Derivatives hintline, methods for their preparation, pharmaceutical composition containing them, and method for producing angiogenic effect and/or the effect of reducing vascular permeability using them

 

(57) Abstract:

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient. The compounds of formula (I) and their pharmaceutically acceptable salts inhibit the effects of VEGF, which is useful for the treatment of many diseases, including cancer and rheumatoid arthritis. The object of the invention is also a method of obtaining antiangiogenic effect and/or the effect of reducing vascular permeability in a warm-blooded animal, including the introduction of specified IV.

The invention relates to the derivatives of hintline, methods for their preparation, pharmaceutical compositions containing them as active ingredient, methods for treating pathological States associated with angiogenesis and/or increased permeability of blood vessels, and to their use in the manufacture of drugs used to ensure antiangiogenic effects and/or effects of reducing the permeability of the blood vessels of warm-blooded animals such as man.

Normal angiogenesis plays an important role in various processes, including embryonic development, wound healing and some components of the reproductive function of women. Undesirable or pathological angiogenesis associated with diseases, including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma (Fan et al., 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). I believe that vascular permeability plays a role in both normal and pathological physiological processes (Cullinan-Bove et al., 1993, Endocrinology, 133: 829-837; Senger et al., 1993, Cancer and Metastasis Reviews, 12: 303-324). Already identified some polypeptides with an activity of stimulating the growth endothelially growth factor (VEGF). Due to limited expression of the VEGF activity, in contrast to the activity of growth factors FGF, relatively it is specific to endothelial cells. Recently it is proved that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al., 1993, Endocrinology, 133: 848-859; Kolch et al. , 1995, Breast Cancer Research and Treatment, 36: 139-155) and vascular permeability (Connolly et al., 1989, J. Biol. Chem. 264: 20017-20024). The antagonism of the actions of VEGF as a result of sequestration with VEGF antibody may lead to suppression of tumor growth (Kim et al. 1993, Nature 362: 841-844).

Receptor tyrosine kinase (RTKs) are important for the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules usually consist of linking the extracellular ligand domain linked via a plot of the plasma membrane from intracellular tyrosine kinase domain. The binding of ligand to the receptor causes the stimulation of tyrosine kinase activity associated with the receptor, leading to phosphorylation of tyrosine residues on the receptor, and other intracellular molecules. These changes in phosphorylation of tyrosine initiate a signaling cascade leading to various cellular responses. Currently identificare is guatelmala. One of these subfamilies today about fms-like tyrosinekinase receptor (Flt or Flt1), the receptor domain containing kinase insert, KDR (also referred to as as Flk-1) and another fms-like tyrosinekinase receptor, Flt4. Two of these related RTK (Flt and KDR) was found to bind VEGF with high affinity (De Vries et al., 1992, Science 255: 989-991; Terman et al., 1992, Biochem. Biophys. Comm. 1992, 187: 1579-1586). The VEGF binding with these receptors expressed in heterologous cells, was due to changes in the state of tyrosine phosphorylation in cellular proteins and threads of calcium.

Compounds that have good activity against receptor tyrosine kinase epidermal growth factor (EGF), disclosed in European patent 0566226. The present invention is based on the discovery of compounds that unexpectedly inhibit the effects of VEGF, which is useful for treatment of diseases associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with the proliferation of retinal vessels. the ditch, than against EGF tyrosine kinase receptor. In addition, the compounds of the present invention exhibit a significantly higher efficacy against tyrosine kinase VEGF receptor tyrosine kinase than against EGF receptor or FGF R1. Thus, the compounds of the present invention, which have already been tested, have activity against tyrosine kinase VEGF receptors, so they can be used in a quantity sufficient for the inhibition of the tyrosine kinase VEGF receptors without showing significant activity against EGF tyrosine kinase receptors or tyrosine kinase FGF R1 receptor.

In accordance with one aspect of the present invention offers the derived hintline formula I

< / BR>
where Y1represents-O-, -S-, -CH2-, -SO-, -SO2-,-NR5CO-,-CONR6-,-SO2NR7-, -NR8SO2- or-NR9- (where R5, R6, R7, R8and R9independently are each hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl);

R1represents hydrogen, hydroxy, halogen, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio or NR10R11(where R10and R11that can be d, hydroxy, halogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro;

m represents an integer from 1 to 5;

R3represents hydroxy, Halogens1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

R4selected from one of the following eight groups:

1) X1(where X1is Spiridonova group, phenyl group or 5 - or 6-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, and Spiridonova, phenyl or heterocyclic group may bear up to 5 substituents selected from halogen, amino, C1-4of alkyl, C1-4alkoxy, C1-4hydroxyalkyl,1-4aminoalkyl,1-4alkylamino,1-4hydroxyalkoxy, carboxy, cyano, -CONR12R13and-NR14COR15(where R12, R13, R14and R15that may be the same or different, are each hydrogen, C1-4alkyl or C1-3alkoxy-C2-3alkyl);

2)1-5alkyl1(where X1such as defined above);

3)2-5alkenyl1(where X1such as defined above);

4)2-5alkynyl1(where X12-, -OCO-, -NR16CO-, -CONR17-, -SO2NR18-, -NR19SO2- or-NR20- (where R16, R17, R18, R19and R20independently are each hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and X1such as defined above);

6) C2-5alkenyl3Xl(where Y3represents-O-, -S-, -SO-, -SO2-, -OCO-, -NR21CO-, -CONR22-, -SO2NR23-, -NR24SO2- or-NR25- (where R21, R22, R23, R24and R25independently are each hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and X1such as defined above);

7) C2-5the quinil4X1(where Y4represents-O-, -S-, -SO-, -SO2-, -OCO-, -NR26CO-, -CONR27-, -SO2NR28-, -NR29SO2- or-NR30- (where R26, R27, R28, R29and R30independently are each hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and X1such as defined above); and

8)1-3the alkyl5C1-3alkyl1(where Y5represents-O-, -S-, -SO-, -SO2-, -NR31CO-, -CONR32-, -SO2NR33-, -NR34SO2- or-NR35- (where R31>laxis2-3alkyl) and X1such as defined above);

Z represents-NH-, -O-, -S - or-CH2-; provided that when R4selected from one of the above groups 1), 2) and (5) and X1represents unsubstituted phenyl or substituted phenyl with 1-2 substituents selected from halogen, C1-4the alkyl and C1-4alkoxy, m is an integer from 3 to 5 and/or Z is-O-, -S - or-CH2-;

and its salts.

Mainly Y1represents-O-, -S-, -CH2-, -NR5CO-, -NR8SO2- or-NR9- (where R5, R8and R9independently are each hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably Y1represents-O-, -S-, -CH2-, -NR5CO-, -NR8SO2- or-NH- (where R5and R8independently are each hydrogen, C1-2alkyl or C1-2alkoxyethyl).

More preferably Y1represents-O-, -S-, -CH2- or-NH-, in particular-O-.

In another embodiment, the present invention Y1represents-O-, -NR5CO - or-NR8SO2-, or-NH- (where R5and R8independently represent each a hydrogen or C1-2alkyl).

the variants of implementation of the present invention R1represents hydrogen, hydroxy, C1-3alkyl, C1-3alkoxy, C1-3alkylthio or NR10R11(where R10and R11such as defined above). However, conveniently, when R1represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, C1-3alkyl, C1-3alkoxy or amino.

R1primarily represents hydrogen, hydroxy, C1-3alkyl, C1-3alkoxy or amino.

R1is preferably hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, more preferably hydrogen, hydroxy, methyl or methoxy, in particular hydrogen, methyl or methoxy, but especially methoxy.

In another embodiment, the present invention R1represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.

R2primarily represents hydrogen, halogen, amino or nitro.

Preferably R2represents hydrogen, chlorine or nitro, but especially hydrogen.

In one of the embodiments of the present invention R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro.

Advantageously, when in drougou or each other selected from halogen and methyl.

In another embodiment of the present invention the phenyl group bearing (R3)mrepresents a group of formula IIA

< / BR>
where Rarepresents hydrogen, methyl, fluorine or chlorine;

Rbrepresents hydrogen, methyl, methoxy, bromine, fluorine or chlorine;

Rcrepresents hydrogen or hydroxy;

Rdrepresents hydrogen, fluorine or chlorine, especially hydrogen or fluorine.

In yet another embodiment of the present invention the phenyl group bearing (R3)mpreferably represents a group of formula IIA,

where: Rarepresents hydrogen, fluorine or chlorine;

Rbrepresents hydrogen, methyl, methoxy, bromine, fluorine or chlorine, especially hydrogen, methyl or chlorine;

Rcrepresents hydrogen or hydroxy; and

Rdrepresents hydrogen;

provided that each of Ra, Rband Rcis not hydrogen.

The phenyl group bearing (R3)mpreferably represents 3-hydroxy-4-methylphenyl, 2-fluoro-5-hydroxy-4-methylphenyl, 2-fluoro-4-bromperidol, 2-fluoro-4-chloro-5-hydroxyphenyl or 4-chloro-2-florfenicol group.

In a specific embodiment, the implementation of ilfenomeno, but especially 2-fluoro-5-hydroxy-4-methylphenylene group.

In another embodiment of the present invention the phenyl group bearing (R3)mrepresents 4-chloro-2-florfenicol group.

Mainly Y2represents-O-, -S-, -SO-, -SO2-, -NR16CO-, -NR19SO2- or-NR20- (where R16, R19and R20independently each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably Y2represents-O-, -S-, -SO-, -SO2- or-NR20- (where R20represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

More preferably Y2is-S-, -O - or-NR20- (where R20represent hydrogen or C1-.2alkyl), and most preferably it represents-O - or-NR20- (where R20such as defined above).

Mainly Y3represents-O-, -S-, -SO-, -SO2-, -NR21CO-, -NR24SO2- or-NR25- (where R21, R24and R25independently are each hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably Y3represents-O-, -S-, -SO-, -SO2- or-NR25- (where R25represents-O - or-NR25- (where R25represents hydrogen or C1-2alkyl).

Mainly Y4represents-O-, -S-, -SO-, -SO2-, -NR26CO-, -NR29SO2- or-NR30- (where R26, R29and R30independently are each hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably Y4represents-O-, -S-, -SO-, -SO2- or-NR30- (where R30represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

More preferably Y4represents-O - or-NR30- (where R30represents hydrogen or C1-2alkyl).

Mainly Y5represents-O-, -S-, -SO-, -SO2- or-NR35- (where R35represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably Y5is-S-, -O - or-NR35- (where R35represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably m is 2 or 3.

Z may, for example, represent-NH - or-O-, but preferably Z is-NH-.

X1preferably represents Spiridonova group or 5 - or 6-membered aromatic heterocyclic group with 1-3 heteroatoms, above.

When X1represents 5 - or 6-membered aromatic heterocyclic group, it preferably has 1 or 2 heteroatoms selected from O, N and S, of which more preferred is N, and can be substituted as described above.

X1is, in particular, Spiridonova, pyridyloxy, imidazolidinyl, thiazolidine, thienyl, triazolyl or pyridazinyl group which may be substituted, as described above, and more specifically Spiridonova, pyridyloxy, imidazolidinyl, thiazolidine or triazolyl group, especially Spiridonova, pyridyloxy, imidazolidinyl or triazolyl group which may be substituted, as described above.

When R4is1-5alkyl1WITH2-5alkenyl1WITH2-5alkynyl1or1-3the alkyl5C1-3alkyl1and X1represents a nitrogen-containing 6-membered aromatic heterocyclic group, this group is mainly connected with alkyl, alkenyl or alkynylaryl fragment via a carbon atom of the group X1and this group is such that the nitrogen atom is in the para-position relative to the carbon atom that is linked to the alkyl, ALK is(CH2)n-.

When R4-Y1is X1- (CH2)n-Y1and n represents an integer from 0 to 5, Y1represents-O-, -NH-, -S - or-CH2and X1represents a nitrogen-containing 6-membered aromatic heterocyclic group, which is predominantly associated with -(CH2)n-Y1through the carbon atom of the group X1and this group is such that the nitrogen atom is in the para-position relative to the carbon atom that is associated with -(CH2)n-Y1-.

In another interesting example, X1represents a pyrimidine, which may be substituted, as described above.

In one of the embodiments of the present invention X1is Spiridonova, phenyl or 5 - or 6-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, and this group may be preferably up to 2 substituents (more preferably one substituent) selected from the group of substituents described above.

In the definition of X1suitable substituents are selected from halogen, C1-4of alkyl, C1-4alkoxy and cyano, and the more appropriate the Deputy:

1) X1(where X1such as defined above);

2)1-5alkyl1(where X1such as defined above);

3)3-5alkenyl1(where X1such as defined above);

4)3-5alkynyl1(where X1such as defined above);

5)1-5the alkyl2X1(where Y2and X1such as defined above);

6)3-5alkenyl3X1(where Y3and X1such as defined above);

7)3-5the quinil4X1(where Y4and X1such as defined above);

8) C2-3the alkyl5C1-2alkyll(where Y5and X1such as defined above).

Preemptive R4choose from the following eight groups:

1) X1(where X1such as defined above);

2)1-5alkyl1(where X1such as defined above);

3) 1-X1prop-1-EN-3-yl, 1-X1but-2-EN-4-yl, 1-X1but-1-EN-3-yl, 1-X1the Penta-2-EN-4-yl or 2-Xlthe Penta-3-EN-5-yl (where X1such as defined above, provided that when R4is 1-X1prop-1-EN-3-yl, X1attached to alkenylphenol group via a carbon atom)>the UNT-3-in-5-yl (where X1such as defined above, provided that when R4is 1-X1prop-1-in-3-yl, X1attached to alkenylphenol group via a carbon atom);

5) C1-5the alkyl2X1(where Y2and X1such as defined above);

6) 1-(X1Y3)prop-1-EN-3-yl, 1-(X1Y3)but-2-EN-4-yl, 1-(X1Y3)-but-1-EN-3-yl, 1-(X1Y3)Penta-2-EN-4-yl or 2-(X1Y3)Penta-3-EN-5-yl (where Y3and X1such as defined above);

7) 1-(X1Y4)prop-1-in-3-yl, 1-(X1Y4)but-2-ine-4-yl, 1-(X1Y4)but-1-in-3-Il,

1-(XlY4)Penta-2-in-4-yl or 2-(X1Y4)Penta-3-in-5-yl (where Y4and X1such as defined above); and

8) C2-3the alkyl5C1-2alkyll(where Y5and X1such as defined above).

Preferred R4choose from the following eight groups:

1) X1(where X1such as defined above);

2)1-5alkyl1(where X1such as defined above);

3) 1-X1but-2-EN-4-yl (where X1such as defined above);

4) 1-X1but-2-ine-4-yl (where X1such as defined above);
Y3)but-2-EN-4-yl (where Y3and X1such as defined above);

7) 1-(X1Y4)but-2-ine-4-yl (where Y4and X1such as defined above); and

8) ethyl5metalh1(where Y5and X1such as defined above).

More preferably the compounds of formula I are compounds of formula Ia:

< / BR>
(where R1, R2, R3, m, X1, Y1and Z is such as defined above, n represents an integer from 0 to 5 and Y6represents a direct bond, -O-, -S-, -SO-, -SO2-, -NR36CO-, -CONR37-, -SO2NR38-, -NR39SO2- or-NR40- (where R36, R37, R38, R39and R40independently are each hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl)).

Mainly Y6represents a direct bond, -O-, -S-, -SO-, -SO2- or-NR40- (where R40represents hydrogen, C1-.2alkyl or C1-.2alkoxyethyl).

Preferably Y6represents a direct bond, -O-, -S - or-NH-.

More preferably Y6is a direct link.

Mainly n represents an integer cyclostomes of the invention the compounds of formula I are compounds of formula Ia, where:

[Y1represents-O-, -NH-, -S - or-CH2-;

n represents an integer from 0 to 5;

X1represents a phenyl group or a 5 - or 6-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, and phenyl or heterocyclic group may bear up to 5 substituents selected from halogen, C1-4of alkyl, C1-4alkoxy, C1-4Hydra-oxyalkyl,1-4hydroxyalkoxy, carboxy, cyano, -CONR41R42and-NR43COR44(where R41, R42, R43and R44that may be the same or different, are each hydrogen or C1-4alkyl);

R1represents hydrogen, hydroxy, C1-3alkyl, C1-3alkoxy, C1-3alkylthio or NR45R46(where R45and R46that may be the same or different, are each hydrogen or C1-3alkyl);

R2represents hydrogen, hydroxy, halogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro;

m represents an integer from 1 to 5;

R3represents hydrogen, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

Z performance, represent unsubstituted phenyl or substituted phenyl with 1-2 substituents, selected from halogen, C1-4the alkyl and C1-4alkoxy, m is an integer from 3 to 5 or Z is-O-];

or their salts.

Preferred compounds of the present invention are:

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(3-pyridyloxy)hinzelin

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(3-teenrotica)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-[N-methyl-N-(4-pyridyl)] aminoethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]hinzelin

7-(4-ziembinski)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-Mei-1-yl)propoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(1-Mei-2-ylthio)propoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-pyridyloxy)ethydoxine)hinzelin

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((2-methylthiazole-4-yl)methoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-((3-thienyl)methoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)hinzelin

4-(4-chloro-2-foronline)-7-(2-(3,5-dimethyl-[1,2,4]-triazole-4-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-7-(2-(2,4-dimethylimidazole-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-7-(2-(2,5-dimethylimidazole-1-yl)ethoxy)-6-methoxyquinazoline

4-(3-hydroxyamino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1,2,4-triazole-4-yl)ethoxy)hinzelin

4-(4-bromo-2-foronline)-7-(2-([1,2,4] -triazole-1-yl)ethoxy)-6-methoxyquinazoline

and their salts, in particular hydrochloride.

The following compounds of the present invention are particularly preferred:

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)hinzelin

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(2-pyridyloxy)hinzelin

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(1-Mei-2-ylethoxy)hinzelin

4-(3-hydroxy-4-methylaniline)-6-methoxythiazole

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridylamine)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridylamine)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)hinzelin

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]hinzelin

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-((2-methylthiazole-4-yl)methoxy)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(4-pyridyloxy)hinzelin

4-(4-chloro-2-foronline)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-((1-Mei-2-yl)methoxy)hinzelin

7-((2-acetamidomethyl-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline

7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyl)propoxy)hinzelin

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(3-(4-pyridyl)propoxy)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-imidazol-1-the

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(3-teenrotica)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)hinzelin

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-((1-methylbenzimidazole-2-yl)methoxy)hinzelin

7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline

4-(4-chloro-2-pertenece)-6-methoxy-7-((4-pyridyl)methoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-((4-pyridyl)methoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-Mei-1-yl)ethoxy)hinzelin

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((4-pyridyl)methoxy)hinzelin

4-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-Mei-2-ylthio)ethoxy)hinzelin

7-(3,4-deferasirox)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((1-Mei-2-yl)methoxy)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-((1-Mei-2-yl)methoxy)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-(1,2,4-triazole-1-yl)ethoxy)hinzelin

4-(4-chloro-2-fluoro-5-Ki-is DIL)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1,2,4-triazole-1-yl)ethoxy)hinzelin

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-((4-pyridyl)carboxamido)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-Mei-2-yl)ethoxy)hinzelin

4-(4-chloro-2-foronline)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline

and their salts, in particular hydrochloride, of which particularly preferred are the following:

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]hinzelin

4-(4-chloro-2-foronline)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyl)propoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-((4-pyridyl)methoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-Mei-1-yl)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-Mei-2-ylthio)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1,2,4-triazole-1-yl)ethoxy)hinzelin

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)Line)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline

and their salts, in particular hydrochloride.

Other interest compound is 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyrimidinylidene)hinzelin and its salts, in particular hydrochloride.

For the avoidance of doubt it should be understood that when in this description of the group referred to as "defined above," it covers the first and most broad definition, and each and all of the preferred definitions for this group.

In this description, the term "alkyl" includes both unbranched and branched alkyl groups but references to individual alkyl groups such as "propyl" are specific to an unbranched chain. The same rule applies to other generic terms. Unless otherwise indicated, the term "alkyl" refers primarily to the chain with 1-6 carbon atoms, preferably 1-4 carbon atoms. Used in this description, the term "alkoxy" includes, unless otherwise specified, "alkyl-O-groups in which "alkyl" is as defined above. The term "aryl" when used in this description refers, unless otherwise specified, C6-10aryl group, which may optionally bear one or more replace Lennie above). The term "aryloxy" when used in this description includes, unless otherwise specified, "aryl-O-group in which "aryl" as defined above. The term "sulfonyloxy" when used in this description refers to alkylsulfonate and arylsulfonate, in which "alkyl" and "aryl" such as defined above. The term "alkanoyl" when used in this description includes, unless otherwise noted, group alkyls=O, in which "alkyl" is as defined above, such as ethanol refers to CH3C=O. In this description, the term "alkenyl" includes, unless otherwise specified, alkeline group with both unbranched and branched chain, but references to individual alkeneamine groups such as 2-butenyl specifically apply only to groups with an unbranched chain. Unless otherwise indicated, the term "alkenyl" refers mainly to the circuit with 2-6 carbon atoms, preferably 4-5 carbon atoms. In this description, the term "quinil" includes, unless otherwise specified, alkyline group with both unbranched and branched chain, but references to individual alkyline groups such as 2-butenyl specifically apply only to groups with an unbranched chain. Ellino with 4-5 carbon atoms.

In particular the above formula I is hydrogen in positions 2 and 8 khinazolinov group.

It should be understood that within the present invention hinzelin formula I or its salt can be tautomerism and that the drawings of the formulas in this specification can represent only one of the possible tautomeric forms. It is clear that the invention encompasses any tautomeric form which inhibits the tyrosine kinase activity of VEGF-receptors, but not limited to any one tautomeric form shown in the drawings formulas.

You should also understand that some hintline formula I and their salts may exist in solvated and resolutional forms, such as hydrated forms. It is clear that the present invention encompasses all such solvated forms which inhibit the tyrosine kinase activity of VEGF-receptors.

In order to avoid any ambiguities need to understand that when Y1is, for example, a group of the formula-NR5CO-bearing nitrogen atom of the group R5attached to hinazolinam ring and the carbonyl (CO) group attached to R4and when Y1is, for example, a group of the formula-CONR6something to chineselanguage rule applies to other groups Y1linking two atoms, such as-NR8SO2- and-SO2NR7-. When Y1is-NR9-, R9carrying the nitrogen atom, is associated with hinazolinam ring and R4. The same rule applies to other groups. It should also be understood that when Y1is-NR9and R9is1-3alkoxy WITH2-3alkyl, C2-3the alkyl fragment is linked to the nitrogen atom of the group Y1and the same rule applies to other groups.

To avoid any doubt, it should be understood that when the compound of the formula I R4is, for example, a group of the formula C1-5the alkyl5C1-5alkyl1then with Y1associated end WITH1-5the alkyl fragment, and when R4is, on the contrary, a group of the formula C2-5alkenyl1then with Y1associated WITH2-5alkanniny fragment, and the same rule applies to other groups. When R4represents a group 1-X1prop-1-EN-3-yl, then to the first carbon atom attached to the group X1and the third carbon atom is associated with the Y1and when R4represents a group 2-Xlthe Penta-3-EN-5-yl, X1joined in the CLASS="ptx2">

To avoid any doubt, you need to understand that when X1is1-4aminoalkyl Deputy, to X1attached WITH1-4the alkyl fragment, and when X1shall be as Deputy1-4alkylamino, then X1attached aminophen, and the same rule applies to other groups.

The present invention relates to compounds of formula I, described above, and their salts. Salts for use in pharmaceutical compositions should be pharmaceutically acceptable salts, but other salts may be useful for producing compounds of formula I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the present invention can, for example, include acid additive salts of the above compounds of formula I which is sufficiently basic for the formation of such salts. Such acid additive salts include, for example, salts with inorganic acids such as kaleidotrope acid (in particular, chloromethane or Hydrobromic acid, of which particularly preferred is chloromethane acid) and sulfuric or phosphoric acid, and salts with organic acids, giving the pharmacist when the compounds of formula I are sufficiently acidic pharmaceutically acceptable salts can be formed with inorganic or organic base, giving a pharmaceutically acceptable cation. Such salts include, for example, salt of an alkali metal such as sodium salt or potassium salt, alkaline earth metal, such as a salt of calcium or magnesium, ammonium salt or salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

The compound of formula I or its salt and other compounds of the present invention (such as those defined above) can be obtained by any known method for producing chemically related compounds. Such methods include, for example, those described in the applications 0520722, 0566226, 0602851 and 0635498 for the European patent. Such methods serve as an additional characteristic of the present invention and described below. The necessary starting materials may be obtained by standard methods of organic chemistry. The receipt of such starting materials is described within the accompanying non-limiting examples. Or the required raw materials can be obtained by methods similar to those described understandable to experts in the field Organicheskaya.

The synthesis of compounds of formula I

(a) the compounds of formula I and their salts can be obtained by interaction of the compounds of formula III

< / BR>
(where R1, R2, R4and Y1such as defined above, and L1represents a leaving group) with a compound of formula IV

< / BR>
(where Z, R3and m are such as defined above) to obtain the compounds of formula I and their salts. A suitable removable group L1is, for example, halogen, alkoxy (preferably1-4alkoxy), aryloxy or sulfonyloxy, for example chlorine, bromine, methoxy, phenoxy, methansulfonate - or toluene-4-sulfonyloxy.

The reaction is mainly carried out in the presence of either acid or base. This acid is, for example, anhydrous inorganic acid, such as chloromethane acid. Such a base is, for example, an organic amine base 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, a carbonate or hydroxide of alkali or alkaline earth metal, for example sodium carbonate, potassium carbonate, calcium carbonate, Hydra is er sodium hydride, or amide of alkaline or alkaline-earth metal, for example sodium amide or bis(trimethylsilyl)amide and sodium. The reaction is preferably carried out in the presence of an inert solvent or diluent, for example ethanol or complex ether, such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride 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 usually carried out at a temperature in the range of, for example, 10-150oWith, preferably in the range of 20-80oC.

The compound of the present invention can be obtained as described in free base form or in salt form with an acid of the formula H-L1where L1shall have the meaning given above. When you want to obtain the free base from the salt, the salt can be treated with a base, as defined above, using conventional methods.

(b) When a group of formula IIb

< / BR>
(where R3and m are such as defined above is whether you can get by

remove protection from the compounds of formula V

< / BR>
(where Y1, m, R1, R2, R3, R4and Z is such as defined above. P represents a phenolic hydroxyamino group, and R1represents an integer from 1 to 5 equal to the number of protected hydroxy groups, and the difference m-R1equal to the number of the substituents R3which are not protected hydroxy). The choice of phenolic hydroxyamino group R can make an ordinary organic chemist of those protective groups which are included in the conventional literature, such as "Protective Groups in Organic Synthesis" T. W. Greene and R. G. M. Wuts, 2nd ed. Willey 1991, including ethers (for example, methyl, methoxymethyl, allyl and benzyl), simple Silovye esters (for example, tert-butyldiphenylsilyl and tert-butyldimethylsilyloxy), esters (for example, acetate and benzoate) and carbonates (e.g., methyl and benzylcarbamoyl). Destruction of such phenolic hydroxyamino group can be carried out by any known method, including the conditions of the reactions listed in the usual literature, such as the above, or similar method. The reaction conditions are preferably so that you can get a hydroxy without unexpected reactions in other places in Exod shall be done by processing the derived hintline base, defined above, including ammonia and its mono - and dialkylamino derivatives, preferably in the presence of proton solvent or co-solvent such as water or alcohol, for example methanol or ethanol. This reaction can be carried out in the presence of an additional inert solvent or diluent, defined above, at a temperature in the range of 0-50oC, preferably at 20oWith or about.

(C) to Obtain the compounds of formula I and their salts, in which the Deputy Y1represents-O-, -S - or-NR9- by communicating (appropriate in the presence of a base, such as defined above) of the compounds of formula VI

< / BR>
(where m, Y1, R1, R2, R3and Z is such as defined above) with the compound of the formula VII

R4-L1(VII)

(where R4and L1such as defined above); L represents a leaving group, for example halogen, or sulfonyloxy, such as bromine or methysulfonylmethane. The reaction is preferably carried out in the presence of a base (such as defined above in method (a)) and preferably in an inert solvent or diluent (such as defined in the>With or about.

(d) the compounds of formula I and their salts can be obtained by interaction of the compounds of formula VIII

< / BR>
with the compound of the formula IX

R4-Y1-H (IX)

(where L1, R1, R2, R3, R4, Z, m and Y1such as defined above). Reaction it is advisable to carry out in the presence of a base (such as defined above in method (a)) and preferably in an inert solvent or diluent (such as defined above in method (a)) mainly at a temperature in the range of, for example, 10-150oC, preferably at 100oWith or about.

(e) Compounds of the formula I and their salts, in which R4is1-5alkyl2[where X2selected from the following three groups:

1) X1(where X1such as defined above);

2) Y7X1(where Y7represents-O-, -S-, -SO2-, -NR47CO-, -NR48SO2- or-NR49- (where R47, R48and R49independently are each hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and X1such as defined above); and

3) Y8C1-3alkyl1(where Y8represents-O-, -S-, -SO2-, -NR1-3alkyl or C1-3alkoxy WITH2-3alkyl) and X1such as defined above);]

can be obtained by interaction of the compounds of formula X

< / BR>
(where L1, Y1, R1, R2, R3, Z and m are such as defined above, and R53represents C1-5alkyl) with a compound of formula XI

X2-H (XI)

(where X2such as defined above) to obtain the compounds of formula I. the Reaction, it is expedient to carry out in the presence of a base (such as described above in method (a)) and preferably in the presence of an inert solvent or diluent (such as described above in method (a)) at a temperature in the range of, for example, 0-150oC, preferably at about 50oC.

(f) the compounds of formula I and their salts, in which the substituent R1presents NR10R11where one or both of the radicals R10and R11submit C1-3alkyl, can be obtained by interaction of the compounds of the formula I, in which Deputy1represents an amino group and an alkylating agent, preferably in the presence of a base, as defined above. Such alkylating agents are Cilgalaikiai, for example, C1-3alkylchloride, -bromide or-iodide. The reaction is preferably carried out in the presence of an inert solvent or diluent (such as defined above in method (a)) at a temperature in the range of, for example, 10-100oC, preferably at about ambient temperature.

(g) the compounds of formula I and their salts in which one or more of the substituents R1, R2or R3represent the amino group, can be obtained by recovering the corresponding compounds of formula I in which the substituent(s) in the appropriate(their) position(s) chineselanguage and/or phenyl ring is(are) the nitro-group(s). Recovery is appropriate to do so, as described below in method (i). The compound of the formula I and salts thereof in which substituent(s) in the appropriate(their) position(s) chineselanguage and/or phenyl ring is(are) the nitro-group(s), can be obtained by the methods described above (a-e) and lower (i-v), using hintline selected from compounds of formulas (I-XXVII) in which the substituent(s) in the appropriate(their) position(s) chineselanguage and/or phenyl ring is(are) the nitro-group(s).

Synthesis of intermediate soedineniya, in which L1is halogen, can be obtained by halogenation of compounds of formula XII

< / BR>
(where R1, R2, R4and Y1such as defined above).

Suitable halogenation agents include halides of inorganic acids, for example thionyl chloride, chloride, phosphorus (III) oxychloride phosphorus (V) chloride, phosphorus (V). The halogenation reaction, it is expedient to carry out in the presence of an inert solvent or diluent, such as, for example, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is expediently carried out at a temperature in the range of, for example, 10-150oWith, preferably in the range of 40-100oC.

The compounds of formula XII and their salts, which constitute an additional characteristic of the present invention may, for example, be obtained by interaction of the compounds of formula XIII

< / BR>
(where R1, R2and L1such as defined above) with a compound of formula IX, as defined above. Reaction it is advisable to carry out in the presence of a base (Takala (such as defined above in method (a)) at a temperature in the range, for example, 10-150oC, preferably at 100oWith or about.

The compounds of formula XII and their salts can also be obtained by cyclization of compounds of formula XIV

< / BR>
(where R1, R2, R4and Y1such as defined above, and1is hydroxy, alkoxy (preferably1-4alkoxy-or amino group) with the formation of compounds of formula XII or salts thereof. The cyclization may be achieved through the interaction of the compounds of formula XIV, where a1represents hydroxy or alkoxygroup, with formamide or its equivalent, can cause cyclization, to obtain the compounds of formula XII or salts thereof, such as [3-(dimethylamino)-2-isoprop-2-enylidene]dimethylammoniumchloride. The cyclization of appropriately be made in the presence of formamide as a solvent or in the presence of an inert solvent or diluent, such as a simple ether, e.g. 1,4-dioxane. The cyclization is advisable to carry out at elevated temperature, preferably in the range of 80-200oC. the compounds of formula XII can also be obtained by cyclization of compounds of formula XIV, where a1represents the amino group, with formic acid or its equivalent, capable of the e to cause cyclization, include, for example, three1-4alkoxylated, for example triethoxysilane and trimethoxymethane. The cyclization of appropriately be made in the presence of catalytic amount of anhydrous acid, such as sulfonic acid, e.g. p-toluensulfonate acid, and an inert solvent or diluent, such as, for example, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, a simple ether, such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene. The cyclization of appropriate conduct at a temperature in the range of, for example, 10-100oWith, preferably in the range of 20-50oC.

The compounds of formula XIV and their salts, which constitute an additional characteristic of the present invention can be, for example, be obtained by recovery of the nitro group in the compound of formula XV

< / BR>
(where R1, R2, R4, Y1and1such as defined above) to obtain the compounds of formula XIV, as defined below. The restoration of the nitrogroup, it is advisable to carry out any method known to perform such a conversion. Recovery may be performed, for example, leave it blank above and in the presence of a metal catalyst, such as palladium or platinum. Another reducing agent is, for example, activated metal, such as activated iron (obtained, for example, by leaching of iron powder with dilute acid solution, such as chloromethane acid). For example, the recovery may be carried out by heating a mixture of nitro compounds, and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range of, for example, 50-150oC, preferably at 70oWith or about.

The compounds of formula XV and salts, which are more characteristic of the present invention may, for example, be obtained by interaction of the compounds of formula XVI

< / BR>
(where R1, R2L1and1such as defined above) with a compound of formula IX, as defined above. The interaction of compounds of formulas XVI and IX, it is advisable to carry out under the conditions described above for the method (d).

The compounds of formula XV and salts may, for example, be obtained by interaction of the compounds of formula XVII
2
-) with the compound of the formula VII, as defined above, to obtain compounds of formula XV as defined above. The interaction of compounds of formulas XVII and VII, it is advisable to carry out under the conditions described above for the method (s).

The compounds of formula III and their salts can also be obtained, for example, by interaction of the compounds of formula XVIII

< / BR>
(where R1, R2and Y1such as defined above, provided that Y1is not-CH2and L2is leaving a protective group) with a compound of formula VII, as defined above, to obtain compounds of formula III in which L1presents L2.

It is advisable to use a compound of the formula XVIII, in which L2is fenoxaprop, which optionally may bear up to 5 substituents, preferably up to 2 substituents selected from halogen, nitro or cyano. The reaction is expediently carried out at the conditions described above for the method (s).

The compounds of formula XVIII and their salts, such as defined above, can be, for example, obtained by removing the protection of the compounds of formula XIX

< / BR>
(where R1, R2, P, Y1and L2such as the be implemented methods, well known from the literature, for example, when R represents a benzyl group, removal of the protection can be carried out by hydrogenolysis or by treatment triperoxonane acid.

One compound of the formula III can be converted into another compound of the formula III, in which the fragment of L1other. For example, the compound of formula III in which L1differs from halogen, for example, is optionally substituted, phenoxy can be converted to the compound of formula III in which L1represents halogen, by hydrolysis of the compounds of formula III (in which L1differs from halogen) to give the compounds of formula XII, as defined above, after which the compound of formula XII obtained as described above, introducing the halide to obtain the compounds of formula III in which L1represents halogen.

(ii) the compounds of formula V and their salts constitute an additional characteristic of the present invention and can be obtained, for example, by interaction of the compounds of formula III, as defined above, with a compound of formula XX

< / BR>
(where R3, m, R1, R and Z are such as defined above). The reaction can be carried out, in which the interaction of the compounds of formula XXI

< / BR>
(where R1, R2L1, Z, R3, m, p,1and P is such as defined above) with a compound of formula IX, as defined above. The reaction can be carried out, for example, as described above for the method (d).

The compounds of formula V and their salts can also be obtained by interaction of the compounds of formula XXII

< / BR>
(where R1, R2, R3, Y1, Z, P, P1and m are such as defined above, provided that Y1is not-CH2-) with the compound of the formula VII, as defined above. The reaction can be carried out, for example, as described above for the method (s).

The compounds of formula XXI and their salts can be obtained, for example, by interaction of the compounds of formula XXIII

< / BR>
(where R1, R2and L1such as defined above, and L1in positions 4 and 7 may be the same or different) with a compound of formula XX, as defined above. The reaction can be carried out, for example, as described above for the method (a).

The compounds of formula XXII and their salts can be obtained by interaction of the compounds of formulas XIX and XX, as defined above, under conditions described above for process (a), obtained with edelenyi above, provided that Y1is not-CH2- and then remove protection from compounds XXIV, for example, as described above in section (i).

(iii) the compounds of formula VI and their salts, as defined above, can be obtained by removing the protection of the compounds of formula XXV

< / BR>
(where R1, R2, R3, P, Z, Y1and m are such as defined above), for example, as described above in section (i).

The compounds of formula XXV and their salts can be obtained by interaction of the compounds of formulas XIX and IV, as defined above, under conditions described above for process (a), obtaining the compounds of formula XXV or its salts.

(iv) the compounds of formula VIII and their salts, as defined above, can be obtained by interaction of the compounds of formulas XXIII and IV, as defined above, the reaction may be carried out by the method described above in (a).

(v) the compounds of formula X, as defined above, and their salts can be obtained, for example, by interaction of the compounds of formula VI, as defined above, with a compound of formula XXVI

L1-R53-L1(XXVI)

(where L1and R53such as defined above) to obtain the compound of formula X. the Reaction can b the same to get for example, by removing the protection of the compounds of formula XXVII

< / BR>
(where L1, R53, Y1, R1, R2, R3, P, m and R1such as defined above), for example, by the method described above in (b).

The compounds of formula XXVII and their salts can be obtained, for example, by interaction of the compounds of formulas XXII and XXVI as defined above, under conditions described above for the method (s).

When the desired pharmaceutically acceptable salt of the compounds of formula I, it can be obtained, for example, by interaction of the compounds, for example, with acid using conventional techniques.

Many of the intermediates defined herein are new compounds, for example, intermediate compounds of formulas III, V, XII, XIV and XV, and these compounds comprise an additional characteristic of the present invention.

As an additional characteristic of the present invention are also intermediate compounds of formulas VIII, X, XXI, XXII, XXIV, XXV and XXVII.

Identification of compounds that potently inhibit the tyrosine kinase activity associated with VEGF receptors such as Flt and/or KDR, and which inhibit the Oia. These properties can be estimated, for example, using one or more of the methods described below.

(a) the Test for inhibition of receptor tyrosinekinase in vitro

This test determines the ability of the test compound to inhibit the activity of tyrosine kinase. DNA-encoded cytoplasmic domains of VEGF receptors or receptors of epidermal growth factor (EGF) can be obtained by total gene synthesis (M. Edwards, International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. Then they can be expressed in a suitable expression system to obtain a polypeptide with tyrosinekinase activity. For example, it was found that the cytoplasmic domains of VEGF - and EGF-receptors, which were obtained by expression of recombinant protein in insect cells, showing significant tyrosinekinase activity. In the case of VEGF receptor Flt ( H catalog GenBank) of 1.7 KB DNA fragment, encoding a large part of the cytoplasmic domain, beginning with methionine 783 and including the termination codon, which (fragment) described by Shibuya et al. (Oncogene, 1990, 5: 519-524), was isolated from cDNA and cloned into the baculovirus vector transfer (for example, pAcYM1 (see The Baculovirus Expression System: A Laboratory Guide, L. A. King and R. D. Possee, Ch is key insects (for example, Spodoptera frugiperda 21 (Sf21) with viral DNA (e.g., Pharmingen BaculoGold)) to obtain a recombinant baculovirus. (Details of methods of Assembly of recombinant DNA molecules and the production and use of recombinant baculovirus can be found in standard handbooks, such as Sambrook et al. , 1989, Molecular cloning - A Laboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press and O'reilly et al, 1992, Baculovirus Expression Vectors - A Laboratory Manual, W. H. Freeman and Co, New York). For other tyrosinekinase for use in testing can be cloned and expressed in a similar way cytoplasmic fragments beginning with methionine 806 (KDR, catalogue L04947 in GenBank) and methionine 668 (EGF-receptor, catalogue H in GenBank).

For the expression of cFlt-tyrosinekinase activity Sf21 cells were infected clean cFlt-recombinant rinderpest virus at multiplicity of infection equal to 3, and collected after 48 hours. The collected cells were washed in ice phosphate-saline buffer solution (PBS) (10 mm sodium phosphate pH 7.4, 138 mm NaCl, 2.7 mm KCl), then resuspendable in ice HNTG/PMSF (20 mm Hepes pH 7.5, 150 mm NaCl, 10%/glycerol, 1%/Triton X100, 1.5 mm MgCl2, 1 mm ethylene glycol-bis(aminoacylase ether)N,N,N',N'-tetraoxane acid (EGTA), 1 mm PMSF (phenylmethylsulfonyl); PMSF was added n is MSF at 10 million cells. The suspension was centrifuged for 10 minutes at 13,000 rpm at 4oS, supernatant (stock enzyme) was removed and kept in aliquot samples at -70oC. Each new sample of the enzyme from stock was titrated in the analysis by dilution with enzyme diluent (100 mm Hepes pH 7.4, 0.2 mm Na3VO4, 0,1%/Triton X100, 0.2 mm dithiotreitol). For a typical sample of the enzyme was diluted in the ratio of 1 to 2000 diluent enzyme and for each cell for analysis using 50 μl of the diluted enzyme.

To prepare the stock substrate solution of a random copolymer containing tyrosine, for example Poly-(Glu, Ala, Tyr) 6:3:1 (Sigma P3899), and kept in PBS (1 mg/ml) at -20oWith and diluted by PBS in the ratio of 1 to 500 to cover the plates.

The day before the test 100 ál of diluted substrate solution was distributed in all cells of the plates for analysis (immunoblotting Nunc maxisorp 96 cells) and closing it was left over night at 4oC.

On the day of the test substrate solution was removed and the cell plates were washed once with PBST (PBS containing 0.05%/Tween 20) and once with 50 mm Hepes with pH 7.4.

Compound was diluted with 10% dimethylsulfoxide (DMSO), and 25 μl of diluted compound was transferred into itrow 40 mm MnCl2containing 8 μm adenosine-5'-triphosphate (ATP ATP), was added in the "all" cell, except "blank" control cells, which contained MnCl2without ATP. To start the reaction, each well was added 50 µl freshly diluted enzyme and the plates were incubated at room temperature for 20 minutes. The liquid is then poured out and washed the cells two times with PBST. In each cell was added one hundred microlitres mouse antibodies to phosphotyrosine IgG (Upstate Biotechnology Inc., product 05-321), diluted in the ratio of 1 to 6000 by PBST containing 0.5% of bovine serum albumin (BSA), and plates were incubated for 1 hour at room temperature, after which the liquid was poured and the cells were washed two times with PBST. Added a hundred microlitres linked to horseradish peroxidase (HRP) sheep antibody to mouse Ig (Amersham, product NXA 931) diluted in the ratio of 1 to 500 by PBST containing 0.5% of BSA and the plates were incubated for 1 hour at room temperature, after which the liquid was poured and washed the cells two times with PBST. In each cell was added one hundred microlitres solution of 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), freshly prepared using one 50 mg tablet ABTS (Boehringer 1204 521) (Sigma P4922) phosphatidate buffer and perborate sodium (PCSB) in 100 ml of distilled water). Then the plates were incubated for 20-60 minutes at room temperature, until the value of optical density of control cells measured at 405 nm using the spectrophotometer to read with plates, not was approximately 1.0. The values in the "empty" (without ATP) and "all" (without connections) control cells were used to determine the dilution of the test compound which gave 50% inhibition of enzyme activity.

(b) Analysis of cell proliferation in HUVEC in vitro

This analysis determines the ability of the test compound to inhibit stimulated growth factor proliferation of endothelial cells, umbilical vein human (HUVEC).

The HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7,5%/serum fetal calf (FCS) and were sown (at passage 2 to 8) in MCDB 131 + 2%/FCS + 3 μg/ml heparin + 1 μg/ml hydrocortisone at a concentration of 1000 cells per cell in plates with 96 wells. A minimum of 4 hours was uploaded growth factor (namely VEGF 3 ng/ml, EGF 3 ng/ml or b-FGF 0.3 ng/ml) and connection. Then the cultures were incubated for 4 days at 37oWith a 7.5% CO2. On the fourth day of culture were subjected to pulse (1 µci/cell) labeled Tricia the boron cells from plates with 96 cells and then analyzed for the incorporation of tritium using a beta counter. The incorporation of radioactivity in the cell, expressed in cpm (counts per minute) was used to measure inhibition of compounds cell proliferation stimulated by a growth factor.

(C) Analysis of in vivo swelling of the uterus rats

This test determines the measure of the ability of compounds to reduce the sharp increase in uterine weight in rats, which occurs in the first 4-6 hours after estrogen stimulation. This is a premature increase in the mass of the uterus caused, as it has long been known, and edema caused by increased permeability of the vascular network of the uterus, and recently Cullinan-Bove and Koos (Endocrinology, 1993, 133: 829-837) demonstrated a close temporal relationship mRNA in the uterus with increased expression of VEGF. These inventors found that the prior administration to rats of neutralizing monoclonal antibodies against VEGF significantly reduces the sharp increase in uterine weight, which confirms the significant influence of VEGF on the increase in weight.

Rats 20-22 days of age were administered a single subcutaneous dose of estradiolbenzoateai (2.5 µg/rat) in a solvent or solvent. In the latter case, these were unstimulated control group rats. At various points prior to the introduction of estradiolbenzoateai of oral womersley and their uteri were cut dried with blotting paper and weighed. Using test Student T, compared to the increase in uterine weight in the groups treated with the test compound and estradiolbenzoatevm and only estradiolbenzoatevm. The inhibition effect of estradiolbenzoateai considered significant at p<0,05.

The composition may be in a form suitable for oral administration, for example in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion) as a sterile solution, suspension or emulsion, for topical administration in the form of ointment or cream or for rectal administration in the form of a suppository. Typically, the above compositions can be prepared in a traditional manner, using traditional fillers.

Is it advisable to have the composition of the present invention in the form of dosage forms. The connection is usually injected taplak-100 mg/kg Dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is considered to be therapeutically effective dose and usually it is. Dosage form such as a tablet or capsule usually contains, for example, about 1-250 mg of the active component.

In accordance with another aspect of the present invention features defined above, the compound of formula I or its pharmaceutically acceptable salt for use in therapeutic treatment of the human or animal.

These inventors now found that compounds of the present invention inhibit tyrosinekinase activity of VEGF-receptors and therefore of interest for their antiangiogenic effects and/or the ability to cause a decrease in vascular permeability.

Thus, according to this aspect of the present invention features the use of the compounds of formula I or its pharmaceutically acceptable salt for the manufacture of medicines, providing antiangiogenic effect and/or the effect of reducing vascular permeability in a warm-blooded animal such as man.

In accordance with another aspect of the present invention predlagemogo animal, such as man, in need of such treatment, which method includes the introduction of specified animal an effective amount defined above of compounds of formula I or its pharmaceutically acceptable salt.

As mentioned above, the dose required for therapeutic or prophylactic treatment of a particular disease, it is necessary to change depending on the subject of treatment, method of administration and the severity of the disease to be treated. Preferably use the daily dose in the range of 1-50 mg/kg, However, the daily dose must be changed depending on the subject of treatment, method of administration and the severity of the disease to be treated. Therefore, the optimal dose can be determined by a medical practitioner treating a particular patient.

The above antiangiogenic treatment and/or treatment to reduce vascular permeability can be used as a single therapeutic method, or may include the application, in addition to the compounds of the present invention, one or more other substances and methods of treatment. This comprehensive treatment can be achieved by simultaneous, sequential or separate pribinova different types of treatment, to cure every cancer patient. In medical Oncology the other(s) component(s) of such a complex treatment, in addition to the above treatment of angiogenesis and/or reduce vascular permeability, may(may) be surgery, radiation therapy or chemotherapy. Such chemotherapy may cover three main categories of drugs:

(i) other antiangiogenic means, mechanism of action differs from that described above (for example, linomide inhibitors steps integrinv3, angiostatin, retuxin, thalidomide);

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, idoxifene), POCs (for example, megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, varsol, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bikalutamid, ciproteron acetate), agonists and antagonists of LHRH (luteinizing hormone releasing hormone) (e.g., goserelin acetate, leuprolide), inhibitors of testosterone-5-dihydroorotase (for example, finasteride), antiinvasive means (for example, inhibitors of metalloproteinases, like marimastat, and inhibitors data include, for example, EGF, factors FGF, platelet-derived growth factor and a growth factor for hepatocytes, and such inhibitors include antibodies to growth factors, antibodies to receptors of growth factors, tyrosine kinase inhibitors and inhibitors of serine-trionychinae);

(iii) antiproliferative and antitumor agents, and combinations thereof, as used in medical Oncology, such as antimetabolites (for example antifolates such as methotrexate, ftorpirimidinu, such as 5-fluorouracil, purine analogues, and adenosine, citizenoriented); antitumor antibiotics (for example anthracyclines, such as doxorubicin, daunomycin, epirubicin and idarubitsin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating means (for example, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoanatabine, totap); antimitoticescoy means (for example, pink Vinca alkaloids, such as vincristine, and taxoid, such as Taxol, Taxotere); topoisomerase inhibitors (for example, epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan).

As indicated above, the compounds of the present invention interesting their antiage Olesky in a wide range of diseases, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with the proliferation of retinal vessels. In particular, as expected, such compounds of the present invention will slow the growth of primary and recurrent solid tumours of, for example, colon, breast, prostate, lungs and skin. More specifically, it can be expected that such compounds of the present invention will inhibit the growth of these primary and recurrent tumors caused by VEGF, especially those tumors, growth and the distribution of which is largely dependent on VEGF, for example, certain tumours of the colon, breast, prostate, lung, external female genital organs, and skin.

In addition to their use in therapeutic medicine, the compounds of formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of test systems for the evaluation of the effects of inhibitors tyrosinekinase activity of VEGF receptors in laboratory animals such as cats, dogs, rabbits, monkeys, "ether" as used in this description means diethyl ether.

The present invention is illustrated in the following non-limiting examples in which, unless otherwise stated:

(i) the evaporation was carried out on a rotary evaporator under vacuum, and the processing operation is carried out after removal of residual solids such as drying, by filtration;

(ii) the work was carried out at ambient temperature, i.e. in the range of 18-25oWith, and in the atmosphere of inert gas, such as argon;

(iii) column chromatography (flash method) and liquid chromatography with an average pressure (GHSD) was performed on silica Merck Kieselgel (art. 9385) or reversed-phase silica Merck Lichroprep RP-18 (art. 9303) manufactured by E. Merck, Darmstadt, Germany;

(iv) the outputs are given for illustration only and are not necessarily the maximum attainable;

(v) melting points are not corrected and were identified using device Mettler SP62 to determine the melting temperature, of the device with oil bath

or device Koffler hot tiles;

(vi) structure of target products of the formula I were confirmed by nuclear methods (generally proton) magnetic resonance (NMR) and mass spectrometry; chemical shift values PR is no, d - doublet, t - triplet, m = multiplet, sh - wide, kV - Quartet;

(vii) intermediate compounds usually are not fully characterized, and the purity was assessed by thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), infrared (IR) spectroscopy or NMR analysis;

(viii) we used the following abbreviations:

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

NMP is 1-methyl-2-pyrrolidone

THF - tetrahydrofuran

TFA - triperoxonane acid.

Example 1

To a solution of 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)hintline (93 mg, 0.2 mmol) in a mixture of methanol (6 ml) and methylene chloride (3 ml) was added at ambient temperature 2M aqueous solution of sodium hydroxide (0.3 ml, 0.6 mmol). The mixture was stirred 10 minutes at ambient temperature, partially evaporated the solvent, to the residue was added water and the solution was acidified with 0.1 M chloroethanol acid to pH 6. The precipitate was filtered, washed with water and dried under vacuum, resulting in 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)chinasingapore (67 mg, 87%).

So pl. 249-251oWITH

1H NMR spectrum: (d6) to 2.13(s,3H); 4,01(s,2H); OF 5.40(BR> Elemental analysis:

C22H20N4O31,8 H2O0,2HCl

found C 61,4 H 5,3 N 12,8

requires C 61,7 H 5,6 N 13,1%

The original material was prepared as follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol) (J. Med. Chem. 1977, T. 20, 146-149) and reagent Golda (7,4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated under reflux for 24 hours. To the reaction mixture were added sodium acetate (3,02 g 0,037 mol) and acetic acid (1.65 ml, 0,029 mol) and the mixture was heated for another 3 hours. The mixture is evaporated, to the residue was added water, the solid was filtered, washed with water and dried (MgSO4). Recrystallization from acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-it (2,82 g, 0.01 mol), thionyl chloride (40 ml) and DMF (0,28 ml) was stirred and heated under reflux for 1 hour. The mixture is evaporated, the residue was dissolved in toluene and evaporated to dryness to obtain 7-benzyloxy-4-chloro-6-methoxybenzonitrile (3,45 g).

A mixture of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (2,18 g, 6,47 mmol), 3-acetoxy-4-methylaniline (1,32 g, 8 mmol) and isopropanol (50 ml) was stirred and heated Yali, washed with isopropanol and ether and the obtained 4-(3-acetoxy-4-methylaniline)-7-benzyloxy-6-methoxybenzonitrile (2,69 g, 89%).

A mixture of 4-(3-acetoxy-4-methylaniline)-7-benzyloxy-6-methoxybenzonitrile (2,68 g of 5.75 mmol), 10% palladium on charcoal (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under a hydrogen environment (1.5 atmospheres) for 30 minutes. The catalyst was filtered and the filtrate evaporated. The residual solid is triturated in ether, filtered and dried under vacuum at 50oC to obtain 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (2.1 g, 100%).

To a solution of 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (375 mg, 1 mmol) in DMF (16 ml) was added at ambient temperature potassium carbonate (415 mg, 3 mmol) and 4-(methyl bromide)pyridinesulfonamide (J. Org. Chem. 1958, 23, 575, 278 mg, 1.1 mmol). The reaction mixture was heated at 60oC for 2 hours. The mixture is evaporated and the residue was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried (MgSO4) and evaporated. The residue was purified by colonos the toxi-7-(4-pyridyloxy)hintline (93 mg, 22%).

So pl. 201-202oWITH

1H NMR spectrum: (d6) a 2.12(s, 3H); of 2.34(s, 3H); was 4.02(s, 3H); of 5.40(s, 2H); 7,27(s, 1H); 7,30(d, 1H); 7,51(d, 2H); a 7.62(s, 1H); the 7.65(d, 1H); to $ 7.91 (s, 1H); of 8.47(s, 1H); 8,63(d, 2H); at 9.53(s, 1H)

MC-ESI: 453 [MNa]+, 431 [MN]+< / BR>
Elemental analysis:

C24H22N4O40,6 H2O

found C 65,4 H 5,5 N 12,7

requires C 65,3 H 5,3 N 12,7%

3-Acetoxy-4-methylaniline, used as starting material, was prepared as follows:

To a mixture of 2-methyl-5-NITROPHENOL (2.5 g, 16.3 mmol) and 1M aqueous sodium hydroxide solution (24.5 ml) was added at ambient temperature acetic anhydride (1.9 ml, 20.3 mmol). The mixture was stirred for 40 minutes, filtered the solid and the filtrate was extracted with ethyl acetate. The organic layers were combined, washed with aqueous saturated sodium chloride solution, dried (MgSO4) and evaporated to obtain 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture of this material (3.1 g, 15.9 mmol) and 10% palladium on charcoal (0.12 g) in ethyl acetate (50 ml) was stirred at ambient temperature under an environment of hydrogen for 2 hours. The catalyst was filtered and the filtrate evaporated to obtain 3-acetoxy-4-methylaniline (2,45 g, 94%).

Example 2

nilina)-7-hydroxy-6-methoxybenzonitrile (750 mg) was subjected to interaction with 3-(methyl bromide)pyridinesulfonamide (Can. J. Chem. 1978, 56, 3068) (378 mg) to give 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-(3-pyridyloxy)hintline (293 mg, 34%).

So pl. 113-115oWITH

1H NMR spectrum: (d6) of 2.09(s, 3H); 2,30(s, 3H); of 3.94(s, 3H); 5,32(s, 2H); 7,27(d, 1H); to 7.32(s, 1H); 7,43-7,46(m, 1H); 7,58(s, 1H); to 7.59-7,63(m, 1H); a 7.85(s, 1H); 7,89-a 7.92(m, 1H); to 8.45(s, 1H); to 8.57(DD, 1H); 8,71(d, 1H); 9,48(c, 1H)

MC-ESI: 453 [MNa]+, 431 [MH]+< / BR>
Elemental analysis:

C24H22N4O40,85 H2O

found C 64,4 H 5,7 N 11,7

requires C 64,7 H 5,4 N 12,6%

Example 3

The compound synthesized in example 2 was further subjected to basic cleavage acetoxy-protective group, using a similar procedure to that described in example 1, and the obtained 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(3-pyridyloxy)hinzelin (215 mg, 83%).

So pl. 258-259oWITH

1H NMR spectrum: (d6) a 2.12(s, 3H); of 3.94(s, 3H); of 5.34(s, 2H); 7,05(s, 2H); to 7.32(s, 1H); to 7.35(s, 1H); 7,46-7,49(m, 1H); 7,88(s, 1H); 7,93-to 7.95(m, 1H); 8,43(s, 1H); at 8.60(DD, 1H); total of 8.74(d, 1H); was 9.33(s, 1H); 9,35(s, 1H)

MC-ESI: 411 [MNa]+, 389 [MN]+< / BR>
Elemental analysis:

C22H20N4O33H2O0,07HCl

found 59,2 C H 5,5 N 12,6

requires C 59,4 H 5,9 N 12,6%

Example 4

4-(3-Acetoxy-4-methylaniline)-6-methoxy-7-(2-pyridylthio, similar to that described in example 1, and the obtained 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(2-pyridyloxy)chinasingapore (58 mg, 38%).

So pl. 236-238oWITH

1H NMR spectrum: (d6) of 2.30(s, 3H); of 3.97(s, 3H); of 5.34(s, 2H); 7,02(s, 2H); 7.23 percent(s, 1H); 7,33(s, 1H); of 7.36-7,39(m, 1H); 7,56(d, 1H); 7,84-7,88(m, 1H); 7,87(s, 1H); 8,39(s, 1H); 8,91(d, 1H); to 9.32(c, 2H)

MC-ESI: 389 [MN]+< / BR>
Elemental analysis:

C22H20N4O33H2O0,75HCl

found C 55,8 H 5,5 11,8 N

requires C 56,2 H 5,7 N 11,9%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 1, 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (376 mg) was subjected to interaction with 2-(chloromethyl)pyridinecarboxamide (328 mg) to give 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-(2-pyridyloxy)hintline (170 mg, 40%).

1H NMR spectrum: (d6) a 2.12(s, 3H); of 2.34(s, 3H); 4,00(s, 3H); lower than the 5.37(s, 2H); 7.29 trend(s, 1H); 7,31(s, 1H); 7,39-7,42(m, 1H); 7,58-7,66 (m, 3H); 7,87-of 7.90 (m, 1H); to $ 7.91 (s, 1H); of 8.47(c, 1H); 8,64(d, 1H); 9,52(s, 1H)< / BR>
Example 5

4-(3-Acetoxy-4-methylaniline)-6-methoxy-7-(2-pyrimidine-4-ylethoxy)hinzelin (496 mg, 1.15 mmol) was subjected to basic cleavage acetoxy-protective group used in the hydroxy-7-(pyrimidine-4-ylethoxy)hinzelin (278 mg, 62%).

So pl. 290-291oWITH

1H NMR spectrum: (d6) to 2.13(s, 3H); was 4.02(s, 3H); 5,43(s, 2H); 7,05(s, 2H); from 7.24(s, 1H); to 7.35(s, 1H); to 7.67(d, 1H); 7,92(s, 1H); to 8.41(s, 1H); 8,89(d, 1H); 9,24(s, 1H); 9,36(s, 1H); 9,38(s, 1H)

MC-ESI: 390 [MN]+< / BR>
Elemental analysis:

C21H19N5O32,2 H2O

found C 58,8 H 5,4 N 16,3

requires C 58,8 H 5,5 16,3 N%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 1, 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (560 mg) was subjected to interaction in the presence of catalytic potassium iodide with 4-(chloromethyl)pyrimidine (375 mg) to give 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-(pyrimidine-4-ylethoxy)hintline (496 mg, 74%).

1H NMR spectrum: (d6) to 2.13(s, 3H); to 2.35(s, 3H); is 4.03(s, 3H); 5,44(s, 2H); 7,27(s, 1H); 7,31(d, 1H); 7,62-to 7.68(m, 3H); to 7.93(s, 1H); of 8.47(s, 1H); 8,89(d, 1H); 9,24(d, 1H); 9,54(s, 1H)

4-(Chloromethyl)pyrimidine was synthesized as follows:

A mixture of 4-methylpyrimidine (2 g, of 21.2 mmol), N-chlorosuccinimide (4.26 deaths / g, 31.9 per mmol) and dibenzoylperoxide (500 mg) in carbon tetrachloride (100 ml) was heated at 80oC for 2 hours. After cooling, the mixture was filtered and the filtrate evaporated. Residual obtained 4-(chloromethyl)pyrimidine as an orange oil (1 g, 37%).

Example 6

A solution of 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (400 mg, 1.06 mmol) (obtained as described for the starting material in example 1), 2-chloromethyl-1-methylimidazolidine (354 mg, 2,12 mmol) and potassium carbonate (585 mg) in DMF (15 ml) was heated at 60oC for 15 hours. After cooling to ambient temperature the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (20 ml) was added 2M sodium hydroxide solution (1 ml). After stirring for 1 hour the reaction mixture was diluted with water (20 ml) was added 2M solution chloroethanol acid (3 ml). The obtained solid was filtered, washed with water and dried under vacuum to obtain 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(1-Mei-2-ylethoxy)chinasingapore (150 mg, 29%).

So pl. 257-260oWITH

1H NMR spectrum: (d6) 2,17(s, 3H); of 3.95(s, 3H); is 4.03(s, 3H); of 5.68 (s, 2H); 7,02(DD, 1H); 7,16(s, 2H); to 7.64(s, 1H); 7,72(s, 1H); 7,80(s, 1H); 8,42(s, 1H); of 8.8(s, 1H); of 9.7(s, 1H); 11,38(s, 1H)

MC-ESI: 392 [MN]+< / BR>
Elemental analysis:

C21H21N5O31,65 H2O1,9HCl
oC for 15 hours. After cooling to ambient temperature the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (10 ml) was added 2M sodium hydroxide solution (2 ml). After stirring for 1 hour the reaction mixture was diluted with water (20 ml) was added 2M solution chloroethanol acid (3 ml). The obtained solid was filtered, washed with water and dried under vacuum to obtain 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(2-methylthiazole-4-ylethoxy)chinasingapore (300 mg, 59%).

So pl. 243-245oWITH

1H NMR spectrum: (d6) 2,17(s, 3H); 2,7(s, 3H); 4.0 a(s, 3H); to 5.35(s, 2H); 7,0(DD, 1H); for 7.12(d, 1H); 7,16(d, 1H); 7,58(s, 1H); of 7.75(s, 1H); to 8.3(s, 1H); of 8.8(s, 1H); to 9.5 and 9.8(W.s, 1H) and 11.3(s, 1H)

MC-ESI: 409 [MN]+< / BR>
Elemental analysis:

C21H20N4O3S1H2O1,7HCl

found C 51,9 H 5,0 11,6 N S 6,8

requires C 51,6 H of 4.9 N FOR 11.5 S TO 6.6%

Example 8

To a solution of 4-(3-acetoxy-ribelli 2M aqueous sodium hydroxide solution (of 0.67 ml, 1.35 mmol). The mixture was stirred for 35 minutes at ambient temperature, the solvent evaporated, to the residue was added water and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, then dried (MgSO4) and evaporated to obtain white solids. Then, this solid was dissolved in a saturated solution chloroethanol acid in methanol (10 ml) and was stirred for 10 minutes. The solid product was filtered and dried under vacuum, resulting in 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(3-teenrotica)chinasingapore (127 mg, 66%).

So pl. 246-248oWITH

1H NMR spectrum: (d6) to 2.15 (s, 3H); 3,98(s, 3H); 5,32(s, 2H); 6,98(DD, 1H); 7,10(s, 1H); 7,14(d, 1H); to 7.25(d, 1H); 7,40(s, 1H); to 7.61(DD, 1H); of 7.70(d, 1H); to 8.12 (s, 1H); total of 8.74(s, 1H); 9,60(s, 1H)

MC-ESI: 394 [MN]+< / BR>
Elemental analysis:

C21H19N3O3S0,2H2O0,95HCl

found C 58,3 H 4,8 N 9,4 S 7,3 7,5 Cl

requires C 58,4 H 4,8 N 7,4 S 7,4 Cl 7,8%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 1, 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (400 mg) was subjected to interaction in the presence of the of aniline)-6 - methoxy-7-(3-teenrotica)hintline (210 mg, 46%).

So pl. 201-203oWITH

1H NMR spectrum: (d6) 2,11(s, 3H); 2,32(s, 3H); of 3.95(s, 3H); at 5.27(s, 2H); 7.23 percent(DD, 1H); 7,28(d, 1H); to 7.32(s, 1H); 7,58-7,66(m, 4H); a 7.85(s, 1H); 8,46(s, 1H); 9,49(s, 1H)

MC-ESI: 436 [MN]+< / BR>
Elemental analysis:

C23H21N3O4S0,3H2O

found C 63,0 H 5,2 N 9,1 S 7,3

requires C 62,7 H 5,0 9,5 N S 7,3%

Example 9

7-(2-Acetamidomethyl-4-ylethoxy)-4-(3-acetoxy-4-methylaniline)-6-methoxyquinazoline (220 mg, 0.44 mmol) was subjected to basic cleavage acetoxy-protective group, using a similar procedure to that described in example 8, and the obtained 7-(2-acetamidomethyl-4-ylethoxy)-4-(3-hydroxy-4-methylaniline)-6-methoxybenzonitrile (41 mg, 19%).

So pl. 202-204oWITH

1H NMR spectrum: (d6) of 2.16(s, 3H); 2,17(s, 3H); 4,01(s, 3H); 5,31(s, 2H); 6,98(DD, 1H); 7,10(d, 1H); 7,17(d, 1H); 7,34(s, 1H); 7,47(s, 1H); by 8.22(s, 1H); 8,80(s, 1H); 9,68(sh.s, 1H)

MC-ESI: 452 [MH]+< / BR>
Elemental analysis:

C22H21N5O4S2H2O2HCl

found C 47,1 H 4,7 12,5 N S 5,8 Cl 12,2

requires C 47,2 H 4,9 12,5 N S 5,7 Cl 12,7%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 1, 4-(3-acetoxy-4-methylaniline)-7-guide is Aliya with 2-acetamido-4-chloromethylthiazole (252 mg) to give 7-(2-acetamidomethyl-4-ylethoxy)-4-(3-acetoxy-4-methylaniline)-6-methoxyquinazoline (220 mg, 42%).

1H NMR spectrum: (d6) to 2.13(s, 3H); of 2.15(s, 3H); to 2.35(s, 3H); of 3.97(s, 3H); of 5.24(s, 2H); 7.24 to 7,31(m, 2H); 7,37(s, 1H); 7,63-7,66(m, 2H); 7,87(s, 1H); 8,48(s, 1H); 9,50(s, 1H)

MC-ESI: 494 [MN]+< / BR>
Example 10

4-(3-Acetoxy-4-methylaniline)-7-(3,5-dimethylisoxazol-4-ylethoxy)-6-methoxyquinazoline (342 mg, from 0.76 mmol) was subjected to basic cleavage acetoxy-protective group, using a similar procedure to that described in example 8, and the obtained 4-(3-hydroxy-4-methylaniline)-7-(3,5-dimethylisoxazol-4-ylethoxy)-6-methoxybenzonitrile (209 mg, 62%).

So pl. 252-254oWITH

1H NMR spectrum: (d6) of 2.20(s, 3H); to 2.29(s, 3H); 2,52(s, 3H); is 4.03 (s, 3H); 5,23 (s, 2H); 7.03 is(DD, 1H); to 7.15(d, 1H); 7,19(d, 1H); 7,44(s, 1H); by 8.22(s, 1H); 8,82(s, 1H); 9,67(s, 1H)

MC-ESI: 407 [MN]+< / BR>
Elemental analysis:

C22H22N4O40,25 H2O1HCl

found C 59,1 H 5,4 N 12,6 Cl 8,0

requires C 59,1 H 5,3 12,5 N Cl 7,9%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 1, 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (400 mg) was subjected to interaction in the presence of potassium iodide (16 mg) with 4-chloromethyl-3,5-dimethylisoxazole (177 mg) to give the> NMR spectrum: (d6) to 2.18(s, 3H); of 2.33(s, 3H); to 2.35(s, 3H); to 2.46(s, 3H); 3,98(s, 3H); to 4.98(s, 2H); 7,00(s, 1H); to 7.15(s, 1H); 7,22-7,25(m, 1H); to 7.32(s, 1H); the 7.43(DD, 1H); 7,51(s, 1H); 8,66(c, 1H)

Example 11

A solution of 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (400 mg, 1.06 mmol) (obtained as described for the starting material in example 1), 4-(3-chlorpropyl)pyridylmethylamine (410 mg, 2.1 mmol), potassium carbonate (438 mg) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60oC for 15 hours. After cooling to ambient temperature the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (20 ml) was added 2M sodium hydroxide solution (2 ml). After stirring for 1 hour the reaction mixture was diluted with water (20 ml) was added concentrated chloroethanol acid (1 ml). The obtained solid was filtered and purified by preparative HPLC C18 using a gradient mixture of methanol-water (0%-80%) as eluent. After evaporation of methanol was added concentrated chloroethanol acid (0.3 ml) and the solution evaporated to dryness. After trituration with acetone was filtered solid substances is of imidachloprid (305 mg, 59%).

So pl. 278-282oWITH

1H NMR spectrum: (d6) to 2.15(s, 3H); 2,3(m, 2H); 3,1 (m, 2H); of 3.96(s, 3H); 4,24(t, 2H); 6,98(DD, 1H); to 7.15(m, 2H); 7,44(s, 1H); of 7.96(d, 2H); 8,31(s, 1H); 8,77(s, 1H); 8,81(d, 2H); 9,7(sh.s, 1H); 11,34(s, 1H)

MC-ESI: 417 [MN]+< / BR>
Elemental analysis:

C24H24N4O30,7 H2O1,95HCl

found C 57,3 H 5,4 11,0 N

requires C 57,6 H 5,5 N 11,2%

The original material was prepared as follows:

Thionyl chloride (1.6 ml) was added to a solution of 4-pyridinemethanol (2 g, 14.5 mmol) in trichloromethane (20 ml), cooled at 0oC. After stirring for 1 hour at ambient temperature and then for 1 hour at 60oWith the solvent evaporated and the residue triturated with ether, resulting in 4-(3-chlorpropyl)pyridylmethylene in the form of a white solid.

1H NMR spectrum: (d6) to 2.15(m, 2H); to 3.02(t, 2H); of 3.69(t, 2H); of 7.96(d, 2H); 8,84(d, 2H).

Example 12

A solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (410 mg, 1.00 mmol), 4-(3-chlorpropyl)pyridylmethylamine (480 mg, 2.5 mmol), potassium carbonate (480 mg) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60oC for 15 hours. After cooling to ambient temperature environments the O4) and evaporated. The residue was diluted with methanol (10 ml) was added 2M sodium hydroxide solution (2 ml). After stirring for 1 hour the reaction mixture was diluted with water (20 ml) was added concentrated chloroethanol acid (0.5 ml). The obtained solid was filtered and purified by preparative HPLC C18 using a gradient mixture of methanol-water (0%-80%) as eluent. After evaporation of methanol was added concentrated chloroethanol acid (0.3 ml) and the solution evaporated to dryness. After trituration with acetone was filtered the solid and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridylamine)chinasingapore (243 mg, 48%).

So pl. 246-248oWITH

1H NMR spectrum: (d6) of 2.16(s, 3H); 2,30(m, 2H); to 3.09(t, 2H); of 3.95 (s, 3H); 4.26 deaths (t, 2H); 6.90 to(d, 1H); 7,11(d, 1H); 7,41(s, 1H); 7,94(d, 2H); to 8.3(s, 1H); 8,77 (s, 1H); 8,80(d, 2H); 9,7(sh.s, 1H); 11,46(s, 1H)

MC-ESI: 435 [MH]+< / BR>
Elemental analysis:

C24H23N4O3F0,9H2O1,95HCl

found C 55,3 H 5,3 N 10,2 13,0 Cl

requires C 55,3 H 5,2 N 10,7 Cl 13.3% of

The original material was prepared as follows:

A solution of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbamate (3 g, 13 mmol) (obtained is at 0.3 atmosphere for 1 hour. After filtration and evaporation of the solvent was allocated 2-fluoro-5-methoxycarbonylamino-4-methylaniline in the form of a solid (2.6 g, 100%).

1H NMR spectrum: (Dl3) 2,07(s, 3H); a 3.87(s, 3H); of 6.52(d, 1H); to 6.80(d, 1H)

A solution of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (800 mg, 2.4 mmol) (obtained as described for the starting material in example 1) and 2-fluoro-5-methoxycarbonylamino-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was heated under reflux for 2 hours. After cooling to ambient temperature the solid was filtered, washed with isopropanol and dried under vacuum to obtain 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxybenzonitrile (1.0 g, 87%).

1H NMR spectrum: (d6; CF3COOD) 2,2(s, 3H); 3,85(s, 3H); 4.0 a(s, 3H); lower than the 5.37(s, 2H); 7.3 to at 7.55(m, 8H); 8,13(s, 1H); 8,86(s, 1H)

MC-ESI: 464 [MN]+< / BR>
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxybenzonitrile (700 mg, 1,45 mmol) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) containing 10% palladium on charcoal (100 mg), was stirred under a hydrogen environment for 1 hour. After filtration and evaporation of the solvent axis 4 methylaniline)-7-hydroxy-6-methoxybenzonitrile (570 mg, 98%).

1H NMR spectrum: (d6) of 2.23(s, 3H); a 3.87(s, 3H); 4,01(s, 3H); 7,37 (s, 1H); was 7.45(d, 1H); 7.5(d, 1H); to 8.20(s, 1H); 8,77(s, 1H); 11,35(s, 1H); to 11.79(s, 1H)

MC-ESI: 374 [MN]+< / BR>
Example 13

Stir a solution of 4-chloro-6-methoxy-7-(4-pyridyloxy)hintline (35 mg, 0.1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (15 mg, 0.1 mmol) in a mixture of ether solution of hydrogen chloride (2 ml) and isopropanol (5 ml) was heated under reflux for 4 hours. Precipitated precipitated product was collected by filtration, washed with acetone and dried under vacuum, resulting in 4- (2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)-chinasingapore (23 mg, 47%).

So pl. 257-260oWITH

1H NMR spectrum: (d6) to 2.15(s, 3H); 4,08(s, 3H); ceiling of 5.60(s, 2H); 6.90 to(d, 1H); 7,07(d, 1H); 7,47(s, 1H); 7,93(sh.d, 2N); a total of 8.74(s, 1H); 8,89(sh.d, 2H); 9,62(sh.s, 1H); 11,46(s, 1H)

MC-ESI: 407 [MN]+< / BR>
Elemental analysis:

C22H19N4O3F1H2O2HCl

found C 52,8 H 4,6 N 10,9

requires C 53,1 H 4,6 11,3 N%

Source chlorination received as follows:

To a solution of phenol (1.26 g, 13.3 mmol) in dry N-organic (20 ml) was added sodium hydride (400 mg, 80% suspension in paraffin oil, 13.3 mmol) and the mixture was stirred for 10 is isano for the starting material in example 1) and the reaction mixture was heated at 110oC for 2 hours. Gave the mixture to cool, added to her water and was extracted with a mixture of ethyl acetate (3 x 100 ml). Then the combined extracts were washed with 2 m sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy-4-phenoxybenzoic (1.6 g, 95%) as a yellowish solid.

1H NMR spectrum: (d6) 3,98(s, 3H); lower than the 5.37(s, 2H); 7,25-7,6(m, 11N); of 7.60(s, 1H); 8,54(s, 1H)

MC-ESI: 359 [MN]+< / BR>
7-Benzyloxy-6-methoxy-4-phenoxybenzoic (160 mg, 0.44 mmol) was heated under reflux for 30 minutes. Was removed by evaporation of the solvent and the residue was treated with an aqueous solution of sodium bicarbonate. Precipitated precipitated product was collected by filtration, washed with water and dried to obtain 7-hydroxy-6-methoxy-4-phenoxybenzamide (105 mg, 88%).

1H NMR spectrum: (d6) 4,00(s, 3H); 7,20(s, 1H); 7,25-7,35(m, 3H); 7,4-of 7.55(m, 2H); 7,58(s, 1H); of 10.73(s, 1H)

MC-ESI: 269 [MN]+< / BR>
A mixture of 7-hydroxy-6-methoxy-4-phenoxybenzamide (95 mg, 0.35 mmol), 4-chloromethylpyridine (120 mg, of 0.74 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (5 ml) was heated at 80oC for 2 hours. The reaction mixture was allowed to cool, added to her SUB>). Was removed by evaporation of the solvent and the residue triturated with a mixture of ethyl acetate-hexane, resulting in 6-methoxy-4-phenoxy-7-(4-pyridyloxy)hinzelin (44 mg, 35%) as a white solid.

1H NMR spectrum: (d6) was 4.02(s, 3H); vs. 5.47(s, 2H); 7,25-7,35(m, 3H); 7,45(s, 1H); 7,4-of 7.55(m, 4H); a 7.62(s, 1H); charged 8.52(s, 1H); 8,63(DD, 2H)

MC-ESI: 360 [MH]+< / BR>
A solution of 6-methoxy-4-phenoxy-7-(4-pyridyloxy)hintline (200 mg, 0,56 mmol) in 2M chloroethanol acid (15 ml) was heated under reflux for 90 minutes. Given the reaction mixture to cool and neutralized her to pH 6-7 with aqueous solution of ammonia. Precipitated precipitated product was extracted with a mixture of methanol-methylene chloride (1/9) and the extract solution was dried (MgSO4). Removal of the solvent by evaporation gave 6-methoxy-7-(4-pyridyloxy)-3,4-dihydroquinazolin-4-one (90 mg, 57%) as a gray solid.

1H NMR spectrum: (d6) 3,93(s, 3H); to 5.35(s, 2H); 7.18 in(s, 1H); of 7.48(s, 1H); to 7.50(m, 2H); 8,04(s, 1H); to 8.62(m, 2H)

MC-ESI: 284 [MN]+< / BR>
To a mixture of 6-methoxy-7-(4-pyridyloxy)-3,4-dihydroquinazolin-4-it (81 mg, 0.29 mmol) and N,N-dimethylaniline (0.1 ml) in toluene (5 ml) were added oxytrichloride phosphorus (0.1 ml) and the mixture was heated under reflux for 1 hour. Delete the aka. Separated organic extract was dried his (MgSO4by way of evaporation is removed from him the solvent. The residue was purified by chromatography on silica, elwira with ethyl acetate passing through a mixture of increasing polarity to a mixture of methanol-methylene chloride (1/9), and the obtained 4-chloro-6-methoxy-7-(4-pyridyloxy)hinzelin (40 mg, 41%).

1H NMR spectrum: (d6) of 4.04 (s, 3H); vs. 5.47(s, 2H); 7,46(s, 1H); 7,50(d, 2H); 7,53(s, 1H); at 8.60(d, 2H); cent to 8.85(s, 1H)

MC-ESI: 302 [MN]+< / BR>
The original aniline was obtained as described below:

Methylchloroform (6.8 ml, 88 mmol) was added during 30 minutes to a solution of 4-fluoro-2-METHYLPHENOL (10 g, 79 mmol) in 6% aqueous sodium hydroxide solution at 0oC. the Mixture was stirred for 2 hours and then was extracted with ethyl acetate (100 ml). An ethyl acetate extract was washed with water (100 ml) and dried (MgSO4), after which it was removed by evaporating the solvent to obtain 4-fluoro-2-methylphenylethylamine (11.4 g, 78%) as oil.

1H NMR spectrum: (d6) and 2.14(s, 3H); 3,81(s, 3H); 7,05(m, 1H); 7,1-7,25(m, 2H)

To a solution of 4-fluoro-2-methylphenylethylamine (11,34 g, 62 mmol) in concentrated sulfuric acid (6 ml) was slowly added a mixture of concentrated nitric acid (the offer was stirred for 2 hours, and then added ice water and was collected in the precipitated product by filtration. The crude product was purified by chromatography on silica, elwira a mixture of methylene chloride-hexane to transition through a mixture of increasing polarity to a mixture of methanol-methylene chloride (1/19), and the result was a 4-fluoro-2-methyl-5-NITROPHENOL (2.5 g, 22%) as a solid.

1H NMR spectrum: (d6; CD3COOD) 2,31(s, 3H); 7,38(d, 1H); 7,58(d, 1H)

MC-ESI: 171 [MN]+< / BR>
A mixture of 4-fluoro-2-methyl-5-NITROPHENOL (2.1 g, 13 mmol), iron powder (1 g, 18 mmol) and iron sulfate (II) (1.5 g, 10 mmol) in water (40 ml) was heated under reflux for 4 hours. Given the reaction mixture to cool, neutralized its 2M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (100 ml). An ethyl acetate extract was dried (MgSO4) and removed from him the solvent by evaporation, resulting in 2-fluoro-5-hydroxy-4-methylaniline (0.8 g, 47%) as a solid.

1H NMR spectrum: (d6) was 1.94(s, 3H); of 4.67(s, 2H); from 6.22(d, 1H); of 6.65(d, 1H); 8,68(s, 1H)

MC-ESI: 142 [MN]+< / BR>
Example 14

A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxybenzonitrile (259 mg, 0,54 mm is sodium hydroxide (1.6 ml), was stirred at ambient temperature for 1 hour. After adding water (15 ml) was added concentrated chloroethanol acid (1 ml) and the mixture was stirred at ambient temperature for 15 minutes. After evaporation of methanol, the precipitate was filtered, washed with water and dried under vacuum to obtain 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxybenzonitrile (192 mg, 80%).

So pl. 294-298oWITH

1H NMR spectrum: (d6) 2,2(s, 3H); of 4.05(s, 3H); to 5.35(s, 2H); to 6.9(d, 1H); for 7.12(d, 1H); of 7.35-7.5(m, 4H); 7,55 and 7.6(m, 2H); of 8.25(s, 1H); of 8.8(s, 1H); of 9.7(s, 1H); 11,35(s, 1H)

MC-ESI: 406 [MN]+< / BR>
Elemental analysis:

C23H20N3O3F0,16H2O1HCl

found C 62,3 H 4,9 N 9,3

requires C 62,1 H 4,8 9,5 N%

Example 15

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, to 0.63 mmol), 2-(2-chloroethoxy)pyridinecarboxamide (120 mg, 0.61 mmol) and potassium carbonate (260 mg, 1.9 mmol) in DMF (25 ml) was heated at 90oC for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried (gSO4and by evaporation of solvent was removed. The residue was purified by column chromatography with elution with mixtures of ethyl acetate-methanol (100/0 to 90/10) and eat white solid.

1H NMR spectrum: (d6) to 3.99(s, 3H); of 4.35(t, 2H); was 4.42(t, 2H); from 6.22(t, 1H); 6,40(d, 1H); 7,42(s, 1H); at 7.55(d, 2H); 7,71(d, 1H); a 7.85(t, 1H); 8,55(d, 1H); 9,62(s, 1H)

MC-ESI: 441 [MN]+< / BR>
The original material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (1,34 g, 4 mmol) (obtained as described for the starting material in example 1) and 4-chloro-2-foronline (444 μl, 4 mmol) in isopropanol (40 ml) was heated under reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol and then with ether, and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-2-foronline)-6-methoxybenzonitrile (1.13 g, 64%).

So pl. 239-242oWITH

1H NMR spectrum: (d6) 4,0(s, 3H); are 5.36(s, 2H); 7,39-7,52(m, N); and 8.1(s, 1H); is 8.75(s, 1H)

MC-ESI: 410 [MN]+< / BR>
Elemental analysis:

C22H17N3ClFO21HCl

found 59,2 C H a 4.3 N 9,4

requires 59,2 C H a 4.1 N 9,41%

A solution of 7-benzyloxy-4-(4-chloro-2-foronline)-6-methoxybenzonitrile (892 g, 2 mmol) in TFA (10 ml) was heated under reflux for 50 minutes. After cooling, the mixture was poured on ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and podslushivaet Oia, washed with water and then with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline in the form of a yellow solid (460 mg, 72%).

So pl. 141-143oWITH

1H NMR spectrum: (d6) of 3.95(s, 3H); 7,05(s, 1H); to 7.35(d, 1H); 7,54-to 7.59(m, 2H); for 7.78(s, 1H); 8,29(s, 1H)

MC-ESI: 320-322 [MN]+< / BR>
To a solution of 2-(2-hydroxyethoxy)pyridine (700 mg, 5,04 mmol) (J. Org. Chem. 1977, 42, 1500) trichloromethane (20 ml) at 5oC was added thionyl chloride (0,55 ml of 7.55 mmol). The mixture was stirred 1 hour at 5oWith, gave her to warm up to ambient temperature and stirred for another 1 hour. Removed volatiles by distillation and azeotropic distillation with toluene and the obtained 2-(2-chloroethoxy)piridinkarboksamid (970 mg, 99%).

1H NMR spectrum: (d6) 3,90(m, 2H); 4,20(t, 2H); from 6.22(d, 1H); 6,40(d, 1H); 7,44(DD, 1H); to 7.64(d, 1H)

MC-ESI: 158 [MN]+< / BR>
Example 16

To a stirred solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (2,23 g, 7 mmol) (obtained as described for the starting material in example 15) in methylene chloride (60 ml) was added under nitrogen triphenylphosphine (5.5 g, 21 mmol) and then 2-[N-methyl-N-(4-pyridyl)]aminoethanol (1,49 g, 9.8 mmol) (obtained as described in EP 0359389 A1). C the overall environment within 2 hours. Were added ethyl acetate (200 ml) and the mixture was stirred for another 2 hours. The solid product was collected by filtration, washed with ethyl acetate, dried under vacuum and finally purified by column chromatography with elution with a mixture of methylene chloride-methanol (75/25, and then 60/40 and 50/50), which gave a white solid. The purified product was dissolved in a mixture of methylene chloride-methanol was filtered and the insoluble materials. To the filtrate was added an ethereal solution of hydrogen chloride (10 ml of a 3M solution) was removed by evaporating volatile substances. The residue is triturated with ether and the solid product was collected by filtration and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-[N-methyl-N-(4-pyridyl)] aminoethoxy)chinasingapore (2,75 g, 75%) as a white solid.

So pl. 222-227oWITH

1H NMR spectrum: (d6; CF3COOD) 3,29(s, 3H); of 3.95(s, 3H); to 4.16(t, 2H); 4,48(t, 2H); 7,05(sh.s, 1H); 7,37(s, 2H); 7,42(d, 1H); 7,58(t, 1H); the 7.65(DD, 1H); 8,18(s, 1H); 8,28(sh.s, 2H); 8,86(s, 1H)

MC-ESI: 454 [MN]+< / BR>
Elemental analysis:

C23H21N5O2ClF0,9H2O2HCl

found C 51,2 H 4,8 N 12,9

requires C 50,9 H 4,6 12,9 N%

Example 17

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (300 mg, 0,94 mmmh, 0,79 mmol) and potassium carbonate (260 mg, 1.9 mmol) in NMP (20 ml) was heated at 90oC for 2 hours, allowed to cool to ambient temperature and stirred for another 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (gSO4by way of evaporation is removed from him the solvent. The residue was purified by column chromatography with elution with mixtures of methyl chloride-methanol (100/0 to 95/5) and the result obtained 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)hinzelin (20 mg, 7%).

So pl. 200-202oWITH

1H NMR spectrum: (d6) 3,90(s, 3H); 4,50(s, 4H);? 7.04 baby mortality(d, 2H); 7,26(s, 1H); 7,33(DD, 1H); 7.5 to about 7.6(m, 2H); 7,80(s, 1H); 8,35(c, 1H); 8,39(d, 2H); 9,52(s, 1H)

MC-ESI: 441 [MN]+< / BR>
The original material was prepared as follows:

To a solution of 4-(2-hydroxyethoxy)pyridine (0.9 g, 6.5 mmol) (J. Chem. Soc. Perkin 11, 1987, 1867) trichloromethane (20 ml) at 5oWith added thionyl chloride (0.75 ml, 10 mmol). The mixture was stirred 1 hour at 5oWith, gave her to warm up to ambient temperature and stirred for another 2 hours. Removed volatiles by distillation and azeotropic distillation with toluene and the obtained 4-(2-chloroethoxy)piridinkarboksamid (1.3 g, 100%).

1H NMR-spectrolino)-7-hydroxy-6-methoxyquinazoline (300 mg, to 0.94 mmol) (obtained as described for the starting material in example 15), 1-(2-chloroethyl)-1,2-dihydro-2-pyridone (175 mg, 1.11 mmol) (J. Am. Chem. Soc. 1951, 73, 3635) and potassium carbonate (260 mg, 1.9 mmol) in DMF (30 ml) was heated at 80oC for 3 hours, allowed to cool to ambient temperature and stirred for another 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4by way of evaporation is removed from him the solvent. The residue was purified by column chromatography with elution with mixtures of methyl chloride-methanol-triethylamine (from 100/0/0 to 70/30/0,5) and the result obtained 4-(4-chloro-2-foronline)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]hinzelin (50 mg, 12%).

So pl. 209-211oWITH

1H NMR spectrum: (d6) of 3.94(s, 3H); of 4.35(t, 2H); to 4.41(t, 2H); from 6.22(DD, 1H); 6,40(d, 1H); 7,14(s, 1H); to 7.35(DD, 1H); 7,42(DDD, 1H); 7.5 to about 7.6(m, 2H); of 7.70(d, 1H); 7,80(s, 1H); 8,35(s, 1H); at 9.53(s, 1H)

MC-ESI: 441 [MN]+< / BR>
Example 19

To a stirred solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (300 mg, of 0.94 mmol) (obtained as described for the starting material in example 15) and tributylphosphine (0,69 ml, 2.8 mmol) in methylene chloride (20 ml) under nitrogen at 5oWith added 1-(3-hydroxypropyl)-1,4-dihydro-4-a feast is stirred at 5oC for 3 hours, allowed it to warm to ambient temperature and stirred for another 18 hours. Solvent was removed by evaporation and the residue was distributed between ethyl acetate and water. The organic phase was separated, dried (MgSO4and by evaporation was removed from the solvent. The residue was purified by column chromatography with elution with mixtures of methyl chloride-methanol-triethylamine (from 100/0/0 to 70/30/0,5) and the result obtained 4-(4-chloro-2-foronline)-6-methoxy-7-[3-(4-oxo-1,4-dihydro-1-pyridyl)propoxy] hinzelin (48 mg, 11%).

So pl.>250oWITH

1H NMR spectrum: (d6) to 3.56(m, 2H); 4,00(s, 3H); 3,54(t,

2H); to 4.38(t, 2H); 7,42(d, 1H); 7.5 to the 7.65(m, 5H); 8,43(s, 1H); 8,65 is 8.75(m, 4H)

MC-ESI: 455 [MH]+< / BR>
The original material was prepared as follows:

To a solution of 4-hydroxypyridine (1.88 g, of 19.7 mmol) in DMF (50 ml) was added sodium hydride (946 mg, 50% suspension in mineral oil, to 19.7 mmol) and the mixture was stirred for 30 minutes. Was added 2-(3-bromopropane)tetrahydropyran (4.0 g, to 17.9 mmol) (J. Chem. Soc. 1963, 3440), and the mixture was heated at 100oC for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4by way of evaporation is removed from a not (from 100/0 to 95/5) and the result obtained 1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro-4-pyridone (1.5 g, 35%).

1H NMR spectrum: (d6) of 1.35 and 1.75(m, 6N); 1,95(t, 2H); at 3.35 to 3.5(m, 2H); 3,65 to 3.8(m, 2H); of 4.12(t, 2H); of 4.57(s, 1H); to 6.95(s, 2H); 7,94(2N)

A solution of 1-[3-(tetrahydropyran-2-yloxy)propyl] -1,4-dihydro-4-pyridone (0.75 g, and 3.16 mmol) in acetic acid (8 ml), THF (4 ml) and water (4 ml) was heated at 50oC for 4 hours. By evaporation to remove volatiles to obtain 1-(3-hydroxypropyl)-1,4-dihydro-4-pyridone (480 mg, 99%) as not quite white solid.

1H NMR spectrum: (MCOd6) 1,9-of 1.95(m, 2H); 1,97-2,05(m, 2H); 4,0-4,1(m, 2H); 6,91(m, 2H); at 8.36(m, 2H)

MC-ESI: 154 [MN]+< / BR>
Example 20

To a stirred solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (230 mg, 0.7 mmol) (obtained as described for the starting material in example 15) and tributylphosphine (of 0.53 ml, 2.1 mmol) in methylene chloride (20 ml) under nitrogen at 5oWith added 1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 1.6 mmol). Portions over 10 minutes was added 1,1'-(azodicarbon)dipiperidino (552 mg, 2.2 mmol) and the mixture was stirred at 5oC for 2 hours, allowed it to warm to ambient temperature and stirred for another 18 hours. The mixture was diluted with ether, was filtered, the insoluble materials and the filtrate evaporated restoreprofile solvent. The residue was dissolved in acetone and was added an ethereal solution of hydrogen chloride (1.2 ml of a 3M solution). The mixture was left to stand for 15 minutes and the precipitated precipitated product was collected by filtration, washed with ether, and dried, resulting in 4-(4-chloro-2-foronline)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]chinasingapore (54 mg, 16%).

1H NMR spectrum: (d6) 3,98(s, 3H); 4,63(DD, 2H); a 4.83(DD, 2H); 7,42(d, 1H); 7.50 for(s, 1H); 7,56(d, 1H); 7,6-the 7.65(m, 3H); 8,39(s, 1H); 8,77(s, 1H); 8,80(c, 2N)

MC-ESI: 441 [MN]+< / BR>
The original material was prepared as follows:

To a solution of 4-hydroxypyridine (2.5 g, 26 mmol) in DMF (50 ml) was added sodium hydride (1.27 g of a 50% suspension in mineral oil of 26.4 mmol) and the mixture was stirred for 30 minutes. Was added 2-(2-bromoethoxy)tetrahydropyran (5.0 g, of 23.9 mmol) (J. Am. Chem. Soc. 1948, 70, 4187) in DMF (5 ml) and the mixture was heated at 80oC for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4by way of evaporation is removed from him the solvent. The residue was purified by column chromatography with elution with mixtures of methyl chloride-methanol (100/0 to 97/3) and the result obtained 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-Digi is 4,20(t, 2H); with 4.64(s, 1H); to 6.95(d, 2H); at 8.36(d, 2H)

MC-ESI: 224 [MN]+< / BR>
A solution of 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (500 mg, of 2.23 mmol) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heated at 45oC for 4 hours. By evaporation to remove volatiles to obtain 1-(2-hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 71%) as not quite white solid.

1H NMR spectrum: (d6) 3,70(t, 2H); 4,06(t, 2H); to 6.95(d, 2H); of 8.37(d, 2H)

Example 21

A solution of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (132 mg, 0.4 mmol) (obtained as described for the starting material in example 1) and 2-fluoro-5-methoxycarbonylamino-4-METHYLPHENOL (96 mg, 0.48 mmol) in pyridine (2 ml) was heated under reflux for 3 hours. Gave the mixture to cool, the solvent evaporated and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (gSO4) and evaporated from it solvent. The residue was purified by column chromatography with elution with a mixture of methylene chloride-ether (70/30). The obtained solid substance was led from methylene chloride and methanol to obtain 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline (120 mg, 64%).


MC-ESI: 454 [MN]+< / BR>
Elemental analysis:

C23H19N2O4F0,1H2O

found C 67,8 H 4,9 N 6,9

requires C 67,7 H 4,7 N 6,9%

The original material was prepared as follows:

A mixture of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbamate (8 g, 35 mmol) (EP 0307777 A2) and platinum oxide (IV) (174 mg) in ethanol (100 ml) and ethyl acetate (70 ml) was stirred under hydrogen at a pressure of 1.3 atmospheres for 1.5 hours. Remove the catalyst by filtration through diatomaceous earth and the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of petroleum ether-ethyl acetate (7/3) and the result was 2-fluoro-5-methoxycarbonylamino-4-methylaniline (6,56 g, 94%) as oil, which crystallized.

1H NMR spectrum: (Dl3) of 2.09(s, 3H); 3,66(sh.s, 2H); 3,90(s, 3H); is 6.54(d, 1H); 6,83(d, 1H)

A solution of sodium nitrite (1.63 g, 23 mmol) in water (19 ml) with ice (48 g) was added dropwise to a solution of 2-fluoro-5-methoxycarbonylamino-4-methylaniline (3,93 g, 20 mmol) in 35% sulfuric acid (48 ml) at 0oC. the Reaction mixture was stirred at 0oC for 30 minutes and added to it a solution of the three-hydrate of copper nitrate (II) (467 g of 1.93 mol) in water (780 ml), and then the copper oxide (II)>, after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of petroleum ether-ethyl acetate (8/2), and the result was 2-fluoro-5-methoxycarbonylamino-4-METHYLPHENOL (2,13 g, 53%) as a yellow solid.

1H NMR spectrum: (Dl3) to 2.13(s, 3H); 3,91(s, 3H); 5,11(sh.s, 1H); is 6.78(d, 1H); 6,93(d, 1H)

Example 22

A mixture of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (470 mg, 1 mmol), 4-chloromethyl-2-methylthiazolidine (368 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60oWith in 24 hours. The mixture was allowed to cool and was distributed between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and evaporated from the solvent. The residue was dissolved in methanol (15 ml) was added 1M sodium hydroxide solution (2 ml), after the mixture was stirred for 30 minutes. Added concentrated chloroethanol acid (0.5 ml). The solvent evaporated. The residue was purified by reverse-phase HPLC with an elution gradient of methanol (0-70%) in water. To the combined fractions of pure product was added concentrated chloroethanol acid (0.3 ml) and the flash steam the PTO at 55oWith obtaining 4-(2-fluoro-5-hydroxy-4-methyl-aniline)-6-methoxy-7-((2-methylthiazole-4-yl)methoxy)chinasingapore (225 mg, 48%).

1H NMR spectrum: (d6) 2,17(s, 3H); 2,69(s, 3H); 4,00(s, 3H); 4,7(sh.s, 1H); of 5.34 (s, 2H); 6,91(d, 1H); and 7.1(d, 1H); of 7.60(s, 1H); 7,74(s, 1H); with 8.33(s, 1H); 8,79(s, 1H); 11,5(s, 1H)

MC-ESI: 427 [MN]+< / BR>
The original material was prepared as follows:

A mixture of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbamate (3 g, 13 mmol) (EP 0307777 A2) and platinum oxide (IV) (300 mg) in ethanol (60 ml) was stirred under hydrogen at a pressure of 0.3 atmosphere for 1 hour. Remove the catalyst by filtration through diatomaceous earth and the solvent evaporated to obtain 2-fluoro-5-methoxycarbonylamino-4-methylaniline (2.6 g, 100%) as a solid.

1H NMR spectrum: (Dl3) 2,07(s, 3H); a 3.87(s, 3H); of 6.52(d, 1H); to 6.80(d, 1H)

A solution of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (800 mg, 2.4 mmol) (obtained as described for the starting material in example 1) and 2-fluoro-5-methoxycarbonylamino-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) was heated under reflux for 2 hours. Gave the mixture to cool to ambient temperature, filtered, precipitated in the sediment solid, washed his isopropanol is insulinrelated (1.0 g, 77%).

1H NMR spectrum: (d6; CF3COOD) 2,2(s, 3H); 3,85(s, 3H); 4.0 a(s, 3H); lower than the 5.37(s, 2H); 7.3 to at 7.55(m, 8H); 8,13(s, 1H); 8,86(s, 1H)

MC-ESI: 464 [MN]+< / BR>
A mixture of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxybenzonitrile (700 mg, 1.4 mmol) and 10% palladium on charcoal (100 mg) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) was stirred under hydrogen at a pressure of 1 atmosphere for 1 hour. The catalyst was filtered through diatomaceous earth and the solvent evaporated. The residue is triturated with ether, collected by filtration and dried under vacuum to obtain 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (570 mg, 98%).

1H NMR spectrum: (d6) of 2.23(s, 3H); a 3.87(s, 3H); 4,01(s, 3H); 7,37(s, 1H); was 7.45(d, 1H); 7.5(d, 1H); to 8.20(s, 1H); 8,77(s, 1H); 11,35(s, 1H); to 11.79(s, 1H)

MC-ESI: 374 [MN]+< / BR>
Example 23

A mixture of 4-chloro-7-(4-pyridyloxy)chinasingapore (350 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol)(obtained as described for the starting material in example 13) in isopropanol (15 ml) was heated under reflux for 1 hour. The precipitate was collected by filtration and was purified by the reversed-Fazli concentrated chloroethanol acid (0.5 ml) and the solvent evaporated, receiving 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(4-pyridyloxy)chinasingapore (140 mg, 28%).

1H NMR spectrum: (d6) of 2.16(s, 3H); 5,69(s, 2H); to 6.19(d, 1H); and 7.1(d, 1H); of 7.48(d, 1H); 7,66(DD, 1H); of 8.06(d, 2H); 8,84(s, 1H); 8,86(d, 1H); 8,90(d, 2H); 9,7(sh.s, 1H); 11,71(s, 1H)

MC-ESI: 377 [MN]+< / BR>
Elemental analysis:

C21H17N4O2F2 4H2O2HCl

found C 50,9 H 4,9 N 11,1

requires C 51,2 H 4,9 11,4 N%

The original material was prepared as follows:

To a solution of 4-hydroxymethylbenzene (4 g, 36 mmol) in THF (30 ml) was added sodium hydride (0,72 g of 60% suspension in mineral oil, 18 mmol) and the mixture was heated under reflux for 15 minutes. Was added 7-fluoro-3,4-dihydroquinazolin-4-one (1 g, 6 mmol) (J. Chem. Soc. Section b, 1967, 449), THF evaporated and the mixture was heated at 120oC for 30 minutes. The mixture was allowed to cool, was diluted with water (40 ml) and concentrated chloroethanol acid brought to pH 8. The precipitate was collected by filtration, washed with water and then with ether, and dried under vacuum to obtain 7-(4-pyridyloxy)-3,4-dihydroquinazolin-4-it (1.12 g, 71%).

1H NMR spectrum: (d6) to 5.35 (s, 2H); 7,15-7,22 (m, 2H); 7.5(d, 2H); with 8.05(d, 1H); 8,07(s, 1H); to 8.6(d, 2H)

A mixture of 7-(4-pyridyl is for 1 hour. Evaporated volatiles and the residue triturated with ether, collected by filtration, washed with ether, and dried under vacuum, resulting in a 4-chloro-7-(4-pyridyloxy)chinasingapore (435 mg, 98%).

1H NMR spectrum: (AMCOd6) to 5.7(s, 2H); to 7.32(s, 1H); to 7.35(d, 1H); of 8.1 to 8.2(m, 3H); to 8.62(s, 1H); 9.0 in(d, 2N)

MC-ESI: 272 [MH]+< / BR>
Example 24

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), tributylphosphine (303 mg, 1.5 mmol) and 2-(imidazol-1-yl)ethanol (67 mg, 0.6 mmol) (J. Med. Chem. 1993, 25, 4052-4060) in methylene chloride (8 ml) was added dropwise a solution of 1,1'-(azodicarbon) dipiperidino (378 mg, 1.5 mmol) in methylene chloride (5 ml) and the mixture was stirred 3 hours at ambient temperature. Was added acetic acid (60 mg, 1 mmol) and the solvent evaporated. The solid residue was adsorbing on silica gel and purified by column chromatography with elution with a mixture of methylene chloride-methanol (9/1 then 8/2). The obtained white solid was dissolved in a mixture of methylene chloride-methanol was added a solution of 5M chloroethanol acid in isopropanol. The solvent evaporated and the solid triturated with ether, filtered off, washed with ether, and dried under vacuum, having resultar-range: (MCOd6) to 4.01 (s, 3H); to 4.62 (t, 2H); was 4.76 (t, 2H); 7,44(DD, 1H); of 7.48(s, 1H); to 7.59(t, 1H); 7,66(DD, 1H); 7,72(s, 1H); to 7.84(s, 1H); to 8.41(s, 1H); 8,78(s, 1H); which 9.22(s, 1H)

MC-ESI: 414 [MN]+< / BR>
Elemental analysis:

C20H17N5O2ClF0,4H2O2HCl

found C 48,3 H 4,1 N 14,0

requires C, 48.6 per H 4,0 N 14,2%

The original material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (1.2 g, 3.6 mmol) (obtained as described for the starting material in example 1) and 4-chloro-2-foronline (444 μl, 4 mmol) in isopropanol (40 ml) was heated under reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol and then with ether, and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-2-foronline)-6-methoxybenzonitrile (1.13 g, 71%).

So pl. 239-242oWITH

1H NMR spectrum: (d6) 4,0(s, 3H); are 5.36(s, 2H); 7,39-7,52(m, N); and 8.1(s, 1H); is 8.75(s, 1H)

MC-ESI: 410 [MN]+< / BR>
Elemental analysis:

C22H17N3O2ClFHCl

found 59,2 C H a 4.3 N 9,4

requires 59,2 C H a 4.1 N 9,4%

A solution of 7-benzyloxy-4-(4-chloro-2-foronline)-6-methoxybenzonitrile (892 g, 2 mmol) in TFA (10 ml) was heated under reflux for 50 minutes. After ohla is up to pH 11 aqueous ammonia. After concentration by evaporation, the solid product was collected by filtration, washed with water and then with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (460 mg, 72%) as a yellow solid.

So pl. 141-143oWITH

1H NMR spectrum: (d6) of 3.95(s, 3H); 7,05(s, 1H); to 7.35(d, 1H); 7,54-to 7.59(m, 2H); for 7.78(s, 1H); 8,29(s, 1H)

MC-ESI: 320 [MN]+< / BR>
Example 25

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol) (obtained as described for the starting material in example 24) and potassium carbonate (676 mg, 4.9 mmol) in DMF (10 ml) was stirred at ambient temperature for 10 minutes. Was added 4-chloromethyl-2-methylthiazolidine (310 mg, 1,68 mmol) and the mixture was heated at 70oWith over 3.5 hours. Given the reaction mixture to cool and was distributed between ethyl acetate and water. Separated the organic layer, washed with water and dried (MgSO4), after which the solvent evaporated. The solid residue was purified by column chromatography with elution with a mixture of methylene chloride-acetonitrile-methanol (50/45/5, and then 50/40/10). Obtained pure solid substance was dissolved in a mixture of methylene chloride-methanol was added a solution of esta. This solid substance was collected by filtration and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-((2-methylthiazole-4-yl)methoxy)chinasingapore (240 mg, 35%).

So pl. 220-225oWITH

1H NMR spectrum: (d6) of 2.68(s, 3H); 4.0 a(s, 3H); are 5.36(s, 2H); 7,46(DD, 1H); rate of 7.54 (s, 1H); to 7.61 (t, 1H); 7.7(d, 1H); 7,71(s, 1H); compared to 8.26(s, 1H); 8,83(s, 1H)

MC-ESI: 431 [MH]+< / BR>
Elemental analysis:

C20H16N4O2ClFS0,3H2O1,5HCl

found C 49,3 H 4,0 11,3 N

requires C 48,9 H 3,7 11,4 N%

Example 26

Using a similar procedure to that described in example 25, chemically connected 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (224 mg, 0.7 mmol) (obtained as described for the starting material in example 24) and 2-chloromethyl-1-methylimidazolidine (140 mg, 0.8 mmol) to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-((1-Mei-2-yl)methoxy)chinasingapore (150 mg, 44%).

1H NMR spectrum: (d6) of 3.94(s, 3H); was 4.02(s, 3H); 5,69(s, 2H); 7,44(DD, 1H); to 7.6(t, 1H); to 7.64(s, 1H); to 7.67(DD, 1H); 7,72(d, 1H); 7,81(d, 1H); 8,46(s, 1H); 8,81(s, 1H)

MC-ESI: 414 [MN]+< / BR>
Elemental analysis:

C20H17N5O2ClF0,5H2O2HCl0,25 isopropanol

found C 48,7 H 4,6 N 13,6

requires C to 48.8 H 4,3 N 13,7%

470 mg, 1 mmol) (obtained as described for the starting material in example 22), 2-chloromethyl-1-methylimidazolidine (335 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (20 mg) in DMF (15 ml) was heated at 60oC for 2 hours. The mixture was allowed to cool and was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated from it solvent. The crude product was dissolved in methanol (20 ml), was added 2M sodium hydroxide solution (1 ml) and the mixture was stirred for 15 minutes. Added concentrated chloroethanol acid (0.5 ml) and the solvent evaporated. The crude product was purified by reversed-phase chromatography with elution with a mixture of methanol-water (1/1). To combined fractions containing pure product were added concentrated chloroethanol acid (0.3 ml) and the solvent evaporated, resulting in 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-((1-Mei-2-yl)methoxy)chinasingapore (100 mg, 21%).

1H NMR spectrum: (d6) 2,17(s, 3H); of 3.95(s, 3H); 4,01(s, 3H); 5,70(s, 2H); 6,92(d, 1H); for 7.12(d, 1H); 7,63(s, 1H); to 7.77(s, 1H); 7,83(s, 1H); 8,43(s, 1H); 8,82(s, 1H); 9,7(sh.s, 1H); from 11,62(sh.s, 1H)

MC-ESI: 410 [MN]+< / BR>
Example 28

1H NMR spectrum: (d6; CF3COOD) of 2.16 (s, 3H); 2,19(s, 3H); 4,00(s, 3H); 5,33(s, 2H); 6,91(d, 1H); for 7.12(d, 1H); 7,33(s, 1H); 7,49(s, 1H); is 8.16(s, 1H); 8,82(s, 1H)

MC-ESI: 470 [MH]+< / BR>
Elemental analysis:

C22H20N5O4FS0,4H2O0,95HCl

found C 51,5 H 4.5 N 13,8

requires C 51,7 H 4,3 N 13,7%

Example 29

A suspension of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (169 mg, 0.5 mmol) (obtained as described for the starting material in example 1) and 4-chloro-2-fluoro-5-hydroxyanisole (97 mg, 0.6 mmol) (EP 061741 A2) in isopropanol (5 ml) was heated under reflux for 2 hours. The precipitate was collected by filtration, washed with isopropanol and ether, and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxybenzonitrile (197 mg, 85%).

1H NMR spectrum: (d6) 4,0 (s, 3H); are 5.36 (s, 2H); to 7.15(d, 1H); of 7.4-7.5(m, 4H); 7,52(s, 1H); rate of 7.54(d, 2H); 8,23(s, 1H); of 8.8(s, 1H); to 10.6(s, 1H); is 11.39(sh.s, 1H)

MC-ESI: 426 [MN]+< / BR>
Elemental analysis the C 56,8 H 4,0 9,0 N%

Example 30

To a solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (448 mg, 1.4 mmol) (obtained as described for the starting material in example 24), tributylphosphine (848 mg, 4.2 mmol) and 4-(3-hydroxypropyl)pyridine (322 mg, 2.4 mmol) in methylene chloride (15 ml) was added dropwise a solution of 1,1'-(azodicarbon)piperidine (1.06 g, 4.2 mmol) in methylene chloride (15 ml) and the mixture was stirred 3 hours at ambient temperature. Was added acetic acid (126 mg, 2.1 mmol) and the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5). The purified product triturated with ether, the resulting solid substance was collected and dissolved in methylene chloride (20 ml). Added 5M solution (0.7 ml) of hydrogen chloride in isopropanol, diluted solution with isopropanol (5 ml) and concentrated by evaporation to a total volume of 4 ml was Added ether and the resulting solid was filtered, washed with ether, and dried under vacuum, resulting in 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyl)propoxy)chinasingapore (520 mg, 73%).

1H NMR spectrum: (d6) 2,30(m, 2H); to 3.09(t, 2H); of 3.97(s, 3H); 4,27(t, 2H); 7,42(s, 1H); 7,44(d, 1H); to 7.59(t, 1H); to 7.67(DD, 1H); to 7.95(d, 2H); to 8.34 (s, 1 is 5H2O2HCl0,1-propanol

found C 53,6 H 4,8 N 10,7

requires C 53,1 H 4,6 N 10,6%

Example 31

To a solution of 4-(4-chloro-2-fluoro-5-methoxycarbonylmethylene)-6-methoxy-7-(3-(4-pyridyl)propoxy)hintline (1.28 g, 2.5 mmol) in methanol (13 ml) was added 2M aqueous sodium hydroxide solution (1.5 ml, 3 mmol) and the mixture was stirred 2 hours at ambient temperature. Was added water and the mixture is brought 2M chloroethanol acid to pH 7. The precipitate was collected by filtration, washed with water and dried under vacuum. This solid was dissolved in methylene chloride (30 ml) and methanol (5 ml) was added 5M solution of hydrogen chloride in isopropanol (2.5 ml). The solution was diluted with isopropanol and concentrated under vacuum to a total volume of 10 ml of the Obtained solid substance was collected by filtration, washed with isopropanol and then with ether, and dried under vacuum, resulting in 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(3-(4-pyridyl)propoxy)chinasingapore (924 mg, 70%).

1H NMR spectrum: (d6) to 2.3(t, 2H); of 3.12(t, 2H); 4.0 a(s, 3H); to 4.28(t, 2H); 7.18 in(d, 1H); to 7.4(s, 1H); 7,52(d, 1H); to 7.95(d, 2H); 8,32(s, 1H); 8,82(s, 1H); 8,84(d, 2H); 10,65(s, 1H); 11,65(sh.s, 1H)

MC-ESI: 455 [MH]+< / BR>
Elemental analysis:

C23H20N4OSW:

To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (1,38 g, 3.5 mmol) (obtained as described for the starting material in example 22), tributylphosphine (2 g, 10.5 mmol) and 4-(3-hydroxypropyl)pyridine (720 mg, the 5.25 mmol) in methylene chloride (25 ml) was added dropwise a solution of 1,1'-(azodicarbon)dipiperidino (2,52 g, 10 mmol) in methylene chloride (10 ml) and the mixture was stirred for 2.5 hours at ambient temperature. The solvent evaporated and the residue triturated with petroleum ether. The solid product was collected by filtration and was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5), resulting in 4-(4-chloro-2-fluoro-5-methoxycarbonylmethylene)-6-methoxy-7-(3-(4-pyridyl)propoxy)hinzelin (1.2 g, 67%).

1H NMR spectrum: (d6) to 2.18(m, 2H); 2,84(t, 2H); 3,90(s, 3H); of 3.97(s, 3H); 4,2(t, 2H); 7,21(s, 1H); and 7.3(d, 2H); 7,72-of 7.82(m, 3H); to 8.41(s, 1H); of 8.47(d, 2H); 9,67(s, 1H)

MC-ESI: 513 [MN]+< / BR>
Example 32

To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (257 mg, 5.5 mmol) in methanol (5 ml) was added 2M aqueous sodium hydroxide solution (0.3 ml, 6 mmol) and the mixture was stirred for 1 hour at 40oC. was Added water and 1M charlesetta was collected by filtration, was dissolved in a mixture of methylene chloride-methanol was added 7M solution of hydrogen chloride in isopropanol (0.4 ml). Evaporated volatile substances, the solid residue triturated with ether, collected by filtration and dried under vacuum, resulting in 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-imidazol-1-yl)ethoxy)-6-methoxybenzonitrile (160 mg, 60%).

So pl. 195-220oWITH

1H NMR spectrum: (d6) of 2.16(s, 3H); 4.0 a(s, 3H); 4,63(t, 2H); was 4.76(t, 2H); 6.90 to(d, 1H); and 7.1(d, 1H); 7,44(s, 1H); 7,72(s, 1H); 7,83(s, 1H); 8,31(s, 1H); 8,76(s, 1H); 9,20(s, 1H); of 9.7(s, 1H); 11.4 in(sh.s, 1H)

MC-ESI: 410 [MN]+< / BR>
Elemental analysis:

C21H20N5O3F0,3H2O1,91HCl0,22 isopropanol

found C 52,3 H 5,1 N 13,7

requires C 52,3 H 4,9 N 14,1%

The original material was prepared as follows:

To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (261 mg, 0.7 mmol) (obtained as described for the starting material in example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(imidazol-1-yl)ethanol (94 mg, 0.84 mmol) (J. Med. Chem. 1993, 25, 4052-4060) in methylene chloride (5 ml) was added diethylazodicarboxylate (160 mg, 1.4 mmol) and the mixture was stirred for 1 hour at ambient temperature. Was added acetic acid (42 mg, 0.7 mmol who ivali under vacuum and purified by chromatography with elution with a mixture of methylene chloride-methanol (9/1, and then 8/2), resulting in 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-(2-(imidazol-1-yl)ethoxy-6-methoxyquinazoline (250 mg, 76%).

Example 33

To a suspension of 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (186 mg, 0.28 mmol) in THF (5 ml) was added 1M solution of tetrabutylammonium in THF (560 μl, of 0.56 mmol) and the mixture was stirred at 40oC for 1 hour. Added water and evaporated organic solvent. The precipitate was filtered off, washed with water and dried by azeotropic distillation with ethanol. The solid was dissolved in a mixture of methylene chloride-methanol was added a 5M solution of hydrogen chloride in isopropanol (0.5 ml). Evaporated volatiles and the residue was dissolved in isopropanol (1 ml) was added ether. The precipitate was filtered off, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxybenzonitrile (110 mg, 78%).

1H NMR spectrum: (d6) to 4.01 (s, 3H); 4,63 (t, 2H); 4.75 V (t, 2H); 7,17(d, 1H); 7,46(s, 1H); 7,51(d, 1H); 7,72(s, 1H); 7,83(s, 1H); at 8.36(s, 1H); 8,79(s, 1H); of 9.21(s, 1H); 10,63(sh.s, 1H); 11,6(sh.s, 1H)

MC-ESI: 430 [MN]+< / BR>
Elemental analysis:

C20H17<4,1 N 13,1%

The original material was prepared as follows:

A mixture of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxyquinazoline (2.35 g, 7 mmol) (obtained as described in example 29), imidazole (1.2 g, 17.5 mmol), tert-butyldiphenylsilyl (2.1 g, 7.7 mmol) and 4-(dimethylamino) pyridine (20 mg, 0.16 mmol) in DMF (10 ml) was stirred 2 hours at ambient temperature. Was added water (100 ml) and ethyl acetate (30 ml), the precipitate was collected by filtration, washed with water and dried under vacuum to obtain 7-benzyloxy-4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-6-methoxyquinazoline (2 g, 43%).

1H NMR spectrum: (d6) 1,09 (s, N); 3,86 (s, 3H); 5.25 in (s, 2H);? 7.04 baby mortality(d, 1H); 7.23 percent(s, 1H); 7,32-7.5(m, 11N); 7,58(d, 1H); 7,65-7,72(m, 5H); and 8.1(s, 1H); 9,25(sh.s, 1H)

MC-ESI: 663 [MN]+< / BR>
A mixture of 7-benzyloxy-4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-6-methoxyquinazoline (2 g, 3 mmol) and 10% palladium on charcoal (400 mg) in DMF (20 ml), methanol (20 ml) and ethyl acetate (20 ml) was stirred under hydrogen at a pressure of 1.7 atmospheres for 2 hours. The catalyst was filtered and the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5, then 90/10). Cleaned iphenyl-tert-butylsilane-2-foronline)-7-hydroxy-6-methoxyquinazoline (1.65 g, 95%).

1H NMR spectrum: (d6) 1,09(s, N); a 3.87(s, 3H); 7,00(s, 1H); 7,07(d, 1H); of 7.4-7.5(m, 6N); at 7.55(d, 1H); a 7.62(s, 1H), and 7.7(m, 4H); 8,04(s, 1H); 9.15, with(W.s, 1H); 10,34(sh.s, 1H)

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-7-hydroxy-6-methoxyquinazoline (288 mg, 0.5 mmol), triphenylphosphine (262 mg, 1 mmol) and 2-(imidazol-1-yl)ethanol (62 mg, 0.55 mmol) (J. Med. Chem. 1993, 25, 4052-4060) in methylene chloride (5 ml) was added diethylazodicarboxylate (174 mg, 1 mmol) and the mixture was stirred for 1 hour at ambient temperature. Was added acetic acid (30 mg, 0.5 mmol) and evaporated volatile substances. The residue is triturated with ether, the solid is collected by filtration and dried under vacuum, resulting in 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (186 mg, 55%).

MC-ESI: 668 [MN]+< / BR>
Example 34

A suspension of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)hintline (300 mg, to 0.63 mmol) and 2M aqueous sodium hydroxide solution (0,38 ml, from 0.76 mmol) in methanol (6 ml) was stirred at ambient temperature for 2 hours. Was added water and the mixture is brought 2M chloroethanol acid to pH 7. The precipitate was collected by filtration, washed with water is of hydrogen chloride in isopropanol (0.5 ml). The mixture was diluted with isopropanol and evaporated solvents (methylene chloride and methanol). The precipitate was collected by filtration, washed with methylene chloride and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)chinasingapore (270 mg, 94%).

1H NMR spectrum: (d6) of 2.16(s, 3H); 3,5(t, 2H); 3,99(s, 3H); of 4.57(t, 2H); 6.89 in(d, 1H); for 7.12(d, 1H); 7,44(s, 1H); 7,98(d, 2H); 8,24(s, 1H); 8,78(s, 1H); 8,81(d, 2H); 9,7(sh.s, 1H); 11,38(sh.s, 1H)

MC-ESI: 421 [MN]+< / BR>
Elemental analysis:

C23H21N4O3F0,3H2O1HCl0,3 isopropanol

found C H 55,5 5,3

requires C 55,6 H 5,1

The original material was prepared as follows:

To a suspension of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (261 mg, 0.7 mmol) (obtained as described for the starting material in example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(4-pyridyl)ethanol (104 mg, 0.84 mmol) (Zhur. Obshchei. Khim. 1958, 28, pp. 103 -- 110) in methylene chloride was added diethylazodicarboxylate (244 mg, 1.4 mmol) and the mixture was stirred for 30 minutes at ambient temperature. The solvent evaporated. The residue is suspended in ether and the ether decanted. The crude oil was purified by column hoxy-4-methylaniline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)hinzelin (300 mg, 90%).

1H NMR spectrum: (d6) to 2.18(s, 3H); and 3.16(t, 2H); of 3.84(s, 3H); to 3.92(s, 3H); of 4.44(t, 2H); from 7.24(s, 1H); 7,29(d, 1H); 7,40(d, 2H); 7,79(s, 1H); 8,35(s, 1H); 8,49(d, 2H); 9,51(s, 1H)

MC-ESI: 501 [MNa]+< / BR>
Example 35

Using a similar procedure to that described in example 34, 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxy-7-(3-teenrotica)hinzelin (220 mg, 0.47 mmol) was treated with 2M aqueous sodium hydroxide solution (0,47 ml) and the obtained 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(3-teenrotica)chinasingapore (180 mg, 86%).

1H NMR spectrum: (d6) 2,17(s, 3H); 3,98(s, 3H); of 5.34(s, 2H); 6.89 in(d, 1H); to 7.15(d, 1H); 7,27(d, 1H); 7,47 (s, 1H); the 7.65(DD, 1H); of 7.75(s, 1H); 8,18(s, 1H); 8,77(s, 1H); 9,7(sh.s, 1H)

MC-ESI: 412 [MN]+< / BR>
Elemental analysis:

C21H18N3O3FS0,2H2O1HCl0,09 isopropanol

found C H 55,5 4,5 9,0 N

requires C 55,9 H 4,4 9,2 N%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 34, chemically connected 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (261 mg, 0.7 mmol) (obtained as described for the starting material in example 22) from 3-thiophenemethyl (96 mg), 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxy-7-(3-teenrotica)hinzelin (220 mg, 67%).

1H NMR spectrum: (d6) to 2.18(s, 3H); 3,85 (s, 3H); 3,93(s, 3H); at 5.27(s, 2H); 7.23 percent(d, 1H); 7,30(d, 1H); to 7.32(s, 1H); 7,40(d, 1H); to 7.59(DD, 1H); 7,66(s, 1H); 7,81 (s, 1H); 8,35(s, 1H); at 9.53(s, 1H)

MC-ESI: 492 [MNa]+< / BR>
Example 36

A mixture of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (187 mg, 0.75 mmol) (obtained as described for the starting material in example 22), 4-bromomethylbiphenyl (147 mg, 0.75 mmol) and potassium carbonate (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 50oC for 1 hour. Was added methanol (5 ml) and potassium carbonate (138 mg, 1 mmol) and the mixture was stirred at 65oC for 2 hours. The solvent evaporated, to the residue was added water and the mixture is brought 2M chloroethanol acid to pH 7. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5). The purified product triturated with ether, collected by filtration and dried. The solid was dissolved in a mixture of methylene chloride-isopropanol was added 5M solution of hydrogen chloride in isopropanol (0.5 ml). The mixture was concentrated by evaporation and the resulting precipitate was filtered, prom is Lino)-6-methoxybenzonitrile (60 mg, 25%).

So pl. 265-270oWITH

1H NMR spectrum: (d6) 2,17(s, 3H); was 4.02(s, 3H); vs. 5.47(s, 2H); 6.89 in(d, 1H); 7,11(d, 1H); 7,38(s, 1H); 7,71(d, 2H); to 7.93(d, 2H); 8,23(s, 1H); is 8.75(s, 1H); 9,67(s, 1H); 11,24(sh.s, 1H)

MC-ESI: 431 [MH]+< / BR>
Elemental analysis:

C24H19N4O3F0,1H2O1HCl

found C 61,2 H 4.5 N 11,7

requires 61,5 C H a 4.3 N 12,0%

Example 37

To a solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319,5 mg, 1 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (524 mg, 2 mmol) and 2-(4-pyridyl)ethanol (160 mg, 1.25 mmol) (Zhur.Obshchei. Khim. 1958, 28, pp. 103 -- 110) in methylene chloride (7 ml) was added dropwise diethylazodicarboxylate (315 μl, 2 mmol). The mixture was stirred for 1 hour at ambient temperature and the solvent evaporated. The residue is triturated with ether and the solid was filtered and purified by column chromatography with elution with a mixture of methylene chloride-acetonitrile-methanol (85/10/5). The purified solid product was dissolved in a mixture of methylene chloride (50 ml) and methanol (50 ml) was added 5M solution chloroethanol acid in isopropanol (0.5 ml). After dilution with isopropanol (20 ml) and the mixture was concentrated by evaporation. Precipitated precipitated solid substance was collected PU is nosologically (125 mg, 25%)

So pl. 189-191oWITH

1H NMR spectrum: (d6; CF3D) 3,55 (t, 2H); 3,99 (s, 3H); with 4.64(t, 2H); 7,46(s, 1H); of 7.48(d, 1H); a 7.62(t, 1H); to 7.67(DD, 1H); 8,16(d, 2H); 8,17(s, 1H); 8,88(s, 1H); to 8.94(d, 1H)

MC-ESI: 425 [MN]+< / BR>
Elemental analysis:

C22H18N4O2ClF0,5H2O1,95HCl

found C 52,0 H 4,3 N 11,1

requires C 52,3 H 4.2 N 11,1%

Example 38

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319,5 mg, 1 mmol) (obtained as described for the starting material in example 24), potassium carbonate (442 mg, 3.2 mmol) and potassium iodide (33 mg, 0.2 mmol) in DMF (25 ml) at ambient temperature was added 3-(chloromethyl)piridinkarboksamid (328 μl, 2 mmol), after which the reaction mixture was heated at 80oC for 2.5 hours. The mixture was allowed to cool and evaporated volatile substances. The residue was dissolved in a mixture of ethyl acetate (19 ml) and methanol (1 ml) and was filtered, the insoluble materials. From the filtrate the solvent evaporated and the residue was purified by column chromatography with elution with a mixture of methylene chloride-acetonitrile-methanol (50/45/5). The purified product was dissolved in hot methylene chloride and was added a saturated ethereal solution of hydrogen chloride. The mixture was concentrated by evaporation to poloviny-2-foronline)-6-methoxy-7-((3-pyridyl)methoxy)chinasingapore (103 mg, 25%)

So pl. 216-221oWITH

1H NMR spectrum: (d6) is 4.03 (s, 3H); of 5.48 (s, 2H); 7,47(d, 1H); rate of 7.54(s, 1H); the 7.65(t, 1H); of 7.7 to 7.8(m, 2H); of 8.25(d, 1H); 8,35(s, 1H); is 8.75(d, 1H); 8,84(s, 1H); of 8.90(s, 1H); 11,65(sh.with. 1H)

MC-ESI: 411 [MN]+< / BR>
Elemental analysis:

C21H16N4O2ClF0,8H2O1,6HCl

found C 51,9 H 4.2 N 11,4

requires C 52,2 H 4,0 11,6 N%

Example 39

Using a similar procedure to that described in example 38, (4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319,5 mg, 1 mmol) (obtained as described for the starting material in example 24) was subjected to interaction with 2-(chloromethyl)pyridinecarboxamide (310 μl, 1.9 mmol) and the obtained 4-(4-chloro-2-foronline)-6-methoxy-7-((2-pyridyl)methoxy)hinzelin (146 mg, 33%)

So pl. 215-218oWITH

1H NMR spectrum: (d6) 3,98(s, 3H); to 5.4(s, 2H); and 7.3(s, 1H); 7,32-7,42(m, 2H); 7,52 to 7.62(m, 3H); a 7.85(s, 1H); of 7.90(t, 1H); 8,35(c, 1H); 8,65(d, 1H); 9,6(c, 1H)

MC-ESI: 411 [MH]+< / BR>
Elemental analysis:

C21H16N4O2ClF0,5H2O

found C 59,7 H 3,9 N 13,1

requires C 60,1 H 4,1 N 13,3%

Example 40

To a solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (410 mg, 1.5 to celestialbody (128 μl, 1.5 mmol) and the mixture was stirred for 30 minutes at ambient temperature. Was added triphenylphosphine (143 mg, 0.52 mmol) and diethylazodicarboxylate (85 μl, 1 mmol) and the mixture was stirred for 1 hour at ambient temperature. The solid product was filtered and washed with methylene chloride. The solid was dissolved in a mixture of methylene chloride (25 ml) and methanol (25 ml) and was added 2.9 M ethereal solution of hydrogen chloride (2 ml). The mixture was concentrated by evaporation and the obtained was collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-Mei-2-yl)ethoxy) chinasingapore (133 mg, 34%)

So pl. 224-229oWITH

1H NMR spectrum: (d6) 3,26(t, 2H); of 3.94(s, 3H); 4.0 a(s, 3H); 4,59(t, 2H); the 7.43(d, 1H); 7,46(s, 1H); to 7.6(t, 1H); of 7.6 to 7.7(m, 3H); to 8.41(s, 1H); 8,78(s, 1H); 11,75(sh.s, 1H)

MC-ESI: 428 [MN]+< / BR>
Elemental analysis:

C21H19N5O2ClF1H2O2HCl

found C to 48.8 H 4,4 N 13,4

requires C, 48.6 per H 4.5 N 13,5%

Example 41

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319,5 mg, 1 mmol) (obtained as described for the starting material in example 24), potassium carbonate (414 mg, 3 mmol) and potassium iodide (16 mg, 0.1 mmol) and 4-chloromethylpyridine (257 Irali with water. The solid is collected by filtration and dried under vacuum. The solid was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5). The purified white solid suspended in methanol (25 ml) and was added 7.5 M solution of hydrogen chloride in methanol (20 ml). The obtained solid product was collected by filtration, washed with methanol and then with pentane and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(pyrimidine-4-yl)methoxy)chinasingapore (172 mg, 42%).

So pl. 237-239oWITH

1H NMR spectrum: (d6; CF3COOD) 4,07(s, 3H); of 5.53(s, 2H); 7,40(s, 1H); 7,46(DD, 1H); the 7.65 (t, 1H); 7.68 per-7,72(m, 2H); compared to 8.26(s, 1H); 8,35(c, 1H); 8,91(d, 1H); 9,25(c, 1H)

MC-ESI: 412 [MH]+< / BR>
Elemental analysis:

C20H15N5O2ClF0,5H2O1,85HCl

found C 49,5 H 3,6 N 14,1

requires C 49,2 H 3,7 N 14,3%

The original material was prepared as follows:

A solution of 4-methylpyrimidine (2 g, of 21.2 mmol), N-chlorosuccinimide (4.26 deaths / g, 31.9 per mmol) and benzoyl peroxide (500 mg, 2.1 mmol) tetrachloride (100 ml) was heated at 80oC for 2 hours. Gave the mixture to cool, was filtered, the insoluble materials and the filtrate evaporated solvent. The residue was purified by 10%).

1H NMR spectrum: (d6) to 4.81(s, 2H); of 7.70(d, 1H); 8,88(d, 1H); of 9.21(s, 1H)

Example 42

To a solution of 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-((1-methylbenzimidazole-2-yl)methoxy)hintline (290 mg, 0.6 mmol) in methanol (15 ml) and methylene chloride (12 ml) was added 2M sodium hydroxide solution (900 μl) and the mixture was stirred for 25 minutes at ambient temperature. The solvent evaporated and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (MgSO4), after which the solvent evaporated. The solid residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (97/3 and 95/5). The purified white solid suspended in methanol (20 ml) and was added 7.5 M solution chloroethanol acid in methanol (2 equivalent). The solid is collected by filtration, washed with methanol and then with pentane and dried under vacuum at 50oWith obtaining 4-(3-hydroxy-4-methylaniline)-6-methoxy-7-((1-methylbenzimidazole-2-yl)methoxy)chinasingapore (106 mg, 37%).

1H NMR spectrum: (d6; CF3D) 2,17(s, 3H); Android 4.04(s, 3H); 4,15(s, 3H); 6,01(s, 2H); 7,0(DD, 1H); 7,11(d, 1H); 7.18 in(d, 1H); of 7.6 to 7.75(m, 3H); 7,89(d, 1H); with 8.05(d, 1H); of 8.27(s, 1H); 8,86(s, 1H)

MC-ESI: the mole) (J. hem. Sc. 1989, 2820-2828) and paraformaldehyde (2 g) was heated at 165oC for 30 minutes. Added additional paraformaldehyde (1 g) and continued heating for another 2 hours. Gave the mixture to cool and was purified by column chromatography with elution with methylene chloride, and then with a mixture of methylene chloride-methanol (95/5), resulting in a received 2-hydroxymethyl-1-methylbenzimidazole (1,34 g, 45%).

1H NMR spectrum: (d6) of 3.84(s, 3H); to 4.73(s, 2H); 5,57(sh.s, 1H); 7,19(t, 1H); to 7.25(t, 1H); rate of 7.54(d, 1H); of 7.60(d, 1H)

MC-ESI: 185 [MNa]-< / BR>
A solution of 2-hydroxymethyl-1-methylbenzimidazole (1.1 g, 6.7 mmol) in thionyl chloride (10 ml) was stirred at ambient temperature for 15 minutes and then was heated under reflux for 15 minutes. Evaporated volatiles and the residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5), resulting in a received 2-chloromethyl-1-methylbenzimidazole (506 mg, 36%).

1H NMR spectrum: (d6; CF3D) 4,07 (s, 3H); 5,38(s, 2H); about 7.6 to 7.7(m, 2H); to 7.9(d, 1H); with 8.05(DD, 1H)

MC-ESI: 181 [MN]+< / BR>
A mixture of 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (240 mg, 0.64 mmol) (obtained as described for the starting material in PR is,7 mmol) in DMF (12 ml) was heated at 65oC for 3 hours. Was added 2-chloromethyl-1-methylbenzimidazole (90 mg, 0.41 mmol) and potassium carbonate (165 mg, 1.2 mmol) and continued heating for another 2 hours. The solvent evaporated and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue is triturated with water and the solid product was collected by filtration, washed with ether, and dried under vacuum to obtain 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-((1-methylbenzimidazole-2-yl)methoxy)hintline (292 mg, 95%).

MC-ESI: 506 [MNa]+< / BR>
Example 43

To a suspension of 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxyquinazoline (360 mg, 0.7 mmol) in methanol (10 ml), cooled at 5oC, was added 2M aqueous sodium hydroxide solution (700 μl, 1.4 mmol) and the mixture is then stirred for 30 minutes at ambient temperature. The solvent evaporated, the residue was diluted with water (10 ml) and the mixture is brought 1M chloroethanol acid to pH 7. The resulting material was filtered, washed with water and ether, and dried under vacuum. This solid was dissolved in methanol (5 ml) and was added 7M solution of hydrogen chloride receiving 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxybenzonitrile (273 mg, 74%).

1H NMR spectrum: (d6; CF3D) to 2.18(s, 3H); 2.50 each(s, 3H); Android 4.04(s, 3H); 5,42(s, 1H); to 6.9(d, 1H); for 7.12(d, 1H); to 7.35(s, 1H); 7,38(s, 1H); 7,42(s, 1H); 8,21(s, 1H); 8,81(s, 1H)

MC-ESI: 455 [MN]-< / BR>
Elemental analysis:

C23H20N4O3ClF1,5H2O1,9HCl

found C 49,8 H 4,8 10,0 N

requires C 50,1 H 4,6 N 10,2%

The original material was prepared as follows:

A solution of 2-chloro-6-methyl-4-pyridineboronic acid (2 g, 12 mmol) in ethanol (100 ml) and concentrated sulfuric acid (10 ml) was heated under reflux for 2 hours. Evaporated volatiles and the residue was dissolved in methylene chloride. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of ethyl acetate-petroleum ether (1/9) and the result obtained ethyl 2-chloro-6-methyl-4-pyridinecarboxylic (2 g, 86%).

1H NMR spectrum: (d6) of 1.41(t, 3H); 2,6 (s, 3H); however, 4.40(q, 2H); 7,63(s, 1H); of 7.69(s, 1H)

MC-ESI: 200 [MN]+< / BR>
Elemental analysis:

C9H10NO2Cl

found C to 54.4 H 5,3 7,0 N

requires C 54,1 H 5,0 7,0 N%

To a solution of 2-chloro-6-methyl-4-pyridinecarboxylic (1.85 g, 9,26 m is eremetical 15 minutes at 0oWith and was added acetic acid (2 ml). The mixture was distributed between ethyl acetate and water and the aqueous layer was brought to 5% aqueous solution of sodium bicarbonate to a pH of 7.5. The organic layer was separated, washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of ethyl acetate-petroleum ether (35/65) and the result obtained 2-chloro-4-hydroxymethyl-4-methylpyridin (1.28 g, 88%).

1H NMR spectrum: (d6) of 1.92 (t, 1H); 2,53(s, 3H); 4,70(d, 2H); 7,06 (s, 1H); 7,16 (s, 1H)

MC-ESI: 157 [MN]+< / BR>
Elemental analysis:

C7H8NOCl

found C 53,1 H 5,3 N 8,7

requires C 53,3 H 5,1 8,9 N%

To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (350 mg, of 0.94 mmol) (obtained as described for the starting material in example 22), triphenylphosphine (492 mg, 1.88 mmol) and 2-chloro-4-hydroxymethyl-6-methylpyridine (170 mg, 1.12 mmol) in methylene chloride (30 ml) was added dropwise diethylazodicarboxylate (296 μl, 1.88 mmol) and the mixture was stirred for 30 minutes at ambient temperature. The solvent evaporated and the residue was purified by column chromatography with elution with a mixture of ethyl acetate-methyl who Ridel)methoxy)-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxyquinazoline (373 mg, 78%).

1H NMR spectrum: (d6) to 2.15(s, 3H); 2,5(s, 3H); 3,85(s, 3H); 3,98 (s, 3H); to 5.35 (s, 2H); to 7.25 (s, 1H); and 7.3 (d, 1H); to 7.35(s, 1H); to 7.4(m, 2H); a 7.85(s, 1H); 8,35(s, 1H); 9,58(s, 1H)

MC-ESI: 513 [MN]+< / BR>
Example 44

A mixture of 4-(4-chloro-2-pertenece)-7-hydroxy-6-methoxyquinazoline (112 mg, 0.35 mmol), potassium carbonate (138 mg, 1 mmol) and 4-(chloromethyl)pyridinecarboxamide (59 mg, 0.36 mmol) in DMF (2 ml) was heated at 80oC for 1 hour. Gave the mixture to cool and was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5) and the result obtained 4-(4-chloro-2-pertenece)-6-methoxy-7-((4-pyridyl)methoxy)hinzelin (115 mg, 80%).

So PL, 197-198oWITH

1H NMR spectrum: (d6) is 4.03(s, 3H); 5,46(s, 2H); was 7.45(d, 1H); 7,49(s, 1H); 7.5(d, 2H); 7,58(t, 1H); a 7.62(s, 1H); 7,22(DD, 1H); 8,58(s, 1H); 8,65(d, 2H)

MC-ESI: 412 [MN]+< / BR>
Elemental analysis:

C21H15N3O3ClF0,8H2O

found C 59,5 H 3,9 N 9,6

requires 59,2 C H a 3.9 N 9,9%

The original material was prepared as follows:

To a solution of 7-benzyloxy-4-chloro-6-methoxybenzonitrile (506 mg, and 1.5 is rfinal (264 mg, 1.8 mmol) and the mixture was heated under reflux for 45 minutes. The solvent evaporated and the residue was distributed between ethyl acetate and water. The organic layer was washed with 0.1 M chloroethanol acid, water and brine and dried (MgSO4), after which the solvent evaporated. The solid residue triturated with petroleum ether and the crude product was collected by filtration and was purified by flash chromatography with elution with a mixture of methylene chloride-ether (9/1), resulting in 7-benzyloxy-4-(4-chloro-2-pertenece)-6-methoxyquinazoline (474 mg, 77%) as a cream solid color.

So pl. 179-180oWITH

1H NMR spectrum: (d6) to 3.99(s, 3H); are 5.36(s, 3H); of 7.35-7.5(m, 4H); 7,55-the 7.65(m, 5H); 7,72(d, 1H); and 8.6(s, 1H)

MC-ESI: 411 [MN]+< / BR>
Elemental analysis:

C22H16ClFN2O30,06 H2O0,05CH2Cl2< / BR>
found C 63,4 H 4,1 N 6,8

requires C 63,6 H 3,9 6,7 N%

A solution of 7-benzyloxy-4-(4-chloro-2-pertenece)-6-methoxyquinazoline (451 mg, 1.1 mmol) in TFA (4.5 ml) was heated under reflux for 3 hours. The mixture was diluted with toluene and evaporated volatile substances. The residue is triturated with methylene chloride, collected by filtration, washed with ether, and dried under vacuum with UB>6
) 4,0(s, 3H); 7,27(s, 1H); the 7.43(DD, 1H); 7,56(t, 1H); EUR 7.57(s, 1H); 7,72(DD, 1H); and 8.5(s, 1H)

MC-ESI: 321 [MN]-< / BR>
Example 45

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol) (obtained as described for the starting material in example 24), potassium carbonate (414 mg, 3 mmol), potassium iodide (40 mg) and 4-(chloromethyl)pyridinecarboxamide (250 mg, 1.5 mmol) in DMF (15 ml) was heated at 60oC for 2 hours. Gave the mixture to cool and was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (gSO4), after which the solvent evaporated. The residue is suspended in ethanol (20 ml) was added concentrated chloroethanol acid (0.5 ml). Evaporated volatile substances and the solid residue was subjected to azeotropic distillation with toluene. The solid product was recrystallized from propanol to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-((4-pyridyl)methoxy)chinasingapore (335 mg, 70%).

1H NMR spectrum: (d6) to 4.1(s, 3H); 5,69(s, 2H); 7,46(DD, 1H); 7,52(s, 1H); a 7.62(t, 1H); of 7.69(DD, 1H); 8,03(d, 2H); 8,55(s, 1H); 8,83(s, 1H); 8,93(d, 2H)

MC-ESI: 411 [MN]+< / BR>
Elemental analysis:

C21H16N4O2ClF0,5H2O1,95HCl

found C 51,0 H 3,9 N 11,2

requires C 51,4 received so as described for the starting material in example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (125 mg, 0.7 mmol) in methylene chloride (5 ml) was added dropwise diethylazodicarboxylate (261 mg, 1.5 mmol) and the mixture was stirred 2 hours at ambient temperature. Was added methanol (10 drops) and the mixture was poured into a column of neutral aluminum oxide and separating the product by elution with a mixture of methylene chloride-acetonitrile-methanol (60/35/35). The purified solid product triturated with ether and collected by filtration. The solid was dissolved in a mixture of methylene chloride-methanol was added a 3 M ether solution of hydrogen chloride (1 ml). The solid was filtered, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-7-(2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethoxy)-6-methoxyquinazoline (170 mg, 61%).

So pl. 208-212oWITH

1H NMR spectrum: (d6; CF3D) 2,52(C, 6N); 3,26(s, 3H); 3,98(s, 3H); of 4.12(t, 2H); to 4.46(t, 2H); 6.8 cm(W.s, 1H); 7,1(sh.s, 1H); 7,38(s, 1H); 7,46(DD, 1H); a 7.62(t, 1H); to 7.67(DD, 1H); 8,18(s, 1H); 8,89(s, 1H)

MC-ESI: 482 [MN]+< / BR>
Elemental analysis:

C25H25N5O2ClF1H2O2HCl

found C 52,2 H 5,2 N 12,2

requires C 52,4 H 5,1 N 12,2%

Ichthyotherapy)ethanol (1.35 g, 18 mmol) and 3 M ether solution of hydrogen chloride (3 drops) was heated at 140oC for 1 hour. The reaction mixture was allowed to cool and diluted with water. Was filtered, the insoluble materials and the aqueous filtrate was poured into a suspension of magnesium sulfate (50 mg) in ethyl acetate (100 ml). Was filtered, the insoluble materials and the filtrate was dried (gSO4), after which the solvent evaporated. The solid residue triturated with ether, collected by filtration and dried under vacuum at 50oWith obtaining 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90%).

So pl. 139-144oWITH

1H NMR spectrum: (Dl3) 2,4(C, 6N); 3,0 (s, 3H); 3,51(t, 2H); 3,81(t, 2H); of 6.26(s, 2H)

MC-ESI: 181 [MN]+< / BR>
Example 47

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(N-(4-pyridyl)amino)ethanol (97 mg, 0.7 mmol) in methylene chloride (8 ml) was added dropwise diethylazodicarboxylate (261 mg, 1.5 mmol) and the mixture was stirred 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (5 ml), the solid product was collected by filtration and was purified by chromatography on a column with hydroxy the ether and collected by filtration. The solid was dissolved in a mixture of methylene chloride-methanol was added a 3 M ether solution of hydrogen chloride (0.5 ml). Evaporated volatile substances and the solid residue suspended in ether, was filtered, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)chinasingapore (95 mg, 37%).

1H NMR spectrum: (d6; CF3D) a 3.87(t, 2H); 4,00(s, 3H); 4,43(t, 2H); 6,97(DD, 1H); to 7.15(DD, 1H); the 7.43(s, 1H); 7,46(DD, 1H); 7,66(t, 1H); to 7.68(DD, 1H); to 8.12(d, 1H); 8,21(s, 1H); to 8.34(d, 1H); 8,89(s, 1H)

MC-ESI: 440 [MN]+< / BR>
Elemental analysis:

C22H19N5O2ClF0,8H2O2HCl

found C H 50,0 4,3 N 13,2

requires C H 50,0 4,3 N 13,2%

The original material was prepared as follows:

Using a similar procedure to that described for the starting material in example 46, 4-chloropyridin (3 g, 20 mmol) was treated with aminoethanol (6,1 g, 0.1 mmol) to give 2-(N-(4-pyridyl)aminoethanol (400 mg, 25%).

So pl. 110-111oWITH

1H NMR spectrum (CDCl3) 3,3(m, 2H); 3,81(m, 2H); 4,94(sh.s, 1H); 6,44(d, 2H); 8,13(d, 2H)

MC-ESI: 138 [MH]+< / BR>
Example 48

Using a similar procedure to that described in example 47, 3-(N-methyl-N-(4-pyridyl)amino)propanol (116 mg, 0.7 mm is Sano for the starting material in example 24) to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(N-methyl-N-(4-pyridyl)amino)propoxy)chinasingapore (150 mg, 55%).

So pl. 243-248oWITH

1H NMR spectrum: (d6; CF3D) 2,2 (t, 2H); 3,21 (t, 3H); 3,82(t, 2H); 4.0 a(s, 3H); or 4.31(t, 2H); 6,95(sh.s, 1H); 7,2(sh.s, 1H); 7,39(s, 1H); 7,46(DD, 1H); a 7.62(t, 1H); to 7.68(DD, 1H); or 8.2(s, 1H); 8.3(the sh.s, 2H); 8,87(s, 1H)

MC-ESI: 469 [MN]+< / BR>
Elemental analysis:

C24H23N5O2ClF1,2H2O1,95HCl

found C 51,4 H 5,1 N 12,9

requires C 51,4 H 4,9 12,5 N%

The original material was prepared as follows:

Using a similar procedure to that described in example 46, 4-chloropyridin (885 mg, 59 mmol) and 3-(methylamino)propanol (2.1 g, 0.23 mmol) (Tetrahedron Lett. 1994, 35, 1545-1548) was heated for 8 hours to obtain 3-(N-methyl-N-(4-pyridyl)amino)propanol (979 mg, 61%).

1H NMR spectrum (CDCl3; CF3D) as 1.8-1.9(m, 2H); and 3.16(s, 3H); 3,6-of 3.75(m, 4H); 6.8 cm(W.s, 2H); 8,30(d, 2H)

MC-ESI: 166 [MN]+< / BR>
Example 49

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (393 mg, 1.5 mmol) and 1-(2-hydroxyethyl)-2-methylimidazole (88 mg, 0.7 mmol) (Chem. Abs. 1964, 60, 2949) in methylene chloride (8 ml) was added dropwise diethylazodicarboxylate (261 mg, 1.5 mmol) and the mixture was stirred 2 hours at ambient temperature. The mixture is methanol and was added 3 M ether solution of hydrogen chloride (0.5 ml). The precipitate was collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-Mei-1-yl)ethoxy)chinasingapore (180 mg, 72%).

1H NMR spectrum: (d6; CF3D) and 2.79(s, 3H); was 4.02(s, 3H); 4,59(t, 2H); 4.72 in(t, 2H); 7,40(s, 1H); was 7.45(d, 1H); of 7.60(s, 1H); a 7.62(t, 1H); to 7.67(DD, 1H); 7,71(s, 1H); 8,23(c, 1H); 8,89(c, 1H)

MC-ESI: 428 [MH]+< / BR>
Elemental analysis:

C21H19N5O2ClF1,4H2O2,1HCl

found C 47,9 H 4,7 N 13,3

requires C 47,6 H 4,6 N 13,2%

Example 50

To a solution of 1-(3-hydroxypropyl)imidazole (102 mg, 0.81 mmol) (EP 0060696 A1), 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, of 0.62 mmol) (obtained as described for the starting material in example 24) and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4 ml) was added dropwise diethylazodicarboxylate (295 mg, 1.8 mmol) and the mixture was stirred 2 hours at ambient temperature. The solvent evaporated and the residue was purified by chromatography with elution with a mixture of methylene chloride-acetonitrile-methanol (60/35/5). The purified solid was dissolved in a mixture of methylene chloride-methanol was added 5 M ethereal solution of hydrogen chloride (2 ml). Evaporated volatiles and solid Osteen 4-(4-chloro-2-foronline)-7-(3-(imidazol-1-yl)propoxy)-6-methoxybenzonitrile (114 mg, 36%).

1H NMR spectrum: (d6; CF3D) to 2.5(m, 2H); 3,99(s, 3H); 4,32(t, 2H); of 4.45(t, 2H); 7,39(s, 1H); was 7.45(DD, 1H); to 7.61(t, 1H); 7,66(DD, 1H); 7,71(s, 1H); to 7.84(s, 1H); 8,19(s, 1H); 8,77(s, 1H); 9,20(s, 1H)

MC-ESI: 428 [MN]+< / BR>
Elemental analysis:

C21H19N5O2ClF1,2H2O1,9HCl

found C 48,2 H 4.5 N 13,2

requires C, 48.6 per H 4.5 N 13,5%

Example 51

To a solution of 4-methyl-4H-1,2,4-triazole-3-thiol (40 mg, 0.34 mmol) and tert-butoxide potassium (36 mg, 0.32 mmol) in DMF (1 ml) was added 7-(2-bromoethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (98 mg, 0.23 mmol) and the mixture was heated at 40oC for 30 minutes. The reaction mixture was allowed to cool and was distributing it between ammonium chloride and ethyl acetate. The organic layer was separated, washed with water and brine and dried (gSO4), and then the solvent evaporated. The residue was purified by column chromatography with elution with a gradient mixture of methylene chloride-methanol (95/5 to 80/20). The purified solid product triturated with ether and collected by filtration. The solid was dissolved in a mixture of methylene chloride-methanol was added a 3 M ether solution of hydrogen chloride (0.5 ml). Evaporated volatiles and the residue was led from methylene chloride and ether. The solid was filtered, ol-3-ylthio)ethoxy)chinasingapore (90 mg, 79%).

1H NMR spectrum: (d6; CF3D) of 3.78(s, 3H); 3,81(t, 2H); 3,99(s, 3H); of 4.57 (t, 2H); 7,40(s, 1H); 7,46(DD, 1H); a 7.62(t, 1H); to 7.67 (DD, 1H); is 8.16(s, 1H); 8,89(s, 1H); 9,68(s,1H)

MC-ESI: 461 [MN]+< / BR>
Elemental analysis:

C20H18N6O2ClFS1H2O2HCl

found C 43,7 H 3,9 N 14,9

requires C 43,5 H 4,0 15,2 N%

The original material was prepared as follows:

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (320 mg, 1 mmol) (obtained as described for the starting material in example 24) and potassium carbonate (552 mg, 4 mmol) in DMF (5 ml), heated at 35oC, was added in portions at 70 μl every 30 minutes, 1,2-dibromethane (725 mg, 4 mmol). After completion of addition, the mixture was stirred for another 30 minutes and then was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue is triturated with a mixture of petroleum ether-ether and the solid was filtered and dried under vacuum, resulting in 7-(2-bromoethoxy-4-(4-chloro-2-foronline)-6-methoxyquinazoline (200 mg, 47%).

1H NMR spectrum: (d6) to 3.89(t, 2H); of 3.96(s, 3H); 4,51(t, 2H); 7.23 percent(s, 1H); to 7.35(DD, 1H); at 7.55(DD, 1H); to 7.59(t, 1H); 7,83(s, 1H); at 8.36(s, 1H); to 9.57(s, 1H, -(2 bromoethoxy-4-(4-chloro-2-foronline)-6-methoxyquinazoline (98 mg, 0.23 mmol) (obtained as described for the starting material and example 51) was treated with 5-mercapto-1-methyltetrazole (40 mg, 0.35 mmol) to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-methyltetrazol-5-ylthio)ethoxy)chinasingapore (55 mg, 44%).

1H NMR spectrum: (d6; CF3OD) to 3.8 (t, 2H); of 3.97(s, 6N); of 4.57 (t, 2H); to 7.35 (s, 1H); 7,46(DD, 1H); a 7.62(t, 1H); of 7.70(DD, 1H); to 8.12(s, 1H); 8,87(s, 1H)

MC-ESI: 462 [MN]+< / BR>
Elemental analysis:

C19H17N7O2ClFS0,5H2O1HCl

found C 45,1 H 3,7 N 19,3

requires C 45,0 H 3,8 N 19,3%

Example 53

To a solution of 2-methyl-1-(3-hydroxypropyl)imidazole (131 mg, of 0.93 mmol) (EP 0060696), triphenylphosphine (492 mg, 1.8 mmol) and 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, of 0.62 mmol) (obtained as described for the starting material in example 24) in methylene chloride (4 ml) was added dropwise diethylazodicarboxylate (295 μl, 1.8 mmol) and the mixture was stirred 2 hours at ambient temperature. Another was added 2-methyl-1-(3-hydroxyprop-saws)imidazole (43 mg, 0.31 mmol), triphenylphosphine (82 mg, 0.31 mmol) and diethylazodicarboxylate (50 μl, 0.31 mmol) and the mixture was stirred for further 3 hours. Evaporated volatile substances and the OST is the substance was dissolved in methylene chloride and was added 3 M ether solution of hydrogen chloride (2 ml). Evaporated volatile substances and the solid residue suspended in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-Mei-1-yl)propoxy)chinasingapore (104 mg, 32%).

1H NMR spectrum: (d6; CF3D) to 2.4 (t, 2H); 2,60(s, 3H); 4.0 a(s, 3H); from 4.3 to 4.4(m, 4H); 7,41(s, 1H); 7,46(DD, 1H); 7,58(s, 1H); a 7.62 (t, 1H); to 7.67(DD, 1H); of 7.70(s, 1H); 8,21(s, 1H); 8,88(s, 1H)

MC-ESI: 442 [MN]+< / BR>
Elemental analysis:

C22H21N5O2ClF1H2O2HCl0,23 broadcast

found C 49,8 H 5,0 12,5 N

requires C 50,1 H 5,0 N 12,7%

Example 54

A solution of hydrate of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylaminorex)chinasingapore (135 mg, 0.3 mmol) and 2-chloropyrimidine (66 mg, 0.6 mmol) in N, N-diisopropylethylamine (2 ml) was heated under reflux for 1 hour. Allowing the mixture to cool, rubbed it with ether. The solid product was collected by filtration and was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5). The purified oil was led from the ether and was filtered solid. Then the solid was dissolved in a mixture of methylene chloride-methanol was added a 3 M ether solution of hydrogen chloride (0.5 ml). A suspension of p is obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(pyrimidine-2-yl)amino)ethoxy)chinasingapore (52 mg, 33%).

1H NMR spectrum: (d6; CF3D) to 3.36(s, 1H); from 3.9(s, 3H); 4,22(t, 2H); 4,51(t, 2H); 6,94(t, 1H); of 7.36(s, 1H); 7,46(d, 1H); 7,63(t, 1H); 7,66(DD, 1H); 8,08(s, 1H); to 8.62(d, 2H); 8,9(s, 1H)

MC-ESI: 455 [MN]+< / BR>
Elemental analysis:

C22H20N6O2ClF1,1H2O1,5HCl

found C 49,8 H 4,4 N 15,9

requires C to 49.9 H 4.5 N 15,9%

The original material was prepared as follows:

To a solution of 2-(methylamino)ethanol (4.52 g, 20 mmol) in water (10 ml) and THF (10 ml) was added a solution of di-tert-BUTYLCARBAMATE (4.52 g, 20 mmol) and the mixture was stirred 18 hours at ambient temperature. Evaporated organic solvents and the residue was distributed between water and ether. The organic layer was separated, washed with 0.1 M solution chloroethanol acid and brine and dried (MgSO4), after which the solvent evaporated to obtain 2-(N-methyl-N-tert-butoxycarbonylamino)ethanol (3 g, 85%) as oil.

1H NMR spectrum: (Dl3) of 1.46(s, N); 2,92(s, 3H); 3,39(t, 2H); 3,74(t, 2H)

MC-ESI: 176 [MN]+< / BR>
A solution of 2-(N-methyl-N-tert-butoxycarbonylamino)ethanol (116 mg, 0.7 mmol) in methylene chloride (1 ml) was added to a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol) (obtained as described for the source diethylazodicarboxylate (261 mg, 1.5 mmol) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a column with silica and suirable gradient mixture of methylene chloride-acetonitrile-methanol (70/30/0 to 70/20/10). Partially purified product was further purified by column chromatography with elution with a gradient mixture of methylene chloride-ether-methanol (60/40/0 to 60/10/30). Clean oil was led from the ether, collected by filtration and washed with obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)hintline (450 mg, 63%).

So pl. 194-196oWITH

1H NMR spectrum: (Dl3) of 1.46(s, N); 3,05(sh. s, 3H); 3.72 points III.s, 2H); was 4.02(s, 3H); 4,27(sh.s, 2H); 7,0(s, 1H); 7,2-7,3(m, 3H); 8,54(t, 1H); 8,69(s, 1H)

MC-ESI: 499 [MNa]+< / BR>
Elemental analysis:

C23H26N4O4ClF0,3H2O

found C 57,2 H 5,7 N 11,5

requires C 57,3 H 5,6 11,6 N%

To a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)hintline (390 mg, 0.82 mmol) in methylene chloride (4 ml) was added TFA (4 ml) and the mixture was stirred 2 hours at ambient temperature. Was added toluene and evaporated volatile substances. The residue was dissolved in methylene chloride and was added 3 M apali under vacuum to obtain a hydrate of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(methylamino)ethoxy)chinasingapore (290 mg, 79%).

1H NMR spectrum: (d6; CF3D) to 2.74 (s, 3H); of 3.53 (t, 2H); of 4.05(s, 3H); 4.53-in(t, 2H); 7,46(d, 1H); 7,47(s, 1H); of 7.6 to 7.7(m, 2H); 8,24(s, 1H); 8,91(s, 1H)

MC-ESI: 377 [MN]+< / BR>
Elemental analysis:

C18H18N4O2ClF1,1H2O2HCl

found C 45,8 H 5,0 12,0 N

requires C 46,0 H 4,8 N 11,9%

Example 55

To a suspension of hydrate of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(methylamino)ethoxy)chinasingapore (90 mg, 0.1 mmol) (obtained as described for the starting material in example 54) in methylene chloride (3 ml) were added isonicotinohydrazide (36 mg, 0.2 mmol) and then was added dropwise a triethylamine (80 mg, 0.8 mmol). The mixture was stirred for 30 minutes at ambient temperature, then the solvent evaporated. The residue was distributed between ethyl acetate and water, the organic layer was separated, washed with brine and dried (MgSO4), after which the solvent evaporated. The residue was dissolved in methylene chloride and was added 3 M ether solution of hydrogen chloride (0.5 ml). The suspension was diluted with ether and the precipitate was collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(pyridylcarbonyl)amino)ethoxy)chinasingapore (75 mg ); 7,4 was 7.45(m, 2H); at 7.55(DD, 1H); the 7.65(t, 1H); 7,9-8,0(sh.s, 2H); of 8.28(s, 1H); of 8.8(s, 1H); 8,95(2N)

MC-ESI: 482 [MN]+< / BR>
Elemental analysis:

C24H21N5O3ClF1H2O1,7HCl

found C 51,7 H 4,6 12,0 N

requires C 51,5 H 4,6 N 12,3%

Example 56

A mixture of 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-it (100 mg, 0.4 mmol), thionyl chloride (20 ml) and DMF (0.1 ml) was heated under reflux for 1.5 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene. The solid residue was added a solution of 3-hydroxy-4-methylaniline (53 mg, 0.04 mmol) in isopropanol (10 ml) and the mixture was heated under reflux for 2 hours. Allowing the mixture to cool, precipitated precipitated product was collected by filtration, washed with isopropanol and dried to obtain 4-(3-hydroxy-4-methylaniline)-7- (4-pyridylthio)chinasingapore (103 mg, 73%).

1H NMR spectrum: (d6) 2,17(s, 3H); 7,05(DD, 1H); 7,17(d, 1H); 7,19(s, 1H); to 7.64(d, 2H); 8,00(d, 1H); to 8.20(s, 1H); 8,66(d, 2H); of 8.92(s, 1H); 9,05(d, 1H)

MC-ESI: 361 [MN]+< / BR>
Elemental analysis:

C20H16N4OS1H2O2HCl

found 53,2 C H 4,6 11,8 N

requires 53,2 C H 4,4 N 12,4%

The original material was prepared as follows:

A solution of 2-amino-4-fermenting acid ice (1/1, 250 ml). Precipitated precipitated solid substance was collected by filtration, washed with water and dried to obtain 7-fluoro-3,4-dihydroquinazolin-4-it (2.6 g, 82%).

To a solution of 4-mercaptopyridine (8,12 g, 73 mmol) in DMF (100 ml) was added sodium hydride (3.3 g, 50% suspension in mineral oil, 69 mmol) and the mixture was stirred for 30 minutes. Was added 7-fluoro-3,4-dihydroquinazolin-4-one (1.5 g, 9 mmol) and the reaction mixture was heated at 100oC for 4 hours. Allowing the mixture to cool, diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (97/3) and the result obtained 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (500 mg, 6%).

1H NMR spectrum: (d6) of 7.24(d, 2H); rate of 7.54(DD, 1H); of 7.70(d, 1H); 8,10(s, 1H); to 8.14(d, 1H); 8,44(d, 2H)

MC-ESI: 256 [MN]-< / BR>
Example 57

A mixture of 4-chloro-2-fluoro-3-hydroxyanisole (118 mg, 0.7 mmol) (EP 061741) and 4-chloro-6-methoxy-7-((4-pyridyl)methoxy)hintline (200 mg, 0.7 mmol) (obtained as described for the starting material in example 13) in isopropanol (10 ml) and the ether solution of hydrogen chloride (5 ml) was heated at 80oWith ivali with isopropanol and dried to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((4-pyridyl)methoxy)chinasingapore (100 mg, 31%).

1H NMR spectrum: (d6) of 3.96(s, 3H); 5,38(s, 2H); 7,14(d, 1H); from 7.24 (s, 1H); 7,38(d, 1H); of 7.48(d, 2H); of 7.82 (s, 1H); 8,32(s, 1H); 8,58(d, 2H); 9,48(s, 1H)

MC-ESI: 427 [MN]+< / BR>
Example 58

A mixture of 7-((2-chloro-4-pyridyl)methoxy-6-methoxy-3,4-dihydroquinazolin-4-it (150 mg, 0.47 mmol), phosphorylchloride (0.2 ml) and N,N-dimethylaniline (0.2 ml) in toluene (5 ml) was heated under reflux for 1 hour. Evaporated volatiles and the residue was distributed between ethyl acetate and a saturated solution of sodium bicarbonate. The organic layer was separated and dried (MgSO4), after which the solvent evaporated. The solid residue was added a solution of 2-fluoro-5-hydroxy-4-methylaniline (67 mg, 0.47 mmol) (obtained as described for the starting material in example 13) and the mixture was heated under reflux for 2 hours. Gave the mixture to cool and loose precipitated product was collected by filtration, washed with acetone and dried to obtain 7-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxybenzonitrile (70 mg, 30%).

So pl. 245-250oWITH

1H NMR spectrum: (d6) of 2.30(s, 3H); 4,10(s, 3H); of 5.45(s, 2H); 6.90 to(d, 1H); 7,10(d, 1H); to 7.35 (s, 1H); 7,50(d, 1H); the 7.65(s, 1H); of 8.25(s, 1H); to 8.45(d, 1H); is 8.75(s, 1H); 9,60(sh.s, 1H); RS 11.30(s, 1H)

MC-E 53,7 H 4,0 N 10,9

requires C 53,4 H 4,3 11,3 N%

The original material was prepared as follows:

To a mixture of 4-(2-chloropyridin)carboxylic acid (950 mg, 6 mmol) and DMF (0.05 ml) in methylene chloride (20 ml) were added oxalicacid (0.5 ml) and the mixture was stirred at ambient temperature for 1 hour. Evaporated volatile substances and to the residue was added ethanol (10 ml), after which the mixture was stirred at ambient temperature for 18 hours. Was added water and the mixture was extracted with ethyl acetate (3 x 25 ml). The extracts were combined, dried (MgSO4) and then the solvent evaporated to obtain 4-(2-chloropyridin)carboxylate (700 mg, 63%) as a brown oil.

1H NMR spectrum: (d6) of 1.30(t, 3H); 4,37(q, 2H); 7,80(m, 2H); at 8.60(d, 1H)

To a stirred solution of 4-(2-chloropyridin)carboxylate (700 mg, 3.8 mmol) in ether (10 ml) at 0oWith added dropwise sociallyengaged (5 ml of 1M solution in ether, 5 mmol). The mixture was allowed to warm to ambient temperature and was washed with ether and 2M sodium hydroxide solution (2 ml). Was filtered, the insoluble materials were separated organic phase and the aqueous layer was extracted with ether (3 x 25 ml). The extracts were combined and dried (MgSO4), after which it was evaporated rastvoritelei.

1H NMR spectrum: (d6) 4,55(s, 2H); 5,50(sh.s, 1H); to 7.32(d, 1H); 7,20(s, 1H); 8.30 to(d, 1H)

A mixture of 2-chloro-4-hydroxymethylbenzene (180 mg, 1.25 mmol), thionyl chloride (0.2 ml) in toluene was stirred at ambient temperature for 1 hour. Evaporated volatiles to obtain 2-chloro-4-chloromethylpyridine (180 mg, 0.9 mmol). To this crude product was added a mixture of 7-hydroxy-6-methoxy-4-phenoxybenzamide (268 mg, 1 mmol) (obtained as described for the starting material in example 13), potassium carbonate (680 mg, 5 mmol) in DMF (10 ml) and the mixture was heated at 90oC for 1 hour. Allowing the mixture to cool, diluted with water and extracted with ethyl acetate (3 x 70 ml). The extracts were combined, washed with water (3 times) and brine and dried (MgSO4), after which the solvent evaporated to obtain 7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-4-phenoxybenzamide (260 mg, 66%) as a solid.

1H NMR spectrum: (d6) 4,00(s, 3H); of 5.45(s, 2H); 7,30(m, 3H); 7,42 (s, 1H); of 7.4-7.5 (m, 3H); of 7.60 (s, 1H); a 7.62 (s, 1H); 8,44(d, 1H); charged 8.52(s, 1H)

MC-ESI: 394 [MN]+< / BR>
A mixture of 7-((2-chloro-4-pyridyl)methoxy-6-methoxy-4-phenoxybenzamide (260 mg, 0.7 mmol) and 2M chloroethanol acid (15 ml) was heated at 85oC for 2 hours. Gave a mixture of OS is tion and dried to obtain 7-((2-chloro-4-pyridyl)methoxy)-6-methoxy)-3,4-dihydroquinazolin-4-it (160 mg, 76%).

1H NMR spectrum: (d6) 3,90(s, 3H); are 5.36(s, 2H); 7.18 in(s, 1H); was 7.45(m, 2H); 7,46(s, 1H); to 7.59(s, 1H); 8,42(d, 1H)

MC-ESI: 318 [MN]+< / BR>
Example 59

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (950 mg, 3 mmol) (obtained as described for the starting material in example 24), 2-bromo-4-pommerellen (765 mg, 3 mmol) and potassium carbonate (2.38 g, 17 mmol) in DMF (10 ml) was heated at 80oC for 2 hours. Allowing the mixture to cool, poured in water and extracted with ethyl acetate. The combined extracts were dried (MgSO4), after which the solvent evaporated and the residue was subjected to azeotropic distillation with toluene. The residue is triturated with a mixture of ethyl acetate-hexane and the solid product was filtered, washed with a mixture of ethyl acetate-hexane and dried to obtain 7-((2-bromo-4-pyridyl)methoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (647 mg, 44%).

So pl. 210-212oWITH

1H NMR spectrum: (d6) 3,98 (s, 3H); of 5.40 (s, 2H); to 7.25 (s, 1H); 7,30(d, 1H); 7.50 for(s, 1H); 7,50(d, 1H); at 7.55(m, 2H); 7,74(s, 1H); 7,86(s, 1H); 8,35(sh.s, 1H); 8,42(d, 1H); of 9.56(s, 1H)

MC-ESI: 489 [MN]+< / BR>
Elemental analysis:

C21H15N4O2BrClF

found C 52,0 H 3.2 N 11,2

requires C 51,5 H 3,1 11,4 N%

The original material was prepared as bretagnolle carbon (200 ml) was heated under reflux for 2.5 hours. The mixture was allowed to cool and was then filtered, the insoluble material. From the filtrate the solvent evaporated and the residue was purified by filtration through a layer of silica with elution with a mixture of ethyl acetate-hexane (10/1), resulting in a 2-bromo-4-bromomethylphenyl.

1H NMR spectrum: (d6) the 4.65(s, 2H); 7,50(d, 1H); 7,42(s, 1H); of 7.70(s, 1H); 8,35(d, 1H)

MC-ESI: 250 [MN]+< / BR>
Example 60

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (600 mg, 2 mmol) (obtained as described for the starting material in example 24), 4-chloromethyl-2-lapiajomatkalla (620 mg, 3 mmol) and potassium carbonate (1.0 g, 7 mmol) in DMF (8 ml) was heated at 80oC for 30 minutes. Allowing the mixture to cool, poured in water and extracted with ethyl acetate. The combined extracts were dried (MgSO4), after which the solvent evaporated and the residue was subjected to azeotropic distillation with toluene. The residue is triturated with a mixture of ethyl acetate-hexane and the solid product was filtered and purified by column chromatography with elution ethyl acetate and additional chromatography with a mixture of methylene chloride-methanol (99/1). The purified product was recrystallized from a mixture of ethyl acetate-hexane to obtain 4-(4-chloro-2-ftoranila the CTD: (d6) 3,98(s, 3H); 5,44(s, 2H); 7,26(s, 1H); 7,34(DD, 1H); 7,53(DD, 1H); 7,58(d, 1H); 7,80(d, 1H); a 7.85(s, 1H); of 8.27(s, 1H); 8,35(s, 1H); 8,80(d, 1H); 9,60(s, 1H)

MC-ESI: 436 [MN]+< / BR>
Elemental analysis:

C22H15N5O2ClF

found C, 60,3 H 3,4 N 16,1

requires C 60,6 H 3,5 N 16,1%

The original material was prepared as follows:

To a solution of 2-cyano-4-dimethyl-tert-butylcyclohexylamine (1.4 g, 5.6 mmol) (J. Het. Chem. 1993, 30, 631) in THF (15 ml) were added tetrabutylammonium (9 ml, 1M solution in THF, 9 mmol) and the mixture was stirred 2 hours at ambient temperature. Added water and evaporated volatile substances. The residue was distributed between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent evaporated to obtain 2-cyano-4-hydroxymethylbenzene (0.55 g, 73%).

1H NMR spectrum: (d6) the 4.65(s, 2H); 5,70(t, 1H); of 7.70(d, 1H); to 7.95(s, 1H); is 8.75(d, 1H)

A mixture of 2-cyano-4-hydroxymethylbenzene (0.51 g, 3.8 mmol) and thionyl chloride (0.6 ml) in toluene (20 ml) was stirred at room temperature for 1 hour. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, resulting in 4-chloromethyl-2-cyanopyridine the measures 61

A mixture of 7-((6-chloro-2-oxo-1,2-dihydropyridin-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-it (190 mg, 0.4 mmol), thionyl chloride (5 ml) and DMF (0.1 ml) was heated under reflux for 2 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene. The solid residue was added a solution of 4-chloro-2-foronline (1 ml) in isopropanol (15 ml) and the mixture was heated under reflux for 3 hours. Gave the mixture to cool and loose precipitated product was collected by filtration, washed with isopropanol and dried to obtain 4-(4-chloro-2-foronline)-7-((6-chloro-2-oxo-1,2-dihydropyridin-4-yl) methoxy)-6-methoxybenzonitrile (110 mg, 41%).

So pl. 271-273oWith (Razlog.)

1H NMR spectrum: (d6) 4,08(s, 3H); to 5.35(s, 2H); 6,70(s, 1H); 7,00 (s, 1H); 7,30 (s, 1H); 7,40(d, 1H); of 7.60(m, 2H); 8,30(s, 1H); is 8.75(s, 1H)

MC-ESI: 461 [MN]+< / BR>
The original material was prepared as follows:

A mixture of 2,6-dichloro-4-hydroxymethylbenzene (1,72 g, 16 mmol) and 40% aqueous sodium hydroxide solution (5 ml) in methanol (50 ml) was heated under reflux for 24 hours. Gave the mixture to cool and then evaporated volatile substances. The residue was extracted with ethyl acetate and the extracts from the solvent evaporated. OS is(490 mg, 28%).

1H NMR spectrum: (d6) of 3.80(s, 3H); of 4.45(d, 2H); of 5.45(t, 1H); 6,70(s, 1H); 6,98(s, 1H)

To a solution of 2-chloro-4-hydroxymethyl-6-methoxypyridine (0.9 g, 5.2 mmol) in toluene (10 ml) was added thionyl chloride (1.0 ml) and the mixture was stirred at ambient temperature

environment for 1 hour. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain 2-chloro-4-chloromethyl-6-methoxyphenylalanine (0.88 g, 74%).

1H NMR spectrum: (d6) 3,85(s, 3H); 4,70(s, 2H); 6.90 to(s, 1H); to 7.15(s, 1H)

A mixture of 7-hydroxy-6-methoxy-4-phenoxybenzamide (1.1 g, 4.1 mmol) (obtained as described for the starting material in example 13), 2-chloro-4-chloromethyl-6-methoxyphenylalanine (0.88 g, 3.9 mmol) and potassium carbonate (2.0 g, 14 mmol) in DMF (20 ml) was heated at 80oC for 1 hour. The mixture was allowed to cool and the precipitated precipitated product was collected by filtration, washed with water and dried to obtain 7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxybenzamide (1,38 g, 79%).

1H NMR spectrum: (Dl3) of 3.95(s, 3H); Android 4.04(s, 3H); 5,20(s, 2H); 6,70(s, 1H); to 6.95(s, 1H); 7.18 in(m, 3H); 7,30(m, 1H); 7,40(t, 2H); 7,58(s, 1H); charged 8.52(s, 1H)

MC-ESI: 424 [MN]+< / BR>
A mixture of 7-((2-chloro-6-methoxy-4-pyridyl)Hladilnika for 3 hours. Allowing the mixture to cool, and drove her to pH 6-7 with aqueous solution of ammonia. The precipitate was collected by filtration, washed with water and dried, resulting in the crude 7-((6-chloro-2-oxo-1,2-dihydropyridin-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (190 mg, 60%).

Example 62

To a solution of 4-hydroxymethyl-2-methoxypyridine (0,59 g, 4.2 mmol) in toluene (10 ml) was added thionyl chloride (0.6 ml) and the mixture was stirred at ambient temperature for 1.5 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain crude 4-chloromethyl-2-methoxyphenylalanine (0.50 g, 2.6 mmol) which was used immediately. This product was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (420 mg, 1.3 mmol) (obtained as described for the starting material in example 24) and potassium carbonate (1.0 g, 7 mmol) in DMF (8 ml) and the resulting mixture was heated at 75oC for 2 hours. Allowing the mixture to cool, washed with water and precipitated precipitated solid substance was collected by filtration, washed with water and dried, resulting in 4-(4-chloro-2-foronline)-7-((2-methoxy-4-pyridyl)methoxy)-6-methoxyquinazoline (140 mg, 25%).


MC-ESI: 441 [MN]+< / BR>
Elemental analysis:

C22H18N4O3ClF

found C to 59.9 H 4,1 N 12,4

requires C to 59.9 H 4,1 N 12,7%

The original material was prepared as follows:

A mixture of ethyl 2-hydroxypyridine-4-carboxylate (1.0 g, 6 mmol) (Chem. Abc. 1957, s), under the conditions (1 ml) and silver carbonate (I) (1.64 g) in toluene (20 ml) was heated under reflux for 2 hours. Gave the mixture to cool and then remove insoluble materials by filtration through diatomaceous earth, and then layer was washed with ethyl acetate. The filtrate was washed with water, dried (MgSO4) and then the solvent evaporated to obtain ethyl 2-methoxypyridine-4-carboxylate (0,93 g, 86%) as a yellow oil.

1H NMR spectrum: (Dl3) of 1.30(t, 3H); 3,90(s, 3H); 4,30(q, 2H); from 7.24(s, 1H); to 7.35(d, 1H); to 8.20(d, 1H)

MC-ESI: 182 [MN]+< / BR>
A mixture of ethyl 2-methoxypyridine-4-carboxylate (0,93 g, 5 mmol) in ether (5 ml) was added to sociallyengaged (0.3 g, 8 mmol) in ether (10 ml), cooled to 5oC, and the mixture was stirred for 2 hours. Was added water, filtered through a mixture of diatomaceous earth and washed this layer with ethyl acetate. The filtrate was extracted with ethyl acetate and the joint shall kemetyl-2-methoxypyridine (0.64 g, 89%) as a yellow oil.

1H NMR spectrum: (Dl3) 3,86(s, 3H); to 4.62(s, 2H); of 6.65(s, 1H); 6,76(d, 1H); with 8.05(d, 1H)

MC-ESI: 140 [MN]+< / BR>
Example 63

To a solution of 4-hydroxymethyl-2-methylpyridine (240 mg, 1.9 mmol) in toluene (10 ml) was added thionyl chloride (0.3 ml) and the mixture was stirred at ambient temperature for 2 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain crude 4-chloromethyl-2-empiricallyderived, which was used immediately. This product was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (510 mg, 1.6 mmol) (obtained as described for the starting material in example 24) and potassium carbonate (1.4 g, 10 mmol) in DMF (8 ml) for 90 hours. The mixture was diluted with water and precipitated precipitated solid substance was collected by filtration, washed with water and dried, resulting in 4-(4-chloro-2-foronline)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)hinzelin (290 mg, 43%), a sample of which was recrystallized from a mixture of ethyl acetate-hexane.

So pl. 221-224oWITH

1H NMR spectrum: (Dl3) of 2.50(s, 3H); 4,00(s, 3H); 5,20(s, 2H); 6,98(s, 1H); to 7.15(d, 1H); to 7.2(m, 4H); to 8.45(m, 2H); at 8.60(s, 1H)

Elemental anal the second material was prepared as follows:

To 2-chloro-6-methylpyridin-4-carboxylic acid (1.7 g, 10 mmol) in methylene chloride (30 ml) were added oxalicacid (1.9 g, 15 mmol) and the mixture was stirred for 2 hours. Evaporated volatile substances and to the residue was added methanol (20 ml). The mixture was stirred 1 hour and then evaporated volatiles to obtain methyl 2-chloro-6-methylpyridin-4-carboxylate (1.85 g, 100%) as not quite white solid.

1H NMR spectrum (CDCl3) to 2.55(s, 3H); 3,90(s, 3H); at 7.55(s, 1H); of 7.60 (s, 1H)

MC-ESI: 186 [MN]+< / BR>
A mixture of methyl 2-chloro-6-methylpyridin-4-carboxylate (1.8 g, 10 mmol) and 10% palladium on charcoal (200 mg) in methanol (100 ml) was stirred under hydrogen at a pressure of 5 atmospheres. The catalyst was filtered and from the filtrate evaporated volatile substances. The residue was treated with 10% aqueous sodium hydroxide solution and was extracted with ether (3 x 30 ml). The combined extracts were dried (gSO4) and the solvent evaporated to obtain methyl 2-methylpyridin-4-carboxylate (800 mg, 53%) as oil.

A solution of methyl 2-methylpyridin-4-carboxylate (800 mg, 6 mmol) in ether (5 ml) was added to sociallyengaged (340 mg, 9 mmol) in ether (10 ml), cooled to 5oC, and the mixture was stirred for 2 hours. Was added water, filter the combined extracts were washed with brine, dried (MgSO4) and then the solvent evaporated to obtain 4-hydroxymethyl-2-methylpyridine (240 mg, 38%) as a yellow oil.

1H NMR spectrum: (Dl3) 2,48(s, 3H); 5,44(s, 2H); 7,00(d, 1H); 7,10(s, 1H); to 8.40(d, 1H)

MC-ESI: 124 [MN]+< / BR>
Example 64

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (350 mg, 0.9 mmol) (obtained as described for the starting material in example 24), 2-(2-chloroethylthio)-1-methylimidazolidine (203 mg, 0.95 mmol) and potassium carbonate (303 mg, 2.2 mmol) in NPM (20 ml) was heated at 90oC for 2 hours. Allowing the mixture to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (gSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (100/0 to 90/10) to give 4-(4-chloro-2-foronline)-6-methoxy-7-(1 Mei-2-ylthio)ethoxy)hintline (75 mg, 17%) as a solid.

MC-ESI: 460 [MN]+< / BR>
1H NMR spectrum: (d6) of 3.46(s, 3H); 3,93(s, 3H); 4,39-of 4.44(m, 4H); 7,13(DD, 2H); 7.23 percent(s, 1H); 7,31(DD, 1H); 7,49-of 7.60(m, 2H); 7,79(s, 1H); of 8.37(s, 1H); 9,51(s, 1H)

Elemental analysis:

C21H19N5O2ClFS1H2O

found C 52,8 H 4,0 N 14,3

is idazole (3,45 g, 30 mmol) in 2M aqueous sodium hydroxide solution (30 ml) was added 2-chloroethanol (3 g, 37 mmol) and the mixture was heated at 100oC for 2 hours. Allowing the mixture to cool, extracted it with ethyl acetate. The combined extracts were dried (MgSO4) and then the solvent evaporated to obtain 2-(2-hydroxyethylthio)-1-methylimidazole (3,9 g, 82%).

1H NMR spectrum: (d6) totaling 3.04(t, 2H); 3,30(s, 3H); of 3.54(t, 2H); 5,00(s, 1H); 6.87 in(s, 1H); 7,20(s, 1H)

To a solution of 2-(2-hydroxyethylthio)-1-methylimidazole (1,81 g, 11 mmol) in trichloromethane (20 ml) at 5oWith was slowly added thionyl chloride (1,41 ml, 19 mmol). The mixture was stirred 1 hour at 5oAnd then 3 hours at ambient temperature. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, resulting in 2-(chloroethylthio)-1-methylimidazolidine (1.5 g, 77%).

1H NMR spectrum: (d6) to 3.58(t, 2H); of 3.78 (s, 3H); of 3.80(t, 2H); for 7.78(d, 1H); 7,83(d, 1H)

Example 65

To a solution of 1-(3-hydroxypropyl)-1,2-dihydro-2-pyridone (770 mg, 5 mmol) in dichloromethane (15 ml) and 5oWith added thionyl chloride (0,55 ml, 7.5 mmol). The mixture was stirred at 5oC for 1 hour and then at ambient temperature for 2 hours. Evaporated volatiles and eliprodil)-1,2-dihydro-2-pyridone (500 mg), used immediately. Part of this product (206 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (obtained as described for the starting material in example 24) and potassium carbonate (303 mg, 2.2 mmol) in NPM (20 ml) and the reaction mixture was heated at 90oC for 2 hours. Allowing the mixture to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 95/5) and the result obtained 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)hinzelin (194 mg, 50%).

So pl. 216-218oWITH

1H NMR spectrum: (d6) to 2.18(m, 2H); 3,90(s, 3H); 4,06(t, 2H); 4,15(t, 2H); 6,18(t, 1H); 6,38(d, 1H); to 7.15(s, 1H); 7,30-7,42(m, 2H); 7,50-to 7.64(m, 3H); 7,79(s, 1H); 8.34 per(s, 3H); 9,50(s, 1H)

MC-ESI: 455 [MN]+< / BR>
Elemental analysis:

C23H20N4O3ClF0,5H2O

found C 59,4 H 4,6 N 12,1

requires C 59,6 H 4,6 N 12,1%

The original material was prepared as follows:

To a solution of 2-hydroxypyridine (2.35 g, 24 mmol) in DMF (50 ml) was added sodium hydride (1.31 g of a 50% suspension in m is ol) (J. Chem. Soc. 1963, 3440), and the mixture was heated at 100oC for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 97/3) and the result obtained 1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.6 g, 30%).

1H NMR spectrum: (d6) 1,39 is 1.75(m, 6N); of 1.85(m, 2H); 3,24-of 3.42(m, 3H); to 3.58-3,74(m, 2H); 3,90(m, 2H); to 4.52(s, 1H); 6,18(t, 1H); 6,35(d, 1H); 7,38(DD, 1H); of 7.60(DD, 1H)

MC-ESI: 238 [MN]+< / BR>
and 2-(3-(2-tetrahydropyranyloxy)propyloxy)pyridine (1,43 g, 27%).

1H NMR spectrum: (d6) 1,38 is 1.70(m, 6N); 1,90(m, 2H); 3,30(m, 3H); 3,34-to 3.50(m, 2H); 3,62-of 3.80(m, 2H); 4,30(t, 2H); to 4.52 (s, 1H); is 6.78(d, 1H); 6,92(DD, 1H); to 7.64(m, 1H); 8,15(DD, 1H)

MC-ESI: 238 [MN]+< / BR>
A solution of 1-(3-(2-tetrahydropyranyloxy)propyl)-1,2-dihydro-2-pyridone (1.0 g, 4.5 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50oC for 4 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, resulting in 1-(3-hydroxypropyl)-1,2-dihydro-2-PI is); to 3.38(m, 2H); 3,90(m, 2H); 4,58(s, 1H); 6,18(DD, 1H); 6,38(d, 1H); 7,38(m, 1H); of 7.60(DD, 1H)

Example 66

To a solution of 2-(3-hydroxypropyl)-1-methylimidazole (1,25 g, 7,3 mmol) in dichloromethane (25 ml) and 5oWith added thionyl chloride (0,80 ml, 11 mmol). The mixture was stirred at 5oC for 1 hour and then at ambient temperature for 2 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain crude 2-(3-chlorpropyl)-1-methylimidazolidine (1.0 g) which was used immediately. Part of this product (226 mg, 1.0 mmol) was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (obtained as described for the starting material in example 24) and potassium carbonate (303 mg, 2.2 mmol) in NPM (20 ml) and the reaction mixture was heated at 90oC for 2 hours. Allowing the mixture to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 95/5) and the result obtained 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(1-Mei-2-ylthio)prop; ,94(s, 3H); 4,10(m, 4H); 7,10(d, 2H); 7,30(DD, 1H); 7,50-of 7.60(m, 2H); 7,79(s, 1H); 8.34 per(s, 1H); 9,50(s, 1H)

MC-ESI: 474 [MH]+< / BR>
Elemental analysis:

C22H21N5O2ClFS2,5H2O

found C 50,9 H 4,8 N 13,2

requires C 50,9 H 5,1 N 13,5%

The original material was prepared as follows:

To a solution of 2-mercapto-1-methylimidazole (of 2.26 g, 19 mmol) in DMF (100 ml) was added sodium hydride (0.95 g of a 50% suspension in mineral oil, 20 mmol) and the mixture was stirred for 30 minutes. Was added 2-(3-bromopropane)tetrahydropyran (5.0 g, to 22.5 mmol) (J. Chem. Soc. 1963, 3440), and the mixture was heated at 100oC for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 97/3) and the result obtained 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole (2.5 g, 55%).

1H NMR spectrum: (d6) 1,38-1,72(m, 6N); of 1.80(m, 2H); 3,0(t, 2H); 3,36-of 3.43(m, 2H); to 3.58(s, 3H); 3,62-of 3.78(m, 2H); 4,50 (s, 1H); 6.90 to (s, 1H); 7,21 (s, 1H)

A solution of 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)-1-imidazo the Wali volatiles and the residue was subjected to azeotropic distillation with toluene, resulting in 2-(3-hydroxypropyl)-1-Mei (1.3 g, 100%) as not quite white solid.

1H NMR spectrum: (d) 1,68(m, 2H); 2,98(t, 2H); 3.42 points(t, 2H); of 3.57(s, 3H); 4,10(s, 1H); 6.90 to(d, 1H); then 7.20(d, 1H)

Example 67

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (obtained as described for the starting material in example 24), 4-(3-chloropropoxy)pyridinecarboxamide (206 mg, 1.0 mmol) and potassium carbonate (303 mg, 2.2 mmol) in NPM (20 ml) was heated at 90oC for 2 hours. Allowing the mixture to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 95/5) to give 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyloxy)propoxy)hintline (257 mg, 56%).

So pl. 138-140oWITH

1H NMR spectrum: (d6) to 2.25(m, 2H); to 3.92(s, 3H); 4,24(t, 2H); 4,30(t, 2H); 6,98(DD, 2H); 7,20(s, 1H); 7,31(DD, 1H); at 7.55(DD, 2H); 7,79(s, 1H); 8,32 is 8.38(m, 3H); 9,50(s, 1H)

MC-ESI: 455 [MH]+< / BR>
Elemental analysis:

C23H20N4O3ClF1H2O

found C 58,4 H 4,7 11,8 N

requires C 58,4 H 4,7 11,8 N%

The original m is rockside sodium (4,67 g, 195 mmol) in DMSO (80 ml) was heated at 100oWith in 24 hours. A large part of the solvent is evaporated and the residue was diluted with ice water. The aqueous mixture was extracted with ethyl acetate, the combined extracts were dried (MgSO4) and then the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 97/3) to obtain 4-(3-hydroxypropoxy)pyridine (3.2 g, 45%).

To a solution of 4-(3-hydroxypropoxy)pyridine (3.1 g, 20 mmol) in trichloromethane (40 ml) at 5oWith was slowly added thionyl chloride (2.2 ml, 30 mmol). The mixture was stirred 1 hour at 5oAnd then 2 hours at ambient temperature. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum, resulting in 4-(3-chloropropoxy)piridinkarboksamid (3,81 g, 91%) as a solid.

1H NMR spectrum: (d6) 2,22(m, 2H); of 3.80(t, 2H); was 4.42(t, 2H); at 7.55(d, 2H); 8,72(d, 2H)

MC-ESI: 172 [MN]+< / BR>
Example 68

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (obtained as described for the starting material in example 24), 4-(2-chloroethylthio)pyridinecarboxamide (252 mg, 1.2 mmol) and potassium carbonate (454 mg, is ovali with ethyl acetate. The combined extracts were washed with water and dried (gSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of ethyl acetate-methanol (100/0 to 75/25) to give 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)hintline (13 mg, 3%).

So pl. 182-186oWITH

1H NMR spectrum: (d6) to 3.58 (t, 2H); 3,90(s, 3H); however, 4.40(t, 2H); 7,20(s, 1H); to 7.32(d, 1H); 7,40(d, 2H); 7,50-of 7.60(m, 2H); 7,80 (s, 1H); 8,32(s, 1H); scored 8.38(d, 2H); to 9.57(s, 1H)

MC-ESI: 457 [MN]+< / BR>
The original material was prepared as follows:

To a solution of 4-mercaptopyridine (2,34 g, 21 mmol) in DMF (75 ml) was added sodium hydride (890 mg, 50% suspension in mineral oil, 19 mmol) and the mixture was stirred for 30 minutes. Was added 2-(2-bromoethoxy)tetrahydropyran (4.0 g, 19 mmol) (J. Am. Chem. Soc. 1948, 70, 4187) and the mixture was heated at 100oC for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 97/3) and the result obtained 4-(2-Tetra); to 3.58-3,82(m, 3H); 4,60(s, 1H); 7,30(DD, 2H); with 8.33(DD, 2H)

A solution of 4-(2-tetrahydropyran-2-yloxy)ethylthio)pyridine (2,73 g, 11 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50oC for 4 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, resulting in 4-(2-hydroxyethylthio)pyridine (1.39 g, 79%) as not quite white solid.

1H NMR spectrum: (d6) 3,10 (t, 2H); of 3.60(q, 2H); 5,00 (t, 1H); 7,22(d, 2H); 8,30(d, 2H)

To a solution of 4-(2-hydroxyethylthio)pyridine (1.39 g, 9.0 mmol) in trichloromethane (25 ml) and 5oWith was slowly added thionyl chloride (0,98 ml, 13.5 mmol). The mixture was stirred 1 hour at 5oAnd then 2 hours at ambient temperature. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain 4-(2-chloroethylthio)pyridinecarboxamide (500 mg, 26%) as a solid.

1H NMR spectrum: (d6) of 3.65(t, 2H); 3,90(m, 2H); of 7.90(d, 2H); at 8.60(d, 2H)

MC-ESI: 174 [MN]+< / BR>
Example 69

A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol) (obtained as described for the starting material in example 24), 3-(2-chloroethoxy)pyridinecarboxamide (234 mg, the, was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 95/5) to give 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)hintline (95 mg, 20%).

So pl. 188-190oWITH

1H NMR spectrum: (d6) 3,90(s, 3H); of 4.45(m, 4H); from 7.24(s, 1H); 7.18 in(DD, 1H); 7,42-of 7.60(m, 3H); 7,80(s, 1H); to 8.20(d, 1H); 8,35(c, 2H); 9,50(s, 1H)

MC-ESI: 441 [MN]+< / BR>
Elemental analysis:

C22H18N4O3ClF2H2O

found C 55,0 H 3,9 11,8 N

requires C 55,4 H 4,6 N 11,7%

The original material was prepared as follows:

To a solution of 3-hydroxypyridine (2,01 g, 21 mmol) in DMF (50 ml) was added sodium hydride (1,02 g of a 50% suspension in mineral oil, 42 mmol) and the mixture was stirred for 30 minutes. Was added 2-(2-bromoethoxy)tetrahydropyran (4.0 g, 19 mmol) (J. Am. Chem. Soc. 1948, 70, 4187) and the mixture was heated at 100oC for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried (gSO4), then the d-methanol (100/0 to 97/3) and the result obtained 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (2.28 g, 48%).

1H NMR spectrum: (d6) 1,38-of 1.65(m, 6N); 3,40(m, 1H); 3,65-with 3.79(m, 2H); 3,85-3,95(m, 1H); 4,20(t, 2H); to 4.62(s, 1H); 7,30(DD, 1H); 7,39(DD, 1H); 8,15(d, 1H); of 8.28(d, 1H)

MC-ESI: 224 [MN]+< / BR>
A solution of 3-(2-tetrahydropyran-2-yloxy)ethoxy)pyridine (1.54 g, 7 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50oC for 4 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, resulting in 3-(2-hydroxyethoxy)pyridine (820 mg, 86%) as not quite white solid.

1H NMR spectrum: (d6) 3,70(t, 2H); of 4.05(t, 2H); 4,85(s, 1H); to 7.25(DD, 1H); 7,37(DD, 1H); 8,10(d, 1H); 8,24(d, 1H)

MC-ESI: 140 [MN]+< / BR>
To a solution of 3-(2-hydroxyethoxy)pyridine (1.13 g, 8.0 mmol) in trichloromethane (20 ml) at 5oWith was slowly added thionyl chloride (0,89 ml, 12 mmol). The mixture was stirred at 5oC for 1 hour and then at ambient temperature for 2 hours. Evaporated volatiles and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain 3-(2-chloroethoxy)pyridinecarboxamide (300 mg, 19%) as a solid.

1H NMR spectrum: (d6) to 3.99(t, 2H); was 4.42(t, 2H); of 7.82(DD, 1H); with 8.05(DD, 1H); 8,42(d, 1H); to 8.62(s, 1H)

Example 70

CI-4-methylaniline (170 mg, 1.3 mmol) (obtained as described for the starting material in example 13) and the mixture was stirred at 120oC for 2 hours. Gave the mixture to cool and the precipitate was collected by filtration, washed with isopropanol and ether, and dried under vacuum at 70oWith obtaining 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylaniline)chinasingapore (331 mg, 80%).

1H NMR spectrum: (d6) of 2.16(s, 3H); are 5.36(s, 2H); to 6.88(d, 1H); for 7.12(d, 1H); 7.3 to the 7.65(m, 7H); 8,68(d, 1H); 8,82(s, 1H); 9,68 (s, 1H); 11.4 in (s, 1H)

MC-ESI: 376 [MN]+< / BR>
Elemental analysis:

C22H18N3O2F1HCl

found C 63,7 H 4,8 10,0 N

requires C 64,2 H 4,7 N 10,2%

The original material was prepared as follows:

To benzyl alcohol (10 ml, 96 mmol) was added sodium (368 mg, 16 mmol) and the mixture was heated at 148oC for 30 minutes. Was added 7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol) (J. Chem. Soc. Section b, 1967, 449) and the mixture was kept at 148oWith in 24 hours. Allowing the reaction mixture to cool, poured in water (170 ml) and the aqueous mixture was brought to pH 3 with concentrated chloroethanol acid. The precipitate was collected by filtration, washed with water and ether, and dried under vacuum to obtain 7-benzyloxy-3,4-dihydroquinazolin-4-she B>; CF3COOD) 5,32(s, 2H); to 7.25(d, 1H); 7,32-7,52(m, 6N); to 8.12(d, 1H); 8,99(s, 1H)

MC-ESI: 252 [MN]+< / BR>
Elemental analysis:

C15H12N2O20,04 H2O

found 71,4 C H a 4.9 N 10,7

requires C H 71,2 4,8 N 11,1%

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-she (800 mg, 3,17 mmol) and DMF (100 μl) in thionyl chloride (20 ml, 0.27 mmol) was heated under reflux for 3 hours. The excess thionyl chloride was removed by evaporation and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain 7-benzyloxy-4-chlorinatedsewage (835 mg, 86%) as a cream solid color.

So pl. 131-132oWITH

1H NMR spectrum: (d6; CF3D) 5,32(s, 2H); 7,29(d, 1H); 7,34-7,52(m, 6N); to 8.12(d, 1H); 9,03(s, 1H)

MC-ESI: 270 [MN]+< / BR>
Example 71

Using a similar procedure to that described in example 70, 7-benzyloxy-4-chlorinecontaining (307 mg, 1 mmol) (obtained as described for the starting material in example 70) was treated with 4-chloro-2-fluoro-5-hydroxyimino (193 mg, 1.2 mmol) (EP 061741 A2) to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)chinasingapore (407 mg, 94%).

So pl. 253-257oWITH

1H NMR spectrum: (d6) lower than the 5.37 (s, 2H); 7 Elemental analysis:

C21H15N3O2ClF0,3H2O1HCl

found C 57,8 H 3,8 N 9,7

requires C 57,6 H 3,8 N 9,6%

Example 72

Using a similar procedure to that described in example 36, 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxybenzonitrile (224 mg, 0.6 mmol) (obtained as described for the starting material in example 22) was treated with 4-methyl bromide-1,2-differentlal (149 mg, to 0.72 mmol) to obtain 7-(3,4-deferasirox)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxybenzonitrile (90 mg, 31%).

1H NMR spectrum: (d6) 2,17(s, 3H); 4.0 a(s, 3H); 5,33(s, 2H); to 6.88(d, 1H); 7,11(d, 1H); 7,38(s, 1H); 7,41(m, 1H); at 7.55(m, 1H); a 7.62(m, 1H); 8,17(s, 1H); is 8.75(s, 1H); 9,68(s, 1H); of 11.15(s, 1H)

MC-ESI: 442 [MN]+< / BR>
Elemental analysis:

C23H18N3O3F30,9HCl0,08 isopropanol

found C 58,0 H 4,3 N 8,7

requires C 58,3 H 4,1 N 8,8%

Example 73

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-6-methoxy-7-((1-Mei-2-yl)methoxy)hintline (207 mg, 0.31 mmol) in THF (5 ml), cooled at 5oWith, were added tetrabutylammonium (563 μl of 1M solution in THF, of 0.62 mmol) and the mixture was stirred for 1 hour at ambient temperature. Added water and evaporated volatile veseel (0.3 ml). The solvent evaporated and the solid residue resuspendable in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((1-Mei-2-yl)methoxy)chinasingapore (99 mg, 63%).

1H NMR spectrum: (d6) 3,93(s, 3H); 4,01(s, 3H); 5,67(s, 2H); 7,16(d, 1H); 7,52(d, 1H); 7,58 (s, 1H); of 7.70 (s, 1H); for 7.78(s, 1H); 8,31(s, 1H); of 8.8(s, 1H); of 10.58(s, 1H); 11,35(sh.s, 1H)

MC-ESI: 430 [MN]+< / BR>
Elemental analysis:

C20H17N5O3ClF1,4H2O2HCl

found C 45,8 H 4,3 N 12,9

requires C 45,5 H 4.2 N 13,3%

The original material was prepared as follows:

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-7-hydroxy-6-methoxyquinazoline (400 mg, 0.7 mmol) (obtained as described for the starting material in example 33), 2-hydroxymethyl-1-methylimidazole (82 mg, 0.83 mmol) (J. Chem. Soc. 1927, 3128-3136) and triphenylphosphine (365 mg, 1.4 mmol) in methylene chloride (12 ml), cooled at 0oC, was added dropwise diethylazodicarboxylate (219 μl, 1.4 mmol). The mixture was stirred for 1 hour at ambient temperature and was added 2-hydroxy-methyl-1-Mei (68 mg, 0.69 mmol), triphenylphosphine (91 mg, 0.34 mmol) and diethylazodicarboxylate (54 μl, 0.34 mmol)column chromatography with elution with a mixture of methylene chloride-methanol (94/6) and the result obtained 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-6-methoxy-7-((1-Mei-2-yl)methoxy)hinzelin (116 mg, 25%).

1H NMR spectrum (CDCl3) to 1.16 (s, 3H); of 3.75(s, 3H); 3,93(s, 3H); 5,28 (s, 2H); at 6.84 (s, 1H); 6,91(s, 1H); 7,02(s, 1H); 7,17(d, 1H); 7,32-of 7.48(m, 8H); 7,78(2D, 4H); 8,08(s, 1H); 8,18(d, 1H)

Example 74

A mixture of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxybenzonitrile (400 mg, 0.98 mmol), 2-chloromethyl-1-methylimidazolidine (210 mg, 1.25 mmol), potassium carbonate (580 mg, 4.2 mol) and potassium iodide (17 mg, 0.1 mmol) in DMF (20 ml) was stirred at 65oWith over 4.5 hours and then at ambient temperature for 17 hours. The solvent evaporated and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated from it solvent. The solid residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (97/3), which gave a yellow solid (258 g). This solid was dissolved in methanol (5 ml) was added 1M aqueous sodium hydroxide solution (660 μl, 0.66 mmol). The mixture was stirred for 15 minutes, water was added and adjust the mixture to pH 7 with concentrated chloroethanol acid. The aqueous mixture was extracted with ethyl acetate and the combined organic extract was washed with water and brine and dried (MgSO4

1H NMR spectrum: (d6) of 2.16(s, 3H); to 3.92(s, 3H); 5,71(s, 2H); 6.90 to(d, 1H); and 7.1(d, 1H); 7,52(d, 1H); to 7.64(d, 1H); 7,71(s, 1H); for 7.78(s, 1H); 8,77(d, 1H); 8,82(s, 1H); 9,7(sh.s, 1H); of 11.45(sh.s, 1H)

MC-ESI: 380 [MN]+< / BR>
Elemental analysis:

C20H18N5O2F0,9H2O1,8HCl

found C 52,2 H 5,0 N 15,1

requires C 52,1 H 4,7 N 15,2%

The original material was prepared as follows:

To benzyl alcohol (10 ml, 96 mmol) was added sodium (368 mg, 16 mmol) and the mixture was heated to 148oC for 30 minutes. Was added 7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol) (J. Chem. Soc., section b, 1967, 449) and the mixture was kept at 148oWith in 24 hours. Allowing the reaction mixture to cool, poured in water (170 ml) and the aqueous mixture was brought to pH 3 with concentrated chloroethanol acid. The precipitate was collected by filtration, washed with water and then with ether, and vesuva.

So pl. 267-269oWITH

1H NMR spectrum: (d6; CF3OD) 5,32(s, 2H); to 7.25(d, 1H); 7,32-7,52(m, 6N); to 8.12(d, 1H); 8,99(s, 1H)

MC-ESI: 252 [MN]+< / BR>
Elemental analysis:

C15H12N2O20,04 H2O

found 71,4 C H a 4.9 N 10,7

requires C H 71,2 4,8 N 11,1%

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-she (800 mg, 3,17 mmol) and DMF (100 μl) in thionyl chloride (20 ml, 0.27 mmol) was heated under reflux for 3 hours. The excess thionyl chloride was removed by evaporation and the residue was subjected to azeotropic distillation with toluene, and dried under vacuum to obtain 7-benzyloxy-4-chlorinate of digidrohlorid (835 mg, 86%) as a cream solid color.

So pl. 131-132oWITH

1H NMR spectrum: (d6; CF3D) 5,32(s, 2H); 7,29(d, 1H); 7,34-7,52(m, 6N); to 8.12(d, 1H); 9,03(s, 1H)

MC-ESI: 270 [MN]+< / BR>
To a solution of 7-benzyloxy-4-chlorinatedsewage (1 g, 3.7 mmol) in pentanol (15 ml) at 120oWith added 2-fluoro-5-methoxycarbonylamino-4-methylaniline (883 mg, 4.4 mmol) (obtained as described for the starting material in example 12), and the mixture was heated under reflux for 4 hours. Gave the mixture to cool and the precipitate was collected by filtration, washed from the-methylaniline)chinasingapore (1.65 g, 97%) as a cream solid color.

So pl. 219-220oWITH

1H NMR spectrum: (d6) 2,22(s, 3H); 3,86(s, 3H); lower than the 5.37(s, 2H); 7,30-of 7.60(m, N); at 8.60(d, 1H); 8,80(s, 1H); and 11.2(s, 1H)

MC-ESI: 434 [MN]+< / BR>
Elemental analysis:

C24H20N3O4F1HCl0,5H2O

found C 60,1 H 4,9 8,5 N

requires C 60,2 H 4,6 N 8,8%

7-Benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)chinasingapore (1,53 g, 3.25 mmol) and 10% palladium on charcoal (180 mg) in a mixture of methanol (75 ml), DMF (6 ml) and trichloromethane (30 ml) was stirred under hydrogen at a pressure of 1.5 atmospheres within 45 minutes. The catalyst was filtered through diatomaceous earth and the filtrate evaporated solvent. The residue is triturated with ether, collected by filtration and dried under vacuum to obtain 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxybenzonitrile (1,23 g, 84%) as a solid orange color.

So pl. 205-210oWITH

1H NMR spectrum: (d6) 2,22(s, 3H); 3,85(s, 3H); from 7.24(d, 1H); to 7.35(DD, 1H); 7,42(d, 1H); was 7.45(d, 1H); 8,58(d, 1H); 8,81(s, 1H); 11,40(s, 1H); 11,76(s, 1H)

MC-ESI: 344 [MN]+< / BR>
Example 75

To a suspension of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (367 mg, 1.4 mmol) and 2-(1,2,4-triazole-1-yl)ethanol (95 mg, 0.84 mmol) (Ann. Pharm. Fr. 1977, 35, 503-508) in methylene chloride (5 ml) was added dropwise diethylazodicarboxylate (244 mg, 1.4 mmol). The mixture was stirred for 1 hour at ambient temperature and in addition was added triphenylphosphine (184 mg, 0.7 mmol), 2-(1,2,4-triazole-1-yl)ethanol (63 mg, 0,56 mmol) and diethylazodicarboxylate (122 mg, 0.7 mmol). The mixture was stirred for further 2.5 hours and the solvent evaporated. The residue was dissolved in methanol (5 ml) was added 2M aqueous sodium hydroxide solution (2 ml). The mixture was stirred 20 minutes and was distributed between ether and water. The aqueous layer was acidified using 2M chloroethanol acid to pH 7 and the precipitate was collected by filtration, washed with water and dried under vacuum. The obtained solid substance was dissolved in a mixture of methylene chloride-methanol was added 5M solution of hydrogen chloride in isopropanol (0.5 ml). Evaporated volatile substances and the solid is again suspended in ether, was filtered, washed with ether, and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-(1,2,4-triazole-1-yl)ethoxy)chinasingapore (180 mg, 56%).

1H NMR spectrum: (d6) of 2.16(s, 3H); of 3.97(s, 3H); 4,59(t, 2H); 4,74 (t, 2H); to 6.9(d, 1H); 7,10(d, 1H); 7,37 (s, 1H); 8,03(s, 1H); 19
N6O3F0,1H2O1,2HCl

found 53,2 C H 4,8 N 18,4

requires C 52,7 H 4.5 N 18,4%

Example 76

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-6-methoxy-7-((3-thienyl)methoxy)hintline (224 mg, 0.33 mmol) in THF (5 ml), cooled at 5oWith, were added tetrabutylammonium (608 μl of 1M solution in THF, 0.67 mmol). After stirring for 1 hour at ambient temperature was added water. Evaporated THF. The precipitate was filtered and was dried by azeotropic distillation with ethanol. The solid was dissolved in a mixture of methylene chloride-methanol was added 5M solution chloroethanol acid in isopropanol. Evaporated volatile substances. The residue is suspended in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((3-thienyl)methoxy)chinasingapore (132 mg, 85%).

So pl. 277-281o< / BR>
1H NMR spectrum: (d6) to 3.99(s, 3H); of 5.34(s, 2H); to 7.15(d, 1H); 7,26(d, 1H); 7,49 (s, 1H); 7,53(d, 1H); to 7.61(m, 1H); of 7.75(s, 1H); by 8.22(s, 1H); of 8.8(s, 1H); 10,59(s, 1H); 11,38(sh.s, 1H)

MC-ESI: 432 [MN]+< / BR>
Elemental analysis:

C20H15N3O3ClFS0,1H2O1HCl

found C 51,0 H 3,5 8,9 N

requires C 51,1 H 3,5 8,9 N%

iLine)-7-hydroxy-6-methoxyquinazoline (400 mg, 0.7 mmol) (obtained as described for the starting material in example 33), 3-thiophenemethyl (119 mg, 1 mmol) and triphenylphosphine (456 mg, 1.7 mmol) in methylene chloride (12 ml), cooled at 0oC, was added dropwise diethylazodicarboxylate (274 μl, 1.7 mmol). The mixture was stirred 2 hours at ambient temperature, the solvent evaporated and the residue was purified by column chromatography with elution with a mixture of methylene chloride-ether (95/5). The purified product was rubbed with a mixture of petroleum ether-ethyl acetate (8/2) and the solid product was filtered, washed with ether, and dried under vacuum, resulting in 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-6-methoxy-7-((3-thienyl)methoxy)hinzelin (223 mg, 47%).

1H NMR spectrum: (d6) 1,09(s, N); 3,85(s, 3H); 5,23(s, 2H);? 7.04 baby mortality(d, 1H); 7,21(d, 1H); to 7.25(s, 1H); of 7.4-7.5(m, 6N); 7,58(m, 2H); 7,62 to 7.75(m, 6N); and 8.1(s, 1H); which 9.22(sh.s, 1H)

Example 77

To a solution of 4-(4-chloro-5-diphenyl-tert-butylsilane-2-foronline)-7-hydroxy-6-methoxyquinazoline (400 mg, 0.7 mmol) (obtained as described for the starting material in example 33), triphenylphosphine (456 mg, 1.7 mmol) and 2-(4-pyridyl)ethanol (128 mg, 1 mmol) (Zhur. Obshchei. Khim. 1958, 28, pp. 103 -- 110) in methylene chloride (12 ml), cooled at 0oWith, were added to Caprivi solvent. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (97/3) and as a result got a white solid (416 mg). A portion of this solid (390 mg) was dissolved in THF (6 ml), the solution was cooled to 0oAnd, adding tetrabutylammonium (1.1 ml of 1M solution in THF, 1.1 mmol), the mixture was stirred for 2 hours at ambient temperature. Was added water, the solvent evaporated and the precipitate was collected by filtration. The solid was dissolved in a mixture of methylene chloride-methanol was added 5M solution of hydrogen chloride in isopropanol (0.5 ml). Evaporated volatile substances and the solid is again suspended in isopropanol, collected by filtration, washed with isopropanol and ether, and dried under vacuum to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(4-pyridyl) ethoxy)chinasingapore (123 mg, 42%).

1H NMR spectrum: (d6; D3D) to 3.49 (t, 2H); 3,99 (s, 3H); 4,6 (t, 2H); 7,16(d, 1H); 7,41(s, 1H); 7,51(d, 1H); 8,05(sh.s, 2H); 8,19(s, 1H); 8,84(s, 1H); 8,86(sh.s, 2H)

MC-ESI: 441 [MN]+< / BR>
Elemental analysis:

C22H18N4O3ClF1,1H2O1,8HCl0,23 isopropanol

found C 50,4 H 4,7 10,0 N

requires C 50,5 H 4.5 N 10,4%

PR is hydroxy-2-foronline)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.52 mmol) (obtained as described for the starting material in example 33) was treated with 4-hydroxymethyl-2-methylthiazole (100 mg, 0.87 mmol) to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((2-methylthiazole-4-yl)methoxy)chinasingapore (132 mg, 52%).

1H NMR spectrum: (d6) of 2.68(s, 3H); 4,00(s, 3H); to 5.35(s, 2H); 7,17(d, 1H); 7,52(d, 1H); 7,56(s, 1H); 7,72(s, 1H); 8,29(s, 1H); 8,83(s, 1H); 10,63(sh.s, 1H); 11,58(s, 1H)

MC-ESI: 447 [MN]+< / BR>
Elemental analysis:

C20H16N4O3ClFS0,6H2O1,2HCl

found C 48,2 H 3,7 N 11,2

requires C 47,9 H 3,7 N 11,2%

The original material was prepared as follows:

A solution of 4-chloromethyl-2-methylthiazole (1.84 g, 10 mmol) in water (9 ml) and concentrated chloroethanol acid (2 ml) was heated under reflux for 20 hours. Allowing the mixture to cool, and drove her 2M aqueous solution of sodium hydroxide to pH 5 and extracted with ethyl acetate. The organic extract was washed with water and brine and dried (gSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (97/3) and the result was a 4-hydroxymethyl-2-methylthiazole (800 mg, 54%).

1H NMR spectrum: (Dl3) of 2.72(s, 3H); 2,92(sh.with, 0.6 mmol) (obtained, as described for the starting material in example 24), 3-thiophenemethyl (107 mg, of 0.93 mmol) and triphenylphosphine (328 mg, 1.2 mmol) in methylene chloride (6 ml), cooled at 0oC, was added dropwise diethylazodicarboxylate (197 μl, 1.2 mmol). The mixture was stirred 2 hours at ambient temperature and in addition was added triphenylphosphine

(157 mg, or 0.57 mmol), 3-thiophenemethyl (107 mg, of 0.93 mmol) and diethylazodicarboxylate (98,5 μl, 0.59 mmol). The mixture was stirred 2 hours at ambient temperature and the solvent evaporated. The residue was dissolved in ethyl acetate and the solution washed with water and brine and dried (gSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-ethyl acetate (4/6). The resulting oil was dissolved in ether and was added 5M solution of hydrogen chloride in isopropanol (1 ml). The precipitate was filtered off, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-((3-thienyl)methoxy)chinasingapore (59 mg, 20%).

1H NMR spectrum: (d6) to 3.99(s, 3H); of 5.34(s, 2H); to 7.25(d, 1H); the 7.43(d, 1H); 7,45(s, 1H); 7,58-7,63(m, 2H), and 7.7(DD, 1H); 7,72(DD, 1H); 8,17(s, 1H); 8,78(s, 1H)

MC-ESI: 416 [MN]+< / BR>
Elemental analysis:

>A mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol) (obtained as described for the starting material in example 24), 2-acetamido-4-chloromethylthiazole (164 mg, 0.86 mmol) and potassium carbonate (216 mg, 1.5 mmol) in DMF (5 ml) was stirred at 40oWith over 7 hours. The mixture was distributed between ethyl acetate and water and the aqueous layer was brought 2M chloroethanol acid to pH 7. The organic phase is washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5). The purified solid was dissolved in a mixture of methylene chloride-methanol was added 5M solution of hydrogen chloride in isopropanol (1.0 ml). Evaporated volatiles to obtain solid, which is triturated with ether, collected by filtration and dried under vacuum, resulting in 7-((2-acetamidomethyl-4-yl)methoxy)-4-(4-chloro-2-foronline)-6-methoxybenzonitrile (96 mg, 24%).

So pl. 194-202oWITH

1H NMR spectrum: (d6) and 2.14(s, 3H); 4.0 a(s, 3H); 5,31(s, 2H); 7,34(s, 1H); was 7.45(DD, 1H); 7,52(s, 1H); of 7.60(t, 1H); to 7.68(DD, 1H); 8.30 to(s, 1H); 8,81 (s, 1H)

MC-ESI: 474 [MN]+< / BR>
Elemental analysis:

C21H17N

So pl. 169-174oWITH

1H NMR spectrum: (d6) to 3.99(s, 3H); 4,60(t, 2H); 4,74(t, 2H); the 7.43(d, 1H); 7,45 (s, 1H); to 7.59 (t, 1H); to 7.67(DD, 1H); of 8.06(s, 1H); to 8.41(s, 1H); 8,68(s, 1H); 8,83(s, 1H)

MC-ESI: 415 [MN]+< / BR>
Elemental analysis:

C19H16N
To a solution of 1-(3-hydroxypropyl)-[1,2,4]triazole (119 mg, of 0.93 mmol) (EP 0060696 A1), 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, of 0.62 mmol) (obtained as described for the starting material in example 24) and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4 ml) was added dropwise diethylazodicarboxylate (295 μl, 1.8 mmol) and the mixture was stirred 3 hours at ambient temperature. The mixture was purified by column chromatography with elution with a mixture of methylene chloride-acetonitrile-methanol (60/32/8). The purified product was rubbed with a mixture of pentane and ether, collected by filtration and dried under vacuum to obtain white solids. The solid was dissolved in a mixture of methylene chloride-methanol was added an ethereal solution of hydrogen chloride (1 ml of a 5M solution). Evaporated volatile substances. The solid residue suspended in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(1,2,4-triazole-1-yl)propoxy)chinasingapore (121 mg, 39%).

1H NMR spectrum: (d6; CF3COOD) of 2.44(t, 2H); 4.0 a (s, 3H); 4,3(t, 2H); to 4.5(t, 2H); to 7.32(s, 1H); 7,47(DD, 1H); a 7.62(t, 1H); of 7.70(DD, 1H); 8,08(s, 1H); to 8.41(s, 1H); 8,87(s, 1H); 9,10(s, 1H)

MC-ESI: 429 [MN]+< / BR>
the duty to regulate C 47,5 H 4,1 N 16,6%

Example 83

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (314 mg, 1.2 mmol) and 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (80 mg, 0.52 mmol) in methylene chloride (5 ml) was added dropwise diethylazodicarboxylate (209 μl, 1.2 mmol) and the mixture was stirred 2 hours at ambient temperature. The solvent evaporated, the residue triturated with ether and the resulting solid was collected by filtration. The solid was purified by column chromatography with elution with mixtures of methylene chloride-methanol (9/1 then 8/2) to obtain white solid. This solid was dissolved in a mixture of methylene chloride-methanol was added an ethereal solution of hydrogen chloride (0.5 ml of a 4M solution). Evaporated volatiles and the residue triturated with ether, collected by filtration and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)chinasingapore (110 mg, 60%).

1H NMR spectrum: (d6) 3,11(s, 3H); to 3.89(s, 3H); of 3.94(t, 2H); 4,37(t, 2H); 6,85(DD, 1H); 7,21(s, 1H); to 7.35(DD, 1H); at 7.55(DD, 1H); to 7.59(t, 1H); 7,8(s, 1H); at 8.36(s, 1H); 8,59(d, 1H); of 8.90(d, 1H); to 9.57(s, 1H)< / BR>
Elementry 4,5 15,0 N%

The original material was prepared as follows:

A solution of 4-bromo-3,6-dichloropyridazine (1,11 g, 5 mmol) (J. Chem. Soc., Perkin Trans I, 1974, 696) and 2-(methylamino)ethanol (0.75 g, 10 mmol) in isopropanol (10 ml) was heated under reflux for 30 minutes. The solvent evaporated, the residue was distributed between methylene chloride and water and the aqueous layer was brought to pH 9 with solid potassium carbonate. The organic layer was separated, washed with brine and dried (MgSO4), after which the solvent evaporated. The residue is triturated with ether, collected by filtration and dried under vacuum to obtain 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (1 g, 90%).

1H NMR spectrum: (Dl3) 2,1(W.s, 1H); to 3.09(s, 3H); 3,71(t, 2H); 3,93(t, 2H); at 6.8(s, 1H)

MC-ESI: 221 [MN]+< / BR>
A mixture of 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (444 mg, 2 mmol) and 10% palladium on charcoal (150 mg) in ethanol (15 ml), methanol (5 ml) and aqueous ammonia (15 ml) was stirred under hydrogen at a pressure of 3 atmospheres for 4 hours. The catalyst was filtered and from the filtrate the solvent evaporated. The residue was dissolved in methylene chloride, was filtered, the insoluble material and the filtrate evaporated solvent. The residue was purified by Colo is m 90/10). The purified product was washed with petroleum ether and the solid product was collected by filtration and dried under vacuum to obtain 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (275 mg, 91%).

1H NMR spectrum (CDCl3) a 3.06(s, 3H); of 3.57(t, 2H); to 3.89(t, 2H); of 6.52(DD, 1H); 8,48(d, 1H); 8,54(d, 1H)

MC-ESI: 153 [MN]+< / BR>
Example 84

To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-((4-pyridyl)carboxamido)hintline (250 mg, of 0.56 mmol) in methanol, cooled at 0oC, was added 2M aqueous solution of sodium hydroxide (560 μl, 1.1 mmol) and the mixture was stirred for 1 hour at ambient temperature. The mixture was diluted with water and brought 2M chloroethanol acid to pH 6. The obtained solid was filtered, washed with water and dried under vacuum. The solid was dissolved in a mixture of methylene chloride-methanol was added isopropanolamine solution of hydrogen chloride (0.7 ml of a 5M solution). Evaporated volatile substances and the solid residue triturated with ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-((4-pyridyl)carboxamido)chinasingapore (241 mg, 93%).

MC-ESI: 390 [MN]+< / BR>
1H NMR spectrum: (d6; CF/BR>C21H16N5O2F1 2H2O1,95HCl

found C 52,0 H 4,3 N 14,3

requires C 52,3 H 4,3 N 14,5%

The original material was prepared as follows:

A mixture of 7-nitro-3,4-dihydroquinazolin-4-it (J. Chem. Soc., 1950, 1104-1111) (5 g, 26 mmol) in thionyl chloride (50 ml) and DMF (1 ml) was heated under reflux for 1.5 hours. Excess thionyl chloride was removed by evaporation and the residue was subjected to azeotropic distillation with toluene. The residue is suspended in ether, collected by filtration and dried under vacuum to obtain 4-chloro-7-nitrobenzotrifluoride (6.4 g, 100%).

1H NMR spectrum: (d6) compared to 8.26(DD, 1H); at 8.36(d, 1H); to 8.40(s, 1H); 8,42(DD, 1H)

MC-ESI: 209 [MN]+< / BR>
A solution of 4-chloro-7-nitrobenzotrifluoride (2,46 g, 10 mmol) and 2-fluoro-5-methoxycarbonylamino-4-methylaniline (2.2 g, 11 mmol) (obtained as described for the starting material in example 12) in isopropanol (25 ml) was heated at 50oC for 1 hour. Gave the mixture to cool and loose precipitated solid substance was collected by filtration and recrystallized from a mixture of methylene chloride-methanol-ISO-propanol to obtain 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-nitrobenzotrifluoride (1.8 g, 45%) as a yellow solid in the, 1H); 8,89(d, 1H)

MC-ESI: 373 [MN]+< / BR>
Elemental analysis:

C17H13N4O5F1HCl

found C H 50,0 3,6 N 13,8

requires C H 50,0 3,5 N 13,7%

A mixture of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-nitrobenzotrifluoride (5,3 g, 13 mmol) and 10% palladium on charcoal (1 g) in ethanol (100 ml), ethanol solution of hydrogen chloride (1.8 ml 7M solution) and methanol (20 ml) was stirred under hydrogen at a pressure of 1.7 atmospheres within 75 minutes. The catalyst was filtered through diatomaceous earth, washed filter layer with methylene chloride, methanol and ether and from the filtrate the solvent evaporated, resulting in 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)chinasingapore (4.8 g, 97%) as a yellow solid.

1H NMR spectrum: (d6) 2,22(s, 3H); a 3.87(s, 3H); 6,77(s, 1H); was 7.08(DD, 1H); to 7.15(m, 2H); 7,41(m, 2H); 8,35(d, 1H); 8,63(s, 1H); 11,03(s, 1H)

MC-ESI: 343 [MN]+< / BR>
A solution of 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)chinasingapore (0.45 g, 1.2 mmol) and isonicotinohydrazide (296 mg, of 1.66 mmol) in pyridine (15 ml) was stirred 2 hours at ambient temperature and then for 1 hour at 40oC. was Added an additional isonicotinohydrazide mixture was diluted with water. The aqueous mixture was brought to pH 7 and extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by flash chromatography by elution with mixtures of methylene chloride-methanol (95/5, and then 92/8). The purified solid is triturated with ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-((4-pyridyl)carboxamido)hintline (264 mg, 49%).

1H NMR spectrum: (d6) 2,19(s, 3H); 3,86(s, 3H); 7,31(d, 1H); was 7.45(d, 1H); 7,92(d, 2H); 7,98(d, 1H); 8,31(s, 1H); 8,43(d, 1H); of 8.47(s, 1H); 8,83(d, 2H); 9,78(sh.s, 1H); 10,89(sh.s, 1H)

Example 85

To a solution of 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)chinasingapore (140 mg, 0.35 mmol) in isopropanol (5 ml) was added 4-chloro-2-ftoranila (77 mg, of 0.53 mmol) and the mixture was heated under reflux for 1 hour. The solvent evaporated and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by flash chromatography with elution with a mixture of metranil is the target of hydrogen chloride (1 ml of a 5M solution). Evaporated volatiles and the residue triturated with ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4- (4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)chinasingapore (75 mg, 39%).

1H NMR spectrum: (d6; CF3COOD) 2,46 and 2,47 (2s, 3H); 3,35 and of 3.42(2s, 3H); 3,97 and 3,98(2s, 3H); 4,2(sh.s, 1H); 4,3(sh.s, 1H); 4.5(W.s, 2H); 7,05 and 7.3 (2s, 1H); 7.4 and 7.5 (m, 2H); a 7.62(t, 1H); 7.7(d, 1H); 8,25(sh.s, 1H); 8.8 and 8.9 in(2C, 2H)

MC-ESI: 469 [MN]+< / BR>
The original material was prepared as follows:

To a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-it (8,46 g, 30 mmol) (obtained as described for the starting material in example 70) in DMF (70 ml) was added in portions over 20 minutes of sodium hydride (1.44 g of 60% suspension in mineral oil, 36 mmol) and the mixture was stirred for 1.5 hours. Was added dropwise chlorocyphidae (5,65 g, 37.5 mmol) and the mixture was stirred 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and was poured into ice water (400 ml) and 2M solution chloroethanol acid (4 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4), after which the solvent evaporated. The residue RA is a vacuum, with a 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).

1H NMR spectrum: (d6) a 1.11(s, N); the 3.89(s, 3H); 5,3(s, 2H); at 5.9(s, 2H); 7,27(s, 1H); 7,35(m, 1H); 7,47(t, 2H); 7,49(d, 2H); 7,51(s, 1H); 8.34 per(s, 1H)

A mixture of 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (7 g, about 17.7 mmol) and 10% palladium on activated carbon (700 mg) in ethyl acetate (250 ml), DMF (50 ml), methanol (50 ml) and acetic acid (0.7 ml) was stirred under hydrogen at atmospheric pressure for 40 minutes. The catalyst was filtered and from the filtrate the solvent evaporated. The residue is triturated with ether, collected by filtration and dried under vacuum, resulting in 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4,36 g, 80%).

1H NMR spectrum: (d6) 1,1(C, N); the 3.89(s, 3H); of 5.89(s, 2H); 7,0(s, 1H); of 7.48(s, 1H); and 8.5(s, 1H)

To a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (918 mg, 3 mmol), triphenylphosphine (1 g, 3.9 mmol) and 2-(N-methyl-N-(tert-butylcarbamoyl)amino)ethanol (682 mg, 3.9 mmol), obtained as described below, in methylene chloride (20 ml) was added dropwise diethylazodicarboxylate (679 mg, 3.9 mmol) and the mixture was stirred 1 hour at the temperature of olfaction (786 mg, 3 mmol) and diethylazodicarboxylate (522 mg, 3 mmol) and the mixture was stirred for 30 minutes at ambient temperature. The mixture was concentrated to half volume by evaporation and purified by column chromatography with elution with mixtures of methylene chloride-ether (from 7/3 to 1/1), which gave 6-methoxy-7-(2-(N-methyl-N-(tert-butylcarbamoyl)amino)ethoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.3 g, 98%).

1H NMR spectrum: (Dl3) 1,2(C, N); 1,45(s, N); 3,05(sh.s, 3H); 3.72 points III.s, 2H); 3,98(s, 3H); 4.25 in(sh. s, 2H); 5,95(s, 2H); 7,1(sh.s, 1H); and 7.6(s, 1H); or 8.2(s, 1H)

A solution of 6-methoxy-7-(2-(N-methyl-N-(tert-butylcarbamoyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (1.39 g, 3 mmol) in methylene chloride (4 ml) and THF (4 ml) was stirred at ambient temperature for 1 hour. Was added toluene and evaporated volatile substances. The residue is triturated with ether and the resulting solid was collected by filtration. The solid was dissolved in water, was added sodium bicarbonate and the aqueous mixture was extracted with methylene chloride. The organic extract was dried (MgSO4) and the solvent evaporated. The residue is triturated with ether and the solid is collected by filtration, resulting in 6-methoxy-7-(2-(methylamino)ethoxy)-3-((beer is from, N); of 2.72(s, 3H); 3.45 points(sh.s, 2H); of 3.95(s, 3H); to 4.5(t, 2H); 5,94(s, 2H); 7,31(s, 1H); and 7.6(s, 1H); of 8.47(s, 1H)

MC-ESI: 364 [MN]+< / BR>
A solution of 6-methoxy-7-(2-(methylamino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (363 mg, 1 mmol) and 4-chloro-6-methylpyrimidine (257 mg, 2 mmol) (J. Het. Chem., 1969, 6, 879) in N,N-diisopropylethylamine (2 ml) was heated under reflux for 30 minutes. Evaporated volatiles and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methanol (95/5) and the result obtained 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (365 mg, 80%).

1H NMR spectrum: (Dl3) to 1.19(s, N); a 2.36(s, 3H); 3,18(s, 3H); of 3.95 (s, 3H); 4.09 to (t, 2H); 4,34 (t, 2H); at 5.9 (s, 2H); 6,3(s, 1H); 7,14(s, 1H); 7,63(s, 1H); 8,17(s, 1H); and 8.5(s, 1H)

MC-ESI: 456 [MN]+< / BR>
A solution of 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (365 mg, 0.8 mmol) in methanol ammonia solution (30 ml of a 3M solution) primatively at ambient temperature for 16 hours. Evaporated volatile substances, okouma, resulting in 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3,4-dihydroquinazolin-4-one (250 mg, 92%).

1H NMR spectrum: (d6; CF3COOD) of 2.44(s, 3H); 3,32 and 3,39(2s, 3H); 3,86 and a 3.87(2s, 3H); 4,12(t, 1H); 4.25 in(t, 1H); was 4.42(m, 2H); 7,02 and 7.23 percent(2s, 1H); from 7.24(t, 1H); 7.50 for(s, 1H); 8,55 and 8.8(2m, 1H); 8,78 and 8,80(2s, 1H)

MC-ESI: 342 [MN]+< / BR>
A mixture of 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3,4-dihydroquinazolin-4-it (250 mg, 0.73 mmol) in thionyl chloride (5 ml) and DMF (0.1 ml) was heated under reflux for 1 hour. The mixture was diluted with toluene and evaporated volatile substances. The residue is triturated with a mixture of methylene chloride-ether and the solid is collected by filtration and dried under vacuum to obtain 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)-amino)ethoxy)chinasingapore (260 mg, 90%).

2-(N-Methyl-N-(tert-butylcarbamoyl)amino)ethanol was prepared as follows:

A solution of di-tert-BUTYLCARBAMATE (4.52 g, 20 mmol) in THF (10 ml) was added to a solution of 2-(N-methylamino)ethanol (1.5 g, 20 mmol) in a mixture of water (10 ml) and THF (10 ml). The mixture was stirred at ambient temperature for 18 hours, the THF evaporated and the aqueous residue was distributed between ether and water. The organic layer was washed with water and races who">

1H NMR spectrum (CDCl3) of 1.46(s, N); 2,92(s, 3H); 3,39(t, 2H); 3.75 to(t, 2H)

MC-ESI: 176 [MN]+< / BR>
Example 86

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, of 0.62 mmol) (obtained as described for the starting material in example 24), 2-(3,5-dimethyl-[1,2,4] triazole-4-yl)ethanol (114 mg, 0.81 mmol) (EP 0329357 A1) and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4 ml) was added dropwise diethylazodicarboxylate (295 μl, 1.8 mmol) and the mixture was stirred for 1 hour at ambient temperature. Precipitated precipitated solid substance was collected by filtration, washed with ether, and dried under vacuum. The solid was dissolved in a mixture of methylene chloride-methanol was added an ethereal solution of hydrogen chloride (2 ml 4.5 M solution). Evaporated volatiles and the residue suspended in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-7-(2-(3,5-dimethyl-[1,2,4] triazole-4-yl)ethoxy)-6-methoxybenzonitrile (184 mg, 54%).

1H NMR spectrum: (d6; CF3COOD) 2,78(C, 6N); a 4.03(s, 3H); of 4.57(t, 2H); 4.75 V(t, 2H); 7,37(s, 1H); 7,46(d, 1H); to 7.64(t, 1H); 7,66(d, 1H); 8,31(s, 1H); 8,87(s, 1H)

MC-ESI: 443 [MN]+< / BR>
Elemental analysis:

C21H20N6O

1H NMR spectrum: (d6; CF3D) of 2.23 and 2.43 (2s, 3H); 2,73 and was 2.76(2s, 3H); was 4.02(s, 3H); 4,6(sh.s, 2H); 4.6 and the 4.75(m, 2H)UB>21
N5O2ClF1,1H2O1,85HCl

found C to 49.9 H 4,6 N 13,3

requires C 50,1 H 4,8 N 13,3%

The original material was prepared as follows:

To a suspension of sodium hydride (936 mg of 60% suspension in mineral oil, 23 mmol) in DMF (8 ml) was added by portions diethylazodicarboxylate (1.5 g, 15.6 mmol) and the mixture was stirred for 30 minutes at ambient temperature. Was added 2-bromoethanol (of 1.66 ml, 23 mmol) and the mixture was stirred at 100oC for 16 hours. The solvent evaporated and to the residue was added concentrated chloroethanol acid (1 ml). The obtained solid was purified by column chromatography on neutral alumina with elution with a mixture of methylene chloride-methanol (97/3) and then column chromatography with elution with mixtures of methylene chloride-methanol (93/7, and then 90/10) and the result was a mixture (75/25) 2-(2,4-dimethylimidazole-1-yl)ethanol and 2-(2,5-dimethylimidazole-1-yl)ethanol (650 mg, 29%).

MC-ESI: 140 [MN]+< / BR>
Example 88

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(3-pyridyl)ethanol (86 mg, 0.7 mmol) (J. Heterocycl. Chem. 1992, 29, 1663) in methylenchloride environment. The mixture was immediately poured into a column with silica and suirable a mixture of methylene chloride-acetonitrile-methanol (60/35/5). The purified solid was dissolved in a mixture of methylene chloride-methanol was added an ethereal solution of hydrogen chloride (1.5 ml 4.5 M solution). Evaporated volatile substances and the solid residue suspended in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-pyridyl)ethoxy)chinasingapore (154 mg, 52%).

1H NMR spectrum: (d6; CF3D) to 3.45 (t, 2H); 4,01(s, 3H); 4,56(t, 2H); 7,44(s, 1H); 7,46(d, 1H); to 7.61(t, 1H); to 7.67(d, 1H); 8,13(t, 1H); 8,19(s, 1H); 8,71(d, 1H); 8,88(s, 1H); 8,9(d, 1H); 9,01(s, 1H)

MC-ESI: 425 [MN]+< / BR>
Elemental analysis:

C22H18N4O2ClF0,8H2O1,8HCl

found C 52,7 H 4,3

requires C 52,3 H 4,3%

Example 89

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol) (obtained as described for the starting material in example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(6-methyl-2-pyridyl)ethanol (96 mg, 0.7 mmol) (J. Chem. Soc. A, 1971, 388) in methylene chloride (6 ml) was added dropwise diethylazodicarboxylate (236 μl, 1.5 mmol) and the mixture was stirred 16 hours at ambient temperature shelled solid was dissolved in a mixture of methylene chloride-methanol was added an ethereal solution of hydrogen chloride (1.5 ml 4.5 M solution). The mixture was diluted with ether and the precipitate was collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(6-methyl-2-pyridyl)ethoxy)chinasingapore (97 mg, 34%).

1H NMR spectrum: (d6; CF3D) 2,78(s, 3H); to 3.64(t, 2H); 3,98(s, 3H); of 4.67(t, 2H); 7,46(s, 1H); of 7.48(sh.s, 1H); a 7.62(t, 1H); to 7.68(DD, 1H); a 7.85(d, 1H); 7,94(d, 1H); 8,19(s, 1H); 8,48(t, 1H); 8,88(s, 1H)

MC-ESI: 439 [MN]+< / BR>
Elemental analysis:

C23H20N4O2ClF1H2O1,8HCl

found C 52,7 H 4.5 N 10,7

requires C 52,9 H 4,6 N 10,7%

Example 90

A mixture of 4-chloro-7-(2-(imidazol-1-yl) ethoxy)-6-methoxyquinazoline (49 mg, 0.16 mmol) and 3-hydroxyanisole (21 mg, 0,19 mmol) in isopropanol (3 ml) and isopropanolate solution of hydrogen chloride (0.2 ml of a 5M solution) was stirred at 80oC for 1 hour. Precipitated precipitated solid was filtered, washed with isopropanol and ether, and dried under vacuum to obtain 4-(3-hydroxyamino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxybenzonitrile (56 mg, 93%).

1H NMR spectrum: (MCOd6; CF3D) to 4.01(s, 3H); with 4.64(t, 2H); 4,78(t, 2H); of 6.71(d, 1H); and 7.1(m, 2H); 7,28(m, 1H); 7,41(s, 1H); 7,74(s, 1H); 7,83(s, 1H); 8,21(s, 1H); 8,87(s, 1H); which 9.22(s, 1H)

MC-ESI: 378 [MN]+< / BR>
Element,9 N 15,4%

The original material was prepared as follows:

To a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (612 mg, 2 mmol) (obtained as described for the starting material in example 85), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol) (J. Med. Chem. 1993, 25, 4052-4060) and triphenylphosphine (655 mg, 2.5 mmol) in methylene chloride (10 ml) and 5oWith added dropwise diethylazodicarboxylate (435 mg, 2.5 mmol). The mixture was stirred 10 minutes with 5oAnd then 1 hour at ambient temperature. The mixture was immediately poured into a column with silica and suirable a mixture of methylene chloride-methanol (95/5) to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (640 mg, 80%).

1H NMR spectrum: (Dl3) to 1.19(s, N); 3,98(s, 3H); 4,34(m, 2H); of 4.45(m, 2H); 5,94(s, 2H); 7,02(s, 1H); 7,07(s, 1H); 7,11(s, 1H); to 7.64(s, 1H); to 7.67(s, 1H); 8,17(s, 1H)

MC-ESI: 423 [MNa]+< / BR>
Elemental analysis:

C20H24N4O50,7 H2O

found C 58,3 H 6,4 N 13,9

requires C 58,2 H 6,2 N 13,6%

A solution of 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-it (640 mg, 1.6 mmol) in a saturated methanol solution of ammonia (10 ml) was stirred 15 hours at ambient temperature. Wypracowa to obtain 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-she (412 mg, 90%).

1H NMR spectrum: (MCOd6) to 3.89(s, 3H); 4.4 to 4.5(m, 4H); 6,9(s, 1H); 7,16 (s, 1H); 7,28 (s, 1H); 7,47(s, 1H), and 7.7(s, 1H); to 7.99(s, 1H)

MC-ESI: 287 [MN]+< / BR>
Elemental analysis:

C14H14N4O30,3 H2O

found C 57,8 H 5,2 N 19,3

requires C 57,7 H 5,1 N 19,2%

A mixture of 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-she (412 mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was heated under reflux for 1 hour. The mixture was diluted with toluene and evaporated volatile substances. The residue is suspended in methylene chloride, cooled to 0oWith and added an aqueous solution of sodium bicarbonate. The precipitate was collected by filtration and dried under vacuum to obtain 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (258 mg, 59%).

1H NMR spectrum: (MCOd6) to 4.01(s, 3H); 4,47(m, 2H); 4.53-in(m, 2H); 6.89 in(s, 1H); 7,27(s, 1H); 7,41(s, 1H); 7,49(s, 1H); of 7.70(s, 1H); 8,88(s, 1H)

MC-ESI: 327 [MNa]+< / BR>
Example 91

To a solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (150 mg, 0.47 mmol) (obtained as described for the starting material in example 24), 2-(1,2,4-triazole-4-yl)ethanol (64 mg, 0,56 mmol) and triphenylphosphine (369 mg, 1.4 mmol) in methylene chloride (5 ml) was added dropwise diethylazodicarboxylate the-4-yl)ethanol (16 mg, 0.14 mmol), triphenylphosphine (37 mg, 0.14 mmol) and diethylazodicarboxylate (22 μl, 0.14 mmol) and the mixture was stirred for 1 hour at ambient temperature. Precipitated precipitated solid substance was collected by filtration, washed with methylene chloride and dried under vacuum. The solid was dissolved in a mixture of methylene chloride-methanol was added an ethereal solution of hydrogen chloride (1.5 ml 2.2 M solution). Evaporated volatile substances and the solid residue suspended in ether, collected by filtration, washed with ether, and dried under vacuum to obtain 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1,2,4-triazole-4-yl)ethoxy)chinasingapore (93 mg, 40%).

1H NMR spectrum: (d6; CF3COOD) was 4.02(s, 3H); of 4.66(t, 2H); 4,85(t, 2H); 7,41(s, 1H); 7,46(DD, 1H); a 7.62(t, 1H); of 7.69(DD, 1H); 8,11(s, 1H); 8,89(s, 1H); of 9.55(s, 2H)

MC-ESI: 415 [MN]+< / BR>
Elemental analysis:

C19H16N6O2ClF0,5H2O2HCl

found C 45,9 H 3,7 N 17,1

requires C 45,9 H 3,9 N 16,9%

The original material was prepared as follows:

A solution of N,N-dimethylformamidine (1 g, 7 mmol) (J. Chem. Soc. With, 1967, 1664), p-toluensulfonate acid (45 mg) and ethanolamine (4.3 g, 70 mmol) in benzene (15 ml) was heated under reflux for 8 hours. Allowing the mixture to cool, viparita (90/10, and then 85/15), resulting in 2-(1,2,4-triazole-4-yl)ethanol (328 mg, 41%).

1H NMR spectrum: (Dl3) of 3.97(t, 2H); 4,11(t, 2H); 4,9(sh.s, 1H); of 8.06(s, 2H)

MC-ESI: 113 [MN]+< / BR>
Example 92

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, to 0.63 mmol), 3-benzyloxyphenol (150 μl, 0.95 mmol) and tributylphosphine (459 μl, of 1.86 mmol) in methylene chloride (20 ml) at 5oWith added portions of 1,1'-(azodicarbon)dipiperidino (480 mg, 1.9 mmol). The reaction mixture was stirred 1 hour at 5oAnd then 18 hours at ambient temperature. The mixture was diluted with ether and stirred for 15 minutes. Was filtered, the insoluble materials and the filtrate evaporated volatile substances. The residue was distributed between ethyl acetate and water and the organic layer was separated and dried (MgSO4), after which the solvent evaporated. To the residue was added 1M ethereal solution of hydrogen chloride, reduces the volume of the resulting solution by evaporation and the precipitate was collected by filtration and dried to obtain 7-(3-benzyloxypropionic)-4-(4-chloro-2-foronline)-6-methoxybenzonitrile (90 mg, 31%).

1H NMR spectrum: (Dl3) a 2.12(t, 2H); 3,62(t, 2H); 4,00(t, 3H); to 4.28(t, 2H); of 4.45(s, 2H); 7,21-7,38(m, 6N); 7,42(d, 1H); of 7.60(t, 1H); to 7.64(etoxification (315 mg, 1 mmol), ethyl 4-hydroxymethyl-2-pyridinecarboxylic (250 mg, 1.4 mmol) (J. Het. Chem. 1993, 30, 631-635) and tributylphosphine (800 μl, 3 mmol) in methylene chloride (50 ml) at 0oWith added portions of 1,1'-(azodicarbon)dipiperidino (840 mg, 3 mmol). Gave the mixture to warm to ambient temperature for 2 hours, was filtered, the insoluble materials and the filtrate was washed with water and brine and dried (Na2SO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (from 10/0 to 9/1). The purified product was recrystallized from a mixture of methylene chloride-hexane to obtain 4-(4-chloro-2-foronline)- 7-(2-ethoxycarbonylphenyl-4-yl)methoxy-6-methoxyquinazoline (285 mg, 60%).

So pl. 212-214oWITH

1H NMR spectrum: (d6) of 1.30 (t, 3H); of 3.96 (s, 3H); of 4.35(q, 2H); of 5.45(s, 2H); 7,14(s, 1H); to 7.35(DD, 1H); 7.5 to about 7.6(m, 2H); a 7.85 (s, 1H); 8,15 (s, 1H); 8,35 (s, 1H); is 8.75(d, 1H); of 9.55(s, 1H)

Elemental analysis:

C24H20ClFN4O40.5 H2O

found C 58,9 H 4,4 12,0 N

requires C 58,7 H 4,4 N 11,5%

Example 94

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), 4-hydroxymethyl-2-(methylamino)pyridine (385 mg, 2.8 mmol) and tributylphosphine (1.6 ml, 6 mmol) in Mei agrotica to ambient temperature for 2 hours, was filtered, the insoluble materials and the filtrate was washed with water and brine and dried (Na2SO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (from 10/0 to 9/1). The purified product was dissolved in a mixture of acetone-methanol and was added 1M ethereal solution of hydrogen chloride. The precipitate was collected by filtration and dried to obtain 4-(4-chloro-2-foronline)-7-(2-(methylamino)pyrid-4-yl)methoxy-6-methoxybenzonitrile (395 mg, 45%).

1H NMR spectrum: (d6) 2,95(d, 3H); of 4.05(s, 3H); 5,42(s, 2H); 6.90 to(d, 1H); to 7.15(s, 1H); 7,40(d, 1H); 7,44(s, 1H); 7,58(t, 1H); a 7.62(DD, 1H); to 7.95(d, 1H); 8,46(s, 1H); is 8.75(s, 1H); 9,06(sh.s, 1H); 11,83(sh.s, 1H)

MC-ESI: 440 [MN]+< / BR>
The original material was prepared as follows:

A mixture of 2-chloro-4-hydroxymethylbenzene (1.0 g, 7 mmol) (obtained as described for the starting material in example 58) and methylamine (30 ml 30% solution in ethanol) was heated in a tube of Karius for 16 hours at 200oC. Allowing the mixture to cool, was distributed between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated and dried (MgSO4), and then evaporated volatile substances. The residue was purified is amino)pyridine (440 mg, 46%) as a yellow oil.

1H NMR spectrum: (d6) of 2.72(d, 3H); of 4.35(d, 2H); further 5.15(t, 1H); 6.30-in(sh.d, 1H); 6,35(d, 1H); 6,38(s, 1H); a 7.85(d, 1H)

Example 95

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), 4-hydroxymethyl-2-(dimethylamino)pyridine (426 mg, 2.8 mmol) and tributylphosphine (1.6 ml, 6 mmol) in methylene chloride (50 ml) at 0oWith added portions of 1,1'-(azodicarbon)dipiperidino (1.68 g, 6 mmol). Gave the mixture to warm to ambient temperature for 2 hours, was filtered, the insoluble materials and the filtrate was washed with water and brine and dried (PA2SO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 95/5). The purified product was dissolved in a mixture of acetone-methanol and was added 1M ethereal solution of hydrogen chloride. The precipitate was collected by filtration and dried to obtain 4-(4-chloro-2-foronline)-7-(2-(dimethylamino)pyrid-4-yl)methoxy-6-methoxybenzonitrile (305 mg, 30%).

So pl. 290oWITH

1H NMR spectrum: (d6) 3,05(C, 6N); of 4.05(s, 3H); of 5.45(s, 2H); to 6.95(d, 1H); to 7.35(s, 1H); 7,42(DD, 1H); 7,56(t, 2H); a 7.62(DD, 1H); 8,00(d, 1H); 8,55(s, 1H); 9,80(s, 1H); 11,95(sh.s, 1H)

MC-ESI: 454 [MH]+< / BR>

The original material was prepared as follows:

A mixture of 2-chloro-4-hydroxymethylbenzene (1.0 g, 7 mmol) (obtained as described for the starting material in example 58) and dimethylamine (30 ml 30% solution in ethanol) was heated in a tube of Karius for 16 hours at 200oC. Allowing the mixture to cool, was distributed between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated and dried (gSO4), and then evaporated volatile substances. The residue was purified by column chromatography with elution by ethyl acetate and the obtained 4-hydroxymethyl-2-(dimethylamino)pyridine (1 g, 94%) as a yellow oil.

1H NMR spectrum: (d6) to 3.00(s, 6N); however, 4.40(d, 2H); 5,20(t, 1H); of 6.45(d, 1H); 6,55(s, 1H); of 7.96(d, 1H)

MC-ESI: 153 [MN]+< / BR>
Example 96

A mixture of 4-(3-hydroxyprop-2-EN-1-yl)pyridine (180 mg, 1.3 mmol) and thionyl chloride (0.3 ml) in toluene (10 ml) was stirred at room temperature for 2 hours. Evaporated volatiles to obtain crude 4-(3-chlorpro-2-EN-1-yl)pyridinecarboxamide (180 mg, of 0.94 mmol). This product was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (500 mg, 1.6 mmol) and potassium carbonate (500 mg, 4.9 mmol) in DMF (20 ml) and the mixture periodoi. The organic layer was separated, washed with water and brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with mixtures of methylene chloride-methanol (100/0 to 95/5) and then by reverse-phase (C18) HPLC with elution with mixtures of methanol-water (from 30/70 to 50/50) and the result obtained 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(pyrid-4-yl)prop-2-EN-1-yloxy)hintline (15 mg, 4%).

1H NMR spectrum: (d6) 4,00 (s, 3H); of 5.05(d, 2H); 6,93(d, 1H); 7,11(dt, 1H); 7,40(s, 1H); 7,40-the 7.43(m, 2H); of 7.60(t, 1H); the 7.65(d, 1H); 7,80(m, 2H); with 8.05(s, 1H); 8,70(sh.s, 2H)

MC-ESI: 437 [MN]+< / BR>
The original material was prepared as follows:

n-Utility (25 ml, 1.6 M solution in hexane, 40 mmol) was added dropwise to a stirred suspension of 2-hydroxyethylidenediphosphonic (7,74 g, 20 mmol) in THF (50 ml) at -70oWith, and gave the mixture to warm to -30oC and stirred for 2 hours. To the resulting red solution was added 4-pyridinecarboxamide (2.16 g, 20 mmol), the mixture was stirred for 1 hour at -30oC and then cooled to -70oC. was Added n-utility (12.5 ml, 1.6 M solution in hexane, 20 mmol) and the reaction mixture was stirred at -70oC for 1 hour. The mixture was suppressed from the ammonium, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine and dried (MgSO4), and then evaporated volatile substances. The residue was purified by column chromatography with elution by ethyl acetate and the obtained 4-(3-hydroxyprop-2-EN-1-yl)pyridine.

MC-ESI: 136 [MN]+< / BR>
Example 97

A suspension of 4-chloro-7-(2-(1,2,4-triazole-1-yl)ethoxy)-6-methoxyquinazoline

(214 mg, 0.7 mmol), 4-bromo-2-foronline (160 mg, 0.84 mmol) in isopropanolate solution of hydrogen chloride (1 ml of a 5M solution) and isopropanol (5 ml) was heated at 80oC for 1 hour. Gave the mixture to cool and the precipitate was filtered, washed with isopropanol and then with ether, and dried under vacuum at 70oWith obtaining 4- (4-bromo-2-foronline)-7-(2-(1,2,4-triazole-1-yl)ethoxy)-6-methoxybenzonitrile (55 mg, 15%).

1H NMR spectrum: (d6) to 3.99(s, 3H); to 4.62(t, 2H); 4.75 V(t, 2H); 7,37(s, 1H); of 7.5 to 7.7(m, 2H); 7,81(d, 1H); 8,04(s, 1H); 8,24(s, 1H); 8,63(s, 1H); 8,84(s, 1H); to 11.52(s, 1H)

MC-ESI: 459 [MN]+< / BR>
Elemental analysis:

C19H16BrFN6O20,8 H2O1,9HCl

found C 41,8 H 3,4 N 15,6

requires C 42,0 H 3,6 N 15.5% OF

The original material was prepared as follows:

To a solution of mg, 7 mmol) (Ann. Pharm. Fr. 1977, 35, 503-508) and triphenylphosphine (1.8 g, 7 mmol), cooled at 5oC, was added dropwise diethylazodicarboxylate (1.1 ml, 7 mmol). The mixture was allowed to warm to ambient temperature and was stirred for 1 hour. Immediately pour the mixture into a column with silica and suirable a mixture of methylene chloride-methanol (95/5) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazole-1-yl)ethoxy-3,4-dihydroquinazolin-4-it (1.64 g, 74%).

1H NMR spectrum: (d6; CF3D) of 1.12 (s, N); a 3.87 (s, 3H); of 4.57(t, 2H); 4,74(t, 2H); of 5.92(s, 2H); from 7.24(s, 1H); 7,51(s, 1H); at 8.36(d, 1H); to 8.41(s, 1H); of 9.02(d, 1H)

MC-ESI: 424 [MNa]+< / BR>
Elemental analysis:

C19H23N5O5< / BR>
found C H 56,5 6,0 N 17,6

requires C 56,9 H 5,8 N 17%

A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazole-1-yl)ethoxy-3,4-dihydroquinazolin-4-it (1.6 g, 4 mmol) in a saturated methanol solution of ammonia (25 ml) was stirred at ambient temperature for 2 days. Evaporated volatile substances and the solid residue triturated with ether, collected by filtration and dried under vacuum to obtain 6-methoxy-7-(2-(1,2,4-triazole-1-yl)ethoxy-3,4-dihydroquinazolin-4-it (1,11 g, 98%).

1H NMR spectrum: (d6) of 3.84(s, 3) - Rev. BR>
C13H13N5O3< / BR>
found C 53.9 H 4.6 N 24.6

requires C, 54.4 H 4.6 N 24.4%

A solution of 6-methoxy-7-(2-(1,2,4-triazole-1-yl)ethoxy-3,4-dihydroquinazolin-4-it (1,11 g, 3,86 mmol) and DMF (0.6 ml) in thionyl chloride (15 ml) was heated under reflux for 1 hour. Allowing the mixture to cool, was added toluene and evaporated volatile substances. The residue was distributed between methylene chloride and water and the aqueous layer was brought to pH 8.5 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine and dried (MgSO4), after which the solvent evaporated. The residue was purified by column chromatography with elution with a mixture of methylene chloride-methylene (95/5). The purified solid is triturated with ether, collected by filtration, washed with water and then with ether, and dried under vacuum to obtain 4-chloro-6-methoxy-7-(2-(1,2,4-triazole-1-yl) ethoxy)hintline (756 mg, 65%).

1H NMR spectrum: (d6) of 3.97(s, 3H); with 4.65(DD, 2H); 4,70(DD, 2H); 7,39 (s, 1H); 7,52 (s, 1H); to 7.99 (s, 1H); to 8.57 (s, 1H); 8,89(s, 1H)

MC-ESI: 306 [MN]+< / BR>
Example 98

Below is a typical dosage forms containing the compound of formula I or its pharmaceutically acceptable salt (hereafter compound X), for terapevticheskii Ph. Eur - 182,75

Sodium croscarmellose to 12.0

The paste of corn starch (5% m/o) was 2.25

Magnesium stearate - 3,0

(b) Tablet II - mg/tablet

Connection X - 50

Lactose Ph. Eur - 223,75

Sodium croscarmellose - 6,0

Corn starch - 15,0

Polyvinylpyrrolidone (5% m/paste) was 2.25

Magnesium stearate - 3,0

(c) Tablet III mg/tablet

Connection X - 1,0

Lactose Ph. Eur - 93,25

Sodium croscarmellose - 4,0

The paste of corn starch (5% m/o) - 0,75

Magnesium stearate - 1,0

(d) Capsule - mg/tablet

Connection X - 10

Lactose Ph. Eur - 488,5

Magnesium stearate and 1.5

(e) Injecting the solution I (50 mg/ml)

Connection X - 5,0% m/o

1 n sodium hydroxide Solution to 15.0% about/on

0.1 N. Chloromethane acid (to control pH to 7.6) - 4,5%

The polyethylene glycol 400

Water for injection Up to 100%

(f) Injecting the solution II (10 mg/ml)

Connection X - 1,0% m/o

Nutrifaster BP - 3,6% m/o

of 0.1 n sodium hydroxide Solution to 15.0% about/on

Water for injection Up to 100%

(d) Injecting a solution of III (1 mg/ml, increased the buffer to a pH of 6)

Compound X 0.1% m/o

Nutrifaster BP of 2.26% m/o

Citric acid - 0,38% m/o

The polyethylene glycol 400 and 3.5% m/o

The waters of the ways, known in the pharmaceutical field. The tablets (a)-(C) can be applied by traditional methods intersolubility coating, e.g. a coating of acetylcellulose.

1. Derivatives hintline formula I

< / BR>
where Y1represents-O-, -S-, -NR5CO-, where R5represents hydrogen;

R1represents hydrogen or C1-3alkoxy;

R2represents hydrogen;

m represents an integer from 1 to 5;

R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy,

WITH1-3alkanoyloxy, trifluoromethyl or cyano;

R4selected from one of the following groups: 1) X1that is Spiridonova group, phenyl group or 5 - or 6-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, and Spiridonova, phenyl or heterocyclic group may bear 1-2 substituent selected from halogen, amino, C1-4of alkyl, C1-4alkoxy, C1-4hydroxyalkyl,1-4aminoalkyl,1-4alkylamino,1-4hydroxyalkoxy, carboxy, cyano, -CONR12R13and-NR14COR15where R12, R13, R14and R15that may be odinakovymi1where X1the same as defined above; 3)2-5alkenyl X1where X1the same as defined above; 4)1-5alkyl Y2X1where Y2represents-O-, -S-, -SO-, -SO2-, -NR16CO-, -NR19SO2- or-NR20- where R16, R19and R20independently are each hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl and X1the same as defined above; and 5)1-3alkyl Y5C1-3alkyl X1where Y5represents-O-, -NR31CO-, -NR34SO2-or-NR35- where R31, R34and R35independently are each hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl and X1the same as defined above; Z represents-NH - or-O-, provided that when R4selected from one of the above groups 1), 2) and 4) and X1represents unsubstituted phenyl or substituted phenyl with 1-2 substituents selected from halogen, C1-4the alkyl and C1-4alkoxy, m is an integer from 3 to 5 and/or Z is-O-;

and their salts.

2. Derivatives hintline under item 1, in which R1represents methoxy.

3. Derivatives hintline according to any one of the preceding points represents hydrogen, methyl, fluorine or chlorine;

Rbrepresents hydrogen, methyl, methoxy, bromine, fluorine or chlorine;

Rcrepresents hydrogen or hydroxy; and

Rdrepresents hydrogen, fluorine or chlorine.

4. Derivatives hintline according to any one of the preceding paragraphs, where Z represents NH.

5. Derivatives hintline according to any one of the preceding paragraphs, where Y1represents-O-.

6. Derivatives hintline according to any one of the preceding paragraphs, in which the fragment X1in the group R4is Spiridonova group or 5 - or 6-membered aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, and Spiridonova or heterocyclic group may optionally be substituted as described in paragraph 1.

7. Derivatives hintline under item 6, in which the fragment X1is Spiridonova, pyridyloxy, imidazolidinyl, thiazolidine, thienyl, triazolyl or pyridazinyl group, which may optionally be substituted as described in paragraph 1.

8. Derivatives hintline according to any one of the preceding paragraphs, in which R4represents a group X1-Y6-(CH2)n- where Y6to provide the tion in any of paragraphs. 1,6 and 7.

9. Derived hintline under item 1, chosen from:

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)-ethoxy] hintline;

4-(4-chloro-2-foronline)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline;

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyl)propoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-((4-pyridyl)methoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-Mei-1-yl)ethoxy)-hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-Mei-2-ylthio)ethoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1,2,4-triazole-1-yl)ethoxy)-hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-(4-pyridyl)amino)ethoxy)-hintline);

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1-Mei-2-yl)ethoxy)-hintline);

4-(4-chloro-2-foronline)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline;

and their salts.

10. Derived hintline under item 1, chosen from:

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)hintline;

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(2-pyridyloxy)hintline;

7-(2-acetamidomethyl-4-ylethoxy)-4-(3-hydroxy-4-methylaniline)-6-methoxyquinazoline;

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridylamine)hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridylamine)-hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(4-pyridyloxy)-hintline;

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline;

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-((2-methylthiazole-4-yl)-methoxy)hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(4-pyridyloxy) hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-((1-Mei-2-yl)methoxy)hintline;

7-((2-acetamidomethyl-4-yl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline;

7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxyquinazoline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(3-(4-pyridyl)propoxy)hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-imidazol-1-yl)ethoxy)-6-methoxyquinazoline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-7-(2-imidazol-1-yl)ethoxy)-6-methoxyquinazoline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-(4-pyridyl)ethoxy)chinasol is iLine)-6-methoxy-7-((1-methylbenzimidazole-2-yl)methoxy)hintline;

7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline;

4-(4-chloro-2-pertenece)-6-methoxy-7-((4-pyridyl)methoxy)hintline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((4-pyridyl)methoxy)-hintline;

4-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline);

7-(3,4-deferasirox)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((1-Mei-2-yl)methoxy)hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-((1-methylimidazole)methoxy)-hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-(1,2,4-triazole-1-yl)ethoxy)-hintline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((3-thienyl)-methoxy)-hintline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)-hintline;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-((4-pyridyl)carboxamido)-hintline;

and their salts.

11. Derived hintline under item 1, chosen from:

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(3-pyridyloxy)hintline;

4-(3-hydroxy-4-methylaniline)-6-methoxy-7-(3-teenrotica)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-pyridyloxy)ethoxy)hintline;

4-(4-chloro-2-(2-oxo-1,2-dihydro-1-pyridyl)-ethoxy] hintline;

7-(4-ziembinski)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline;

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-Mei-1-yl)propoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-((2-methyl-4-pyridyl)methoxy)-hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)-propoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(1-Mei-2-ylthio)propoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-pyridyloxy) propoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)jinsona;

7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylaniline)hintline;

7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)hintline;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-((2-methylthiazole-4-yl)-methoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-((3-thienyl)methoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)-amino)ethoxy)hintline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)hintline;

4-(4-chloro-2-foronline)-7-(2-(3,5-dimethyl-[1,2,4] -triazole-4-yl)ethoxy)-6-methoxyquinazoline;

4-(4-chloro-2-ftorn the l-1-yl)ethoxy)-6-methoxyquinazoline;

4-(3-hydroxyamino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline;

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(1,2,4-triazole-4-yl)ethoxy)hintline;

4-(4-bromo-2-foronline)-7-(2-([1,2,4] -triazole-1-yl)ethoxy)-6-methoxyquinazoline;

and their salts.

12. Derivatives hintline according to any one of the preceding paragraphs in the form of pharmaceutically acceptable salts.

13. The method of obtaining derivatives of hintline formula I or their salts under item 1, characterized in that interact the compounds of formula III

< / BR>
where R1, R2, R4and Y1such as defined in paragraph 1;

L1represents a leaving group, with a compound of formula IV

< / BR>
where Z, R3and m are such as defined in paragraph 1,

obtaining compounds of formula I and their salts, and, if necessary, when you want pharmaceutically acceptable salt chineselanguage derivative of the formula I, interact obtained compound with an acid or a base to obtain the desired pharmaceutically acceptable salt.

14. The method of obtaining derivatives of hintline formula I or their salts under item 1, in which the group of formula IIb

< / BR>
where R3and m are such as defined in paragraph 1,

the protective group from compounds of formula V

< / BR>
where Y1, m, R1, R2, R3, R4and Z is such as defined in paragraph 1;

P represents a phenolic hydroxyamino group;

R1represents an integer from 1 to 5 equal to the number of protected hydroxy groups, and the difference m-p1equal to the number of the substituents R3which are not protected hydroxy,

and, if necessary, when you want pharmaceutically acceptable salt chineselanguage derivative of the formula I, interact obtained compound with an acid or a base to obtain the desired pharmaceutically acceptable salt.

15. The method of obtaining derivatives of hintline formula 1 or their salts under item 1, in which the Deputy Y1represents-Oh, -S-, wherein interact the compounds of formula VI

< / BR>
where m, R1, R2, R3and Z is such as defined in paragraph 1;

Y1has the above values,

with the compound of the formula VII

R4-L1(VII)

where R4such as defined in paragraph 1;

L1- withdrawing group,

and, if necessary, when you want pharmaceutically acceptable salt chineselanguage derivative of the formula I, osushestvlyaem salt.

16. The method of obtaining derivatives of hintline formula I or their salts under item 1, characterized in that interact the compounds of formula VIII

< / BR>
where R1, R2, R3, Z and m are such as defined in paragraph 1;

L1- withdrawing group,

with the compound of the formula IX

R4-Y1-H (IX)

where R4and Y1such as defined in paragraph 1,

and when you want pharmaceutically acceptable salt chineselanguage derivative of the formula I, interact obtained compound with an acid or a base to obtain the desired pharmaceutically acceptable salt.

17. The method of obtaining derivatives of hintline formula I or their salts under item 1, in which R4is1-5alkyl X2where X2selected from the following three groups: 1)X1where X1such as defined in paragraph (1; 2)Y7X1where Y7represents-O-. -S-, -SO-, -SO2-, -NR47CO-, -NR48SO2- or-NR49- where R47, R48and R49independently are each hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl and X1such as defined in paragraph (1; 3) Y8C1-5alkyl X1where Y8represents-O-, -NR1-3
alkyl or C1-3alkoxyl2-3alkyl and X1such as defined in paragraph 1, wherein interact compounds of the formula X

< / BR>
where Y1, R1, R2, R3, Z and m are such as defined in paragraph 1;

L1-withdrawing group;

R53is1-5alkyl with a compound of formula XI

X2-H (XI)

where X2such as defined in the paragraph above,

obtaining the compounds of formula I, and, if necessary, when you want pharmaceutically acceptable salt chineselanguage derivative of the formula I, interact obtained compound with an acid or a base to obtain the desired pharmaceutically acceptable salt.

18. Pharmaceutical composition that creates an antiangiogenic effect and/or the effect of reducing vascular permeability, containing as an active ingredient derived hintline formula I, as defined in paragraph 1, or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable excipient or carrier.

19. The method of obtaining the antiangiogenic effect and/or the effect of reducing vascular permeability in a warm-blooded animal, Ormolu I or its pharmaceutically acceptable salt according to p. 1.

Priority points and features:

18.12.1995 under item 1 for compounds in which Y1represents-O - or-S-, R1, R2, R4and m have the meanings defined in paragraph 1 and R4selected from the following groups: 1) X1where X1matter specified in paragraph 1, except for X1- Spiridonova group or substituted specified in paragraph (1 substituents Spiridonova group; 2)1-5alkyl X1where X1the same as defined above; under item 2 above definitions, R4and X1; under item 3 (except for Ra- methyl) and PP. 4-5 for the above definitions of R4and X1; PP. 6 and 7 except for X1is unsubstituted or substituted Spiridonova group; under item 8 for compounds where Y6direct link, R4and X1have the above values; p. 10 for the first 9 compounds; p. 11 for the first 2 connections; under item 12 of part of the compounds defined above; on PP. 13-16 and 18 and 19, which receive and apply defined above under item 1 of the connection.

15.10.1996 under item 1 for connections with other values radicals and groups, not listed above; p. 2 for other values of the groups R4and X1is unsubstituted or substituted as specified in paragraph 1 replace the PP R4and X1is unsubstituted or substituted pyridine group; PP. 6 and 7, where X1is unsubstituted or substituted Spiridonova group; under item 8 for connection with the rest of the values Y6and X1; according to p. 9 for the first two compounds; p. 11 from the third to the fifth connection; p. 12 other connections; PP. 13-16 and 18-19, where the receive and apply defined above under item 1 of connection with the rest of the values radicals and groups, and on p. 17.

13.12.1996 for the remaining compounds listed in paragraphs. 9-11.

 

Same patents:

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to a new, more thermodynamically stable crystalline form of the hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-chroman

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to a medicinal product on the basis of derivatives of thiazole or thiadiazole of the formula I, where a denotes a linear or branched C1-C18-alkylenes group which may contain at least one group selected from the group consisting of: O, S, NR3, СОNR3, NR3CO, COO, OCO or double or triple bond; In denotes the radical of the formula II, R1denotes H, halogen JV CO2R2, NR2R3, OR SIG3, CF3or C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen; R2denotes H, C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen, or phenyl-C1-C8-alkyl; R3has the meanings given for R2or indicate СОR2or CO2R2; X represents N or CR4where R4denotes H, C1-C8-alkyl, which is not substituted or is substituted by IT, OS1-C8-alkyl or halogen, or denotes phenyl which is not substituted or substituted with halogen, CF3C1-C8-alkyl or C1-C8-alkoxy; Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl,

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol
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