MXPA94005451A - Quinazoline derivatives - Google Patents

Abstract

The invention concerns quinazoline derivatives of the formula I wherein R1 includes hydroxy, amino, hydroxyamino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;R3 is halogeno;n is 1, 2 or 3 and R2 includes hydrogen, hydroxy, halogeno and (1-4C)alkyl;or a pharmaceutically-acceptable salt thereof;processes for their preparation;pharmaceutical compositions containing them;and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of cancer.

Description

QUINAZOLINE DERIVATIVES OWNER: ZENECA LIMITED, a company of British nationality, domiciled at: 15 Stanhope Gate, London W1Y 6 LN, GREAT BRITAIN.

INVENTOR: ANDREW JOHN BARKER, British national, residing at: Alderley park, Macclesfiel, Cheshire, SK 10 4TG, GREAT BRITAIN. ri? a haHMii.HüMii ^ ai ^ MÉ EXTRACT OF THE INVENTION The present invention relates to the quinazoline derivatives of the formula I wherein R comprises hydroxy, amino, hydroxyamino, (1-4C) alkoxy, (1-4C) alkylamino, and di- ((1-4C) alkyl-amino-R3 is halogen, n is 1, 2, a, 3, and R includes hydrogen, hydroxy, halogen, and (1-4C) alkyl, or a pharmaceutically acceptable salt thereof, to a process for their preparation, to pharmaceutical compositions containing them, and use of the inhibitory properties of the kinase of the titosin receptor of the compounds in the treatment of cancer.

DERIVATIVES OF OUINAZOLINE This invention relates to quinazoline derivatives, or pharmaceutically acceptable salts thereof, which have activity against cancer, and are accordingly useful in methods of cancer treatment in humans or animals. The invention also relates to the processes for obtaining the quinazoline derivatives, to the pharmaceutical compositions containing them, and to their use in obtaining the drugs of use in obtaining an anti-cancer effect in an animal. of warm blood such as man. Most common treatment regimens, for cancer that uses compounds which inhibit DNA synthesis. Such compounds are generally toxic to cells, but their toxic effect on rapidly dividing tumor cells may be beneficial. Alternative researches, to anti-cancer agents by means of different mechanisms at inhibition of synthesis of DNA which has potential, having the increased selectivity of action against cancer cells. In recent years, it has been discovered, that a cell can begin to be cancerous, by virtue, of the transformation of a portion of its DNA, into an oncdgene, for example a gene, into activation, which leads to the formation of cells of malignant cancer (Bradshaw, Mutagenisis, 1986, 1, 91). Several such proteins must elevate the production of the peptides, which are the receptors for the growth factors. The growth factor receptor complex, subsequently leads to an increase in the proliferation of the cells. It is known, for example, that the various oncegens encode the enzymes of the tyrosine kinase and that certain of the growth factor receptors are also the enzymes of the tyrosine kinase (Yarden et al., Ann Rev. Biochem. , 1988, 57, 443, Larsen et al., Ann Reports in Med. Chem, 1989, chapter 13). The tyrosine kinases of the receptor are important in the transmission of biochemical signals which initiate the replication of cells. These are long enzymes, which expand the cell membrane and have an extracellular binding domain, for growth factors, such as epidermal growth factor, and an intracellular portion, which functions as a kinase to phosphorylate amino acids of tyrosine, in proteins and therefore the influence of cell proliferation. It is known that such kinases are frequently present in common human cancers such as breast cancer, (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncoqene Res., 1988, 3, 21), gastrointestinal cancer such as cancer of the colon, rectal or stomach cancer - (Bolen et al., Oncogene Res., 1987, 1, 149), leukemia (Konaka et al., Cell, 1984, 37 , 1035), and ovarian, bronchial or pancreatic cancer (Description of European Patent No. 0400586). Let the tissues of human tumors be tested, for receptor tyrosine kinase activity, it is expected to prevail widely, to be established in additional cancers, such as thyroid cancer and uterine cancer. It is also known that tyrosine kinase activity is rarely detected in normal cells, which is more often detectable in malignant cells (Hunter Cell, 1987, 50, 823). It has been shown more recently (WJ Gullick, Brit Med. Bull, 1991, 47, 87), that the epidermal growth factor receptor to which it has tyrosine kinase activity is over expressed in the majority of cancers humans such as tumors in the brain, in the squamous cells of the lung, liver, cancer & Gastric, breast, head, neck, esophagus, gynecological or thyroid. Accordingly, it has been recognized that a receptor tyrosine kinase inhibitor will be of importance as a selective inhibitor of the growth of mammalian cancer cells, (Yaish et al., Science, 1988, 242, 933. ). Support for this view is provided by the demonstration that erbstatin, an inhibitor of receptor tyrosine kinase, specifically attenuates the growth in the athymic time of a transplanted human breast carcinoma, which expresses the epidermal growth factor (EGF) of receptor tyrosine kinase, but without effect on the growth of another carcinoma, which does not express the tyrosine kinase of the EGF receptor (Toi et al., Eur. J Cancer Clin. Oncol., 1990, 26, 722). Various styrene derivatives are also mentioned that possess the inhibitory properties of tyrosine kinase (European Patent Application Nos. 0211363, 03004493, and 0322738), and of the use for anti-tumor agents. The inhibitory effect in vivo of the two styrene derivatives has been demonstrated against the growth of carcinoma of human squamous cells inoculated in the clean mouse (Yoneda et al, Cancer Re search, 1991, 51, 4430). According to this it has been indicated that the receptor tyrosine kinase inhibitors which provide utility in the treatment of a variety of human cancers. The various known tyrosine kinase inhibitors are mentioned in more recent journals by T. R. Burke Jr. (Drugs of the Future, 1992, 17, 119). We have now found that certain quinazoline derivatives possess anti-cancer properties, which are thought to elevate their inhibitory properties of the tyrosine kinase of the receptor. It is known from patent application WO 92/20642 that certain aryl and heteroaryl compounds inhibit the receptor tyrosine kinase. It exists in the description of certain quinazoline derivatives, but it is not mentioned that it is made of the 4-anilinoquinazoline derivatives. It is also known from the Socility of European Patent No. 92305703.8 (publication No. 520 722), that certain 4-anilinoquinazoline derivatives which are unsubstituted at positions 5 to 8 of the quinazoline ring or which has a substituent of halogen, trifluromethyl, or nitro, to one of the positions that are tiltile as the inhibitors of the receptor tyrosine kinase. The 4-anilinoquinazoline derivatives, which may have an amino, alkylamino, acylamino or alkoxy substituent, in any of positions 5 to 8 are NOT mentioned in the description of the application. We have now discovered that certain derivatives of 4-anilinoquinazoline, may have a halo substituent in the 7-position and which may be an amino, alkylamino, acylamino, or alkoxy substituent, in the 6-position, which are useful as the tyrosine kinase inhibitors of the receiver.

According to the invention there is provided a quinazoline derivative of the formula I (as mentioned # after) wherein R is hydroxy, amino, hydroxyamino, trifluoromethoxy, (1-4C) alkoxy, (1-4C) alkylamino, di-alkylamino e (1-4C), aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazin-1-yl of (1-4C), alkylthio of (1-4C), hyalin-alkoxy (2-4C), hydroxy-alkoxy (2.4C), (1-4C0) alkoxy (2-4C) alkoxy, (1-4C) phenylalkoxy, (2-4C) haloalkylamino; -alkylamino of (2-4C), alkoxy of (1-4C) -alkylamine of (2-4C), phenyl-alkylamino of (1-4C), alkanoynyl of (2-4C) ° benzamido, 2- oxopyrrolidin-l-yl, 2-oxopiperdin-l-yl, halogen-alkanoylamino of (2-4C), hydroxy-alkanoylamino-de (2-4C), alkoxy of (l-4C) -alkanoylamino of (2-4C) , (3-4C) alkenoylamino, (3-4C) alkanoylamino, (1-4C) N-alkyl, -alkanoylamino, (1-4C) N-alkylbenzamido, (L-4C) -alkylolamine N-alkylhalogen of ( 2-4C), N- (1-4C) -hydroxy-alkanoylamino (2-4C) alkyl, (1-4C) N-alkyl ((1-4C) talcanoylamino of (2-4C), N- (1-4C) -alkeneoylamino of (3-4C), or N- (1-4C) -alkeneoylamino of (3-4C), or (1-4C) -alkyl-noylamino N-alkyl of (3-4C), and wherein the benzamido or substituent of N-alkylbenzamido of (1-4C) * or any phenyl group in a substituent of R may optionally have one or two halogens, alkyl of (1) -4C), or (1-4C) alkoxy. R is halogen, and n is an integer of 1,2, or 3, and each of R is independently hydrogen, hydroxy, halogen, tri-fluoromethyl, amino, nitro, cyano, (1-4C) alkyl, alkoxy ( 1-4C), or (2-4C) alkanoylamino; or a pharmaceutically acceptable salt. of the same. The chemical formulas referred to with Roman numerals are mentioned for convenience on a separate sheet 'after'. In this description, the term "alkyl" includes both straight chain or branched chain alkyl groups, but references to individual alkyl groups such as "propyl" are specific to the straight chain version only. A similar convention applies to other generic terms. Within the present invention, it will be understood that a quinazoline of the formula can have the phenomenon of tautomerism, and that the drawings of the formulas within the description may represent only one of the possible tautomeric forms. It will be understood that the invention comprises any tautomeric form, which has activity against cancer, and is not limited to only, any of the tautomeric forms, used within the drawings of the formulas. The quinazolian of the formula I are insubstantiated in the 2-, 5- and 8-positions. It will also be understood that certain quinazolines of the formula I can exist in the solvate as well as in the unsolvated forms, such as, for example, the hydrated forms. It will be understood that the invention will comprise such solvated forms, which have anti-cancer activity. Itk According to a further aspect of the invention there is provided a quinazoline derivative of the formula I in doftde j R is hydroxy, amino, hydroxyamino, trifluoromethoxy, alkoxy of (1-4C), alkylamino of (1-4C), di -alkylamino of (1-4C), aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazin-1-yl of (1-4C) , alkylthio of (1-4C), has l-geno-alkoxy of (2-4C), hydroxy-alkoxy of (2-4C), alkoxy 9- of (l-4C) -alkoxy of (2-4C), phenyl-(1-4C) alkoxy, (2-4C) halalgeno-alkylamino, (2-4C) hydroxy-alkylamino, (1-4C) alkoxy- (2-4C) alkylamino, phenyl-alkylamino (1-4C), (2-4C) alkanoylamino, benzamido, 2-oxopyrrolidin-l-yl, 2-oxopiperidin-l-yl, haldino-alkanoylamino of (2-4C), hydroxy-alkanoylamino of (2-4C) ), or (1-4C) -alkylamino of (2-4C), and wherein the benzamido substituent or any phenyl group in the substituent of R may optionally have one or two halogens, -4C), or the (1-4C) alkoxy substituent; R is halogen; and n is an integer of 1,2, or 3, and each of R 2 is independently hydrogen, hydroxy, halogen, tri-fluromethyl, amino, nitro, cyano, (1-4C) alkyl, (1-4C) alkoxy , or (2-4C) alkanoylamino; or a pharmaceutically acceptable salt thereof. Suitable substituents for the generic radicals referred to above include? those mentioned-; down . 2 A suitable substituent for R when it is (1-4C0) alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, when it is alkoxy is, for example, methoxy, ethoxy, propoxt, isopropoxy, or butoxy, and when it is alkanoylamino of (2-4C), it is for example, acetamido, propione gone, or butyrate gone.The substituents suitable for each of R, which can be on the quinazoline ring include, for example: for (1-4C) methoxy, ethoxy, propoxy, isopropoxy, and butoxy alkoxy, for (1-4C) methylamino, ethylamino, and propylamino, for di-alkylamino of (1- 4) dimethylamino, diethylamino, N-ethyl-N-methylamino and dipropylamino; - - for (1-4C) alkylthio methylthio, ethylthio, and propylthio for alkyl of 4- (l-4C) -pi-perazin-1-yl 4-methylpiperazin-1-yl and 4-ethylpiperazin-1-yl; for halogen = (1-4C) 2-fluroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy; for hydroxy (1-4C) alkoxy-2-hydroxyethoxy, 3-hydroxypropyl and 4-hydroxybutoxy; for (1-4C) -alkoxy 2-4C alkoxy. 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, and 3-ethoxypropoxy; for phenyl (1-4C) alkoxybenzyloxy, 2-phenylethoxy, and 3-phenylpropoxy; for (2-4C) 2-fluoroethylamino haloalkylamino. 2-chloroethylamino, 2-bromoethylamino, 3-fluropropylane and 3-chloropropylamino; for hydroxy-alkylamino of (2-4C) 2-hydroxyethylamino, 3-hydroxypropylamino and 4-hydroxybutylamino; -alkyl (1-4C) -alkylamino of (2-4C) 2-methoxyethylamino; 2-ethoxyethylamino; 3-methoxypropylamino and 3-ethoxypropylamino; for phenyl-alkylamino of (1-4C) benzylamino, phenethylamino, and 3-phenylpropylamino, for (2-4C) alkylated alkanoylamino, propionamido and 2-butyramino; for halogeno-alkanoylamino of (2-4C) 2-chloroacetamido, 2-bromoacet mido, 3-chloropropioamino, 3-bromopropionamido, and 4-chlorobutyrami; for hydroxy-alkanoylamino of (2-4C) 2-hydroxyacetamido, 3-hydroxy propioamido and 4-hydroxybutyram; for (l-4C) -alkanoyl-amino (2-4C) alkoxy; 2-methoxyacetamido, 2-ethoxy-acetamido-, 2-propoxyacetamido 3-methoxypropioamido; 3-ethoxypropioamido and 4-methoxybutyramido; for (3-4C) alkanoylamino acrylate, methacrylamide, cro- W ^ tonamido, and isochotone gone; for (3-4C) propiolamino alkynylamino; for (1-4C) N-alkyl- (2-4C) alkylamino-N-methylacetamido, N-ethylacetated, and N-methylpropioamido; for N-alkylbenzamido of (1-4C) N-methylbenzamido; for (l-4C) -halogen-alkanoylamino (1-4C) 2-chloro-N-methylacetamido alkyl; # 2-chloro-N-ethylacetamido and 3-chloro-N-methylpropionamido; for N-alkyl-hydroxy (1-4C) -alkylamino of (2-4C) 2-hydroxy-N-methylacetamido, N-ethyl-2-hydroxyacetamido and 3-hydroxy-N-methylacetamido; for N-alkyl (1-4C) -alkoxy (1-4C0-alkanoylamino # of (1-4C) 2-methoxy-N- -methylacetamido, N-ethyl-2-methoxyacetamido, 2-ethoxy-N -methylacetamido and 2-ethoxy-N-ethylacetamio; for N-alkyl of (l-4C) -alkanoylamino of (3-4C) N-methylacrylamido, N-ethylacrylamido, and N-methylmethacrylamido; - - for (3-4C) N-alkyl (3-4C) -alylamino; N-methylpropiolamido and N-ethyl propylamido. Suitable substituents for the values which are present on the phenyl ring, when R 1 is -benzamido or N-alkylbenzamido of (1-4C) / or on a substituent of R which contains an incidental phenyl group, for example : for halogen: fluro, chlorine and bromine; for (1-4C) alkyl methyl, ethyl and propyl; for (1-4C) methoxy, ethoxy and propoxy alkoxy. A suitable substituent for R2 and R3 when it is halogen is, for example, fluorine, chlorine, bromine or iodine. A pharmaceutically acceptable salt of a quinazoline derivative of the invention is, for example, an acid addition salt, and a quinazoline derivative of the invention, which is sufficiently basic, eg, an acid addition salt. , with, for example, an inorganic acid, or an organic acid, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition, a pharmaceutically acceptable salt of a quinazoline derivative of the invention which is sufficiently acidic is an alkali metal salt, for example the sodium salt or the potassium salt, an alkaline earth metal salt, for example the salt calcium salt or the magnesium salt, an ammonium salt, or a salt with an organic base, which gives a physiologically acceptable cation, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Particular novel compounds of the invention include, for example, the quinazoline derivatives of the formula I or the pharmaceutically acceptable salts thereof, wherein: - (a) R is hydroxy, amino, hydroxyamino, trifluoromethoxy, alkoxy, (1-4C), (1-4C) alkylamino, (1-4C) alkylamino, aziridin-1-yl azetidin-1-yl, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1- ilo, 4-alkylpiperazin-1-yl of (1-4C), alkylthio of (1-4C), halogen-alkoxy of (2-4C), hydroxy-alkoxy of (2-4C), alkoxy of (1-4C) -alkoxy of (2-4C), hydroxy-alkylamine.no.- c of(2-4C), (1-4C) alkoxy- (2-4C) alkylamino, alkanoylamino (2-4C), 2-oxopyrrolidin-1-yl, halogen-alkanoylamino of (2-4C), hydroxy-alkanoylamino of (2-4C), or (1-4C) -alkoxylamino alkoxy of (2-4C) , and n, R 2 and R 3 have any of the meanings mentioned above, or in this section refer to the novel novel compounds in particular of the invention. (b) R is amino, hydroxyamino, (1-4C) alkylamino-di (1-4C) alkylamino, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidino, morpholino, piperazin -1-ilo, • 4-alkyl (1-4C) -piperazin-1-yl, hiroxy-alkylamino of (2-4C), alkoxy of (1-4C) -alkylamino of (2-4C), alkanoylamino of (2-4C) , 2-oxopyrrolidin-l-yl, halo-alkanoylane of (2-4C), hydroxy-alkanoylamino of (2-4C), or (1-4C) alkoxy-alkanoylamino of (2-4C), and n, R2 and R can have any of the meanings mentioned above, or in this section with respect to the particular novel compounds of the invention; (c) R1 is amino, hydroxyamino, (1-4C) alkylamino, (1-4C) alkylamino, and (2-4C) alkanoylamino, 2-oxopyrrolidin-l-yl, halogen-alkanoylamino of (2-4C), alkenoylamino of (3-4C), alkanoylamino of (3-4C), N-alkyl of (l-4C) -alkanoylamino of (2-4C) ), and N-alkyl of (1-4C) -halogen-alcananoylamino of (2-4C) ° and n, R? and R3 have any of the meanings mentioned above, or in this section with respect to the novel novel compounds in particular of the invention; (d) R ^ s hydroxy, trifluoroethoxy, (1-4C) alkoxy, (1-4C) alkylthio, (2-4C) halogen-alkoxy, (2-4C) hydroxy-alkoxy, or alkoxy of (1-4C) -alkoxy of (1-4C), and n, RR have any of the meanings mentioned above, or in this section with respect to the novel novel compounds in particular of the invention, or (e) ) n is 1 or 2, and each of R is independently hydrogen, hydroxy, halogen, trifluromethyl, amino, nitro, cyano, or (1-4C) alkyl, and R 1 and 3 have any of the meanings mentioned above , or in this section in relation to the novel compuetos of the invention.

A further particular compound of the invention is a quinazoline derivative of the formula I: wherein R is hydroxy, amino, hydroxyamino, methylamino, ethylamino, dimethylamino, diethylamino, aziridin-1-yl, azetidin-1-yl, pyrrolidin -1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, acetamido, propioamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, 3-chloropropionamido, 4-chlorobutyramido, 2-hydroxyacetamido , or 2-methoxyacetamido; -a RJ is fluro, or chloro, and 2 (R) n is 4'-fluro, 3'-clro-. 3'-bromo, 3 ', 4' -dichloro, 3'-chloro-4'-fluro, 3'-trifluoromethyl, 4'-fluoro-3'-tr-fluoromethyl, 3'-nitro, 4'-chloro-3 '-nitro, 4'-fluoro-3' -nitro, or 3 '-methyl; or a pharmaceutically acceptable salt thereof.

A particular compound in addition is a quinazoline derivative of formula I; wherein R is hydroxy, amino, hydroxyamino, methylamino, ethyl-amino, dimethylamino, diethylamino, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, acetamido, propionamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, 3-chloropropioamido, 4-chlorobutyramido, 2-hydroxyacetamido, 2-methoxyacetamido, acrylamido, methacrylate, N-methylacetamido, N -ethylacetamido, N-methyl-propionamido, 2-chloro-N-methylacetamido, or 2-chloro-N-ethylace-tamido; 3 R is fluorine, or chlorine, and 2 (R) is 4-fluoro, 3'-chloro, 3'-bromo, 3 ', 4'-dichloro, n 3'-chloro-4'-fluoro, 3 * - trifluoromethyl, 4 * -fluro-3 * -tri-fluromethyl, 3'-nitro, 41-chloro-3 • -nitro, 4 '-fluor, 3'-nitro, or 3 * -methyl; or a pharmaceutically acceptable salt thereof. A further particular compound of the invention is a quinazoline derivative of the formula I: wherein R is methoxy, ethoxy, methylthio, 2-chloroethoxy, 2-bro-moetoxy, 2-hydroxyethoxy, or 2-methoxyethoxy; 3 R is fluro, or chloro, and 2 (R) is 4'-fluro, 3'-chloro-, 3'-bromo, 3 ', 4'-dichloro, 3'-chloro-4'-fluro, 3 '-trifluromethyl, 4' -fluro, 3 * -trifluoromethyl, 3'-nitro, 4'-chloro-3'-nitro, 4'-fluoro-3'-nitro, or 3'-methyl; or a pharmaceutically acceptable salt thereof.

A preferred compound of the invention is a quinazoline derivative of the formula I wherein R is amino, hydroxyamino, methylamino, dimethylamine -no, acetamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, or 4-chlorobutyramido; R3 is fluorine, or chlorine; and (R2) is 3'-chloro, 3 ', 4'-dichloro, 3'-chloro-4' -fluro, or 3'-methyl or a pharmaceutically acceptable salt thereof. A preferred compound of the present invention is a quinazoline derivative of the formula I wherein R is amino, hydroxyamino, methylamino, dimethylamino, acetamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, 4-chloro-butyramido, acrylamido, or 2-chloro-N-methylacetamido; 3 R is fluorine, or chlorine; and (R) is 3'-chloro, 3 ', 4'-dichlor, 3 • -chloro-4' -fluor, or 3'-methyl; or a pharmaceutically acceptable salt thereof. A further preferred compound of the invention is a quinazoline derivative of the formula I wherein R is methoxy or ethoxy; 3 R is fluorine, or chlorine, and 2 (R) is 3'-chloro, 3 ', 4'-dichloro, 3'-chloro-4' -fluro, or n 3 '-methyl; or a pharmaceutically acceptable salt thereof. A specific preferred compound of the invention is the following quinazoline derivative of the formula I, 6-amino-7-fluro-4- (3'-methylanilino) quinazoline, Jm 6- (2-chloroacetamido) -7-fluor- 4- (3'-methylanilino) quinazoline, 6-amino-4- (3'-chloro-4 '-fluroanilino) -7-fluoroquinazoline, 7-chloro-6-methylamino-4- (3'-methylanilino) quinazoline, 7-chloro-6- (2-chloroacetamide) ) -4- (3'-methylanilino) quinazoline and 7-chloro-6- (2-chloroacetamido) -4- (3 ', 4'-dicloreanilino) quinazoline, or a pharmaceutically acceptable acid addition salt of the same. A further specific preferred compound of the invention is the following quinazoline derivative of the formula I 7-fluro-6-hydroxyamino-4- (3'-methylanilino) quinazoline, 4- (3'-chloro-4 '-fluroanilino) - 7-fluro-6-hydroxyaminoquinazoline, 6-acrylamido-7-fluro-4- (3'-methylanilino) quinazoline, 4- (3'-chloro-4'-fluoroanilino) -7-fluro-6-methylaminoquinazo- lina, 6- (2-chloroacetamido) -4- (3'-chloro-4 * -fluroanilino) -7-fluroquinazoline, 6- (4-chlorobutyramido) -4- (3'-chloro-4'-fluroanilino) ) -7- fluorinaquinazoline, or 4- (3'-chloro-41-fluoanilino) -7-fluro-6- (2-oxopyrrolidin-1-yl) quinazoline; or a pharmaceutically acceptable acid addition salt.

A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, can be prepared by any of the known methods, which are applicable to the preparation of the chemically related compounds. A suitable method is, for example, that illustrated in European Patent Application No. 0520 722. Such methods, when used, for preparing a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, which are provided as a further embodiment of the invention, and are illustrated by the following representative examples, in which, at least without being mentioned otherwise, R, n, R and R have any of the meanings mentioned above, for a derivative of quinazoline of the formula I. The necessary starting materials can be obtained by the normal procedures, of the IK-organic chemistry. The preparation of such materials is described within, of the non-limiting Examples. The necessary alternative starting materials are obtained by analogous methods, to those illustrated which are within the common knowledge of an organic chemist. (a) The reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula II (as mentioned below), wherein Z is a displaceable group, with an aniline of the formula III. A suitable displaceable group of Z is, for example, a halogen, alkoxy, aryloxy, or a sulfonyloxy group by, for example, chloro, bromo, methoxy, phenoxy, methanesulfinloxy, or a toluene-p-sulfonyloxy group. A suitable base is, for example, an organic amine base, such as, for example, pyridine, &; 2,6-lutidine, collidine, 4-dlmethylaminopyridine, triethylamine, morpholine, N-methylmorpholine, or diazabicyclo (5.4.0) -undec-7-ene, or, for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, or potassium hydroxide. Alternatively, the suitable base is, for example, an alkali metal amide or an alkaline earth metal amide, for example, a sodium amide or sodium bis (trimethylsilyl) amide. The preferred reaction is carried out in the presence of an inert solvent or diluent, for example an alkanol or ester, such as methanol, ethanol, isopropanol, or ethyl acetate, a halogenated solvent, such as methylene chloride, chloroform, or carbon tetrachloride, a ester such as tetrahydrofuran, or 1,4-dioxane, an aromatic solvent, such as toluene, or an aprotic dipolar solvent, such as N, N-dimethylformamide, N, N- dimethylacetamide, N-methylpyrrolidin-2-one, or dimethylsulfoxide. The reaction is suitably carried out at a temperature in the range of for example 10 to 150 ° C, preferably in the range of 20 to 80 ° C. The quinazoline derivative of the formula I can be obtained from this process, in the form of a free base or alternatively, it can be obtained in the form of a salt with the acid of the formula HZ, wherein Z has the meanings before mentioned. When it is desired to obtain the free base of the salt, the salt can be treated with a suitable base as defined above using a conventional procedure. (b) For the production of those compounds of the formula I, wherein R or R is hydroxy, the division of the quinazoline derivative of the formula I, wherein R or R is (1-4C) alkoxy. The division reaction is conveniently carried out by any of the known methods for such transformation. The reaction can be carried out, for example, by treatment of the quinazoline derivative with an alkali metal (1-4C) alkylsulfide, such as sodium ethanethiolate, or, for example, by treatment, with a diarylphosphide. of alkali metal, such as lithium diphenylphosphide. Alternatively, the cleavage reaction is conveniently carried out, for example, by treatment of the quinazoline derivative, with a boron or aluminum trihalogenide such as boron bromide. Such preferred reactions are carried out in the presence of a suitable inert solvent or diluent as defined above and at a suitable temperature as mentioned in the accompanying Examples, (c) For the production of those compounds of the Formula I, wherein R 1 is amino or hydroxyamino, the reduction of a quinazoline derivative of the formula I wherein R 1 is nitro. The reduction is carried out by any of the known methods for such transformation. The reduction is carried out, for example, by the hydrogenation of a solution of the nitro compound in an inert solvent or diluent as defined above in the presence of a suitable metal catalyst, such as palladium or platinum. Further suitable reducing reagent is, for example, an activated metal such as activated iron (produced by washing the powdered iron with a dilute solution of an acid, such as hydrochloric acid). Thus, for example, the reduction is carried out by heating a mixture of the nitro compound and the activated metal in a suitable solvent or diluent such as a mixture of water and an alcohol, for example methanol or ethanol, to a temperature on the scale of for example 50 to 150 ° C, conveniently at or near 70 ° C. (d) For the production of those compounds of "i the formula I wherein R is (2-4C) alkanoylamino, substituted (2-4C) alkanoylamino, benzamido, (3-4C) alkynolamino, -4C), N_ (1-4C) alkyl-alkanoylamino of (204C), (1-4C) -alkanoylamino- (2-4C) -substituted, N-(1-4C) -alkeneoylamino-N-alkyl of (3-4C), N- (1-4C) -alkanoylamino of (2-4C) or N-alkylbenzamido of (1-4C), or R2 is (2-4C) alkanoylamino, the acylation of a quinazoline derivative of the formula I wherein R 1 or R 2 is amino.

A suitable acylating agent is, for example, any agent known in the art, for the acylation of the amino to the acylamino, for example, an acyl halide, for example (2-4C) alkanoyl chloride, or bromide, or a benzoyl chloride or bromide, conveniently in the presence of a suitable base, as mentioned above, an anhydride of alcandic acid, or a mixed anhydride, for example an anhydride of alkanoic acid of (2-4) such as anhydride acetic acid or the mixed anhydride formed by the reaction of an alkanoic acid, and a (1-4C) alkoxycarbonyl halide, for example a (1-4C) alkoxycarbonyl chloride, in the presence of a suitable base such as has defined before. In the presence of a base # adequate as it was defined before. In general, the acylation is carried out in a solvent or inert diluent as defined above, and at a temperature on the scale of, for example, -30 to 120 ° C, conveniently at or near room temperature. (e) For the production of the compounds of the formula I 1 wherein R is (1-4C) alkoxy, substituted (1-4C) alkoxy, or R is (1-4C) alkylamino, di-alkylamino of (1-4C), or substituted alkylamino of (1-4C), is carried out in the presence of a base, as defined above, or a quinazoline derivative of the formula I wherein R1 is hydroxy or an amino according to be appropriate. A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy, or substituted alkoxy, or for the alkylation of the amino to the alkylamino or substituted alkylamino, for example, an alkyl halogenide or of substituted alkyl, for example (1-4C) alkyl chloride, bromide or iodide, or an alkyl chloride of (1-4C), bromide or iodide, in the presence of a suitable base is as defined above, in a suitable inert solvent or diluent as defined above, and at a temperature on the scale, for example from 10 to 140 ° C, conveniently at or near room temperature. When a pharmaceutically acceptable salt of a quinazoline derivative of the formula I is required, for example, an acid addition salt of the quinazoline derivative of the formula I can be obtained, for example, by the reaction of the compound, with , for example, a suitable acid, using a conventional method. As mentioned above, the quinazoline derivative defined in the present invention has anti-cancer activity, which is thought to elevate the inhibitory activity of the receptor tyrosine kinase of the compound. These properties can be tested, for example, using one or more of the methods as mentioned below: (a) An in vitro assay which determines the ability of the test compound to inhibit the tyrosine kinase of the enzyme receptor . The receptor tyrosine kinase is obtained in partially purified form from A-431 cells (derived from human vulval carcinoma) by procedures related to those described by Carpenter and col. , J. Biol. Chem, 1979, 254, 4884, Cohen _col., J. Biol Chem., 1982 257, 1523, and by Braun et al. , J. Biol. Chem. 1984, 250, 2051. All cells A-431, grow at the confluence of Dubelco modified Eagle's medium (DMEM), which contains 5% of fetal bovine serum (FCS). The obtained cells are homogenized in a hypotonic borate / EDTA regulation solution at pH 10.1. The homogenate is centrifuged at 400 g., Per minute, at 0-4 ° C. The supernatant is centrifuged at 25,000 g., For 30 minutes at 0-4 ° C. The pellet material is suspended in a regulation solution of 30 mM Hepes at pH 7.4, containing 5% glycerol, 4 mM benzamidine and 1% Triton X-100, stirred for 1 hour at 0-4 ° C , and centrifuged again at 100,000 g for 1 hour at 0-4 ° C. The supernatant it contains, the receptor tyrosine kinase solubilized, it is stored in liquid nitrogen. For the purpose of testing, 40 ul of the solution of the enzyme thus obtained is added to a mixture of 400 ul, of a mixture of 150 mM of the buffer solution of 150 mM Hepes at pH 7.4, 500 uM of orthovanadate of sodium, 0.1% triton X-100, 10% glycerol, 200 ul, water, 80 ul DTT 25 mM, and 80 ul, a mixture of 12.5 mM manganese chloride, 125 mM magnesium chloride, and distilled water. The solution of the test enzyme is thus obtained. Each of the test compounds is dissolved in dimethyl sulfoxide (DMSO), whereby a 50 mM solution is obtained which is diluted with a buffer solution of 40 mM Hepes, containing 0.1% Triton X-100, 10 % glycerol, and 10% DMSO with which a 500 uM solution is obtained. The equal volumes of -is solution, and a solution of the epidermal growth factor (EGF); 20 ug / ml.), Mixed. (f32-P) ATP (3000 Ci / mM, 250 uCi), diluted to a volume of 2 ml, by the addition of an ATP solution (100 uM), in distilled water. A volume equal to 4 mg / ml, of the peptide solution Arg-Arg-Ley-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala_Arg-Gly in a mixture of the regulation solution of Hepes 40 mM at pH 7.4, 0.1% Triton X-100, and 10% glycerol is added. The test compound / mixture of EGF (5ul) solution is added to a solution of the test enzyme (10 ul), and the mixture is incubated at 0-4 ° C, for 30 minutes. The mixture of ATP / peptide (10 ul) is added and the mixture is incubated at 25 ° C for 10 minutes. The phosphorylation reaction is terminated by the addition of 5% trichloroacetic acid (40 ul), and bovine serum albumin (BSA, lmg / ml., 5 ul). The mixture is allowed to stand at 4 ° C, for 30 minutes, and then centrifuged. An aliquot (40ul) of the supernatant is placed in Whatman p 81 phosphocellulose paper. The filter is washed in 75 mM phosphoric acid (4 x 10 ml.), And the stain is dried. The radioactivity present in the filter paper is measured using a liquid scintillation counter (sequence A). The sequence of the reaction is repeated in the absence of EGF (sequence B), and again in the absence of the test compound (Sequence C). Inhibition of receptor tyrosine kinase is calculated as follows: % Inhibition * 100 - (A -B)? l 8 C - B The degree of inhibition is determined over a range of the concentrations of the test compound as given in the IC (b) values. An in vitro assay, which determines the ability of a test compound to inhibit the growth of the line of human naso-pharyngeal cancer cells KB. The cells are placed in the orifices at a density of 1 x 10 - 1.5 x 10 cells per hole and allowed to grow for 24 hours in DMEM, supplemented with 5% -ECS (activated carbon). The growth of the cells is determined after incubation for 3 days, by the degree of metabolism of the tetrazolium dye MTT to give a blue color. The growth of the cells is determined after etv la. presence of. EGF "(10 ng / ml.), Or in the presence of EGF (10 ng / ml.), And a test compound at a concentration range.An IC value is then calculated. (c) One trial in. I live in a group of male rats which determines the ability of the test compound (usually administered orally as a ground suspension in a 0.5% polysorbate ball mill to inhibit growth stimulation. of the hepatocyte of the liver, caused by the administration of the growth factor TGF (400 ug / g., subcutaneously, usually in two doses, 3 and 7 hours respectively, after the administration of the test compound.) In a control group of the rats , the administration of TFR results in an average of a 5-fold stimulation of liver hepatocyte growth.The growth of the cells in the test animals and in the control animals is determined as follows: On the morning of the next day of the dosage of the test compound (or 0.5% polysorbate in the control group), the animals are dosed with bromodeoxyuridine (BrdU, 100 mg / kg intraperitoneally The animals are sacrificed after 4 hours, and the livers are eliminated. Strips are cut from each of the livers and the BrdU entry is determined by a conventional immunohistochemistry technique similar to that described on pages 267 and 268 of an article by Goldsworthy et al., In the Proliferation of Chemically Induced Cells . The Implications for the Risk Test, Wiley -Liss Inc., 1991, pages 253-284. In addition, the tests are carried out in a range of doses of the test compounds that allow the - - - for the inhibition of the proliferation followed by the inhibition of BrdU entry. Although the pharmacological properties of the compounds of the formula I vary with the structural change, as expected, in general the activity of the compounds of the formula I can be demonstrated in the following concentrations or doses in one or more of the previous tests ( a), (b) and (c): - Test (a): - IC in the range, for example # 50 0.0001-1 uM; Test (b): - IC_? In the randjo, for example 0.01 50 - 10 uM Test (c): ED 50 in the range, for example, 1-100 mg / kg. Thus, by way of example, the 6-amino-7-fluro-4- (3'-methylanilino) quinazoline compound has an IC5 mi of 0.075 uM in the test (a), an IC 50 of 0.68 uM in the test (b) and an ED? Q of 40 mg / kg in the test (c); the compound of 6- (2-chloroacetamido) -7-fluoro-4- (3'-methyl-anilino) -guinazoline has an IC 50 of O.OluM in the test (a) and an IC 50 of 0.02 uM in the test (b); and the compound of 4- (3'-chloro-4'-fluoroanilino) -7-fluoro-6-methoxyquinazoline has an IC 50 of 0.07 uM in test (a), and an IC5 of 0.53 uM in the test (b) and an ED 5Q of 12.5 mg / kg in the - test (c).

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as mentioned above, in association with a diluent or with a pharmaceutically carrier acceptable. The composition may be in the form suitable for oral administration, for example as a tablet or a capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascu- lar or infusion), as a sterile solution, suspension or emulsion, for topical administration as an ointment or as a cream or for rectal administration as a suppository. In general, the above compositions can be prepared in a conventional manner, using conventional excipients. Quinazoline is usually administered to a # warm-blooded animal at a dose within the range of 5-5000 mg per m2 of the body area of the animal, eg, about 0.1 - 100 mg / kg, and this normally provides a tetramethically effective dose. A unit dose form, such as a tablet or a capsule usually contains, for example, 1-250 mg. , of the active ingredient. Preferably, a daily dose in the range of 1-50 mg / kg is used. However, the daily dose will necessarily vary depending on the host treated, the route of administration in particular, and the severity of the disease in question. According to the optimal dose can be determined by the doctor who deals with the patient in particular. According to a further aspect of the present invention there is provided a quinazoline derivative of the formula I as defined above, in a method of treating humans or the body of the animal in therapy. We have now found that the compounds of the present invention have anti-cancer properties, which are thought to rise from their inhibitory activity on receptor tyrosine kinase. In accordance with the compounds of the present invention, they are expected to be useful in the treatment of diseases or myotic symptoms regulated alone or in part by the tyrosine kinase of the enzyme receptor, for example, the compounds can be used to produce a inhibitory effect of receptor tyrosine kinase, in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention provide a method for the treatment of the proliferation of malignant cells characterized by the inhibition of the receptor tyrosine kinase of the enzyme, for example the compounds can be used for the production of an anti-inflammatory effect. -proliferative regulated only or in part by the inhibition of tyrosine kinase # of the enzyme receptor. Accordingly, the compounds of the present invention are expected to be useful in the treatment of cancer by providing an anti-proliferative effect, particularly in the treatment of sensitive cancers of receptor tyrosine kinase such such as cancers of the breast, lung, coldn, rectum, stomach, prostate, liver, pancreas, and ovaries. Thus, according to this aspect, the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as mentioned above, in obtaining a medicament for the use thereof is provided. in the production of an effect against cancer, in warm-blooded animals such as man. According to a further aspect of this invention there is provided a method for obtaining an effect against cancer in a warm-blooded animal, such as man, in need of such treatment, which comprises the administration to the animal of an amount effective of a quinazoline derivative as mentioned above. As mentioned before, the amount and dose required for the therapeutic or prophylactic treatment of a particular cancer, which will necessarily vary depending on the host treated, the route of administration and the severity of the disease being treated. A dose in the range, for example / 1-100 mg / kg, preferably 1-50 mg / kg is preferred. The aforementioned cancer treatment can be applied as a single therapy, or it can comprise, in addition to the quinazoline derivative of the invention, one or more other anti-cancer substances, for example, those selected, for example, the mitotic inhibitors, for example yinblsatin, alkylating agents, for example cis-platinum, carboplatin, and cyclophosphamide, antimetabolites, for example 5-fluoracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites, mentioned in European Patent Application No. 239362, such as N- (5- (N- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N) -methylamino) -2-teonyl-L-gluticum; intercalation antibiotics, for example adriamycin, and bleomycin; enzymes, for example asparaginase, inhibitors of topoisomersa, for example eletoposide, biological response modifiers, for example interferon; and anti-hormones, for example antiestrogens, such as' NOLVADEX '(tamoxifen), or, for example antiandrogens, such as - • CASODEX', a (4'-cyano-3- (4-flurophenylsulfonyl) -2 -hydroxy-2-methyl-3 '- (trifluoromethyl) propionanilide Such a joint treatment can be achieved by the simultaneous, sequential or separate dosing of the individual components of the treatment In accordance with this aspect, the invention is provides a pharmaceutical product comprising a quinazoline derivative of the formula I as mentioned above, and a substance against the additional tumors, as defined above, for the overall treatment of the cancer. of quinazoline defined in the present invention is an effective anti-cancer agent, property that is achieved increased, of its receptor tyrosine inhibitory properties Such quinazoline quinazoline derivative of the invention is expected to have a n wide range of anti-cancer properties, such as receptor tyrosine kinase, which has been implicated in most common human cancers, such as leukemia and breast cancer, lung, colon, rectal, stomach , prostate, kidney, pancreas, and ovary. Therefore, a derivative of the quinazoline of the invention having anti-cancer activity in these types is expected. Furthermore, it is expected that the quinazoline tub of the present invention has activity against the range of leukemines, malignant-lymphoid tumors, and solids, such as carcinomas and sarcomas, in tissues such as the kidney, hunger, prostate and pancreas. . The invention is now illustrated in the following non-limiting Examples, in which, unless otherwise mentioned: (i) the evaporations are carried out by rotary evaporation to the vacuum, and the process is carried out after the removal of residual solids, such as the agents, is dried by filtration; ^ (Ii) the stages are carried out at the W ambient temperature, this is in the range of 18-25 ° C, under an atmosphere of an inert gas such as argon; (iii) column chromatography (rapid procedure), and medium pressure liquid chromatography (MHPL) 0 is carried out in the form of Kiselgel Merck (Art. 9385), or with a reverse phase column of Lichroprep RP-18 Merck (Art. 9303), sold by E. Merck, Darmstadt, Germany. (iv) the returns are given for purposes of illustration only, and are not necessarily the maximum obtainable; (v) the melting points are uncorrected and are determined using a melt puy determination apparatus, Mettler SP 62 automatic, an oil bath apparatus, or a Koffler hot plate apparatus. (vi) the structures of the final products of formula I, are confirmed by magnetic resonance • Nuclear (usually proton), (NMR), and mass spectral techniques (NMR), and mass spectral techniques, the values of the chemical changes of the proton magnetic resonance, are measured on the delta scale and the multiple peaks, are shown as follows: s, singlet, d, doublet, t, triplet,, multiplet; (vi i) the intermediates are not fully characterized, and the purity is tested by thin layer chromatography (TLC), infra-red (lR), or NMR analysis; (viii), the following abbreviations are those that are used; DMF N, N-dimethylformamide; DMA N, N-dimethylacetamide; EXAMPLE A mixture of 7-fluro-4 - (: 3'-methylanilino) -6- nitroquinazoline () .25g.), A palladium-on-carbon cataloger allO% (0.03g.), And ethanol (10ml.), Stir under a hydrogen atmosphere pressure for 16 hours. The mixture is filtered, and the filtrate is evaporated. The residue is triturated with diethyl ether. Thus, 6-amino-7-fluoro-4- (3'-methylanilino) quinazoline (O.ldg.) Is obtained, p.de f. 205- 206 ° C.

Spectrum: (CD SOCD) 2.33 (s, 3H), 5.67 (s, broad, 2H), 6. 9 (m, lH), 7.24 (m, lH), 7.4 (d, lH) ° 7.6 (m, 3H), 8.3 (s, lH) ° 9. 35 (s broad, 1H). Elemetal Analysis: Found C 67.1, H 4.9, N 20.8 C JÍ JN requires, C 67.2, H 4.9, N 20.9%. The 7-fluro-4- (3f-methylanilino) 6-nitroquinazo-line used as the starting material is obtained as follows A mixture of 4-fluroantranilic acid (15g.), And formamide (30ml.), Is stirred and stirred. heat to reflux for 6 hours. The mixture is cooled to room temperature. The mixture is triturated with water. The solid is isolated, washed with water and dried. Thus, 7-fluroquinazolin-4-one (13.8 g.) Is obtained. A portion of (4g.) Of the material thus obtained is added in portions to a stirred mixture of concentrated sulfuric acid (8 ml.) And fuming nitric acid (8 ml.), Which is cooled to 0 ° C. The mixture is stirred at room temperature for 30 minutes, and then heated to 110 ° C, for 30 minutes. The mixture is cooled to room temperature and emptied into a mixture of ice and water. The precipitate is isolated, washed with water and dried. 7-fluro-6-nitroquinazolin-4-one (4.3 g.), P.def. 268-270 ° C. A mixture of one portion (2.09g.) Of the material thus obtained, thionyl chloride (16mlo.), And DMF (8 drops) is stirred and heated at reflux for 2 hours. The mixture is evaporated, toluene (20 ml.) Is added, and the mixture is again evaporated. Thus, 4-chloro-7-fluoro-6-nitroquinazoline is obtained as a solid which is * use without additional purification. A mixture of the solid thus obtained, 3'-methylaniline (1 ml.) 0 and isopropanol (40 ml.), Is stirred and heated at reflux for 2 hours. The mixture is cooled to room temperature and stored at 3 ° C for 16 hours. The precipitate is isolated, washed with isopropane, and with diethyl ether and dried. The solid well A (2.7 g) is dissolved in a mixture of methylene chloride and methanol and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase is washed with water, dried with MgSO and evaporated. The residue is purified by chromatography column using a 4: 1 mixture., of methylene chloride and ethyl acetate, as the eluent. 7-Fluoro-4- (3'-methylanilino) 6-nitroquinazoline (1.69 g) is thus obtained. Example 2 A mixture of 7-fluro-4- (3'-methylanilino) -6- nitroquinazoline (0.12g.), A 10% palladium on carbon catalyst (0.02 g.), And ethanol (10 ml.) ° it is stirred under an atmosphere of hydrogen pressure for 1 hour. The mixture is filtered and the filtrate is evaporated. The residue is purified by chromatography column using increased polar mixtures of methylene chloride and methanol as the eluent. The material thus obtained is triturated with methanol and the resulting solid is recrystallized with a mixture of methanol and water. SE 7-Fluoro-6-hydroxyamino-4- (3'-methylanilino) quinazoline (0.051 g), p.def. 228-230 ° C. NMR spectrum: (CD3 SOCD 3), 2.33 (s, 3H), 6.9 (d, lH), 7.25 (m, lH), 7.4 (d, lH), 7.63 (m, 2H), 8.1 (d, lH) , 8.4 (s, lH), 8.8 (s broad, 1H), 8.9 (s broad, 1H), 9.7 (s broad, 1H). Elemental Analysis: Found C 63.8, H 4.6, N 19.6 C15 13FN requires c, 63.8, H, 4.5, N 19.1%. Example 3 Acetic anhydride (0.11 ml) is added to a stirred solution of 6-amino-7-fluoro-4- (3'-methylanilino) -quinazoline (0.268 g) in DMA (2 ml.), And The mixture is stirred at room temperature for 24 hours. Water is added (10ml.). The precipitate is isolated, washed with water, and dried. This gives 6-acetamido-7-fluoro-4- (3'-methylanilino) quinazoline (0.204.), P. 269-270 ° C NMR spectrum: (CD 3SO CD3): 2.15 (s, 3H), 2.3 (s, 3H), 6.9 (d, lH) 7.2 (t, lH), 7.6 (m, 3H), 8.5 (s, lH), 8.8 (d, lH), 9.7 (s broad, 1H), 10.0 Elemental Analysis: Found C 65.5, H 4.9, N 17.9 C 17H15 FN 40, requires C, 65.8, H 4.8, N 18.1% Example 4 2-Chloroacetyl chloride (0.12 ml.) Is added to a stirred solution of 6-amino-7-fluro-4- (3'-methylanilino) quinazoline (0.268 g.). in DMA (2 ml.), and the mixture is stirred at room temperature for 3 hours. The precipitate is isolated and washed with diethyl ether. This gives 6- (2-chloroacetamido) -7-fluoro-4- (3'-methyl-anilino) quinazoline as the hydrochloride (0.315 g.), P.def. 320 ° C NMR spectrum; (CD- SO CD3) 2.36 (s, 3H), 4.5 9s, 2H), 7.15 (d, lH), 7.4 (m, 3H), 7.9 (d, lH) ° 8.9 (s, lH) ° 9.2 (d , lH), 10.8 (s broad, 1H), 11.5 (s broad, 1H). Elemental Analysis: Found C, 54.0, H 4.2, N 14.6 C? ^ H? ACl FN4 0 1HC1 requires C 53.5, H, 3.9, N 14.7% Example 5 4-Chlorobutyryl chloride (0.4ml.) Is added to a stirred solution of 6-amino-7-fluro-4- (3'-methylanilino) quinazoline (0.8g.) ° in DMA (6ml.), and the mixture is stirred at room temperature for 4 hours. The precipitate is isolated and washed with diethyl ether. This gives 6- (4-chlorobutyramido) -7-fluoro-4- (3'-methyl-anilino) quinazoline (0.76 g). NMR spectrum: (CD 3 SO CD 3): 2.1 (m, 2H), 2.36 (s, 3H), 2.66 9t, 2H), 3.74 (t, 2H), 7.14 (d, lH), 8.8 (s, lH ), 9.2 (d, 1H), 10.3 (broad s, 1H), 11.4 (broad s, 1H); Elemental Analysis: Found C, 56.1, H 4.6, N, 13.7 ClgH18ClFN 40; requires C, 55.8, H, 4.7, N 13.7% Example 6 • A solution of 6- (4-chlorobutyramido) -7-fluoro-4- (3'-methylanilino) quinazoline (0.64 g) in DMF (20 ml.) Is added to a stirred solution of sodium hydride. (80% dispersion in mineral oil, 0.15tg), in DMA (2ml.). The mixture is stirred at room temperature for 20 minutes. The mixture is emptied on ice and extracted with methylene chloride. The organic phase is washed with water, dried with MgSO. and it evaporates. The residue is recrystallized with a mixture of methylene chloride and ethyl acetate. This gives 7-fluoro-4- (3'-methylanilino) -6- (oxopyrrolidin-1-yl) quinazoline (0.35 g.), P.def. 218-220 ° C. NMR spectrum: (CD 3 SOCD 3): 2.2 (M, 2H), 2.35 (s, 3H) ° 2.5 (m, 2H), 3.9 (t, 2H) ° 7.0 (m, lH), 7.3 (m, lH ), 7.6 (m, 3H), 8.56 (s, lH), 8.65 (m, 1H), 9.75 (s broad, 1H), Elemental Analysis: Found C 67.4, H 5.1, N 16.5; C19 H 17FN4 ° rec3uiere '67.8, H 5.1, N 16.7%. Example 7 A sample of 4- (3'-chloro-4'-fluoroanilino) -7-fluoro-6-nitroquinazoline (O.llg.), A 30% palladium on carbon catalyst (O.Olg.), And acetic acid (10m.), are stirred under an atmosphere of hydrogen pressure for 30 minutes. The mixture is filtered, and the filtrate is evaporated. The residue is triturated with methanol. This gives 6-amino-4- (3, -chloro-4, -fluor-anilino) -7-fluo-quinazoline (0.037 g.), P.def. 250 ° C.

NMR spectrum: (CD SOCD) 5.8 (broad s, 2H), 7.4 (m, 2H), 7.75 (d, lH) ° 7.8 (m, lH), 8.1 (m, lH), 8.4 (s, lH), 9.7 (s, broad, 1H). The 4- (3'-chloro-4'-fluoroanilino) -7-fluoro-6-nitroquinazoline used as the starting material is obtained by the reaction of 4-chloro-7-fluoro-6-nitroqui-nazoline and 3 ' -chloro-4 '-fluoraniline, using a procedure analogous to that described in the last paragraph of the portion of Example 1, which relates to the preparation of the starting materials. The required starting material is thus obtained. NMR spectrum: (CD 3 SO CD): 7.5 (t, lH), 7.8 (m, 2H), 8.1 (m, lH), 8.7 (s, lH), 9.6 (d, lH), 10.5 (s, wide) , 1 HOUR). Example 8 A mixture of 4- (3'-chloro-4'-fluoroanilino) -7-fluoro-6-nitroquinazoline (O.llg.), And a 30% palladium on carbon catalyst (O.Olg.) And Ethanol (lOml.), is stirred under a hydrogen atmosphere pressure for 30 minutes. The mixture is filtered and the filtrate is evaporated. The residue is triturated with methanol. Thus, 4- (3'-chloro-4'-fluroanilino) -7-fluro-6-hydroxyaminoquinazoline (0.065g) is obtained. NMR spectrum: (CD 3 SO CD ^ 7.4 (m, 2H), 7.8 (m, lH), 8.1 (m, 2H), 8.47 (s, lH), 8.8 (s broad, 1H), 8.97 (s, wide) , 1H), 9.85 (broad s, 1H).

Elemental Analysis: Found C, 50.5, H 3.0 N, 16.2 C14H8C1F2N4 ° ° '75 H2 ° '"wants C, 50.0; H 3.1, N 16.7% Example 9 Iron weight (5g.), It is added in portions during 5 minutes to a stirred mixture of 7-chloro-4- ( 3'-methylanilino) -6-nitroquinazoline (5g.), In water (lOml.), And glacial acetic acid (lOOml.), Which has been heated to 50 ° C. The mixture is heated to 50 ° C., The mixture is cooled to room temperature and filtered, the filtrate is evaporated and the residue is purified by a chromatography column using a 9: 1 mixture of methylene chloride and methanol as the eluent. 6-amino-7-chloro-4- (3 '-methylanilino) -quinazo-lina (2.1g.), P.def.> 270 ° C NMR spectrum: (CD 3 SO CD3): 2.35 (s, 3H ), 6.0 (s broad, 2H), 7.0 (d, lH) ° 7.3 (t, lH), 7.55 (m, lH), 7.6 (m, lH) ° 7.7 (s, lH), 7.8 (s, lH) ), 8.5 (s, lH), 10.2 (s broad, 1H) The 7-chloro-4- (3'-methylanilino) -6-nitroquinazoline used as the starting material is obtained as follows A mixture of the acid 4-chloroanthranilic (17. 2 g), and formamide (lOml.), Is stirred and heated at 130 ° C, for 45 minutes, and at 175 ° C, for 75 minutes. The mixture is allowed to cool to about 100 ° C, and 2- (2-ethoxyethoxy) ethanol (50 ml.) Is added. The solution thus formed is poured into a mixture of (250 ml.), Water and ice. The precipitate is isolated, washed with water and dried. 7-chloroquinazolin-4-one (15.3 g, 85%) is thus obtained. A portion (6g.) Of the material thus obtained is added in portions to a stirred mixture of concentrated sulfuric acid (12ml.), and fuming nitric acid (12 ml.), which has been cooled to 0 ° C, the mixture is stirred at room temperature for 30 minutes and then heated at 110 ° C, for 30 minutes. The mixture is cooled to room temperature and emptied into a mixture of ice and water. The precipitate is isolated, washed with water, and dried. 7-Chloro-6-nitroquinazolin-4-one (6.89 g) is thus obtained. A mixture of a portion (4 g.) Of the material thus obtained, thionyl chloride (30 ml.), Phosphoryl chloride (5 ml.), And DMF (10 drops) are stirred and heated at reflux for 4 hours. The mixture is evaporated, toluene (20 ml.) Is added, and the mixture evaporates again. Thus, 4,7-dichloro-6-nitroquinazoline is obtained as a solid which is used without further purification, c A mixture of the solid thus obtained , 3'-methylaniline (1.89g.), And isopropanol (25ml.), Is stirred and heated at reflux for 2 hours. The mixture is filtered while it is hot. The solid thus isolated, washed with isopropanol, and with diethyl ether and dried. This gives the 7-chloro-4- (31-methylanilino) -6-nitroquinazoline hydrochloride (3.74 g), p.def. 271-274 ° C.

Example 10 < a glacial acetic acid (0.85 ml.) is added to a stirred mixture of 6-amino-7-chloro-4- (3'-methylanilino) quinazoline (lg), formaldehyde (37% solution in water, 2.28 ml.), And ethanol (80 ml.). The mixture is stirred at room temperature for 10 minutes. Sodium cyanoborohydride (0.443 g.) Is added in portions, and the mixture is stirred at room temperature for 16 hours. The mixture is neutralized by the addition of bicarbonate of Sodium The mixture is evaporated and the residue is divided between methylene chloride and water. The organic phase is dried with MgSO and evaporated. The residue is purified by a chromatography column using a mixture of 48: 1, methylene chloride and methanol as the eluent. The following is obtained: - 7-chloro-6-dimethylamino-4- (3'-methylanilino) quinazoline (0. 043 g.), P. 150-152 ° C. Mass spectrum: (CD-S0CD-) 2.35 (s, 3H0, 2.9 (s, 6HÍÍ, 7.0 (d, lH), 7.3 (t, lH), 7.6 (m, 2H, 7.8 (s, lH0, 8.07 (s, lH $), 8. 47 (s, lH), 9.7 (broad s, 1H). and 7-chloro-6-methylamino-4- (3 * -methylanilino) quinazoline (0. 171 g.). p.def. 149-152 ° C. NMR spectrum: (CD3SOCD3) 2.35 (s, 3H), 2.95 (d, 3H) 6.03 (m, 1H), 6.9 (d, lH), 7.26 (t, lH), 7.36 (s, lH), 7.6 (s, lH), 7.65 (d, broad, 1H) ° 7.7 (s, lH), 8.34 (s, lH), 9.44 (s, broad, 1H) Example 11 < f & > Using a procedure analogous to that described in Example 4, the 6-amino-7-chloro-4- (3'-methylanilino) -quinazoline is reacted with 2-chloroacetyl chloride, whereby the hydrochloride of 7-chloroacetyl is obtained. -chloro-6- (2-chloroacetamide) -4- (3'-methylanilino) quinazoline in a yield of 79%. NMR spectrum: (CD 3SOCD3); 2.35 (s, 3H), 4.5 (s, 2H), 7.15 (d, lH), 7.4 (t.lH) ° 7.5 (m, 2H), 8.15 9s, lH), 8.88 (s, lH), - f 9.02 < t) s, lHd., 10.55 (s broad, 1H), 11.4 (s broad, 1H), Example 12 Using a procedure analogous to that described in Example 9, 7-chloro-4- (3 ', 4 • -dichloroanilino) ) -6-nitroquina-soliria, which is reduced with iron in acetic acid, whereby 6-amino-4- (3 ', 4'-dichloroanilino) -quinazoline is obtained in a yield of 20%. NMR spectrum (CDgSOCDg): 6.0 (s, broad, 2H), 7.65 (m, 2H), 7.8 (m, 2H), 8.22 (d, lH), 8.55 (s, lH), 10.25 (s, aplia, lH ). The 7-chloro-4- (3 ', 4 * -dichloroanilino) -6-nitroquinazoline used as the starting material is obtained by the reaction of 4,7-dichloro-6-nitroquinazoline and 3', 4'- dichloroaniline using a procedure analogous to that described in the last paragraph of the portion of Example 9, which relates to the preparation of the starting materials. Example 13 Using a procedure analogous to that described in Example 4, 6-amino-7-chloro-4- (3 ', 4'-dichloroaniline) quina-zoline is reacted with 2-chloroacetyl chloride whereby 7-chloro-6- (2-chloroacetamido) -4- (3 ', 4'-dichloroanilino) quinazolin hydrochloride in a yield of 76%, p.def. 280 ° C NMR spectrum: (CD 3 SOCD3), 4.5 (s, 2H), 7.75 (m, 2H), 8.1 (m, 2H), 8.9 (s, lH), 8.95 9s, lH), 10.5 (s broad) , 1H), 11.3 (broad s, 1H). Example 14 A mixture of 4-chloro-7-fluoro-6-methoxyquinazoline (~ 32g.) -, 3 * -raethylaniline (0.16g.), And isopropanol (5ml.), Is stirred and heated to reflux by 90 minutes. The precipitate is isolated, washed with isopropanol, and with diethyl ether and dried. Thus, 7-fluro-6-methoxy-4- (3 • -methylanilino) quinazoline hydrochloride (0.468 g.), P.def. 265-267 ° C. NMR spectrum: (CD S0CD3): 2.37 (s, 3H), 4.1 (s, 3H), 7.16 (d, 1H), 7.37 (s, lH), 7.50 (m, 2H), 7.82 (s, lH), 8.77 (s, lH), 8.84 (s, lH), 11.66 (s broad, 1H). Elementary Analysis; Found C, 60.2, H 4.7, N 13.0 C16H14FN3 ° 1HC1 requires C, 60.1, H 4.7, N 13.1%. The 4-chloro-7-fiuro-6-methoxyquinazoline used as the starting material is obtained as follows: Concentrated citric acid (70%, 4.8 ml.) Is added in portions over 20 minutes to a stirred mixture of water. Methyl 4-fluro-3-methoxybenzoate (14 g.), And concentrated sulfuric acid (140 ml.), Which has been cooled to -10 ° C.

The mixture is allowed to warm to 5 ° C, and is stirred at a ^ k > temperature for 15 minutes, the mixture is emptied on ice and extracted with ethyl acetate. The organic phase is washed with water, dried with MgSO and evaporated. The residue is purified by a chromatography column using amounts that increase its polarity of hexane and methylene chloride as the eluent. Methyl 4-fluoro-5-methoxy-2-nitrobenzoate (11.8 g) is thus obtained. A mixture of a portion (10.3 g.) Of the material thus obtained, a palladium on carbon catalyst,% O (lg.), And ethanol (500 ml.), Is stirred under a hydrologic atmosphere pressure for 3 hours. The mixture is filtered and the filtrate is evaporated. The methyl ester of 4-fluoro-5-methoxyanthranic acid (9 g) is thus obtained. Using the procedures analogous to those described in the first and the third paragraph of the portion of Example 1, which relates to the preparation of the starting materials, the methyl ester of 4-fluro-5-methoxy acid -antranyl, is converted to 4-chloro-7-fluro-6-methoxyquinoline in a yield of 3-0%. Example 15 Using a procedure analogous to that described in Example 14, 4-chloro-7-fluoro-6-methoxyguinazoline is reacted with 3'-chloro-41-fluoraniline, whereby the hydrochloride of 4- (3 '-chloro-4 • -fluoroanilino) -7- Wf¿ fluro-6-methoxyquinyanoline in a yield of 80%, p.def. 274-275 ° C; NMR spectrum: (CDg SO CD3): 4.08 (s, 3H $, 7.54 (m, lH), 7.77 (m, 2Hf, 8.04 (m, lH), 8.60 (d, lH), 8.86 (s, lH) Elemental Analysis: Found C, 50.5, H, 3.1, N 11.3 CH C1F N 0 1HC1 requires C, 50.3, H 3.1, N 11.7% 15 10 2 3 Example 16 Glacial acetic acid (0.46 ml.) Is added to a stirred mixture of 6-amino-7-fluoro-4- (3 '-methylanilino) quinazoline (1.07 g), formaldehyde (37% solution, in water, 0.7 ml.), and ethanol (100 ml.), and the mixture is stirred at room temperature for 5 minutes. Sodium cyanoborohydride (0.51g.) Is added, and the mixture is stirred at room temperature for 24 hours. The mixture is evaporated and the residue is neutralized by the addition of a saturated aqueous sodium bicarbonate solution. The mixture is divided between methylene chloride and water. The organic phase is washed with water, dried with MgSO 4 and evaporated. The residue is evaporated by a chromatography column using a 9: 1 mixture of methylene chloride and methanol as the eluent. You get this way the 7-fluro-6-methylamino-4- (3'-methylanilino) quinazoline as a solid (0.62g.). NMR Espcetro: (CD 3 S0CD3) 2.3 (s, 3H), 2.9 (d, 3H), 6.2 (d, lH), 6.95 (d, lH), 7.25 (t, lH), 7.4 (m, 2H0, 7.6 (m, 2H), 8.3 (s, lH), 9.4 (s broad, 1H) .M Example 17 Using a procedure analogous to that described in Example 16, 6-amino-7-fluro-4- (3 '- Methylanilino) quinazoline (0.268g.), is reacted with formaldehyde (a 37% solution in water, 0.65ml.), and sodium elccianoborohydride (0.126g.), for 24 hours.The second portions of the same amounts of formaldehyde and sodium cyanoborohydride are added and reacted continuously by 24 chores, the third portions of the same quantities of the two Numbers are added and the reaction is continued for an additional 24 hours. The reaction mixture is processed using the analogous method to that described in Example 16. 7-Fluoro-6-dimethylamino-4- (3'-methylanilino) -quinazoline is thus obtained as a solid (0.132 g.) NMR spectrum: ( CD3SOCD3): 2.3 (s, 3H), 2.9 (s, 6H), 6.99 (d, 1H, 7.3 (t, lH), 7.45 (d, lH), 7.6 (m, 2H0, 7.8 (d, lH0, 8.45 (s, lH), 9.65 (s broad, 1H) Example 18 Using a procedure analogous to that described in Example 4, 7-fluro-6-methylamino-4- (3'-methylanylino) quinazoline it is reacted with 2-chloroacetyl chloride, whereby the 6- (2-chloro-N-methyl-acetamido) -7-fluoro-4- (3'-methylamino) -quinazoline hydrochloride, (0.097 g) is obtained. .), NMR spectrum: (CD ^ OCD + CD CO D, at 100 ° C.) ° 2.3 (s, 3H), 3.4 (s, 3H), 4.2 9s, 2H), 7.1 (d, lH), 7.3 (t, lH), 7.5 (m, 2H >, 7.7 (d, lH), 8.7 (s, lH), 8.9 (d, lH) Example 19 Acryloyl chloride (O.lml.) is added, to a stirred solution of 6-amino-7-fluro-4- (3'-methylanilino) quinazoline (0.268 g.), in DMA (2 ml.), and the The mixture is stirred at room temperature for 2 hours. Diethyl ether is added to the mixture and the resulting precipitate is isolated and washed with diethyl ether. The solid dissolves in a -J mixture of methylene chloride and methanol and the solution is washed with a solution of saturated aqueous sodium bicarbonate. The organic phase is dried with MgSO * and evaporated. The residue is purified by a chromatography column using a 9: 1 mixture of methylene chloride and methanol as the eluent. Thus, 6-acrylamido-7-fluoro-4- (3'-methylanilino) quinazoline is obtained as a solid (0.062 g); NMR spectrum: (CD-jSOCD.,): 2.3 (s, 3H), 5.9 ((m, lH), 6.4 - (m, lH), 6.7 (m, lH), 7.0 (d, lH), 7.3 ( m, lH), 7.6 (m, 3H), 8.5 (s, lH), 9.0 (d, lH), 9.8 (s, broad, 1H), 10.2 (s broad, 1H) Example 20 Using a procedure analogous to described in Example 16, 6-amino-4- (3'-chloro-4'-fluoroanilino) -7-fluoroquinoline is reacted with sodium cyanoborohydride, whereby 4- (3'-chloro) is obtained -4'-fluoroanilino) -7- fluoro-6-methylaminoquinazoline as a solid in a yield of 19%; 99- NMR spectrum: (CDgSOCDg) 2.9 (d, 3H0, 6.3 (broad s, 1H), 7.4 (m, 3H), 7.8 (m, lH), 8.1 (m, lH ?, 8.4 9s, lH? / 9.5 (s broad, 1H) Example 21 Using a procedure similar to that used in Example 17, the 6-amino-4- (3'-chloro-4'-fluoroanilino) 7-fluoroquinazoline is reacted with sodium cyanoborohydride to give 4- (3 * -chloro-41-fluoroanilino) -6- dimethylamino-7-fluoroqui¬ • Nazoline as a solid in a 29% yield. NMR spectrum: 2.95 (fs, 6H), 7.5 (m, 2H), 7.75 (m, 2H), 8.1 (m, lH), 8.5 (s, lH), 9.7 (broad s, 1H). EXAMPLE 22 Using a procedure analogous to that described in Example 4, 6-amino-4- (3"-chloro-4 '-fluoroanilino) -7-fluoroquinazoline is reacted with 2-chloroacetyl chloride to obtain a precipitate which is isolated The solid is dissolved in methylene chloride and triethylamine is added The precipitate is isolated and purified by a chromatography column using a mixture of 1: 1 methylene chloride and acetone as the eluent Thus, 6- (2-chloroacetamido) -4- (3'-chloro-41-fluoroanilino) -7-fluoroquinazoline is obtained as a solid in a yield of 23% A. NMR spectrum: (CD SOCD) 4.4 (s) , 2H0, 7.45 (t, lH), 7.7 (d, 1H), 7.8 (m, lH), 8.1 (m, lH), 8.6 9s, lH), 8.9 (d, lH0, 10.1 (s broad, 1H) , 10.4 (s, lH) EXAMPLE 23 Using an analogous procedure to that described in Example 5, the 6-amino-4- (3'-chloro-4 * -fluoroanilino) -7-fluoroquinazoline is reacted with the 4-chlorobutyryl with which the hydrochloride of 6- (4-chlorobutyramido) -4- (3'-chloro-4'-fluoroani lino) 7-fluoroquinazoline, as a solid in 91% yield. NMR spectrum: (CD SOCD) 2.15 (m, 2H), 2.7 (t, 2H0, 3.8 (t, 2H), 7.55 (t, lH), 7.7 (m, lH), 7.9 (d, lH), 8.0 ( m, lH), 8.9 (s, lH), 9.15 (d, lH), 10.4 (broad s, 1H), 11.5 (s broad, 1H) Example 24 A solution of 6- (4-chlorobutyramido) -hydrochloride 4- (3'-chloro-4'-fluoroani lino) -7-fluoro-quinazoline (0.64 g), in DMA (6 ml.), Is added to a stirred suspension of sodium hydride (80% dispersion in mineral oil (0.14 g.), from which, the oil is washed with hexane) in DMA (2 ml.) The mixture is stirred at room temperature for 1 hour.A mixture of ice with water (40 ml.), is added The resulting mixture is stirred for 30 minutes.The precipitate is isolated, washed with water, a small amount of isopropanol and diethyl ether and dried.The solid ßt is purified by a chromatography column using a mixture. of 9: 1 of methylene chloride and methanol as the eluent, thus obtaining 4- (3'-chloro-4 '-fluoroanilino) -7-flur-6- (2-oxopyrrolidin-1-yl) ) quinazoline, as a solid (0.13g.); NMR spectrum: (CD3SOCD3) 2.2 (m, 2H), 2.5 (m, 2H), 3.9 (t, 2H), 7.5 (t, lH), 7.7 (d, lH), 7.8 (m, lH), 8.15 ( m, lH), 8.6 (m, 2H), 9.9 (s, broad, 1H). Example 25 • A mixture of 4,7-dichloro-6-methoxyquinazoline (1.19g.), 3'-chloro-4 * -fluoroaniline (0.76g.), And isopropanol (25ml.), Is stirred and heated to reflux for 2 hours. The mixture is cooled to room temperature. The precipitate is filtered. The solid dissolves in a 9: 1 mixture of methylene chloride and methaneand the solution is washed with a saturated aqueous sodium bicarbonate solution.The organic phase is dried with MgSO and evaporated.The residue is purified by a chromatography column, using a 9: 1 mixture of methylene chloride and ethyl acetate as the eluent, 7-chloro-4- (3 * -chloro-4'-fluoroanilino) -6-methoxyquinazoline (0.32 g) is obtained, mp 223 ° C - 224 ° C; Elemental Analysis: Found C, 53.0, H 2.8, N 12.2 C15H10C12 FN3 ° reFliere '53.5, H 3.0, N, 12.4% The 4,7-dichloro-6-methoxyquinazoline used as a starting material is obtained as follows: A mixture of 7-hydroxy-6-methoxy-4- (3, -methyl-anilino) -quinazoline (European Patent Application No. 0566 226 (Example 19 thereof), 8.3g.), concentrated hydrochloric acid; (100 ml.), and ethanol (100 ml.), are stirred and heated at reflux for 72 hours. The mixture is evaporated, water (50 ml.) Is added, and the mixture is made basic by the addition of a saturated aqueous ammonium hydroxide solution. The precipitate is isolated, washed with water, and dried. Thus, 4,7-hydroxy-6-methoxyquinazoline (4g.) Is obtained. A mixture of 4,7-dihydroxy-6-methoxyquinazole (lg.) And thionyl chloride (14 ml.) Are heated at reflux for 2 hours. The mixture is evaporated, whereby 4,7-dichloro-6-methoxyquinazoline is obtained, which is used without further purification.

CHEMICAL FORMULAS H2N

Claims (4)

1. NOVELTY OF THE INVENTION Having described the invention, we consider: as a novelty and therefore we claim as our property what is contained in the following: R E I V I N D I C A C I O N E S 1.- A quinazoline derivative of the formula I wherein R is hydroxy, amino, hydroxyamino, trifluoromethoxy, (1-4C) alkoxy, (1-4C) alkylamino, (1-4C) alkylamino, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperdino, morpholino, piperazin-1-yl, 1-alkylpiperazin of (1-4C) -l-yl, (1-4C) alkyl, halo (1-4C) alkoxy, hydroxy- (1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) phenyl-alkoxy, (2-4C) haloalkylamino, hydroxy-alkylamino -4C), (1-4C0-alkylamino of (2-4C) alkoxy, phenyl-(1-4C) alkylamino, (2-4C) alkanoylamino, benzamido, 2-oxopyrrolidin-1-yl,
2. 2-oxopiperidin-1-yl, haldino-alkanoylamino of (2-4C), hydroxy-alkanoylamino of (2-4C), alkoxy of (l-4C) -alcanoyl-amino of (2-4C), alkenoylamino of (
3. 3 -4C), alkynylamino of (3-4C), N-alkyl of (1-4C) -alkylamino of (2-4C),? Fj N-alkylbenzamido of (1-4C), N-alkyl of (1-4C) ) -halogen-alkanoylamino of (2-4C), N-alkyl of (l-4C) -hydroxy-alkanoylamino of (2-4C), N- = alkyl of (l-4C) -alkoxy of (l-4C) -alkylamino of (2-4C), N-alkyl of (1-4C) -alkenoylamino of (3-4C), or N-alkyl of (1-4C) -alkynylamino of (3-4C), and wherein the Benzamido or N-alkylbenzamido substituent of (1-4C), or any phenyl group, in a substituent of R may optionally have one or two halogens, (1-4C) alkyl, or an alkoxy substituent of (1-) 4C), R 3 is halogen, and n is an integer of 1,2, or 3, and each of R 2 is independently hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano, (1-4C) alkyl , (1-4C) alkoxy, or (2-4C) alkanoylamino, or a pharmaceutically acceptable salt thereof. 2. A quinazoline derivative of the formula I, according to clause 1, wherein R 1 is hydroxy, amino, hydroxyamino, methylamino, ethylamino, dimethylamino, diethylamino, aziridin-1-yl, azetidin-1-yl, pyrrolidin- 1-yl, piperidine, morpholino, piperazin-1-yl,
4. 4-methylpiperazin-1-yl, acetamido, propionamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, 4-chlorobutyramido, 2-hydroxyacetamido, or -methoxyacetamido; 3 R is fluorine, or chlorine, and . 2 (R) n is 4'-fluoro, 3'-chloro, 3'-bromo, 3 ', 4'-dichloro, 3 * -chloro-4' -fl or, 3 '-trifluromethyl, 4' -fluor, 3 '-trifluoromethyl 4, -fluor-3 * -trifluromethyl, 3, -nitro, 4'-chloro-3'-nitro, 4'-fluoro-3'-nitro or 3'-methyl, or a pharmaceutically acceptable salt of the same. 3. A quinazoline derivative of formula 1, according to clause 1, wherein R is hydroxy, amino, hydroxyamino, methylamino, ethylamino, dimethylamino, diethylamino, azi-ridin-1-yl, azetidin-1-yl, pyrrolidin -1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, acetami-dom propionate, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, 3-chloropropionamido, 4-chlorobutyramido, 2 -hydroxyacetamido, 2-methoxyacetamido, acrylamido, methacrylamido, N-methylacetamido, N-ethylacetamido, N-methylpropionamido, 2-chloro-N-methylacetamido, or 2-chloro-N-ethylacetamido; 3 R is fluorine, or chlorine, and 2 (R) is 4'-fluor, 3'-chloro, 3'-bromo, 3 ', 4'-dichlor, n 3f-chloro-4'-fluor, 3' - trifluoromethyl, 4'-fluoro-3'-trifluoro-methyl, 3'-nitro, 4'-chloro-3 * -nitro, 4'-fluoro-3 * -nitro, or 3'-methyl; or a pharmaceutically acceptable salt thereof. 4. A quinazoline derivative of the formula I, according to clause 1, wherein R is methoxy, ethoxy, methylthio, 2-chloroethoxy, 2-bromoethoxy, 2-hydroxyethoxy, 2-methoxy-ethoxy; 3 R is fluorine, or chlorine; and, 2 (R) is 4'-fluoro, 3'-chloro, 3'-bromo, 3 ', 4'-dichloro, n 3'-chloro-4'-fluoro, 3'-trifluoromethyl, 4'-fluor , 3'-trifluoromethyl, 3'-nitro, 4'-chloro-3 * -nitro, 4'-fluoro-3'-nitro, or 3'-methyl, or a pharmaceutically acceptable salt thereof. 5. A quinazoline derivative of the formula I, according to clause 1, wherein R is amino, hydroxyamino, methylamino, dimethylamino, acetamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, or 4-chlorobutyr- * h * ami, do, R 3 is fluro, or chloro, and 2 (R) n is 3'-chloro, 3 ', 4'-dichloro, 3'-chloro-4'-fluoro, or 3'-methyl, or a pharmaceutically acceptable salt thereof. 6. - A quinazoline derivative of the formula I according to clause 1, wherein R is amino, hydroxyamino, methylamino, dimethylamino, acetamido, 2-oxopyrrolidin-1-yl, 2-chloroacetamido, 4-chloroacetamide, acrylamido, or 2-chloro-N-methylacetamido; R3 is fli? Or, or chlorine; and (, R 2,) is 3'-chloro-, 3 ', 4'-dichlor, 3 * -chloro-4' -f luor, or n 3 * -methyl, or a pharmaceutically acceptable salt thereof. 7. A quinazoline derivative of the formula I, according to clause 1, wherein R is methoxy or ethoxy; R is fli? Or, or chloro, and 2 (R) n is 3'-chloro, 3 ', 4'-dichloro, 3'-chloro-4' -fluor, or 3'-methyl or a pharmaceutically acceptable salt of the same. 8. A quinazoline derivative of the formula I according to clause 1, selecting from 6-amino-7-fluoro-4- (3'-methylanilino) quinazoline, 6- (2-chloroacetamido) -7-fluoro-4- (3'-methylanilino) quinazoline, 6-amino-4- (3'-chloro-4'-fluoroanilino) 7-fluoroquinazoline, 7-chloro-6-methylamino-4- (3'-methylanilino) quinazoline, 7-chloro -6- (2-chloroacetamido) -4- (3'-methylanilino) quinazoline and 7-chloro-6- (2-chloroacetamido) -4- (3 ', 4'-dichloroanilino) quinazoline, or a pharmaceutically acceptable salt acceptable of it. 9. A quinazoline derivative of the formula I, according to clause 1, selected from: 7-fluro-6-hydroxyamino-4- (3'-methylanilino) quinazoline; 4- (3 '-chloro-4' -fluoroanilino) -7-fluoro-6-hydroxyamino-nazoline, 6-acrylamido-7-flu'or-4- (3'-methylanilino) quinazoline; 4_ (3 * -chloro-4 '-fluoroanilino) -7-fluoro-6-methylaminoquinoline, 6- (2-chloroacetamido) -4- (3'-chloro-4'-fluoroanilino) -7-fluoro-quinazoline , 6- (4-chlorobutyramido) -4- (3'-chloro-4'-fluoroanilino) -7-fluoro-quinazoline and 4- (3'-chloro-4 '-fluoroanilino) -7-fluoro-6- ( 2-oxopyrrolidin-1-yl) -quinazoline; or a pharmaceutically acceptable salt thereof. 10. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as mentioned in clause 1, which comprises: (a) the reaction of a quinazoline of the formula II Z where Z is a displacement group, with an aniline of formula III (b) for the production > ln of those compounds of the formula I wherein R or R2 is hydroxy, the division of a quinazoline derivative of the formula I, wherein R or R is (1-4C) alkoxy; (c) for the production of those compounds of the formula I wherein R is amino or hydroxyamino, the reduction of a quianzoline derivative of the formula I wherein R is nitro; (d) for the production of those compounds of formula I wherein R is (2-4C) alkanoylamino, (2-4C) alkanoylamino, benzamido, (3-4C) alkenoylamino, (3-4C) alkanoylamino) , (1-4C) N-alkyl (2-4C) alkyl, N (1-4C) -alkanoylamino (2-4C) -substituted alkyl, N- (1-4C) -alkanoylamino-alkyl (3-4C), N-(1-4C) -alkylamino of (2-4C), or N-alkylbenzamido of (1-4C), or R is (2-4C) alkanoylamino, the acylation of a 1 - 2 d of quinazoline of the formula I wherein R or R is amino; or (e) for the production of those compounds of the formula I, wherein R is (1-4C) alkoxy, or (1-4C) -substituted alkoxy, or R is (1-4C) alkylamino, alkylation of (1-4C0, or (1-4C) -substituted alkylamino, the alkylation of a quinazoline derivative of the formula I wherein R is hydroxy, or an amino as appropriate, or when a pharmaceutically acceptable salt of a quinazoline derivative of the formula I, it is required that it can be obtained using a conventional method 11. A pharmaceutically composition which comprises a quinazoline derivative of the pharmaceutically acceptable pharmaceutically acceptable salt. thereof, as mentioned in clauses 1 to 9, in association with a diluent or with a pharmaceutically acceptable carrier thereof 12. The use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, according to any of clauses 1 to 9, to obtain a medically parai used in the production of an effect against cancer in a warm-blooded animal. Under protest to tell the truth, I state that the best method to carry out the present invention is the one mentioned in this application. In testimony of which we sign the present in Mexico, D.F., on July 18, 1994 ZENECA LIMITED