Derivatives hintline, the method of production thereof, pharmaceutical composition and method of achieving the antiproliferative effect

 

(57) Abstract:

The invention relates to the derivatives of hintline formula (I), where n = 2 and each R2independently halogen; R3- (1-4C)alkoxy; R1di-[(1-4C)alkyl]amino(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-[(1-4C)-alkoxy-(2-4C)alkyl] amino-(2-4C)alkoxy, and any R1containing methylene group, which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy, or their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of inhibitory activity of compounds to inhibit the receptor tyrosinekinase in the treatment of proliferative diseases such as cancer. 6 C. and 14 C.p. f-crystals, 3 PL.

The invention relates to the derivatives of hintline or their pharmaceutically acceptable salts, which possess antiproliferative action, such as an anti-cancer effect, and accordingly can be used in the treatment of humans or animals. This is their basis and their use for the production of pharmaceuticals, providing anti-proliferative effect in a warm-blooded animal, in particular in humans.

Many modern methods of treatment of diseases associated with cell proliferation such as psoriasis and cancer, include compounds that inhibit DNA synthesis. Such compounds are usually toxic to cells, but their toxicity with the rapid proliferation of cells, such as tumor cells, may be desirable. Alternative approaches to antiproliferative drugs acting by a different mechanism than the inhibition of DNA synthesis, suggest achieving high selectivity of action.

In recent years it was found that cells can become malignant due to the partial transformation of the DNA into an oncogene, that is, a gene that when activated causes the formation of malignant tumor cells (Bradshaw, Mytaqenesis, 1986, 1, 91). Some of these oncogenes cause an increase in the formation of peptides, which are receptors for growth factors. Complex receptor growth factor in further causes an increase in cell proliferation. It is known, for example, that some oncogenes encode tyrosine kinase and that certain receptors growth factor S="ptx2">

The receptor tyrosine kinase plays an important role in the transmission of biochemical signals that initiate cell reproduction. They are large enzymes that act on the cell membrane and occupy the extracellular binding region for growth factors such as epidermal growth factor (EGF), and the intracellular portion, which functions as a kinase through phosphorylation of tyrosinaemia in proteins and thereby affecting cell proliferation. There are various classes of receptor tyrosinekinase (Wilks Advancesin Cancer Research, 1993, 60, 43-73), including a family of growth factors that are associated with different receptor tyrosinekinase. The classification includes Class I receptor tyrosinekinase containing EGF family receptor tyrosinekinase, such as EGF. TGF. N EL erbB. X mrk HER and let 23 receptors, Class II receptor tyrosinekinase comprising the insulin family of receptor tyrosinekinase, such as insulin, ICF I and insulin-like receptor (IRR) receptors, and Class III receptor tyrosinekinase containing family thrombocytopoenia growth factor (PDGF) receptor tyrosinekinase, such as PDGF, PDGF, and receptor colony stimulating factor I (CSFI. It is known that the kinase of owaka, such as breast cancer (Sainsbury et al., Brit.J.Cancer, 1988, 58, 458; Guerin et al., Oncoqene Res, 1988, 3, 21 and Klijn et al., Breast Cancer Res.Treat., 1994, 29, 73), large-cell cancers of the lung (NSCL Cs), including adenocarcinoma (Cerny et al., Brit.J.Cancer, 1989, 54, 265; Reubi et al. Int.J.Cancer, 1990, 45, 269; and Rusch et al. Cancer Research, 1993, 53, 2379), and this form may cell lung cancer (Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer (Neal et al., Lancet, 1985, 366), esophageal cancer (Mukaida Cancer, 1991, 68, 142), cancer of the gastrointestinal tract, such as colon, rectum and stomach (Bolen et al., Oncoqone Res., 1987, 1, 149), cancer of the prostate (Visakorpi et al., Hitstochem. J., 1992, 24, 481), leukemia (Konaka et al. Cell, 1984, 37, 1035) and ovarian cancer, bronchial or pancreatic cancer (European Patent description N 0400586). When other human tumor tissue was tested on a family of EGF receptor tyrosinekinase, it was expected that this is found to be a significant prevalence of other cancers, such as thyroid cancer and uterine cancer. It is also known that tyrosinekinase activity of EGF-type rarely found in normal cells, while more frequently detected in malignant cells (Cell, 1987, 50, 823). Recently it was shown (W. J. Gullick, Brit. Med.Bull.,1991,47, 87) that EGF receptors, which have tyrosinekinase activity, are present in substantial excess in the of ludka, breast cancer, head and neck, oesophageal, gynecological tumors of the thyroid gland.

Accordingly, it is recognized that the inhibitor of receptor tyrosine kinase should be valuable selective inhibitor of the growth of cancerous breast cells (Yaish et al. Science, 1988, 242, 933). In favor of this view says that erbstein, EGF receptor tyrosinekinase inhibitor, specifically slowing growth in alimony Nude mice transplanted human breast carcinoma, which enhances EGF receptor tyrosinekinase, but has no effect on the growth of other carcinomas, which are not sensitive to EGF receptor tyrosinekinase (Toi et al., Eur.J. Cancer Clin. Oncol. , 1990, 26, 722). Also indicates that various derivatives of styrene have the ability to inhibit tyrosinekinase (European patent application NN 0211363, 0304493 and 0322738) and can be used as antitumor agents. Ingibiruty effect in vivo of two such styrene derivatives, which are inhibitors of EGF receptor tyrosine kinase, was demonstrated by inhibition of growth of squamous carcinoma cells human input naked mice (Yoneda et al., Cancer Research,1991, 51, 4430). In a recent review (Burke TR Jr.Druqs of the Future, 1992, 17, 119) RA describes the STN, certain derivatives of hintline are anilinopiperidine in position 4, is able to inhibit the activity of receptor tyrosine kinase. It is known that certain derivatives of hintline that have in position 4 heterooligomerization also have the ability to inhibit the activity of receptor tyrosine kinase (European patent application N 0602851).

In addition, it is known that certain aryl - or heteroarylboronic inhibit EGF and/or PDGF receptor tyrosine kinase (international patent application WO 92/20642). In the application disclosed certain derivatives hintline, but there is no mention of the 4-anilinoquinazoline derivatives.

Antiproliferative effect in vitro 4-aniline-chineselanguage derived disclosed Fry et al. Science, 1994, 265, 1093. It is argued that 4-(3'-bromoaniline)-6,7-dimethoxyquinazolin showed high efficacy as an inhibitor of EGF receptor tyrosine kinase.

Inhibitory effect in vivo 4,5-vaniljdoftande derivative, which is an inhibitor of the EGF family of receptor tyrosine kinase, is illustrated in relation to the growth in BALB/C Nude mice epidermoid carcinoma human A-431 or ovarian carcinoma person is certain tricyclic compounds which include five - or six-membered ring condensed with the benzene nucleus of hintline, possess inhibitory activity against receptor tyrosine kinase. It is also known from European patent application N 0635498 that certain derivatives of hintline that contain the amino group in position 6 and the halogen in position 7, show inhibitory activity against receptor tyrosine kinase.

Accordingly, it was found that inhibitors of receptor tyrosine kinase Class I can be used in the treatment of various cancers in humans.

With receptor tyrosine kinases EGF also associated non-malignant proliferative disorders, such as psoriasis (Elder et al. Science, 1989, 243, 811). Therefore, it can be expected that inhibitors of receptor tyrosinekinase type EGF can be used in the treatment of non-malignant forms of excessive cellular proliferation such as psoriasis (which is believed to TGF is the most important growth factor), benign prostatic hypertrophy (BPH), atherosclerosis and restenosis.

None of these links are not disclosed derivatives hintline that contain in position 4 anilinopiperidine in position 7 also, such compounds have antiproliferative properties in vivo, which we believe arise as a result of their inhibitory activity against receptor tyrosine kinase Class I.

In accordance with this invention features derived hintline formula I:

< / BR>
where n = 1, 2, or 3 and each R2independently halogen, trifluoromethyl or (1-4C)alkyl; R3- (1-4C) CNS group, and R1di[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino- (2-4C)alkoxy, piperazine-1-yl(2-4C)alkoxy, 4-(1-4C)alkylpiperazine - 1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C) alkoxy, di-[(1-4C)alkoxy(2-4C)alkyl] amino-(2-4C)alkoxy, thiomorpholine- (2-4C)alkoxy, 1-oxathiolane(2-4C)alkoxy or 1,1-dioxothiazolidine-(2-4C)alkoxy, and where any of the above R1deputies, including CH2(methylene) group which is not associated nor nitrogen atom or oxygen atom, contains arbitrarily specified in CH2the hydroxyl group Deputy; or its pharmaceutically acceptable salt.

In accordance with another aspect of the present invention features derived hintline formula I where n is 1, 2 or 3 and each R2independent pre-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)-alkoxy, piperazine-1-yl-(2-4C) alkoxy, 4-(1 - 4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C) alkoxy or di[(1-4C) alkoxy(2-4C) alkyl] amino-(2-4C) alkoxy, and where any of the above-mentioned R1substituents containing CH2(methylene) group which is not associated with nitrogen atoms or oxygen, contains arbitrarily specified in CH2the hydroxyl group Deputy; or its pharmaceutically acceptable salt.

In the present description, the term "alkyl" refers to alkyl groups with straight or branched chain, but references to individual alkyl group, such as "propyl", used to denote a group with a straight chain. For example, when R1represents a di-[(1-4C) alkyl] amino-(2-4C) alkoxy, acceptable values for the generic radicals include 2-dimethylaminoethoxy, 3 dimethylaminopropoxy, 2-dimethylaminopropoxy and 1-dimethylamino-2-yloxy. A similar approach is used to denote other common terms.

It should be borne in mind that the present invention, since certain compounds of formula I may exist in optically active or racemic forms, due to the presence of odnoshevnyy form or racemate, that exhibit antiproliferative activity. Synthesis of optically active forms may be carried out by standard methods of organic chemistry which are well known in the art, for example by synthesis from optically active starting reagents or by splitting of racemic forms.

Hintline formula I are unsubstituted in the positions 2, 5 and 8.

It should also be borne in mind that certain derivatives of hintline formula I can exist in solvated as well as in resolutional forms, such as, for example, hydrated forms. It is obvious that the present invention encompasses all such solvated forms which possess antiproliferative activity.

Acceptable values for the radicals in the General form above include those listed below.

Acceptable value of R2in the case when it is a halogen, and includes, for example, fluorine, chlorine, bromine or iodine; when a represents (1-4C)alkyl includes, for example, methyl, ethyl, propyl, isopropyl or butyl.

Acceptable value of R3in the case where it represents in a General form (1-4C)alkoxy, may be chosen, for example, what about the R1substituent which may be present in hinazolinam cycle are, for example:

for di-[(1 - 4C)alkyl]amino-(2-4C)alkoxy: 2-dimethylaminoethoxy, 2-(N-ethyl-N-methylamino)ethoxy, 2-diethylaminoethoxy, 2-dipropylamino, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-dimethylaminopropoxy, 2-diethylaminoethoxy, 1-dimethylaminopropyl - 2-yloxy, 1-diethylaminopropyl-2-yloxy, 1-dimethylamino-2-methylprop - 2-yloxy, 2-dimethylamino-2-methylpropoxy, 4 dimethylaminoethoxy, 4-diethylaminoethoxy, 3 dimethylaminoethoxy, 3 diethylaminoethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 1-dimethylamino-2 - yloxy and 1-diethylamino-2-yloxy;

for pyrrolidin-1-yl-(2-4C)alkoxygroup: 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy and 4-(pyrrolidin-1-yl)butoxy;

for piperidino-(2 - 4C)alkoxygroup: 2-piperidinoethyl, 3 piperidinedione and 4 piperidinyloxy;

for morpholino-(2-4C)alkoxygroup: 2-morpholinoethoxy, 3 morpholinopropan and 4 morpholinoethoxy;

for piperazine-1-yl-(2-4C)alkoxygroup: 2-(piperazine-1-yl)ethoxy, 3-(piperazine-1-yl)propoxy and 4-(piperazine-1-yl) butoxy;

4-(1-4C)alkylpiperazine-1-yl(2-4C)alkoxygroup: 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-metapopulation-1 - yl)propoxy and 4-(4-methylpiperidin-1-yl)butoxy;

for di-[(1-4C) alkoxy(2-4C)alkyl]amino-(2-4C) alkoxygroup: 2-[di-(2-methoxyethyl)amino] ethoxy, 3-[di-(2-methoxyethyl)amino] propoxy, 2-[di-(3-methoxypropyl) amino]ethoxy and 3-[di-(3-methoxypropyl)amino]propoxy;

for thiomorpholine-(2-4C)alkoxygroup: 2-thiomorpholine, 3 thiomorpholine and 4 thiomorpholine;

for 1 oxathiolane-(2-4C)alkoxygroup: 2-(1-oxathiolane)ethoxy, 3-(1-oxathiolane)propoxy and 4-(1-oxathiolane)butoxy;

for 1,1-dioxothiazolidine-(2-4C)alkoxygroup: 2-(1,1-dioxothiazolidine)ethoxy, 3-(1,1-dioxothiazolidine) propoxy and 4-(1,1-dioxothiazolidine)butoxy.

Acceptable substitutes obtained when any one of R1deputies, including CH2the group, which is not bound to the nitrogen atom or oxygen, carries on the specified CH2the hydroxyl group Deputy, are, for example, substituted di-[(1-4C) alkyl]amino-(2-4C)alkoxygroup, for example hydroxy-di-[(1-4C) alkyl]amino-(2-4C)alkoxygroup, such as 3-dimethylamino-2 - hydroxypropoxy.

Acceptable pharmaceutically suitable salt derived hintline of the present invention is, for example, additive salt of the acid derived hintline this izobreteny the coy acid, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric, maleic, tartaric, fumaric, methansulfonate or 4-toluenesulfonic acid.

Specifically, the new compounds of the present invention include, for example, derivatives of hintline formula I or their pharmaceutically acceptable salts, in which:

a) n is 1 or 2 and each R2independently represents a fluorine atom, chlorine, bromine, methyl or trifluoromethyl; and R3and R1take any of the values defined above or in this section relating to particular new compounds of the present invention;

b) n is 1, 2 or 3 and each R2independently represents a fluorine, chlorine or bromine; and R3and R1take any values above or in this section relating to particular new compounds of the present invention;

c) R3- methoxy - or ethoxypropan and n, R2and R1take any of the values defined above or in this section relating to particular new compounds of the present invention;

d) R1is a 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminoethoxy, 3 morpholinopropan, 2-(piperazine-1-yl)ethoxy, 3-(piperazine-1 - yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4 - methylpiperazin-1-yl)propoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy, 2-[di-(2-methoxyethyl)amino]ethoxy, 3-[di-(2-methoxyethyl)amino]propoxy, 3-dimethylamino - 2-hydroxypropoxy, 3 diethylamino-2-hydroxypropoxy, 3-(pyrrolidin-1-yl)-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy, 3 morpholino-2-hydroxypropoxy, 3-(piperazine-1-yl)-2 - hydroxypropoxy or 3-(4-methylpiperazin-1-yl)-2-hydroxypropoxy;

and n, R2and R3take any of the values defined above or in this section relating to particular new compounds of the present invention;

e) R1is a 3 dimethylaminopropoxy, 3 diethylaminopropyl, 3-(pyrrolidin-1-yl)propoxy, 3-piperidinyloxy, 3 morpholinoethoxy, 3- (piperazine-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)propoxy, 3-(imidazol-1-yl)propoxy, 3-[di-(2-methoxyethyl)amino] propoxy, 3-dimethylamino-2-hydroxypropoxy, 3 diethylamino-2-hydroxypropoxy, 3-(pyrrolidin-1-yl)-2-hydroxypropoxy, 3-piperidino-2 - hydroxypropoxy, 3 morpholino-2-hydroxypropoxy, 3-(piperazine-1 - yl)-2-hydroxypropoxy or 3-(4-methylpiperazin-1-yl)-2 - hydroxypropoxy; and n, R2th compounds of the present invention;

f) R1is a 3 dimethylaminopropoxy, 3 diethylaminopropyl, 3-(pyrrolidin-1-yl)propoxy, 3-morpholinopropan or 3-morpholino-2-hydroxypropoxy; and n, R2and R3take any of the values defined above or in this section relating to new compounds of the present invention;

q) R1is a 3-morpholinopropan; and n, R2and R3take any of the values defined above or in this section relating to particular new compounds of the present invention.

The preferred compound of the present invention is derived hintline formula I, where (R2)nrepresents a 3'-fluoro-4'-chloro or 3'-chloro-4'-vorgruppe;

R3- methoxy group and R1there is a 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-(pyrrolidin-1-yl) ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2 - piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-(4-methylpiperazin-1-yl)-ethoxy, 2-(imidazol - 1-yl) ethoxy, 3-(imidazol-1-yl)propoxy, 2-[di-(2 - methoxyethyl)amino]ethoxy or 3-morpholino-2 - hydroxypropoxy;

or their pharmaceutically acceptable additive with the water hintline formula I, where (R2)nis 3'-chloro, 3'-bromo, 3'-methyl, 2', 4'-dichloro, 3', 4'-debtor, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro - 4'-vorgruppe; R3- methoxy group and R1is a 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-(pyrrolidin-1-yl) ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 2-[di-(2-methoxyethyl)amino]ethoxy or 3-morpholino-2-hydroxypropoxy; or its pharmaceutically acceptable additive salt of the acid.

Another preferred compound of the present invention is derived hintline formula I, where (R2)nthere are 3'-chloro, 3'-bromo, 3'-methyl, 2'-4'-debtor, 2', 4'-dichloro, 3',4'-debtor, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro; R3- methoxy group and R1is 3 - dimethylaminopropoxy, 3 diethylaminopropyl, 3-(pyrrolidin-1-yl) propoxy, 3-morpholinopropan or 3-morpholino-2-hydroxypropoxy; or its pharmaceutically acceptable additive salt of the acid.

Further preferred compound of the present invention is derived hintline formula I, where (R2)nis 3',4'-debtor, 3', 4'-dichloro, 3'-fluorine is the Rupp; or its pharmaceutically acceptable salt additive acid.

A particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(2-pyrrolidin-1-yl - ethoxy)hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(2-morpholino - ethoxy)hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-[2-(4 - methylpiperazin-1-yl)ethoxy] hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-{ 2-[di-(2-methoxyethyl)amino] ethoxy} -hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound according nastolatki)-7 - methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-6-(2-diethylaminoethoxy)-7 - methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(2', 4'-diptiranjan)-6-(3-dimethylaminopropoxy)- 7-methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-6-(2-hydroxy-3 - morpholinoethoxy)- 7-methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(2', 4'-diptiranjan)-7-methoxy-6-(3-morpholinopropan) hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3 whom I am the salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-6-(3-diethylaminopropyl)-7 - methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-pyrrolidin-1-yl propoxy)hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-6-(3-dimethylaminopropoxy)-7 - methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3', 4'-diptiranjan)-6-(3-dimethylaminopropoxy)-7 - methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid adduct.

Another particularly preferred compound of the present invention is the following derived hintline formula I: the effective salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

6-(3-diethylaminopropyl)-4-(3', 4'-diptiranjan)-7 - methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(3 - piperidinyloxy)hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(2 - piperidinoethyl)hinzelin or its pharmaceutically acceptable additive salt of the acid.

Another particularly preferred compound of the present invention is the following derived hintline formula I:

4-(3'-chloro-4'-foronline)-6-(3-imidazol-1-yl-propoxy)- 7-methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

In accordance with an additional characteristic of the present invention, certain compounds according to the invention not only possess potentially to stop tumor growth and in high doses causes decrease of the initial tumor volume.

In accordance with this aspect of the present invention features derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-morpholinopropan) hinzelin or its pharmaceutically acceptable additive salt of the acid.

Also available hydrochloric acid salt derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-morpholinopropan) hintline.

Also available dihydrochloride salt derived hintline formula I:

4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-morpholinopropan) hintline.

Derived hintline formula I or its pharmaceutically acceptable salt can be synthesized by any known means used to obtain chemically related compounds. Acceptable methods include, for example, those disclosed in European patent applications N 0520722, N 0566226, N 0602851, 0635498, N 0635507. Such methods are used to prepare derivative hintline formula 1 or its pharmaceutically acceptable salts, are disclosed as an additional characteristic of the invention and are illustrated by the following accompanying examples in which, unless otherwise stated, n, R2, R3and R1can take lublicant standard methods of organic chemistry. The receipt of such reagents are described in the accompanying examples, which should not be construed as a limitation of the patent claims. Alternatively, the required basic reagents can be synthesized by similar methods, which relate to the practice of a specialist in this field.

a) the Reaction, preferably in the presence of reasonable grounds, hintline formula II:

< / BR>
where Z is a substituted group, with an aniline of the formula III:

< / BR>
Suitable substituted by a group Z can be, for example, halogen, alkoxy, aryloxy or sulfonyloxy, for example, chlorine, bromine, methoxy, phenoxy, methansulfonate or toluene-4-sulfonyloxy.

Acceptable base is, for example, an organic amine, such as, for example, pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0]undec-7-ene, or, for example, carbonates or hydroxides of alkali or alkaline earth metals, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Alternative acceptable base can be, for example, amide alkali or alkaline earth metal, for example amide acceptable inert solvent or diluent, for example alkanol or complex ether, such as methanol, ethanol, isopropyl alcohol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, simple ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine-2-one or dimethylsulfoxide. The reaction is preferably carried out at a temperature in the range, for example, 10-150oC, more preferably in the range of 20oC to 80oC.

Derived hintline formula I can be obtained in accordance with the present method in the form of a free base or as a salt of the acid of the formula H-Z, where Z takes the values indicated above. If you want salt to obtain the free base, salt can be handled acceptable basis, as defined above, in a standard way.

b) For those compounds of formula I, in which R1represents aminosilane (2-4C)CNS group, carry out the alkylation, preferably in the presence of a suitable base, as defined above, derived Chinas the example can be used any substance, providing the alkylation of the hydroxyl group in aminosilane CNS group, for example, aminosilanes alkylhalogenide, for example aminosilanes (2-4C)alkylchloride, bromide or iodide, in the presence of reasonable grounds specified above, acceptable inert solvent or diluent as defined above, and at a temperature in the range of, for example, from 10 to 140oC, preferably at or approximately at 80oC.

c) For compounds of formula I, where R1represents aminosilane (2-4C) CNS group, carry out the reaction, preferably in the presence of reasonable grounds specified above, the compounds of formula I, where R1represents a hydroxy-(2-4C) CNS group, or its reactive derivative, with the appropriate amine.

The reactive derivative of the compound of the formula I, where R1represents a hydroxy-(2-4C) CNS group is, for example, halogeno or sulfonyloxy-(2-4C)CNS group, such as bromine or methansulfonate-(2 - 4C)CNS group.

The reaction preferably takes place in the presence of acceptable ine>C, preferably at or approximately at the 50oC.

d) For compounds of formula I, where R1is a hydroxy-amino(2-4C)alkoxygroup carry out the reaction of the compounds of formula I, where R1represents a 2,3-epoxypropoxy - or 3,4-epoxybutane, with the appropriate amine.

The reaction is preferably carried out in the presence of acceptable inert solvent or diluent, as defined above, and at a temperature in the range of, for example, 10 to 150oC, preferably at or approximately at 70oC.

In that case, when the desired pharmaceutically acceptable salt derived hintline formula I, for example mono - or deduct acid derivative hintline formula I, it may be obtained, for example, by reaction of the compounds with, for example, the appropriate acid using standard methods.

As mentioned previously, derivatives hintline of the present invention possess anti-proliferative activity, which we believe is the result of inhibiting the ability of compounds against receptor tyrosinekinase Class I. These properties can be assessed using one or more procedures, rosiekins. Receptor tyrosinekinase cooked in partially purified form from cells A-431 (taken from carcinoma of the external female genital organs), following the methods described below and taken from Carpenter et al., J. Biol. Chem., 1979, 254, 4884; Cohen et al., J. Biol. Chem., 1982, 257, 1523 and Braun et al., J. Biol. Chem., 1984, 259, 2051.

Cells A-431 were grown to confluence, using a modified Dulbecco Wednesday Needle (DMEM), using 5% fetal calf serum (FCS). The obtained cells are homogenized in hypotonic buffer boric acid/EDTA at a pH of 10.1. The homogenate was centrifuged at 400 q for 10 minutes at 0-4oC. the Supernatant was centrifuged at 25000 q for 30 minutes at 0-4oC. the Precipitate after centrifugation suspended in 30 mm buffer HEPES at a pH of 7.4, containing 5% glycerol, 4 mm benzamide and 1% Triton X-100, stirred for one hour at 0-4oC and again centrifuged at 100000 q for hours at 0-4oC. the Supernatant containing dissolved receptor tyrosinekinase, kept in liquid nitrogen.

For the experiment, 40 μl of an enzyme solution thus obtained was added to a mixture of 400 μl of a mixture of 150 mm buffer HEPES at a pH of 7.4, 500 μm of orthovanadate sodium, 1% Triton X-100, 10% glycerol, 200 ml of water, 80 μl of 25 mm DTT and 80 μl of the enzyme solution.

Each test compound was dissolved in dimethyl sulfoxide (DMSO), receiving 50 mm solution, which was diluted in 40 mm buffer HEPES, containing 0.1% Triton X-100, 10% glycerol and 10% DMSO, getting a 500 μm solution. Mixed equal volumes of this solution and of a solution of epidermal growth factor (EGF, 20 μg/ml).

[32P] ATP (3000 Ci/mM, 250 Ci; =11.11013location./hmm, 9.2510' u./C. ) was diluted to a volume of 2 ml by the addition of a solution of ATP (100 μm) in distilled water. Added an equal volume of 4 mg/ml solution of the peptide Arg-Arg-Leu-Ile - Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly in a mixture of 40 mm buffer HEPES at a pH of 7.4, 0.1% Triton X-100 and 10% glycerol.

To the subject an enzyme solution (10 μl) was added 5 μl of a solution of a mixture of test connection/EGF and the mixture is incubated at 0-4oC for 30 minutes. Added 10 ml of a mixture of ATP/Pete and the mixture incubated at 25oC for 10 minutes. The phosphorylation reaction was interrupted by adding 5% trichloroacetic acid (40 μl) and cow serumalbumin (BSA, 1 mg/ml, 5 μl). The mixture was stirred at 4oC for 30 minutes and then centrifuged. An aliquot (40 μl) of the supernatant liquid was applied on a strip of Whatman p-81 phosphocellulose paper. The strip was washed in 75 mm phosphoric acid (4 x 10 ml) and dried by soaking. Measured radioactivity is at B) and again in the absence of the test compound (result C).

Inhibition of receptor tyrosine kinase was calculated as follows:

< / BR>
The degree of inhibition was determined for a range of concentrations of the test compounds, to obtain the value of the IC50.

b) Tested in vitro to determine the ability of test compounds to inhibit EGF-stimulated growth of human nasopharyngeal cancer cell line KB.

KB cells were cultivated in the filters 1104- 1,5104cells on the filter and were grown for 24 hours in DMEM with the addition of 5% FCS (processed coal). Cell growth was determined after incubation for three days according to the degree of metabolism of MTT tetrazolium dye to the disappearance of blue color. Determined the growth of cells in the presence of EGF (10 ng/ml) and in the presence of EGF (10 ng/ml) and test compounds in a concentration range. Calculate the value of the IC50.

c) Evaluation of in vivo on the group animicheskih naked mice (genus ONU: Alpk) to determine the activity of the tested compounds (usually introduced orally in the form of a suspension, prepared in a ball mill in 0.5% Polysorbate) in suppressing the growth of transplants of human epidermoid carcinoma cells external genital female organo cells were collected by trypsinization and were injected with subcutaneous (107cells/0.1 ml/mouse) into both flanks donor naked mice. When it was cooked enough tumor material (approximately 9-14 days), fragments of tumor tissue transplanted bare mice-recipients in side-by-day test 0). Usually on day 7 after transplantation (day test 7th) has selected a group of 7-10 mice with tumors of the same size and started typing test connection. The rate of injection of the test compound 13 days, one per day on days 7-19 testing inclusive). In some experiments the injection of the test compounds were continued and after 19 days, for example, up to 26 days of testing. In each case the next day after the last injection the animals were wordplays and determined the final tumor volume by measuring the length and width. The results were calculated as the percentage of tumor suppression in comparison with control animals that did not receive medication.

Although the pharmacological properties of the compounds of the formula I vary with changes in the total activity of the compounds of formula I can be demonstrated at the following concentrations or doses in one or more experiments (a), (b), (c).

Experiment (a): IC50in di 20-90% suppression of tumor at a daily dose in the range, for example, a 12.5-200 mg/kg

Some compounds described in the earlier filed application EPA 0566226 were also tested using each of the test methods outlined above in sections a), b) and c).

These test compounds correspond to examples 26, 41 and 61 of the patent. These examples are derivatives of 4-(3'- methylaniline)hintline, which is characterized by the substituents on the 6-th and 7-th positions (see table. A).

The results that were obtained for these examples mentioned patent application are included below for the purposes of comparative analysis in tables 1 and 2.

It should be noted that fragments of tumor tissue were implanted and then they were left to grow for 7 or 8 days. The dosage of the test compounds were introduced on the 7th or 8th day of the test. The percentage suppression of tumor volume was determined relative to the minimum observed at 0 day, and not in relation to the volume on the 7th or 8th day of the experiment. Accordingly, compounds that caused a reduction in tumor volume compared with that on the 7th (or 8th) day of the experiment, will show a high percentage of suppression of tumor volume, usually more than 90%, but it will not show the compounds of examples 26, 41 and 64 applications EPA 0566226 and compounds of the examples of the present application, shows:

(i) that, in General, both groups of compounds show similar activity in vitro as inhibitors of EGF-receptor tyrosine kinase;

(ii) that, in General, the compounds of examples 26, 41 and 64 applications EPA 0566226 surprisingly are less active than the compounds of the examples of this application in vitro as inhibitors of EGF-stimulated growth of a tumor cell line KB and

(iii) in particular, when tested doses of 50 and/or 200 mg/kg / day of the compounds of examples 26, 41 and 64 applications EPA 0566226 not show statistically overwhelming actions in vivo against growth in Nude mice transplanted tumor fragments A-431 human and do not show more than 50% suppression of tumor development;

while, in General, the compounds of the examples of this application unexpectedly show a statistically significant inhibitory activity in vivo in the same antitumor test at test doses of 50 mg/kg / day, and the connections of the 13 examples of the 20 that were tested, exhibit such activity;

whereas, in particular, the compounds of examples 1 and 3 of this application unexpectedly show more than 50% suppression of tumors in the test dose of 12.5 mg/to the giving of tumor volume compared with the volume of the tumor, which took place on 7-8th day of testing, when I started the dose) when the test dose of 100 or 200 mg/kg / day.

Accordingly, another aspect of the present invention is a pharmaceutical composition that includes a derived hintline formula I or its pharmaceutically acceptable salt with a pharmaceutically acceptable diluent or carrier.

The composition can be in the form acceptable for oral administration, for example in the form of tablets or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration in the form of ointments or creams, or for rectal administration in the form of candles.

Typically, the compositions can be prepared by standard methods, using standard inert fillers.

Derived hintline usually do a warm-blooded animal in a dose in the range of 5-10000 mg/m2the body surface of the animal, i.e. approximately 0.1-200 mg/kg, and this is usually therapeutically effective dose. Single dosage form such as a tablet or capsule usually contains, for example, about 1-250 mg of the active ingredient. its pharmaceutically acceptable salt daily dose equal to about 1-20 mg/kg, preferably 1-5 mg/kg, However, the daily dosage depends on the patient, the specific course of treatment and the severity of the disease. Accordingly, the optimal dose is determined by your doctor.

Accordingly, another aspect of the present invention features derived hintline formula I, as defined above, for use in therapy of the human or animal.

It is established that the compounds of the present invention possess anti-proliferative properties such as anti-cancer action, which, as you can assume, derived from the inhibitory activity of the receptor tyrosine kinase Class I. Accordingly, it can be expected that the compounds of the present invention can be used in the treatment of diseases or conditions defined or only partially receptor tyrosine kinases Class I, i.e. compounds can be used to achieve the inhibitory effect against the receptor tyrosinekinase Class I in warm-blooded animals in need of such treatment. Thus, the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of the receptor tyrosinekinase To the th or partial inhibition of the receptor tyrosinekinase Class I. Accordingly, it can be expected that the compounds of the present invention are useful in the treatment of psoriasis and/or cancer by creating an anti-proliferative effect, particularly in the treatment of cancers that are sensitive to the receptor tyrosine kinases of Class I, such as breast, lung, rectum, colon, stomach, prostate, bladder, pancreas and ovary.

Thus, in accordance with this aspect of the invention it is proposed to apply the derived hintline formula I or its pharmaceutically acceptable salt as defined above in the manufacture of medicines, which have antiproliferative effect on warm-blooded living organism, such as a person.

In accordance with another feature of this aspect of the invention, a method of achieving the antiproliferative action in warm-blooded animal, such as man, in need of such treatment, which includes the introduction of specified animal an effective amount of a derivative hintline, as defined directly above.

As previously mentioned, the dosage in the treatment or prevention of specific proliferative ill-200 mg/kg, preferably 1-100 mg/kg, more preferably 1-10 mg/kg

Antiproliferative treatment, as defined above, may include the use of one of the derived hintline of the present invention or in addition to its application one or more other anti-tumor substances, for example cytotoxic or cytostatic anti-tumor substances, for example, selected from the class mitotic (mitotic inhibitors such as vinblastine, vindesine and vinorelbine; tubulidentata inhibitors such as Taxol; alkylating agents, for example CIS-platinum, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, tegafur, methotrexate, citizenoriented, hydroxyacetone, or, for example, one of the preferred antimetabolites, disclosed in European patent application N 239362 such as N-{5-[N-(3,4-dihydro-2 - methyl-4-oxadiazolyl-6-yl-methyl)-N-methylamino] -2-thenoyl}-L - glutamic acid; intercalatory antibiotics, for example adriamycin, mitomycin and bleomycin; enzymes, for example asparaginase; topoisomerase inhibitors, such as etoposide and Campomarino; biological reaction modifiers, for example interferon; antihormonal substances neprimerov-2-methyl-3'-(trifluoromethyl) propionanilide or for example, LHRH antagonists or LHRH agonists, such as goserelin, leuprorelin or buserelin, and inhibitors of the synthesis of hormones, such as aromatase inhibitors, such as disclosed in European patent application N 0296749, for example 2,2'-[5-( 1,2,4-triazole-1-ylmethyl)-1,3-phenylene] bis (2-methylpropionitrile), and, for example, inhibitors of 5 - reductase, such as 17- (N-tert-butylcarbamoyl)-4-Aza-5 - androst-1-EN-3-one. Such joint treatment can be achieved by simultaneous, sequential or separate individual funds for treatment. In accordance with this aspect of the invention features a pharmaceutical product containing the derived hintline formula I, defined above, and additional antitumor substance for joint treatment of cancer.

As previously mentioned, the derived hintline of the present invention is effective as an anticancer agent whose effectiveness results from inhibiting properties against receptor tyrosine kinase Class I Derived hintline has a broad spectrum anti-cancer properties, as receptor tyrosine kinase Class I are involved in many cancers, such as leukemia and R is. the thus, it can be expected that the derived hintline of the present invention will possess anticancer activity against such cancers. In addition, it can be expected that the proposed derivative hintline has activity against leukemia, lipoid malignancies and solid tumours such as carcinoma and sarcomas in tissues such as lung, kidney, prostate and pancreas.

You can also expect that the derived hintline of the present invention have activity against other diseases characterized by excessive cell proliferation such as psoriasis and benign prostatic hypertrophy (BPH).

You can also expect that the proposed derivative hintline effective in the treatment of other disorders of cell growth, involving aberrant cell signaling through enzyme receptor tyrosine kinase or enzymes preceptory tyrosinekinase, including as yet unidentified tyrosine kinase enzymes. Such diseases include, for example, inflammation, angiogenesis, vascular restenosis, immunological disease, pancreatitis, kidney disease and maturely of blastocytes and implantation.


I) carry out evaporation on a rotary evaporator and the procedure of processing carried out after removal of the solid residue, such as dried agent by filtration. As drying agent for organic solutions were used, unless otherwise noted, magnesium sulfate;

II) was carried out at ambient temperature, in other words in the range of 18-25oC and in an atmosphere of inert gas, such as argon;

(III) chromatography on a column (via evaporation) and liquid chromatography with an average pressure (MPLC) was performed on Merck Kieselgel of the silica compound (Merck Kieselgel Art. 9385) or Merck, Micropar RP-18 (Merck Lichroprer RP-18, Art. 9303) silica gel, supplied by E. Merck. (Darmstadt, Germany);

IV) output was cited for illustration only, not striving for the achievement of maximum;

V) the melting point was determined on the apparatus by Mettler (Mettler SP 62), the device with oil bath or apparatus hot plate Koffler;

VI) the structure of the final products was determined by nuclear magnetic resonance and mass spectral; the value of the chemical shift was measured on the Delta scale and peak resonance is shown as follows: singlet, doublet, triplet, multiplet. If not mentioned specifically, as the solvent used CD3SOCD3;

VII) about what cromatografia infrared and NMR spectra;

VIII) adopted the following abbreviations: DMF - N,N-dimethylformamide, DMSO is dimethylsulfoxide, THF-tetrahydrofuran; DMA is N,N-dimethylacetamide.

EXAMPLE 1

A mixture of 1 g of 4-(3'-chloro-4'-foronline)-6-hydroxy-7 - methoxyquinazoline, and 0.62 g of 3-morpholinopropan (J. Amer.Chem. Soc. 1945, 67, 736), 2.5 g of potassium carbonate and 50 ml of dimethylformamide is stirred and maintained at a temperature of 80oC for two hours. Add an extra dose of 0.1 g 3 - morpholinopropan and the mixture was kept at 80oC for one hour. The mixture is filtered and the filtrate evaporated. The residue is purified chromatographically on a column, using as eluent a mixture of 4:1 ethyl acetate/methanol. The resulting material is recrystallized in toluene. The result is 0.69 g (yield 50%) of 4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-morpholinopropan) hintline. So pl. 119-120oC.

NMR spectrum: 2.0 (multiplet, 2H), 2,45 (multiplet, 6H), 3,6 (multiplet, 4H), 3,95 (singlet, 3H), 4.2V (triplet, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

Elemental analysis.

Found: C, 58.7 Percent, H 5,3%, N 12,2%.

Calculated for C22H24ClFN4O3: C 59,1%, H 5.4%, AND N OF 12.5%.

The source reagent emeu methansulfonate added dropwise with 26.5 g of 6,7-dimethoxy-3,4-dihydroquinazolin-4-it (European patent application N 0566226, example 1). Add 22 g L-methionine and the resulting mixture was refluxed under heating for five hours. The mixture is cooled to room temperature and poured into 750 ml of a mixture of ice and water. The mixture is neutralized by adding concentrated (40%) solution of sodium hydroxide in water. The precipitate was separated, washed with water and dried. So get of 11.5 g of 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-it.

After repetition of the previous reaction mixture 14,18 g of 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-it, 110 ml of acetic anhydride and 14 ml of pyridine is stirred and heated to 100oC for two hours. The mixture is poured into 200 ml of a mixture of ice and water. The precipitate was separated, washed with water and dried. The result is 13 g (yield 75%) of 6-acetoxy-7-methoxy-3,4 - dihydroquinazolin-4-it.

NMR spectrum: 2,3 (singlet, 3H), 3.8 (singlet, 3H), 7,3 (singlet, 1H), 7,8 (singlet, 1H), 8.1 (singlet, 1H), and 12.2 (broad singlet, 1H).

After repeating the preceding stages is stirred and heated for 4 hours at 90oC a mixture of 15 g of 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-it, 215 ml of thionyl chloride and 4.3 ml of dimethylformamide. The mixture is cooled to room temperature and thionyl chloride is evaporated. The result is a 6-mesh obtained substances - was 9.33 g of 3-chloro-4-foronline and 420 ml of isopropanol is stirred and maintained at 90oC with heating for five hours. The mixture is cooled to room temperature and the precipitate was separated, washed in turn with isopropanol and methanol and then dried. The result is a 6-acetoxy-4-(3'-chloro-4'-foronline)- 7-methoxyquinazoline hydrochloride (14.0 g, yield 56%).

NMR spectrum: 2.4GHz (singlet, 3H), 4.0 (ice singlet, 3H), 7.5 (a triplet, 1H), 7,6 (singlet, 1H), 7,75 (multiplet, 1H), 8,05 (multiplet, 1H), 8,8 (singlet, 1H), 8,95 (singlet, 1H), and 11.5 (broad singlet, 1H).

of 7.25 ml of concentrated aqueous ammonium hydroxide (30% wt. /about.) add to the mix a mixture of the obtained material and 520 ml of methanol. The mixture is stirred at room temperature for 17 hours and then heated to 100oC for 1.5 hours. The mixture is cooled and the separated precipitate, which is dried. The result is to 10.62 g (95% yield) of 4-(3'-chloro-4'- foronline)-6-hydroxy-7-methoxyquinazoline. So pl. above 270oC (decomposition).

NMR spectrum: 4,0 (singlet, 3H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (singlet, 1H), 7,85 (multiplet, 1H), and 8.2 (multiplet, 1H), 8,5 (singlet, 1H), 9,45 (singlet, 1H), 9,65 (singlet, 1H).

EXAMPLE 2

A mixture of 1.14 g of 4-(3'-chloro-4'-foronline)-6-hydroxy-7 - methoxyquinazoline 90oC for five hours. The mixture was then cooled to room temperature and poured into water. The precipitate was separated, dried and purified chromatographically on a column using the elution of a mixture of 9:1 methylene chloride/methanol. The resulting material is subjected to recrystallization from ethanol. The result is a 0,813 g (55% yield) of 4-(3'-chloro-4'-foronline) -7-methoxy-6-(2-pyrrolidin-1-yl-ethoxy)hintline. So pl. 187-188oC.

NMR spectrum: 1,7 (multiplet, 4H), and 2.6 (multiplet, 4H), 2,9 (triplet, 2H), 3.9 (singlet, 3H), 4.2V (triplet, 2H),7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

Elemental analysis.

Found: C, 60.1 Percent, H 5.4%, And N Of 13.4%.

Calculated for C21H22ClFN4O2: C 60,5%, H 5,3%, N 13,4%.

EXAMPLE 3

A mixture of 1.62 g of 4-(3'-chloro-4'-foronline)-6-hydroxy-7 - methoxyquinazoline, 0.95 g of 2-morpholinoethyl hydrochloride, 3.6 g of potassium carbonate and 40 ml of dimethylformamide is stirred and heated at 90oC for 1.5 hours. The mixture is cooled to room temperature and poured into water. The precipitate was separated, dried and purified chromatographically on a column using a mixture of 9:1 methylene chloride/methanol as eluent. The resulting substance paracrystalline)hintline. So pl. 229-230oC.

NMR spectrum: 2,6 (multiplet, 4H), 2,85 (triplet, 2H), 3,6 (multiplet, 4H), 3.9 (singlet, 3H), 4,3 (triplet, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

Elemental analysis.

Found: C, 57.5%, Respectively, H Is 4.9%, N 12.7 Per Cent.

Calculated for C21H22ClFN4O30,3 H2O: C 61,0%, H 5.7% OF N 14,2%.

4-(2', 4'-diptiranjan)-6-hydroxy-7-methoxyquinazoline used as a starting reagent, prepared according to the following procedure.

A mixture of 5.4 g of 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride, 2.5 ml of 2,4-diptiranjan and 100 ml of isopropanol is stirred and heated to boiling point under reflux for two hours. The precipitate was separated, washed with acetone and ethyl ether and then dried. The result of 3.9 g (yield 53%) of 6-acetoxy-4-(2',4'-diptiranjan)-7 - methoxyquinazoline hydrochloride. So pl. 207-210oC.

NMR spectrum: 2.4GHz (singlet, 3H), 4,05 (singlet, 3H), 7,25 (multiplet, 1H), of 7.48 (multiplet, 1H), 7,55 (singlet, 1H), 7,63 (multiplet, 1H), 8,7 (singlet, 1H), cent to 8.85 (singlet, 1H), and 11.6 (broad singlet, 1H).

At room temperature for two hours stirred mixture of 3.7 g of the obtained substances, 2 ml of concentrated the result of 1.3 g of 4-(2',4'-diptiranjan)-6-hydroxy-7-methoxyquinazoline (yield 40%).

NMR spectrum: 3,97 (singlet, 3H), 7,1 (multiplet, 1H), 7,2 (singlet, 1H), 7,54 (multiplet, 1H), to 7.67 (singlet, 1H), 8.3 (the singlet, 1H), 9,3 (singlet, 1H), 9,65 (broad singlet, 1H).

EXAMPLE 9

A mixture of 2 g of 4-(3'-chloro-4'-foronline-6-(2,3-epoxypropoxy)- 7-methoxyquinazoline, 0.5 ml of the research and 20 ml of isopropanol is stirred and heated to boiling under reflux for 1 hour. The mixture is cooled to room temperature and evaporated. The residue is purified chromatographically on a column, using as eluent a mixture of 9:1 methylene chloride/methanol. The resulting product is recrystallized from ethyl acetate. Obtain 1.4 g (yield 57%) of 4-(3'-chloro-4'-foronline)-6-(2-hydroxy-3 - morpholinoethoxy)-7-methoxyquinazoline. So pl. 206-207oC.

NMR spectrum: 2,5 (broad multiplet, 6H), 3,6 (triplet, 4H), 3.9 (singlet, 3H), 4,1 (broad multiplet, 3H), 5,0 (broad multiplet, 1H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

Elemental analysis.

Found: C To 57.0%, H 5,2%, N 11.9 Per Cent.

Calculated for C22H24ClFN4O4: C 57,1%, H 5,2%, N 12,1%.

Used as a source of reagent 4-(3'-chloro-4' -foronline)-6-(2, 3 epoxypropoxy)-7-methoxyquinazoline get the following OID, 5 g of potassium carbonate and 50 ml of dimethylsulfoxide is stirred at room temperature for 16 hours. The mixture is poured into water with ice, the precipitate is separated, washed with water and dried. The result is the desired source reagent, which was used without further purification and showed the following data. So pl. 125-126oC (decomposition).

NMR spectrum: 2,8 (multiplet, 1H), 2,9 (multiplet, 1H), 3.5 (multiplet, 1H), 4.0 (ice singlet, 3H), 4.1 (multiplet, 1H), 4.5 (multiplet, 1H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 1H), 7,85 (singlet, 1H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

EXAMPLE 10

A mixture of 13.75 ml of the research, 2,94 g of 6-(3-bromopropane)-4-(3'- chloro-4'-foronline)-7-methoxyquinazoline and 67 ml of dimethylformamide was stirred at ambient temperature for 30 minutes. The mixture is extracted with ethyl acetate and water. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue is purified through column chromatography using a mixture of 9: 1 methylene chloride/methanol as eluting solvent. The resulting product is recrystallized from toluene. The result 0,78 g (yield 27%) of 4-(3'-chloro-4'-foronline)-7-methoxy-6-(3 - morpholinopropan reply, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

Used as a source of reagent 6-(3 - bromopropane)- 4-(3'-chloro-4'-foronline)-7-methoxyquinazoline receive the following way.

For one hour at room temperature stirred mixture of 2 g of 4-(3'-chloro-4'-foronline)-6-hydroxy-7-methoxyquinazoline, 6,36 ml of 1,3-dibromopropane, 4 g of potassium carbonate and 200 ml of dimethylformamide. The mixture is filtered and the filtrate evaporated. The residue is purified on a chromatographic column, using as eluent ethyl acetate. The result is 6-(3-bromopropane)-4-(3'-chloro-4'- foronline)-7-methoxyquinazoline with quantitative yield and derived hintline used without further purification.

NMR spectrum: 2.4GHz (multiplet, 2H), 3,7 (triplet, 2H), 3,95 (singlet, 3H), 4,3 (triplet, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

EXAMPLE 11

A mixture of 0.17 ml of the research, 0.4 g of 6-(2-bromoethoxy)-4-(3'- chloro-4'-foronline)-7-methoxyquinazoline and 12 ml of ethanol is stirred and heated to boiling point under reflux for 27 hours. The mixture is evaporated and the residue distributed between ethyl acetate and water. Organizes the Russian column, using a mixture of 9:1 methylene chloride/methanol as eluting solvent. Obtain 0.14 g (35% yield) of 4-(3'-chloro-4'-foronline)-7 - methoxy-6-(2-morpholinoethoxy) hintline.

NMR spectrum: 2,6 (multiplet, 4H), 2,85 (triplet, 2H), 3,6 (multiplet, 4H), 3.9 (singlet, 3H), 4,3 (triplet, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H), 9,5 (singlet, 1H).

EXAMPLE 12

A mixture of 1.1 g of 4-(3'-chloro-4'-foronline)-6-hydroxy-7 - methoxyquinazoline, 0.7 g of the hydrochloride of 3-diethylaminopropylamine, 3 g of potassium carbonate and 30 ml of dimethylformamide is stirred and heated to 80oC for three hours. The mixture is cooled to room temperature and filtered. The filtrate is evaporated and the residue purified through column chromatography using elution mixture of 4:1 methylene chloride/methanol. The resulting product is triturated in a mixture of 5:1 methanol/water. The obtained solid mass is dried. The result of 1.03 g (yield 70%) of 4-(3'-chloro - 4'-foronline)-6-(3-diethylaminopropyl)-7-methoxyquinazoline.

NMR spectrum: 0.95 (triplet, 6H), 1,9 (multiplet, 2H), 2,5 (multiplet, 6H), 3,95 (singlet, 3H), 4.2V (triplet, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), 8.1 (multiplet, 1H), 8,5 (singlet, 1H).

Elemental analysis.

Found: C, 59.4 per cent, H 6.2 percent,MEASURES 25

Odnokolernyh solution of hydrogen chloride in 15 ml of sulphuric ether are added to a solution of 2.2 g of 4-(3'-chloro-4'-foronline)-7 - methoxy-6-(3-martinaerospace)hintline in 20 ml of dimethylformamide and the mixture is stirred at room temperature for two hours. The precipitate was separated, washed with ethyl ether and dried under vacuum at 80oC. Obtain 2.3 g dihydrochloride salt of 4-(3'-chloro-4'-foronline)- 7-methoxy-6-(3-morpholinopropan)hintline.

NMR spectrum: 2,3 (multiplet, 2H), 3,2-3,6 (multiplet, 6H), 4.0 (ice multiplet, 7H), 4,35 (triplet, 2H), and 7.4 (singlet, 1H), 7,55 (triplet, 1H), 7,8 (multiplet, 1H), 8,15 (multiplet, 1H), 8,6 (singlet, 1H), 8,9 (singlet, 1H).

Elemental analysis.

Found: C, 50.7 Per Cent, H 5,0%, N 10,5%, Cl 13.1 Per Cent.

Calculated for C22H24ClFN4O32 fumaric acid: C 51,5%, H 5,2%, N 8,0%.

EXAMPLE 28

A solution of 1.4 g of 4-(3'-hpar-4'-foronline)-7-methoxy-6-(3 - morpholinopropan)hintline minimum amount of Tetra - hydrofuran added to a solution of citric acid (1.5 g) in 30 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 16 hours. The precipitate was separated and triturated in acetone. The result of 1.3 g of 4-(3'-chloro-4'- foronline)-7-methoxy-6-(3-morpholinopropan) hintline, soderjat, 8H), 3,65 (triplet, 4H), 3,95 (singlet, 3H), 4.2V (triplet, 2H), 7,2 (singlet, 1H), and 7.4 (triplet, 1H), 7,8 (multiplet, 2H), and 8.2 (multiplet, 1H), 8,48 (singlet, 1H), 9,6 (singlet, 1H).

Elemental analysis.

Found: C 50,0% H 5.2%, And N Of 7.2%.

Calculated for C22H24ClFN4O32 CH3SO3H: C 43,7% H 5.2%, AND N OF 8.5%.

EXAMPLE 30

To a mixture of 1.5 ml of concentrated sulfuric acid and 20 ml of methylene chloride add a solution of 1.5 g of 4-(3'-chloro-4'- foronline)-7-methoxy-6-(3-morpholinopropan) hintline in a mixture of 10 ml of dimethylacetamide and 50 ml of methylene chloride. The resulting mixture was stirred at room temperature for 16 hours. The precipitate was separated, washed in acetone and dried. The result is 2.7 g of di-acid salt of 4-(3'-chloro-4'- foronline)-7-methoxy-6-(3-morpholinopropan)hintline. So pl. above 250oC.

NMR spectrum: 2,3 (multiplet, 2H), 3.0 to 3.8 (multiplet, 10H), was 4.02 (singlet, 3H), 4,35 (triplet, 2H), 7,38 (singlet, 1H), 7,53 (triplet, 1H), to 7.77 (multiplet, 1H), 8,05 (multiplet, 1H), 8,15 (singlet, 1H), 8,92 (singlet, 1H).

Elemental analysis.

Found: C To 39.0%, H 4.2%, N 8,2%.

Calculated for C22H24ClFN4O32 H2SO4: C 38,9%, H 4,75%, N 8,3%.

EXAMPLE 31

A solution of 1.12 ml of 4-toluensulfonyl is propoxy) hintline in 60 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for four hours. The precipitate was separated, washed in turn with tetrahydrofuran and acetone and dried. The result of 1.54 g of di-4-toluensulfonate salt of 4-(3'-chloro-4'-foronline)- 7-methoxy-6-(3-morpholinopropan) hintline. So pl. 169-173oC.

NMR spectrum: 2,3 (multiplet, 8H); a 3.0-3.8 (multiplet, 10H); 4,0 (singlet, 3H); 4,3 (triplet, 2H), 7,1 (doublet, 4H); 7,34 (singlet, 1H); 7.5 (a doublet, 4H); 7,54 (triplet, 1H); 7.7 (multiplet, 1H); 7,95 (multiplet, 1H); 8.1 (singlet, 1H); 8,9 (singlet, 1H); 11.0 in (broad singlet, 1H).

Elemental analysis.

Found: C, 52.8 Per Cent, H Is 4.9%, N 6.8 Per Cent.

Calculated for C22H24ClFN4O32 CH3C6H4SO3H: C 52,8%, H 5,3%, N 6,85%.

EXAMPLE 32

The following illustrates samples of pharmaceutical dosage forms containing the compound of formula I or its pharmaceutically acceptable salt (denoted below by X), for therapeutic and prophylactic human use:

a) Tablet I mg/tablet:

Connection X - 100

Lactose Ph.Eur. - 182,75

Croscarmellose sodium to 12.0

Paste of maize starch (5% wt./about.paste) was 2.25

Magnesium stearate - 3,0

b) Tablet II, mg/tablet:

Connection X - 50
< 2,25

Magnesium stearate - 3,0

(c) Tablet III mg/tablet:

Connection X - 1,0

Lactose Ph.Eur. - 93,25

Croscarmellose sodium - 4,0

Corn starch paste (5% wt./about.paste) - 0,75

Magnesium stearate - 1,0

d) the Capsule mg/capsule:

Connection X - 10

Lactose Ph.Eur. - 488,5

Magnesium stearate and 1.5

e) Injection I (50 mg/cm3); % wt./about.:

Connection X - 5,0

1 M sodium hydroxide solution 0.1 M hydrochloric acid (to adjust pH to 7.6) - 15,0

Polietilenglikol 400 - 4,5

Water for injection to 100%

f) Injection II (10 mg/cm3); % wt./about.:

Connection X - 1,0

Sodium phosphate BP - 3,6

0.1 M sodium hydroxide solution to 15.0

Water for injection to 100%

q) Injection III (1 mg/ml, buffer to pH 6); % wt./about.:

Connection X - 0,1

Sodium phosphate BP 7,6 - of 2.26

Citric acid - 0,38

Polietilenglikol 400 - 3,5

Water for injection to 100%

Note. The above forms can be prepared by standard methods well known in the pharmaceutical industry. The tablets (a) - (c) can be used for absorption in the intestine and to have a standard coating, for example, of cellulose acetate phthalate.

1. Derived hintline formula I

< / BR>
where n = 2;

RRaiden-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazine-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazine-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)-alkoxy or di-[(1-4C)alkoxy(2-4C)alkyl]amino-(2-4C)alkoxy, and any R1including methylene group which is not linked to the nitrogen atom or oxygen atom, and optionally contains in the indicated methylene group, a hydroxyl Deputy,

or its pharmaceutically acceptable salt.

2. Derived hintline formula I under item 1, in which R2)n- 3'-fluoro-4'-chloro or 3'-chloro-4'-fluoro-group; R3- methoxy group and R1- 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3 dimethylaminopropoxy, 3 diethylaminopropyl, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethyl, 3 piperidinyloxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy, 2-[di-(2-methoxyethyl)amino] ethoxy or 3-morpholino-2-hydroxypropoxy, or its pharmaceutically acceptable additive salt of mono - or decollate.

3. Derived hintline formula I on p. 1, where (R2)n- 2',4'-debtor, 2', 4'-dichloro, 3',4'-debtor, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-vorgruppe; R3the methoxy group is one-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-morpholinoethoxy, 3 morpholinopropan, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy, 2-[di-(2-methoxyethyl)amino]ethoxy or 3-morpholino-2-hydroxypropoxy, or its pharmaceutically acceptable additive salt of the acid.

4. Derived hintline formula I on p. 1, where (R2)n- 2',4'-debtor, 2', 4'-dichloro, 3',4'-debtor, 3',4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-vorgruppe; R3- methoxy group and R1- 3-dimethylaminopropoxy, 3 diethylaminopropyl, 3-(pyrrolidin-1-yl)propoxy, 3-morpholinopropan or 3-morpholino-2-hydroxypropoxy, or its pharmaceutically acceptable additive salt of the acid.

5. Derived hintline formula I on p. 1, where (R2)n- 3',4'-debtor, 3', 4'-dichloro, 3'-fluoro-4'-chloro or 3'-chloro-4'-vorgruppe; R3- methoxy group and R1- 3-morpholinopropan; or its pharmaceutically acceptable additive salt of the acid.

6. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline)-7-methoxy-6-(2-pyrrolidin-1 ylethoxy)hinzelin or its pharmaceutically acceptable additive salt of the acid.

7. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline>/P>8. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline)-6-(3-diethyl-aminopropoxy)-7-methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

9. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-pyrrolidin-1 ipropose)hinzelin or its pharmaceutically acceptable additive salt of the acid.

10. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline)-6-(3-dimethylaminopropoxy)-7-methoxyquinazoline or its pharmaceutically acceptable additive salt of the acid.

11. Derived hintline formula I on p. 1, a 4-(3', 4'-diptiranjan)-7-methoxy-6-(3-morpholinopropan)hinzelin or its pharmaceutically acceptable additive salt of the acid.

12. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-piperidinyloxy)hinzelin or its pharmaceutically acceptable additive salt of the acid.

13. Derived hintline formula I on p. 1, a 4-(3'-chloro-4'-foronline)-7-methoxy-6-(3-morpholinopropan)hinzelin or its pharmaceutically acceptable additive salt Kilgore derived hintline formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 14, characterized in that carry out the reaction hintline formula II

< / BR>
where Z is a substituted group,

with an aniline of the formula III

< / BR>
and, when the desired pharmaceutically acceptable salt derived hintline formula I, it can be obtained by reaction of a specified derivative with a suitable acid using standard methods.

16. The method of obtaining the derived hintline formula I, in which R1represents aminosilane (2-4C)CNS group, or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 14, characterized in that carry out the alkylation derived hintline formula I, where R1represents a hydroxyl group, and, when necessary pharmaceutically acceptable salt derived hintline formula I, it can be obtained by reaction of the compounds with a suitable acid using standard methods.

17. The method of obtaining the derived hintline formula I, in which R1represents aminosilane (2-4C)CNS group, or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 14, characterized in that carry out the reaction of the compounds of formula I, where R1p is increasing and, when necessary its pharmaceutically acceptable salt, carry out the reaction of this derivative hintline with a suitable acid using standard methods.

18. The method of obtaining the derived hintline formula I, in which R1is a hydroxy-amino(2-4C)alkoxygroup, or its pharmaceutically acceptable salt according to any one of paragraphs.1 to 14, characterized in that carry out the reaction of the compounds of formula I, in which R1represents a 2,3-epoxypropoxy or 3,4-epoxybutane, with the appropriate amine, and, when necessary pharmaceutically acceptable salt derived hintline formula I, it can be obtained by reaction of the compounds with a suitable acid using standard methods.

19. Pharmaceutical composition, causing the warm-blooded animal an antiproliferative effect by inhibiting the activity of a receptor tyrosine kinase, characterized in that it includes the derived hintline formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 14 in combination with a pharmaceutically acceptable diluent or carrier.

20. Derived hintline formula I or its pharmaceutically privnic animals antiproliferative action.

 

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