 412; δ H (d6-DMSO) 8.62 (1H, s), 8.00 (1H, d), 7.53 (1H, dd), 7.2-7.4 (7H, m), 7.03 (1H, s), 5.61 (2H, s), 4.02 (6H, 2 s), 4.02 (6H, 2 × s).

Isomers are determined using the non-nuclear Overhauser effect.

Example 8

4-(1-benzyl-5-indazolylamino)-quinazoline hydrochloride

4-Chloroquinazoline (0.08 g, 0.488 mmol) and 5-amino-1-benzylindazole (0.109 g, 0.488 mmol) were reacted in acetonitrile (10 ml) according to the general procedure, the desired compound was collected by filtration in in the form of a pale yellow solid (0.14 g, 74%); m/z (M + 1)+ 352; δ H (d6-DMSO) 8.88-8.92 (2H, m), 8.21 (1H, s), 7.8-8.15 (5H, m), 7.64 (1H, dd), 7.2-7.35 (5H, m), 5.72 ( 2H, s).

Example 9

4-(1-phenylsulfonyl-5-indolylamino)-6,7-dimethoxyquinazoline

4-Chloro-6,7-dimethoxyquinazoline (0.132 g, 0.587 mmol) and 5-amino-1-phenylsulfonylindole (0.160 g, 0587 mmol) were reacted in acetonitrile (15 ml) according to the general procedure. Upon cooling, a yellow solid is formed, which is collected by filtration and then chromatographed on silica gel (Merck 9385, 30 g). Elution with CH2Cl2 with EtOH NH3 200:8:1 gave a colorless solid (0.146 g, 54%); m/z (M + 1) 461; δ H (CDCl3) 8.61 (1H, s), 7.8-8.0 (3H, m), 7.4-7.65 (4H, m), 7.2-7.3 (3H, m), 7.03 (1H, s), 6.68 (1H, d), 4.02 (6H, 2 × s).

Example 10

4-(1-benzyl-2,3-dihydroindole-5-amino)-6,7-dimethoxyquinazoline hydrochloride

4-Chloro-6,7-dimethoxyquinazoline (0.158 g, 0.703 mmol) and 5-amino-1-benzyl-2,3-dihydroindole (0.158 g, 0.703 mmol) were reacted in 2-propanol (10 mL) in according to the general procedure, the desired product is obtained by filtration in the form of a yellow solid (0.264 g, 847.); m/z (M + 1)+ 413; δ H (d6-DMSO) 8.75 (1H, s), 8.20 (1H, s), 7.20-7.40 (8H, m), 6.65 (1H, d), 4.35 (2H, s), 3.97 (6H, s) , 3.34 (2H, t), 2.97 (2H, t).

Example 11

4-[3-(4-fluorophenyl)-6-indazolylamino]-6,7-dimethoxyquinazoline hydrochloride

4-Chloro-6,7-dimethoxyquinazoline (0.064 g, 0.286 mmol) and 6-amino-3-(4-fluorophenyl)-indazo1 (0.065 g, 0.286 mmol) were reacted in acetonitrile (5 mL) according to by general procedure. The desired compound was collected by filtration as a beige solid (0.115 g, 89%); m/z (M+1)+ 416; δ H (d6-DMSO) 8.88 (1H, s), 8.34 (1H, s), 8.03-8.20 (4H, m), 7.53 (1H, dd), 7.23-7.42 (3H, m), 4.02 (6H, 2 × s).

Example 12

4-(1-Benzyl-5-indolylamino)-6,7-diethoxyquinazoline hydrochloride

Prepared from 4-chloro-6,7-diethoxyquinazoline and 5-amino-1-benzylindole in an analogous manner as in example 2. M. pt. 251-258°C; Analysis result C, 67.64; H, 5.19; N, 11.69; C27H28N4O2 HCl requires C, 67.92; H, 5.75, N, 11.67%.

Example 13

4-[1-[2-(1,3-dioxolan-2-yl)ethyl]-5-indazolylamino]-6,7-dimethoxyquinazoline

4-Chloro-6,7-dimethoxyquinazoline (0.358 g, 1.595 mmol) in 5-amino-1-[2-(1,3-dioxolan-2-yl)ethyl]indazole (0.350 g, 1.596 mmol) was placed in reaction in acetonitrile (20 ml) according to the general procedure. Upon cooling, a yellow precipitate is formed, which is collected by filtration. This material is chromatographed on silica gel (Merck 9385, 40 g). Elution with CH2Cl2:EtOH; NH3 100:8:1 gives an off-white foam (0.486 g, 75%); LC/MS - one isomer with (M + 1)+ 408; δ H (CDCl 3 ) 8.63 (1H, s), 8.02 (1H, s), 7.99 (1H, s); 7.57 (2H, s), 7.28 (1H, s), 7.06 (1H, s), 5.31 (1H, t), 4.58 (2H, d), 4.02 (6H, 2 × s), 3, 85 (4H, s).

Example 14

4-(1-Benzyl-6-indolylamino)-6,7-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 minutes in accordance with the general procedure. The light orange solid thus obtained is 4-(1-benzyl-6-indolylamino)-6,7-dimethoxyquinazoline hydrochloride (0.045 g, 627.); M. pt. 241-242°C; Analysis result C, 66.97; H, 5.19; N, 12.34; C25H22N4O2 HCl requires C, 67.18; H, 5.19; N, 12.53%; δ H (d6 -DMSO) 11.15 (1H, br s, NH), 8.68 (1H, s, 2-H), 8.14 (1H, s, 8-H), 7.72 (1H, s, 7'-H) , 7.64 (1H, d, J 9, 4'-H), 7.58 (1H, s, 2'-H), 7.35-7.20 (9H, m, 5-H, 5'-H, 2"'-H , 3'"-H, 4"-H, 5"-H, 6'"-H), 6.56 (1H, s, 3'-H), 5.42 (2H, s, CH2), 3.99 (6H, 2 × s, 2 × OCH3); m/z (%) 411 (100, M + 1+); (KBr disc)/cm-1 2623, 1634, 1578.

Example 15

4-(2-phenyl-5-benzimidazolamino)-6,7-dimethoxyquinazoline hydrochloride

4-Chloro-6,7-dimethoxyquinazoline (0.18 g, 0.803 mmol) and 5-amino-2-phenylbenzimidazole (0.168 g, 0.803 mmol) were reacted in acetonitrile (10 ml) according to the general procedure, the desired compound collected by filtration as a beige solid (0.295 g, 85%): m/z (M + 1)+ 398; δ H (d6-DMSO) 8.79 (1H, s), 8.2-8.3 (3H, m), 8.02 (1H, s), 7.73 (1H, d), 7.5- 7.65 (4H, m ), 7.32 (1H, s), 4.01 (6H, 2 × s).

Example 16

4-(1-benzyl-5-indolylamino)-6,7-methylenedioxyquinazoline hydrochloride

It was prepared from 4-chloro-6,7-methylenedioxyquinazoline and 5-amino-1-benzylindole using an analogous method as in example 2. M. pt. 282-284°C; Analysis finding C, 66.13; H, 4.28, N, 12.86; C24H18N4O2 HCl requires C, 66.19, H, 4.40, N, 12.86%.

Example 17

4-(3-benzyl-5-benzimidazolylamino)-quinazoline hydrochloride

4-Chloroquinazoline (0.05-3 g, 0.322 mmol) and 5-amino-3-benzylbenzimidazole (0.72 g, 0.322 mmol) are reacted in 2-propanol (5 ml) according to the general procedure, the desired compound is obtained by filtration in the form of a pale yellow solid (0.05 g, 407.); m/z (M+1+) 352; S H (d 6 -DMSO) 9.35 (1H, s), 8.9 (2H, m), 7.5-8.2 (6H, m), 7.3-7.5 (5H, m), 5.65 (2H, s).

Example 18

4-(1-Benzyl-5-benzimidazoli1amino)-quinazoline hydrochloride

4-Chloroquinazoline (0.083 g, 0.50 mmol) and 5-amino-1-benzylbenzimidazole (0.112 g, 0.50 mmol) were reacted in 2-propanol. (10 ml) according to the general procedure. the desired compound was collected by filtration as a yellow solid (0.073 g, 38%); m/z (M + 1)+ 352; δ H (d6-DHSO) 9.35 (1H, s), 8.95 (1H, d), 8.9 (1H, s), 7.7-8.2 (6H, m), 7.3-7.5 (5H, m), 5., 7 (2H, s).

Example 19

4-(2-benzyl-5-benzotriazolylamine)-6,7-dimethoxy quinazoline

4-Chloro-6,7-dimethoxyquinazoline (0.480 g, 2.006 mmol) and an isomeric mixture of 1-, 2-, and 3-benzyl-5-aminobenztriazole (0.450 g, 2.006 mmol) were reacted in acetonitrile (30 mL) in in accordance with the general procedure. The mixture is cooled and a yellow precipitate is collected by filtration. This material is then chromatographed on silica gel (Merck 9385, 70 g). Elution with CH2Cl2: EtOH; NH3 200:8:1 gives a blue-green solid (0.139 g, 17%); LC/MS - one isomer (M+1)+ 413; δ H (d6-DMSO) 9.65 (1H, s), 8.51 (1H, s), 8.48 (1H, s), 7.91 (1H, d), 7.87 (1H, s), 7.75 (1H, d) , 7.3-7.4 (5H, m), 7.20 (1H, s), 5.92 (2H, s), 3.97 (6H, 2s).

This chromatography also isolated a pale green solid (0.262 g, 32%) which LC/MS showed to have 2 isomers (both different from the first isolation) and both with (M+1)+ 413.

By nmr, the major isomer was determined as 4-(1-benzyl-5-benzotriazolylamino)-6,7-dimethoxyquinazoline and the minor isomer was determined as 4-(3-benzyl-5-benzatriazolylamino)-6,7-dimethoxyquinazoline.

Larger isomer δ H (d6-DMSO) 9.68 (1H, s), 8.48 (1H, s), 8.45 (1H, s), 7.86 (1H, s), 7.92 (2H, s), 7.3-7.4 (5H, m), 7.19 (1H, s), 5.96 (2H, s), 3.97 (6H, 2 × s).

Minor isomer δ H (d6-DMSO) 9.72 (1H, s), 8.49 (1H, s), 8.37 (1H, d), 8.02 (1H, d), 7.86 (1H, s), 7.71 (1H, dd) , 7.3-7.4 (5H, m), 7.20 (1H, s), 5.93 (2H, s), 3.97 (6H, 2 × s) .

Isomers are determined by means of the nuclear Overhauser effect.

Example 20

4-(2-phenethyl-5-indazolylamino)-6,7-dimethoxyquinazoline

4-Chloro-6,7-dimethoxyquinazoline (0.189 g, 0.842 mmol) and an isomeric mixture of 1- and 2-phenethyl-5-aminoindazole (0.200 g, 0.842 mmol) were reacted in acetonitrile (15 mL) according to by general procedure. Upon cooling, a pale yellow precipitate is formed, which is collected by filtration. This material is chromatographed on silica gel (Merck 9385, 45 g). Elution with CH 2 Cl 2 : EtOH with NH 3 200:8:1 gave a pale green foam (0.039 g, 117.); m/z [M + 1]+ 426; δ H (CDCl3) 8.66 (1H, s), 8.05 (2H, s), 7.78 (1H, s), 7.69 (1H, s), 7.03-7.41 (6H, m), 4.64 (2H, t), 4.02 (6H, 2 × s), 3.32 (2H, t).

This chromatography also isolated 4-(1-phenethyl-5-indazolylamino)-6,7-dimethoxyquinazoline (0.145 g, 40%) as a colorless foam; m/z [M + 1]+ 426; δ H (CDCl3) 8.63 (1H, s), 8.00 (2H, 2 × s), 7.49 (1H, d), 7.1-7.3 (7H, m), 7.04 (1H, s), 4.60 (2H, t), 4.03 (6H, 2 × s), 3.. 23 (2H, t).

Example 21

4-(2-(2-pyridyl)-5-benzimidazolylamino)-quinazoline hydrochloride

4-Chlorovinazoline (0.063 g, 0.38 mmol) and 5-amino-2-(2-pyridyl)-benzimidazole (0.080 g, 0.38 mmol) were reacted in 2-propanol (5 ml) according to the general procedure, the desired the product is obtained by filtration as a yellow solid (0.072 g, 507.); m/z (M + 1+) 339; δ H (d6-DMSO) 8.93 (1H, s), 8.88 (1H, d), 8.78 (1H, d), 8.38 (1H, d), 7.86-8.15 (5H, m), 7.75 (1H, d) , 7.55-7.64 (2H, m).

Example 22

4-(2-Benzylsulfonyl-5-benzimidazolylamino)-6,7-dimethoxy quinazoline

4-Chloro-6,7-dimethoxyquinazoline (0.112 g, 0.497 mmol) and 5-amino-2-benzylsulfonylbenzimidazole (0.143 g, 0.497 mmol) were reacted in acetonitrile (15 ml) according to the general procedure. Upon cooling, a yellow precipitate is formed, which is collected by filtration. This material is chromatographed on silica gel (Merck 9385, 35 g). Gradient elution with CH2Cl2:EtOH:NH3 100:8:1 to 10:8:1 gave a yellow solid (0.103 g, 44%); m/z (M + 1)+ 476; δ H (d6-DMSO) 8.61 (1H, s), 7.7-8.2 (4H, m), 7.0-7.4 (6H, m), 5.04 (2H, s), 4.02 (6H, 2 × s).

Biological data

The compounds of this 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 recombinant construct of the intracellular domain of c-erbB-2 that is constitutively active. This method measures the ability of an isolated enzyme to catalyze the transfer of 33p-labeled γ-phosphate from ATP to a tyrosine residue in a synthetic peptide. The enzyme is incubated for 1 hour, at room temperature, with 100 μM ATP, 10 mM MnCl2, 1 mg/ml PolyGluAlaTyr (6:3:1) and the compound to be tested (diluted from a 5 mM stock dilution in DMSO, the final DMSO concentration is 2%) in 40 mM HEPES buffer, pH 7.4. The reaction is stopped by adding EDTA (final concentration 0.1 M) and the peptide is then precipitated onto ion exchange filter paper and the incorporated radioactivity determined. Inhibition of c-erbB-2 kinase is compared with EGF-R TK activity, measured by the same test method, using soluble A431 membranes as a source of enzymatic activity. The results are shown in Table 1 below as IC50 values in μM.

Table 1

[image]

The cell proliferation assay uses cell culture of immortalized human breast epithelial cells (HB4a) transformed by over-expression of c-erbB-2. Growth of these cells in low serum is dependent on c-erbB-2 tyrosine kinase activity. The specificity of the effect of test compounds on tyrosine kinase-dependent growth over general toxicity is determined by comparison with HB4a cell culture transfected with ras. The cells are seeded at 3000/well in a microtiter plate of 96 wells in 0.1 ml of medium and left overnight to accept. The test compound is added to 0.1 ml medium with a final concentration of 0.5% DMSO, and the plates are incubated for 4 days at 37°C. The cells are then examined under a microscope to record morphological detransformation and the cell mass is determined by staining with methylene blue and measuring the absorbance at 620 nm. The results are shown in Table 2 below as IC50 values in μM.

Table 2

[image]

Claims (19)

1. Compound of formula (I): [image] or a pharmaceutically acceptable salt thereof, indicated as such; X is N or CH; Y is a group W(CH 2 ), (CH 2 )W, or W, wherein W is O, S(O)m where m is 0, 1 or 2, or NRa where Ra is hydrogen or a C 1-8 alkyl group; U represents a 5- to 10-membered mono- or bicyclic ring system in which one or more carbon atoms is optionally substituted with a heteroatom independently selected from N, O, and S, which ring system is substituted with at least one independently selected R6 group and is optionally substituted with by at least one independently selected R4 group; R 1 , R 2 , R 3 and R 4 are the same or different and are each selected from amino, hydrogen, halogen, hydroxy, nitro, carboxy, trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 4- 8AlkylcycloAlkoxy, C1-8Alkoxycarbonyl, N-C1-4Alkylcarbamoyl, N,N-Di-[C1-4Alkyl]Carbamoyl, Hydroxyamino, C1-4Alkoxyamino, C2-4Alkanoyloxyamino, C1-4Alkylamino, Di[C1-4Alkyl]amino, Pyrrolidine-1 -yl, piperidine, morpholine, piperazin-1-yl, 4-C1-4alkylpiperazin-1-yl, C1-4alkylthio, arylthio, C1-4alkylsulfinyl, C1-4alkylsulfonyl, arylsulfonyl, halo-C1-4alkyl, hydroxy-C1-4alkyl . ,N-di-[C1-4alkyl]carbamoyl-C1-4alkyl, amino-C1-4alkyl, C1-4alkylamino-C1-4alkyl, di-[C1-4alkyl]amino-C1-4alkyl, piperidine-C1-4alkyl, morpholine -C1-4alkyl, Piperazin-1-yl-C1-4alkyl, 4-C1-4alkylpiperazin-1-yl-C1-4alkyl, Hydroxy-C2-4Alkoxy-C1-4alkyl, C1 -4Alkoxy-C2-4Alkoxy-C1-4Alkyl, Hydroxy-C2-4Alkylamino-C1-4Alkyl, C1-4Alkoxy-C2-4Alkylamino-C1-4Alkyl, C1-4Alkylthio-C1-4Alkyl, Hydroxy-C2-4Alkylthio-C1-4Alkyl , C1-4Alkoxy-C2-4alkylthio-C1-4alkyl, Phenoxy-C1-4alkyl, Aniline-C1-4alkyl, Phenylthio-C1-4alkyl, Cyano-C1-4alkyl, Halogen-C2-4Alkoxy, Hydroxy-C2-4Alkoxy, C2 -4alkanoyloxy-C2-4Alkoxy, C1-4Alkoxy-C2-4Alkoxy, Carboxy-C1-4Alkoxy., C1-4Alkoxycarbonyl-C1-4Alkoxy, Carbamoyl-C1-4Alkoxy, N-C1-4Alkylcarbamoyl-C1-4Alkoxy, N,N- di[C1-4alkyl]carbamoyl-C1-4Alkoxy, Amino-C2-4Alkoxy, C1-4Alkylamino-C2-4Alkoxy, Di-[C1-4Alkyl]Amino-C2-4Alkoxy, C1-4Alkanoyloxy, Hydroxy-C2-4alkanoyloxy, C1-4 -4Alkoxy-C2-4Alkanoyloxy, Pheny1-C1-4Alkoxy, Phenoxy-C2-4Alkoxy, Aniline-C2-4Alkoxy, Phenylthio-C2-4Alkoxy, Piperidine-C2-4Alkoxy, Morpholine-C2-4Alkoxy, Piperazin-1-yl-C2 -4Alkoxy, 4-C1-4alkylpiperazin-1-yl-C2-4Alkoxy, Halogen-C2-4Alkylamino, Hydroxy-C2-4Alkylamino, C2-4alkanoyloxy-C2-4Alkylamino, C1-4Alkoxy-C2-4Alkylamino, Carboxy-C1-4alk ylamino, C1-4alkoxycarbonyl-C1-4alkylamino, carbamoyl-C1-4alkylamino, N-C1-4alkylcarbamoyl-C1-4alkylamino, N,N-di-[C1-4alkyl]carbamoyl-C1-4alkylamino, amino-C2-4alkylamino, C1 -4alkylamino-C2-4alkylamino, di-[C1-4alkyl]amino-C2-4alkylamino, phenyl-C1-4alkylamino, phenoxy-C2-4alkylamino, aniline-C2-4alkylamino, phenylthio-C2-4alkylamino, C2-4alkanoylamino, C1- 4Alkoxycarbonylamino, C1-4alkylsulfonylamino, benzamido, benzenesulfonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, Halogen-C2-4alkanoylamino, hydroxy-C2-4alkanoylamino, C1-4alkoxy-C2- 4alkanoylamino, Carboxy-C2-4alkanoylamino, C1-4Alkoxycarbonyl-C2-4alkanoylamino, Carbamoyl-C2-4alkanoylamino, N-C1-4alkylcarbamoyl-C2-4alkanoylamino, N,N-di-[C1-4alkyl]carbamoyl-C2-4alkanoylamino, amino -C2-4alkanoylamino, C1-4alkylamino-C2-4alkanoylamino or di-[C1-4alkyl]amino-C2-4alkanoylamino, and indicated that said benzamido or benzenesulfonamido substituent or any aniline, phenoxy or phenyl group on R1 the tuent can optionally carry one or more halogen, C1-4alkyl or C1-4alkoxy substituents; or any adjacent pair of R1, R2, R3 and R3' together form an optionally substituted methylenedioxy or ethylenedioxy group; each R4 is independently hydrogen, hydroxy, halogen, C1-4alkyl, C1-4alkoxy, C1-4alkylamino, di-[C1-4alkyl]amino, C1-4alkylthio, C1-4alkylsulfinyl, C1-4alkylsulfonyl, C1-4alkylcarbonyl C1-4alkylcarbamoyl, di-[C 1-4 alkyl]carbamoyl, carbamyl, C 1-4 alkoxycarbonyl, cyano, nitro or trifluoromethyl; R 5 is hydrogen, halogen, trifluoromethyl, C 1-4 alkyl or C 1-4 alkoxy; each R6 is independently a group ZR7 which Z is attached to R7 via a (CH2)p group where p is 0, 1 or 2 and Z represents the group V(CH2), V(CF2), (CH2)V, (CF2)V , V(CRR1), V(CHR) or v where R and R1 are each C1-4alkyl and wherein V is a hydrocarbyl group containing 0, 1 or 2 carbon atoms, carbonyl, CH(OH), sulfonamide, amide, O, S(O)m or NRb where Rb is hydrogen or Rb is C1-4alkyl; and R7 is optionally substituted C3-6cycloalkyl; or an optionally substituted 5, 6, 7, 8, 9 or 10 membered carbocyclic or heterocyclic moiety; or R6 is a group ZR7 in which Z is NRb, and NRb and R7 together form an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety. 2. A compound as claimed in claim 1, wherein 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 1-4 alkylamino, or R 1 and R2 or R1 and R3 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 alkyl]amino, nitro or trifluoromethyl; R 5 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy; Z is absent or represents CH2, oxygen, S(O)m wherein m is 0, 1 or 2 or NRb wherein Rb is hydrogen, or Rb is C1-4alkyl, and R7 is optionally substituted phenyl, benzyl, pyridyl , dioxolanyl, phenoxy, benzyloxy, phenylamino, benzylamino, phenimercapto or benzylmercapto group, preferably phenyl, fluorophenyl, pyridyl, 1,3-dioxolanyl or benzyl group. 3. A compound as claimed in claim 1 or 2 characterized in that R1, R2 and R3 are each selected from hydroxy, C1-4alkyl, C1-4alkoxy or a fused, methylenedioxy or ethylenedioxy group. 4. A compound as claimed in claim 1, 2 or 3 characterized in that R 6 is a ring distant from Y when U represents a bicyclic group. 5. A compound as claimed in claim 1, 2, 3 or 4 wherein X is N 6. A compound as claimed in any preceding claim, wherein Y is NRb, NRb(CH2), or (CH2)NRb, preferably Y is NRb. 7. A compound as claimed in any preceding claim wherein U is indolyl, isoindolyl, indolinyl, isoindolinyl, 1-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro- 1H-benzimidazolyl or 1H-benztriazolyl group. 8. A compound as claimed in any preceding claim, wherein R 6 is phenyl, fluorophenyl, phenethyl, benzyl, pyridyl, phenylsulfonyl, benzylsulfonyl, phenoxy, benzyloxy or 1,3-dioxalanyl. 9. A compound as claimed in any preceding claim, wherein R 1 and R 2 are independently hydrogen, C 1-4 alkyl or C 1-4 alkoxy. 10. A compound as claimed in claim 1 selected from the group consisting of: 4-(1-benzyl-5-indolylamino)quinazoline 4-(1-benzyl-5-indolylamino)-6,7-dimethoxyquinazoline; 4-(2-benzyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline; 4-(2-benzyl-5-benzimidazolylamino)-quinazoline; 4-(2-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline; 4-(1-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline; 4-(1-benzyl-5-indazolylamino)-quinazoline; 4-(1-phenylsulfonyl-5-indolylamino)-6,7-dimethoxyquinazoline; 4-(1-benzyl-2,3-dihydroindolyl-5-amino)-6,7-dimethoxyquinazoline; 4-[3-(4-fluorophenyl)-6-indazolylamino]-6,7-dimethoxyquinazoline; 4-(1-benzyl-5-indolylamino)-6,7-diethoxyquinazoline; 4-[1-[2-(1,3-dioxolan-2-yl)-ethyl]-5-indazolylamino]-6,7-dimethoxyquinazoline; 4-(1-benzyl-6-indolylamino)-6,7-dimethoxyquinazoline; 4-(2-phenyl-5-benzimidazolylamino)-6,7-dimethoxyquinazonine; 4-(1-benzyl-5-indolylamino)-6,7-methylenedioxyquinazoline; 4-(3-benzyl-5-benzimidazolylamino)-quinazoline; 4-(1-benzyl-5-benzimidazolylamino)-quinazoline; 4-(2-benzyl-5-benzotyrazolylamino)-6,7-dimethoxyquinazoline; 4-(1-benzyl-5-benzotriazolylamino)-6,7-dimethoxyquinazoline; 4-(3-benzyl-5-benzotriazolylamino)-6,7-dimethoxyquinazoline; 4-(2-phenethyl-5-indazolylamino)-6,7-dimethoxyquinazoline; 4-(1-phenethyl-5-indazolylamino)-6,7-dimethoxyquinazoline; 4-(2-(2-pyridyl)-benzimidazolylamino)-quinazoline; 4-(2-benzylsulfonyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline; and their salts, especially pharmaceutically acceptable salts. 11. A compound as claimed in claim 1, selected from the group consisting of: 4-(2-benzyl-5-benzimidazolylamino)-6,7-dimethoxyquinazoline; 4-(2-benzyl-5-indazolylamino)-6,7-dimethoxyquinazoline; 4-(1-benzyl-5-indazolylamino)-quinazoline; 4-(1-phenylsulfonyl-5-indolylamino)-6,7-dimethoxyquinazoline; and their pharmaceutically acceptable salts. 12. A method of treating a human or animal organism suffering from disorders mediated by aberrant tyrosine kinase activity characterized by the application of an effective amount of the compound of formula (I), or its physiologically acceptable salt, to the sick human or animal. 13. Pharmaceutical preparation characterized in that it contains one or more compounds of formula (I), or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable carriers. 14. The form of the dosage unit characterized by the fact that it contains the compound of formula (I) or its physiologically acceptable salt in the amount of 70 to 700 mg. 15. Process for obtaining the compound of formula (1), indicated by the fact that the process includes a step in which the compound of formula (II) reacts: [image] with a compound of formula (III); UYH (III) wherein L is a residue and U, X, Y and R1 to R6 are as defined in claim 1. 16. The method as claimed in claim 14, characterized in that the method includes the step of transforming a compound of formula (I) into another compound of formula (I). 17. A compound of formula (I), or a pharmaceutically acceptable salt thereof, indicated to be used in treatment. 18. The use of a compound of formula (I), or its pharmaceutically acceptable salt, characterized in that it is used for the preparation of drugs for the treatment of malignant tumors. 19. Use of the compound of formula (I), or its pharmaceutically acceptable salt, indicated by its use, in the preparation of drugs for the treatment of atherosclerosis, restenosis and thrombosis.