Derivatives hintline and their use as inhibitors of growth factor vascular endothelial

 

(57) Abstract:

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts. Proposed five methods of obtaining the above-described compounds. The compounds of formula I have antiangiogenic and/or reducing vascular permeability effect in warm-blooded animals and are intended for use as drugs with the specified action. The invention also relates to pharmaceutical compositions containing the above compounds, and to the way ingebretsen. 8 C. and 13 C.p. f-crystals, 1 PL.

The present invention relates to the derivatives of hintline, methods of producing these compounds, pharmaceutical compositions containing them as active ingredient, methods for treating diseases associated with angiogenesis and/or increased vascular permeability, to the use of these substances as drugs and for the manufacture of medicines, providing antiangiogenic effect and/or reduce vascular permeability in warm-blooded animals, particularly humans.

Normal development of blood vessels plays an important role in several processes, including embryonic development, wound healing, and some components of reproductive function of women. Undesirable or pathological angiogenesis is associated with several 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). It is believed that the vascular permeability changes is set as in 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). Identify the basic fibroblast growth factors (aFGF & bFGF), as well as growth factor vascular endothelial (VEGF). Due to limited expression of VEGF receptors activity of this growth factor in contrast to FGF is limited mainly by endothelial cells. Recent evidence indicates 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). Inhibition of VEGF activity in removing antibodies allows to inhibit the growth of tumors (Kirn et al., 1993, Nature 362: 841-844).

Tyrosine kinase receptors (RTK) are important for the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules consist of extracellular landscapebased domain, which is connected with the segment in the plasma membrane to the intracellular tyrosine kinase domain. The binding of ligand to the receptor stimulates the tyrosine kinase activity of the receptors, which in turn causes phosphorylation of tyrosine residues in the receptor and other intracellular molecules. Changes in the phosphorylation of tyrosine, initiate signal sequence, viocemail RTK, defined by amino acid sequence homology. One of these subfamilies is fms-like tyrosine kinase receptor, Flt or Flt1 containing the kinase domain insert, KDR (defined as Flk-1), and another fms-like tyrosine kinase receptor Flt4. It is established that two of the related RTK receptors, Flt and KDR, bind VEGF with a high degree of epinasty (De Vries et al., 1992, Science 255: 989-991); Terman et al. , 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). The VEGF binding to these receptors expressed in heterologous cells, is associated with changes in cellular proteins and threads of calcium due to phosphorylation of tyrosine.

Compounds that effectively affect epidermal growth factor (EGF) tyrosine kinase receptors, are discussed in the publication of the European patent 0566226, but this patent does not suggest that these compounds inhibit the action of VEGF. In the publication of the European patent 0326330 describes fungicides plants based on quinoline, hinzelin and cinnoline. This patent also indicates that some of these fungicides possess insecticidal and acaricidal action. However, it doesn't say that any of the described compounds can be used for the treatment of Ms. the project, regarding angiogenesis and/or increased vascular permeability that occurs under the action of these growth factors like VEGF.

The basis of the present invention lies in the discovery of compounds that inhibit the action of VEGF, which is important for the treatment of diseases associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma and hemangioma, acute and chronic neuropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases caused by proliferation of cells in the retinal vessels. Compounds of the present invention effectively affect tyrosinekinase of VEGF receptors and have an insignificant impact on tyrosinekinase of EGF receptors. In addition, the compounds of the present invention are much more active against the tyrosine kinase VEGF receptors, tyrosine kinase than against EGF receptor or tyrosine kinase FGF receptors R1. Thus, as shown by the test results, the compounds of the present invention effectively affect tyrosinekinase VEGF receptors, so they can be used in required for inhibition of quantities, not fear One object of the present invention are derivatives of hintline formula I:

< / BR>
[where:

Z represents-O-, -NH - or-S-;

m is an integer from 1 to 5, provided that when Z represents-NH-, m is an integer from 3 to 5;

R1denotes hydrogen, hydroxy, halogen, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio or-NR5R6(where each of R5and R6that may be the same or different values, denotes hydrogen or C1-3alkyl);

R2denotes hydrogen, hydroxy, halogen, methoxy, amino or nitro;

R3denotes hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;

X1denotes-O-, -CH2-, -S-, -SO-, -SO2-, -NR7-, -NR8CO-, -CONR9-, -SO2NR10- or-NR11SO2(where each of R7, R8, R9, R10and R11denotes hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl);

R4choose one of the following seven groups, which contain:

1) hydrogen, C1-5alkyl, C1-5hydroxyalkyl (preferably2-5hydroxyalkyl)1-5foralkyl,1-5aminoalkyl;

2)1-5alkyl2CR12axis2-3alkyl) and R12represents C1-3alkyl, -NR14R15or16(where each of R14, R15and R16that may be the same or different values, denotes hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl));

3)1-5alkyl3R17(where X3denotes-O-, -S-, -SO-, -SO2-, -OCO-, -NR18CO-, -CONR19-, -SO2NR20-, -NR21SO2- or-NR22- (where R18, R19, R20, R21and R22independently of one another denote hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and R17denotes hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from one another from O, S and N, with C1-3the alkyl group may have one or two substituent selected from oxo, hydroxy, halogen and C1-4alkoxy and a cyclic group can have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy);

4)1-5R23(where R23denotes a 5 - or 6-membered saturated heterocyclic group with a substituent, selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy);

5)2-5R23(where R23has the above values);

6)2-5R23(where R23has the above values); and

7)1-5alkyl4C1-5alkyl5R24(where each of X4and X5that may be the same or different values, denotes-O-, -S-, -SO-, -SO2-, -NR25CO-, -CONR26-, -SO2NR27-, -NR28SO2- or-NR29- (where R25, R26, R27, R28and R29independently of one another denote hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and R24denotes hydrogen or C1-3alkyl);] excluding

4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazolin,

4-(3-methoxybenzylthio)-6,7-dimethoxyquinazolin,

4-(3-chlorophenylthio)-6,7-dimethoxyquinazolin,

4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin,

4-(3-chlorophenylthio)-6,7-dimethylindoline and

4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin,

and their salts.

Z mainly represents-S-, preferably-O - and most preferably-NH-.

When Z represents-S - or-O -; m is the integer is P>R1denotes hydrogen, hydroxy, cyano, nitro, trifluoromethyl, C1-3alkyl, C1-3alkoxy or amino.

R1preferably represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, more preferably hydrogen, cyano, nitro, trifluoromethyl, hydroxy, methyl or methoxy, and most preferably methoxy.

When X1refers to-NR8CO-, R1preferably denotes hydrogen.

R2preferably represents hydrogen, fluorine, amino or nitro, and most preferably hydrogen.

In accordance with one variant of the present invention R3denotes hydroxy, halogen, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro, preferably hydroxy, halogen or C1-2alkyl and most preferably hydroxy or halogen.

In accordance with another variant of the present invention, one substituent R3mainly is hydroxy, preferably Metagalaxy, and the other substituents are selected from halogen, methyl and methoxy.

In accordance with another variant of the invention the phenyl group-containing (R3)mEOS, preferably hydrogen, fluorine or chlorine, and most preferably fluorine;

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

Rcdenotes hydrogen or hydroxy, preferably hydroxy;

Rddenotes hydrogen, fluorine or chlorine, preferably hydrogen or fluorine.

In accordance with another variant of the invention, two Deputy R3preferably represent halogen, preferably ortho, ortho'-debtor, and the other substituents are selected from halogen, hydroxy and methyl, preferably from halogen and methyl.

A distinctive feature of the present invention is that the phenyl group-containing (R3)mrepresents 2-fluoro-5-hydroxy-4-methylphenyl group, 4-bromo-2,6-differenly group, 4-chloro-2-fluoro-5-hydroxyphenyl group, 4-chloro-2,6-differenly group or 2,4-debtor-5-hydroxyphenyl group or, when Z represents O or S, 4-chloro-2-florfenicol group.

Phenyl group containing (R3)mpreferably is 4-chloro-2-fluoro-5-hydroxyproline group or 2-fluoro-5-hydroxy-4-methylphenylene group or, when Z represents O or S, 4-chloro-2-forfamilies group. Nabol group.

X1usually denotes-O-, -S-, -CH2-, -NR8CO-, -CONR9-, -NR11SO2- or-NR7- (where R7, R8, R9and R11independently of one another denote hydrogen, C1-3alkyl (in particular, C1-2alkyl) or (C1-2alkoxyethyl).

X1mainly denotes-O-, -S-, -NR8CO-, -NR11SO2- or-NR7- (where R7, R8and R11independently of one another denote hydrogen, C1-2alkyl or C1-2alkoxyethyl).

X1preferably represents-O-, -S-, -NR8CO-, -NR11SO2- (where R8and R11independently of one another denote hydrogen or C1-2alkyl) or NH.

X1more preferably represents-O-, -S-, -NR8CO- (where R8denotes hydrogen or methyl) or NH.

X1most preferably denotes-O - or-NHCO-, in particular-O-.

X2mainly denotes-O - or-NR13- (where R13denotes hydrogen, C1-3alkyl or C1-2alkoxyethyl).

X3mainly denotes-O-, -S-, -SO-, -SO2-, -NR18CO-, -NR21SO2- or-NR22- (where R18, R21and R22independently from each other about the em-O-, -S-, -SO-, -SO2- or-NR22- (where R22denotes hydrogen, C1-2alkyl or C1-2alkoxyethyl).

X3more preferably represents-O - or-NR22- (where R22denotes hydrogen or C1-2alkyl).

X4and X5that may have identical or different meanings, mainly represent-O-, -S-, -SO-, -SO2- or-NR29- (where R29denotes hydrogen, C1-3alkyl or C1-2alkoxyethyl).

X4and X5that may be the same or different values, preferably denotes-O-, -S - or-NR29- (where R29denotes hydrogen, C1-2alkyl or C1-2alkoxyethyl).

X4and X5, each of which may be the same or different values, more preferably denotes-O - or-NH.

R4usually choose one of the following nine groups that contain:

1) C1-5alkyl, C2-5hydroxyalkyl,1-5foralkyl,1-5aminoalkyl;

2)1-5alkyl2R12(where X2has the above meaning and R12represents C1-3alkyl, -NR14R15or15(where each of R14, R15and R16to whom SUB>2-3alkyl));

3)1-5alkyl3R17(where X3has the above meaning and R17denotes hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from each other O, S or N, with C1-3the alkyl group may have one or two substituent selected from oxo, hydroxy, halogen and C1-3alkoxy and a cyclic group can have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy);

4)1-5R30(where R30denotes a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from one another from O, S and N, which joined WITH1-5the alkyl with carbon atoms and may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy) or (C2-5R31(where R31denotes a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the second independently from others who may have one or two substituent, selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy);

5)3-4R30(where R30has the above values);

6)3-4R30(where R30has the above values);

7)3-4R31(where R31has the above values);

8)3-4R31(where R31has the above values);

9)1-5alkyl4C1-5alkyl5R24(where X4and X5have the above meanings and R24denotes hydrogen or C1-3alkyl).

R4mainly choose one of the following nine groups that contain:

1) WITH THE1-5alkyl, C2-5hydroxyalkyl,1-5foralkyl,2-4aminoalkyl;

2) C2-3alkyl2COR12(where X2has the above meaning and R12represents C1-3alkyl, -NR14R15or16(where each of R14, R15and R16that may be the same or different values, represents C1-2alkyl or C1-2alkoxyethyl));

3)2-4alkyl3R17(where X3has the above meaning and R17about the which is attached to X3with the help of carbon atoms, with C1-3the alkyl group may have one or two substituent selected from oxo, hydroxy, halogen and C1-2alkoxy, and cyclopentene, tsiklogeksilnogo, pyrrolidinyl or piperidinyl group may have one Deputy, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy);

4)1-4R30(where R30denotes a group selected from pyrrolidinyl, piperazinil, piperidinyl, 1,3-dioxolane-2-yl, 1, 3-dioxane-2-yl, 1,3-ditiolan-2-yl and 1,3-dition-2-yl, which is attached to1-4the alkyl with carbon atoms and may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2-hydroxyalkyl and C1-2alkoxy) or (C2-4R31(where R31denotes a group selected from morpholino, thiomorpholine, pyrrolidin-1-yl, piperazine-1-yl and piperidino, which may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy);

5)3-4R30(where R30has the above values);

6)3-4R30(where RCane);

8)3-4R31(where R31has the above values);

9)2-3alkyl4C2-3alkyl5R24(where X4and X5have the above meanings and R24denotes hydrogen or C1-3alkyl).

R4preferably choose one of the following five groups, which contain:

1) C1-3alkyl, C2-3hydroxyalkyl, C1-3foralkyl,2-3aminoalkyl;

2) 2-(3,3-dimethylurea)ethyl, 3-(3,3-dimethylurea)propyl, 2-(3-methylurea)ethyl, 3-(3-methylurea)propyl, 2-braidouts, 3-ureidopropionic, 2-(N, N-dimethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl, 2-(N-methylcarbamoyl)ethyl, 3-(N-methylcarbamoyl)propyl, 2-(carbamoylated)ethyl, 3-(carbamoylated)propyl;< / BR>
3) C2-3alkyl3R17(where X3has the above meaning and R17denotes a group selected from C1-2of alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl that is attached to X3using carbon atom, WITH1-2the alkyl group may have one or two substituent selected from hydroxy, halogen and C1-2alkoxy, and cyclopentene, tsiklogeksilnogo, pyrrolidinyl or SUB> hydroxyalkyl and C1-2alkoxy);

4)1-2R30(where R30denotes a group selected from pyrrolidinyl, piperazinil, piperidinyl, 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl and 1,3-dition-2-yl, which is attached to1-2the alkyl with carbon atoms and may have one alternate, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy) or (C2-3R31(where R31denotes a group selected from morpholino, thiomorpholine, piperidine, piperazine-1-yl and pyrrolidin-1-yl, which may have one Deputy, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy); and

5) C2-3alkyl4C2-3alkyl5R24(where X4and X5have the above meanings and R24denotes hydrogen or C1-2alkyl).

R4more preferably denotes methyl, ethyl, trifluoromethyl, 2,2,2-triptorelin, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-sulphatoethyl, 2-(N,N-dimethylamino)ethyl, 3-(N, N-dimethyl who piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolane-2-yl)methyl, 2-(1,3-dioxolane-2-yl)ethyl, 2-(2-methoxyethylamine)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamine)propyl, 3-(2-hydroxyethylamino)propyl, 2-thiomorpholine, 3-thiomorpholine, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl or 2-(2-methoxyethoxy)ethyl.

R4in particular represents 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulfinyl) ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropan, 2-piperidinoethyl, 3-piperidinoethyl, 2-(piperazine-1-yl)ethyl, 3-(piperazine-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolane-2-yl)methyl, 2-(1,3-dioxolane-2-yl)ethyl, 2-(2-methoxyethylamine)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamine) propyl, 3-(2-hydroxyethylamino)propyl, 2-thiomorpholine, 3-thiomorpholine, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl or 2-(2-methoxyethoxy)ethyl. The preferred compounds are:

4-(4-bromo-2,6-diptiranjan)-6,7-dimethoxyquinazolin;

4-(4-bromo-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-thiomorpholine)-6-methoxy-7-(3-morpholinopropan)hinzelin;

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethoxy)hinzelin;

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

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazolin;

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

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

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

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethylamine)hinzelin;

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

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

4-(2,4-debtor-5-hydroxyimino)-6,7-dimethoxyquinazoline)-6-methoxy-7-(3-morpholinopropan)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetophenone;

4-(4-bromo-2,6-diptiranjan)-6-methoxy-7-(3-morpholinopropan)hinzelin and their salts, in particular, hydrochloric salt.

More preferred compounds are:

4-(4-bromo-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

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

6,7-dimethoxy-4-(3-hydroxy-4-methylphenoxy)hinzelin;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(3-morpholinopropan)hinzelin;

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethoxy)hinzelin;

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

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazolin;

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

7-(2-acetoacetate)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyindole is of aniline)-6-methoxy-7-(2-piperidinoethyl)hinzelin;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethylamine)hinzelin;

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

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

4-(2,4-debtor-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2,4-debtor-5-hydroxyimino)-6-methoxy-7-(2-methoxyethoxy)hinzelin;

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

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetophenone;

4-(4-bromo-2,6-diptiranjan)-6-methoxy-7-(3-morpholinopropan)hinzelin and their salts, in particular, hydrochloric salt.

Particularly preferred compounds are:

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazolin;

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

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-morpholinoethoxy the PRS-5-hydroxyimino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethylamine)hinzelin;

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

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

4-(2,4-debtor-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2,4-debtor-5-hydroxyimino)-6-methoxy-7-(2-methoxyethoxy)hinzelin;

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

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetophenone;

4-(4-bromo-2,6-diptiranjan)-6-methoxy-7-(3-morpholinopropan)hinzelin and their salts, in particular, hydrochloric salt.

Even more preferred compounds are:

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hinzelin;

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazolin;

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

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

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetanilide salt.

The most preferred compounds are:

4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazolin;

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

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetophenone;

4-(4-bromo-2,6-diptiranjan)-6-methoxy-7-(3-morpholinopropan)hinzelin and their salts, in particular, hydrochloric salt.

To avoid any doubt, it is necessary to clarify that in cases where in this description, the group is defined as "above" or "with the above values, it means that this group covers the first-mentioned and most broad definition, as well as all of the preferred definitions given for this group.

In this description, the term "alkyl" means alkyl groups of straight and branched chain, and references to individual alkyl groups such as "propyl" are only to groups with a direct chain. A similar definition applies to other generic terms. Except where otherwise indicated, the term "alkyl" refers to groups having 1-6 carbon atoms, preferably 1-4 carbon atoms. The term "alkoxy" means alkyl groups of the dust, which optionally can have one or more substituents selected from halogen, alkyl, alkoxy, cyano, nitro or trifloromethyl (where the alkyl and alkoxy have the above values). The term "aryloxy" means the above-mentioned aryl group attached to the oxygen atom. The term "sulfonyloxy" means alkylsulfonate, arylsulfonate, where "alkyl" and "aryl" are the above values. The term "alkanoyl" except where otherwise indicated, means alkyls=O groups in which "alkyl" has the above values, for example, ethanol means of CH3C= O. except where otherwise indicated, the term "alkenyl" means alkeneamine group with straight and branched chain, and links to individual alkeneamine groups such as 2-butenyl apply only to groups with a direct chain. Except where otherwise indicated, the term "alkenyl" mainly means a group having 2-5 carbon atoms, preferably 3-4 carbon atoms. Except where otherwise indicated, the term "quinil" means alkyline group with straight and branched chain, and links to individual alkyline groups such as 2-butenyl apply only to groups with a direct chain. With the exception of osoba carbon.

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

For hintline formula I or its salts is characterized by the phenomenon of tautomerism, despite the fact that the chemical formula given in the description of the invention, can Express only one of the possible tautomeric forms. It is quite clear that the scope of the present invention includes all tautomeric forms, which inhibit the tyrosine kinase activity of VEGF receptors, and the invention is not limited to any one tautomeric form depicted in the drawings, the chemical formulas.

In addition, certain hintline formula I and their salts can be solvated and nonsolvated forms, for example, hydrated forms. It is quite clear that the scope of the present invention includes all of solvated forms which inhibit the tyrosine kinase activity of the VEGF receptors.

To avoid any doubt, it is necessary to clarify that in cases where X1is, for example, a group of the formula-NR8CO-, a nitrogen atom linking group, R8attached to hinazolinam ring and the carbonyl (CO) group attached to R4and when X1is, for example, a group of four is9attached to R4. The same applies to the other two binding groups X1such as-NR11SO2- and-SO2NR10-. When X1is-NR7-, the nitrogen atom linking group, R7attached to hinazolinam ring and R4. The same applies to other groups. Next, you need to understand that when X1refers to-NR7and R7is C1-3alkoxy WITH2-3the alkyl, C2-3alkyl part is attached to the nitrogen atom of the group X1. A similar explanation holds true for other groups.

To avoid any doubt, it is necessary to clarify that when the compound of the formula I R4is, for example, a group of the formula C1-5R23WITH1-5alkyl part is attached to X1similarly, when R4is, for example, a group of the formula C2-5R23WITH2-5Alchemilla part attached to X1. A similar explanation holds true for other groups. When R4is a group 1-R23prop-1-EN-3-yl, R23attached to the first carbon atom, and the third carbon atom attached to X1. A similar explanation holds true for other groups.

The present izobrajat only a pharmaceutically acceptable salt, but to obtain the compounds of formula I and their pharmaceutically acceptable salts can be used, and other salts. Pharmaceutically acceptable salts of the present invention include, for example, salts of accession acid compounds of the formula I, which are quite essential for the formation of such salts. Salts accession acids include, in particular, salts with inorganic or organic acids which form pharmaceutically acceptable anions, such as hydrogen halides (in particular, hydrochloric or Hydrobromic acid, of which preference is given to hydrochloric acid), sulfuric or phosphoric acid or with triperoxonane, citric or maleic acid. In addition, in those cases where the compounds of formula I are sufficiently acid, pharmaceutically acceptable salts can be obtained by the interaction with an inorganic or organic base, which gives a pharmaceutically acceptable cation. Such salts with inorganic or organic bases are, for example, alkali metal salts, such as salts of sodium or potassium, salts of alkaline earth metals such as calcium salts or magnesium salts, ammonium salts or salts with mediaevalia formula I or their salts and other compounds of the present invention (above) can be obtained according to any known means of obtaining related chemically compounds. Such methods are described, for example, in the publication of applications at the European patent 0520722, 0566226, 0602851 and 0635498. These methods are another object of the present invention and described in detail below. Getting these starting compounds are described in the accompanying examples, not limiting scope of this invention. Other necessary educt receive in accordance with methods that are similar to those described herein and well known to chemists organikum.

Thus, the following methods (a)-(g) and (i) to(v) are another object of the present invention.

The synthesis of compounds of formula I

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

< / BR>
(where R1, R2X1and R4have the abovementioned meanings and L1is replaced part) with the compound of the formula IV:

< / BR>
(where Z, R3and m have the above values), which gives the compounds of formula I and their salts. Acceptable replaced part of the L1is, for example, halogen, alkoxy (preferably WITH1-4alkoxy), aryloxy or sulfonyloxy, in particular, chlorine, bromine, methoxy, phenoxy, methansulfonate or toluene-4-sulfonyl is This acid is for example, anhydrous inorganic acid, in particular, hydrogen chloride. Such a base is, for example, an organic amine base, in particular, pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0] undec-7-ene, or a carbonate or hydroxide of an alkaline or alkaline-earth metal, in particular sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. This may also be an alkali metal hydride, e.g. sodium hydride or amide of alkaline or alkaline-earth metal, for example, amide or sodium bis(trimethylsilyl)amide and sodium. This reaction is preferably carried out in the presence of an inert solvent or diluent, for example, alkanol or complex ether, such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, simple ether such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine-2-one or dimethylsulfoxide. This reaction which allows persons to obtain the compounds of the present invention in the form of free bases or salts with an acid of the formula H-L1where L1has the above meaning. When salt is necessary to obtain the free base, this salt is treated with the above basis in accordance with the known method.

(b) When a group of formula IIA:

< / BR>
(where R3and t have the values indicated above) is a phenyl group having one or more hydroxyl groups, compounds of formula I and their salts can be obtained by removing the protection of the compounds of formula V:

< / BR>
(where X1, m, R1, R2, R3, R4and Z have the above values, P represents a phenolic hydroxyamino group, and R1is an integer from 1 to 5, which is equal to the number of protected hydroxyl groups, with m-R1equal to the number of the substituents R3that are not protected hydroxyl groups). You have the option to use the well-known phenolic hydroxyamine group R, for example, the groups described in such works as "Protective Groups in Organic Synthesis" T. W. Greene and R. G. M. Wuts, 2ndEd. Wiley 1991, including ethers (for example, methyl, methoxymethyl, allyl and benzyl), Silovye esters (for example, tert-butyldiphenylsilyl and tert-butyldimethylsilyloxy), esters (should be removed by any known method, creating reaction conditions specified in scientific works, such as the above, or similar ways. Reaction conditions preferably should provide hydroxyl derivative without adverse reactions at other sites of the original substances or receive connections. For example, when the protective group P is acetate, this transformation can be achieved by processing the derived hintline the above basis, including ammonia, and its mono - and dialkylamino derivatives, preferably in the presence of proton solvent or co-solvent such as water or an alcohol, e.g. methanol or ethanol. This reaction can be performed in the presence of more of the above inert solvent or diluent and at a temperature of from 0 to 50oWith, typically at a temperature of approximately 20oC.

(C) the compounds of formula I and their salts, in which the Deputy X1is-O-, -S - or-NR7- you can get as a result of interaction, usually in the presence of the above reasons, the compounds of formula VI:

< / BR>
(where m, X1, R1, R2, R3and Z have the values indicated above) with the compound of the formula VII:

the th part, for example, a halogen or sulfonyloxy, such as bromine or methysulfonylmethane. This reaction is preferably carried out in the presence of a base (specified above in method (a)) and preferably in the presence of an inert solvent or diluent (as specified above in method (a)) at a temperature of from 10 to 150oUsually about 50oC.

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

< / BR>
with the compound of the formula IX:

R4-X1-H, (IX)

(where L1, R1, R2, R3, R4, Z, m and X1have the above values). This reaction can be performed in the presence of base (above in method (a)) and preferably in the presence of an inert solvent or diluent (as specified above in method (a)) at a temperature of from 10 to 150oUsually about 100oC.

(e) Compounds of the formula I and their salts, in which R4stands WITH1-5R32[where R32choose one of the following four groups, which contain:

1) X6C1-3alkyl (where X6denotes-O-, -S-, -SO2-, -NR33CO - or-NR34SO2- (where R33and R34R36(where each of R35and R36that may be the same or different values, denotes hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl);

3) X7C1-5alkyl5R24(where X7denotes-O-, -S-, -SO2-, -NR37CO-, -NR38SO2- or-NR39(where R37, R38and R39independently of one another denote hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and X5and R24have the above values); and

4) R31(where R31has the above values);]

you can get as a result of interaction of the compounds of formula X:

< / BR>
(where L1X1, R1, R2, R3, Z and m have the above meanings and R40stands WITH1-5alkyl) with a compound of formula XI:

R32-H (XI)

(where R32has the above values), giving the compound of formula I. This reaction can be performed in the presence of base (above in method (a)) and preferably in the presence of an inert solvent or diluent (as specified above in method (a)) at a temperature of from 0 to 150oUsually about 50oC.

(f) the compounds of formula I and their salts, in which semistability as a result of interaction of the compounds of formula I, in which the substituent R1is an amino group, alkylating agent, preferably in the presence of the above reasons. Such alkylating agents are C1-3alkyl

parts having the above substituted part, in particular, C1-3alkylhalogenide, for example, C1-3alkylchloride, bromide or iodide. This reaction is preferably carried out in the presence of an inert solvent or diluent (as specified above in method (a)) at a temperature of from 10 to 100oUsually at about room temperature. This method can also be used to obtain compounds in which R4-X1is alkylamino or dialkylamino.

(g) the compounds of formula I and their salts in which one or more of the substituents R1, R2or R3are amino group, or R4-X1is an amino group, can be obtained by recovery of the corresponding compounds of formula I in which one or more of the substituents in the relevant provisions of hintline and/or phenyl ring is a nitro group. Recovery can be accomplished as described in the following way (i). The compounds of formula I and their with the CA are nitro groups, can be obtained as described in the above and following methods (a-e) and (i-v) using the connection of hintline selected from compounds of formulas (I-XXVII) in which one or more of the substituents in the relevant provisions of hintline and/or phenyl ring is a nitro group.

Synthesis of intermediate compounds

(i) the compounds of formula III and their salts are another object of the present invention. Such compounds in which L1is halogen, it is possible, for example, be obtained by halogenation of compounds of formula XII:

< / BR>
(where R1, R2, R4and X1have the above values).

Acceptable halogenation agents are halides of inorganic acids, for example, thionyl chloride, chloride, phosphorus (III) oxychloride phosphorus (V) chloride, phosphorus (V). Halogenoalkane usually produced in the presence of an inert solvent or diluent, for example, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. This reaction is usually carried out at a temperature from 10 to 150oC, preferably from 40 to 100oC.


< / BR>
(where R1, R2and L1have the above values) with the above compound of formula IX. This reaction is usually carried out in the presence of a base (specified above in method (a)) and preferably in the presence of an inert solvent or diluent (as specified above in method (a)) at a temperature of from 10 to 150oUsually about 100oC.

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

< / BR>
(where R1, R2, R4and X1have the above values and a1is hydroxy, alkoxy (preferably1-4alkoxy or amino group), which gives the compound of formula XII or salt. The cyclization can be accomplished by the interaction of the compounds of formula XIV, in which1is hydroxyl or CNS group, formamide or similar connection, causing cyclization, giving the compound of formula XII or salt, such as chloride[3-(dimethylamino)-2-isoprop-2-enylidene]dimethylammonio. The cyclization is usually carried out in the presence of formamide used as a solvent or in the presence of an inert solvent or diluent, for example, a simple ester,Les from 80 to 200oC. the compounds of formula XII can also be obtained by cyclization of compounds of formula XIV, in which AND1is an amino group, with formic acid or a similar compound, causing cyclization, giving the compound of formula XII or salt. Substitute formic acid, effectively causing cyclization is, for example, three1-4alkoxylates, in particular, triethoxysilane and trimethoxymethane. The cyclization is usually carried out in the presence of catalytic amount of anhydrous acid, such as acid, for example, paratoluenesulfonyl, and an inert solvent or diluent, for example, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, simple ether, such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene. The cyclization is usually carried out at a temperature from 10 to 100oC, preferably from 20 to 50oC.

The compounds of formula XIV and their salts, which are another object of the present invention, can be obtained by restoring the nitro group in the compound of formula XV:

< / BR>
(where R1, R2, R4X1and1have ukazannymi ways. Recovery can be accomplished, for example, by hydrogenation of a solution of the nitro compounds in the presence of the above inert solvent or diluent and metal, effectively catalyzing hydrogenation reactions, such as palladium or platinum. Another reducing agent is, for example, activated metal, in particular, activated iron (resulting from leaching of iron powder diluted aqueous acid, e.g. hydrochloric acid). Thus, recovery can be accomplished by heating nitrosoaniline and the activated metal in the presence of a solvent or diluent, for example, a mixture of water and alcohol, such as methanol or ethanol, to a temperature in the range from 50 to 150oUsually about 70oC.

The compounds of formula XV and salts, which are another object of the present invention, can be obtained by the interaction of the compounds of formula XVI:

< / BR>
(where R1, R2L1and1have the above values) with the above compound of formula IX, which gives the compound of formula XV. The interaction of compounds of formulas XVI and IX are usually carried out under the conditions described for process (d).

Connection fo>
, R2X1and1have the above values are under the condition that X1is not-CH2-) with the compound of the formula VII, which gives the above compound of formula XV. The interaction of compounds of formulas XVII and VII usually carried out under the conditions described for the method (s).

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

< / BR>
(where R1, R2and X1have the above values are under the condition that X1is not-CH2and L2is replaced protective part) with the above compound of formula VII, which gives the compound of formula III in which L1presents L2.

Usually used as a compound of the formula XVIII, in which L2denotes fenoxaprop, with optionally up to 5 substituents, preferably up to 2 substituents selected from halogen, nitro and cyano. This reaction is usually carried out under the conditions described for the method (s).

The above compounds of formula XVIII and their salts can be obtained by removing the protection of the compounds of formula XIX:

< / BR>
(where R1, R2, P, X1and L2have the above values are under the condition that X1not benzyl group, to remove the protection by hydrogenolysis or by treatment triperoxonane acid.

One compound of the formula III can be optionally converted into another compound of the formula III, in which part of the L1has a new meaning. For example, the compound of formula III in which L1is not halogen, and optionally substituted by fenoxaprop can be converted to a compound of formula III in which L1is halogen, by hydrolysis of the compounds of formula III (where L1is not halogen), which gives the above compound of formula XII, and the subsequent introduction of the halide in the compound of formula XII, resulting in the receive connection of the formula III in which L1is halogen.

(ii) the compounds of formula V and their salts are another object of the present invention and can be obtained by the interaction of the above compounds of formula III with the compound of the formula XX:

< / BR>
(where R3, m, R1, R and Z have the above values). This reaction can be carried out in accordance with the above-described method (a).

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

< / BR>
(where R1, R IX. This reaction can be carried out in accordance with the above method (d).

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

< / BR>
(where R1, R2, R3X1, Z, P, P1and m have the above values are under the condition that X1is not-CH2- with the above compound of formula VII. This reaction can be carried out in accordance with the above-described method (C).

The compounds of formula XXI and their salts can be obtained by the interaction of the compounds of formula XXIII:

< / BR>
(where R1, R2and L1have the abovementioned meanings and L1in 4 - and 7-positions may be the same or different values) with the above compound of formula XX. This reaction can be carried out in accordance with the above-described method (a).

The compounds of formula XXII and their salts can be obtained by the interaction of the above compounds of formulas XIX and XX in the conditions described for method (a), which gives the compound of formula XXIV:

< / BR>
(where R1, R2, R3, P, Z, X1, R1and m have the above values are under the condition that X1is not-CH2- ) and follow the above compounds of formula VI and their salts can be obtained by removing the protection of the compounds of formula XXV:

< / BR>
(where R1, R2, R3, P, Z, X1and m have the above values) in accordance with the above-described method (i).

The compounds of formula XXV and their salts can be obtained by the interaction of the above compounds of formulas XIV and IV under conditions described in method (a), which gives the compound of formula XXV or its salt.

(iv) the compounds of formula VIII and their salts can be obtained by the interaction of the above mentioned compounds of the formulae XXIII and IV. This reaction can be carried out in accordance with the above-described method (a).

(v) the above compounds of formula X and their salts can be obtained by the interaction of the above compounds of formula VI with the compound of the formula XXVI:

L1-R40-L1, (XXVI)

(where L1and R40have the above values), giving the compound of formula X. This reaction can be carried out in accordance with the above-described method (C).

The compounds of formula X and their salts can also be obtained by removing the protection of the compounds of formula XXVII:

< / BR>
(where L1, R40X1, R1, R2, R3, Z, R, m, and R1have the above values) as described in method (b).

Pharmaceutically acceptable salt of the compounds of formula I can be obtained, for example, as a result of interaction of the compounds with acid in accordance with the known method, the acid must be pharmaceutically acceptable anion.

Many considered here, the intermediate compounds possess the characteristics of novelty, for example, compounds of formulas III, V, XII, XIV and XV, which is another object of the present invention.

Intermediate compounds of formulas VIII, X, XXI, XXII, XXIV, XXV and XXVII are also the object of the present invention.

In addition, an object of the present invention is a very useful method for the identification of compounds that effectively inhibit the tyrosine kinase activity associated with the VEGF receptors such as Flt and/or KDR, and inhibit angiogenesis and/or increased vascular permeability. These properties can be determined using one or more of the following methods:

(a) the Test for inhibition of tyrosine kinase receptors in vitro

This analysis allows to determine the ability of the test compound to inhibit the activity of tyrosine kinase. DNA encoding the cytoplasmic domains of receptiondesk genes (Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or cloning. They can be expressed in acceptable expressing the system in order to obtain a polypeptide with the activity of tyrosine kinase. For example, it is established that the cytoplasmic domains of the receptors for VEGF and EGF obtained by expression of recombinant protein in insect cells, possess inherent initially tyrosine kinase activity. For analysis of VEGF receptor Flt (number H catalog gene Bank) a DNA fragment of 1.7 T. p. N., encoding a large part of the cytoplasmic domain, starting with methionine 783 to the termination codon, described Shibuya and others (Shibuya et al., Oncogene, 1990, 5: 519-524), isolated from cDNA and cloned in the vector transfer-based baculovirus (e.g., pAcYMl (see The Baculovirus Expression System: A Laboratory Guide, L. A. King and R. D. Possee, Chapman and Hall, 1992), RAS or pBlueBacHis (provided by the company Invitrogen Corporation). These recombinant constructs were cotranslational cells insects (e.g., Spodoptera frugiperda 21 (Sf21)) together with the viral DNA (e.g., Pharmingen BaculoGold) to obtain a recombinant baculovirus. (Assembly methods of recombinant DNA molecules, receipt and use of recombinant baculovirus are detailed in such works as, for example, Sambrook et al., 1989, Molecular cloning - A Laborator is aizvesti analysis of other types of tyrosine kinase, cytoplasmic fragments, starting with methionine 806 (KDR, room L04947 catalog gene Bank) and methionine 668 (EGF receptor number H catalog gene Bank), it is possible to clone and Express in the same way.

For the expression of tyrosine kinase activity cFlt cells Sf21 thrice infected: not containing plaques of recombinant virus cFlt and collected cells after 48 hours. The collected cells were washed in ice saline phosphate buffer (PBS) (10 mm phosphate, pH 7.4, 138 mm sodium chloride, 2.7 mm potassium chloride), then re-suspended in ice mixture HNTG/PMSF (20 mm HEPES, pH 7.5, 150 mm sodium chloride, 10% glycerol in volume, 1% Triton X100 in volume, 1.5 mm magnesium chloride, 1 mm ethylene glycol-bis (-aminoacylase ether)N,N,N',N'-tetraoxane acid (EGTA), 1 mm phenylmethylsulfonyl (PMSF); PMSF added just before use from a 100 mm freshly prepared solution in methanol) using 1 ml of a mixture of HNTG/PMSF per 10 million cells. The suspension was centrifuged for 10 minutes at a speed of 13000 rpm/minute at a temperature of 4oS, after which the supernatant (enzyme) was removed and stored in aliquot at -70oC. Each but% Triton X100 in volume, 0.2 mm of dithiothreitol). To obtain a typical portion of the enzyme was diluted in the ratio of 1: 2000 enzyme diluent and in each analysis used 50 ál of diluted enzyme.

The substrate solution was obtained from an arbitrary copolymerizing tyrosine, for example, Poly(Glu, Ala, Tight) 6:3:1 (Sigma R), was stored at a concentration of 1 mg/ml of physiological solution with phosphate buffer at -20oC and diluted with saline phosphate buffer in the ratio of 1:500 to cover the tablet.

On the day prior to analysis, all wells analytical plates (96-well immunoplate Nunc maxisorp) were administered 100 μl of diluted substrate solution, then they were sealed and left overnight at a temperature of 4oC.

On the day of analysis, the substrate solution was removed, the wells analytical tablets once were washed in PBST (saline phosphate buffer containing 0.05% tween-20 in volume ratio) and once with 50 mm HEPES, pH 7.4.

Compound was diluted in 10% dimethylsulfoxide (DMSO) and 25 μl of diluted compound was transferred into the wells washed analytical tablets. "Full" control wells instead of the test compound contained is about 8 μm adenosine-5'-triphosphate (ATP), and in the "blank" control wells were injected chloride manganese (II) adenosine-5'-triphosphate. To initiate the reaction, each well was added 50 μl of just diluted enzyme and the plates were incubated at room temperature for 20 minutes. The liquid is then decanted and the wells washed twice PBST. To each well was added a hundred microlitres antibodies against phosphotyrosine IgG mice (product 05-321 firm Upstate Biotechnology Inc.), diluted in a ratio of 1:6000 PBST containing 0.5% bovine serum albumin (BSA) in respect of mass to volume, and the plates were incubated for 1 hour at room temperature, after which the liquid was decanted and the wells washed twice PBST. Then he added one hundred microlitres antibodies against mouse immunoglobulin sheep, bound peroxidase from horseradish (product NXA 931 company Amersham), diluted in a ratio of 1:500 in PBST containing 0.5% bovine serum albumin in a ratio of mass to volume, and the plates were incubated for 1 hour at room temperature, after which the liquid was decanted and the wells washed twice PBST. To each well was added a hundred microlitres solution of 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic) (ABTS), freshly prepared from one 50 mg tablet ABTS (Boehringer 1204 521) in 50 ml of tol is phat-citrate buffer with perborate sodium (PCSB) (Sigma P4922) in 100 ml of distilled water). The plates were incubated for 20-60 minutes at room temperature to achieve all of the control holes of the optical density equal to about 1.0, which was measured at 405 nm by using a spectrophotometer to read the tablets. The values obtained for "empty" (without ATP) and "full" (without connections) control wells were used to determine the degree of dilution of the test compounds, which achieved 50% inhibition of enzyme activity.

(b) Analysis of proliferation of endothelial cells of the umbilical vein in human in vitro

This analysis allows to determine the ability of test compounds to inhibit the proliferation of endothelial cells, umbilical vein human (HUVEC) stimulated by the growth factor.

The HUVEC cells were isolated in MCDB 131 (Gibco BRL) + 7,5% fetal calf serum (FCS) and cultured on tablets (2-8-fold passirovannye) in MCDB 131+2% fetal calf serum in a volume ratio of + 3 μg/ml heparin + 1 μg/ml hydrocortisone at a concentration of 1000 cells/well on 96-well plates. No earlier than 4 hours per well) was added the appropriate growth factor (that is 3 ng/ml VEGF, 3 ng/ml EGF or 0.3 ng/ml b-FGF) and test the connection. Cultures were incubated for 4 days of the new-thymidine (product TRA 61 company Amersham) and incubated for 4 hours. Cells were collected using a harvester 96-hole tablet (Tomtek) and analyzed for incorporation of tritium using counter beta-radiation tablets. The incorporation of radioactive label into cells, expressed as the number of pulses per minute, was used for the measurement of inhibition of test compounds cell proliferation stimulated by the growth factor. The results of the tests on the above described tests are presented in the table.

(C) Analysis of uterine oedema in rats in vivo

This analysis allows to determine the ability of compounds to reduce the sharp increase in uterine weight in rats, occurring within the first 4-6 hours after estrogen stimulation. It has long been known that this initial increase in uterine weight due to edema caused by increased permeability of the vascular network of the uterus. Cullinan-Scale and CEP (Cullinan-Bove and Koos, Endocrinology, 1993, 133: 829-837) recently demonstrated that there is a close temporal relationship with increased expression of VEGF mRNA in the uterus. We found that pretreatment of the rats neutralizing monoclonal antibodies against VEGF significantly reduces the rapid increase in uterine weight. This confirms the assumption that the increase in m which it was subcutaneously injected a single dose of estradiolbenzoateai (2.5 µg/rat) in a solvent or solvent. The last group consisted of unstimulated control animals. Compound is administered orally through different periods of time prior to the introduction of estradiolbenzoateai. Five hours after the introduction of extrativista-the rats were killed humanely, they have the uterus was dissected, blotted and weighed. The increase in uterine weight in the groups treated with the test compound and estradiolelisaut or only estradiolelisaut, were compared with each other using the t-test, Syudent. The inhibition of estradiolbenzoateai was considered statistically significant when p<0,05.

These compositions can be used for oral administration, for example, in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), for example, in the form of a sterile solution, suspension or emulsion, for topical application, for example, in the form of ointment or cream or for rectal administration, for the use of conventional fillers.

The compositions of the present invention mainly get in dosed form. These compounds enter the warm-blooded animal in the number of 5-5000 mg per square meter body surface of the animal, i.e. approximately 0.1-100 mg/kg Standard dose is usually 1-100 mg/kg, preferably 1-50 mg/kg and usually gives a good therapeutic effect. Dosage form, e.g. tablet or capsule usually contains about 1-250 mg of the active ingredient.

Another object of the present invention is the use of compounds of the formula I or their pharmaceutically acceptable salts for the treatment of humans or animals.

We have found that the compounds of the present invention inhibit the activity of tyrosine kinase receptors, VEGF and therefore are of interest due to its antiangiogenic action and/or the ability to reduce vascular permeability.

Another object of the present invention are the compounds of formula I or their pharmaceutically acceptable salts for use as pharmaceuticals, in particular, the compounds of formula I or their pharmaceutically acceptable salts, for use as Lech man.

Thus another object of this invention is the use of compounds of the formula I or their pharmaceutically acceptable salts to obtain drugs that reduce angiogenesis and/or vascular permeability in a warm-blooded animal such as man.

Another object of this invention is the method of treatment aimed at reducing angiogenesis and/or vascular permeability in a warm-blooded animal, such as man, in need of such treatment, which is that specified the animal is administered an effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

As mentioned above, the amount of drug doses required for the treatment or prevention of a specific disease, may vary depending on the state of need of the subject, the route of administration and the severity of the disease. Daily dose is preferably 1-50 mg/kg, However, the daily dose must be different depending on the state of need of the subject, the route of administration and the severity of the disease. Therefore, the optimal dose can be determined only by the attending physician.

Treatment aimed at slimming the joining of the present invention, the treatment may include the introduction of one or more other substances. Joint treatment involves the simultaneous, sequential or separate introduction of multiple drugs. In Oncology commonly practiced different forms of treatment of subjects suffering from cancer. Treatment with drugs that reduce angiogenesis and/or vascular permeability, complemented by surgery, radiation therapy or chemotherapy. Chemotherapy may cover three main categories of drugs:

(i) other antiangiogenic tools that have other mechanisms of action compared to the above (for example, linomide, inhibitors of integrin function v3, angiostatin, retuxin, thalidomide);

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, idoxifene), POCs (for example, magistralata), aromatase inhibitors (e.g. anastrozole, letrozole, varsol, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bikalutamid, tsiproteronatsetat), agonists and antagonists of LHRH (for example, gosereline, leuprolide), inhibitors of testosterone-5-dihydroorotase (for example, finasteride), antiinvasive means (for example, inhibitors of metalloprotein the ora function growth factor (such growth factors are for example, EGF, FGF released from platelet growth factor and hepatocytic growth factor; these inhibitors include antibodies to growth factors, antibodies to the receptor of the growth factor, tyrosine kinase inhibitors and inhibitors of serine/trionychinae);

(iii) antiproliferative and antineoplastic drugs and their combinations used in Oncology, such as antimetabolites (for example antifolates like methotrexate, ftorpirimidinu similar to 5-fluorouracil, purine analogues, and adenosine, citizenoriented); antitumor antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubitsina, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example, nitrosoaniline mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosamine, thiotepa); antimitoticescoy means (for example, vinylchloride, such vincristine, and taxoid, like Taxol, Taxotere); topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan).

As mentioned above, the compounds of the present invention are Expected the compounds according to this invention may be useful for treating a number of diseases, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma and haemangioma, acute and chronic neuropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases caused by proliferation of cells in the retinal vessels. In addition, it is believed that the compounds according to this invention are able to effectively slow the growth of primary and recurrent solid tumors, called VEGF, in particular, tumors, development and growth are heavily dependent on VEGF, including, for example, some tumors of the colon, breast, prostate, lung, external female genital organs, and skin.

Besides the fact that the compounds of formula I and their pharmaceutically acceptable salts are useful drugs, they can also be used as pharmacological tools for the development and standardization of in vitro and in vivo test systems to determine the effectiveness of inhibitors of the tyrosine kinase activity of VEGF receptors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, in the process of Nauchi of the invention, the term "ester" means diethyl ether.

This invention is further illustrated by the following examples without limiting its scope, which, except where otherwise stated:

[(i) evaporation carried out by rotary evaporation in vacuo and the processing is performed after removal by filtration of residual solids such as drying;

(ii) all operations are performed at room temperature, i.e. in the range of 18-25oWith and in the atmosphere of inert gas, such as argon;

(iii) chromatography on columns (flash method) and the liquid medium pressure chromatography performed on silica gel Merck Kieselgel ( 9385) or on silica gel for chromatography with reversed phase Merck Lichroprep RP-18 ( 9303) Merck, Darmstadt, Germany;

(iv) the magnitude of the output are given for illustration only, and are not necessarily the maximum possible;

(v) the melting temperature is not adjusted and determined by using an automatic device for determining the melting temperature Mettler SP62, the device with an oil bath or a heating plate Kofler;

(vi) the structures of the final products of the formula I were confirmed by spectroscopy (generally proton) magnetic resonance (NMR) and mass spectrometry (MS); the e chemical shifts and multipletness peaks are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, Quartet;

(vii) intermediate compounds are usually not fully investigated, and their purity determined by thin-layer chromatography, liquid chromatography high-resolution analysis by the method of infrared spectroscopy (IR) or analysis by the method of nuclear magnetic resonance (NMR);

(viii) in the examples used the following abbreviations:

DMF - N,N-dimethylformamide;

DMSO - dimethyl sulfoxide (DS);

DMA is N,N-dimethylacetamide;

TFU - triperoxonane acid.]

Example 1

To a solution of 4-chloro-6,7-dimethoxyquinazoline (202 mg, 0.9 mmol) and 4-bromo-2-fluoro-5-hydroxyanisole (described in European patent 61741 A2) (206 mg, 1 mmol) in 2-butanol (8 ml) add a solution of hydrogen chloride in isopropanol (0.1 ml, 5 M solution). The mixture is heated under reflux for 45 minutes and leave to cool. The precipitated product is collected by filtration, washed with 2-butanol and ether and dried in vacuo, giving a hydrate of the hydrochloride of 4-(4-bromo-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazoline (340 mg, 87%) as a white solid.

So pl. 265-270oC.

Range1H NMR: (DMSO-d6) 4,0 (2s, 6H); 7,13 (d, 1H); to 7.32 (s, 1H); to 7.64 (d, 1H); /SUB>rFN3ABOUT31l 1,05 N2O

Found, %: C 43,42; N 3,68; N Was 9.33.

Calculated, %: C 42,75; N 3,61 N 9,35.

The original substance is obtained in the following way:

A mixture of 4,5-dimethoxyaniline acid (19.7 g) and formamide (10 ml) is stirred and heated to 190oC for 5 hours. This mixture is allowed to cool to approximately 80oWith and add water (50 ml). The mixture was kept at room temperature for 3 hours. The precipitate was separated, washed with water and dried to obtain 6,7-dimethoxy-3,4-dihydroquinazolin-4-it (3,65 g).

A mixture of a portion (of 2.06 g) thus obtained substance, thionyl chloride (20 ml) and DMF (1 drop) was stirred and heated to the boiling temperature under reflux for 2 hours. The mixture is evaporated and the residue distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is washed with water, dried (gSO4) and evaporated. The residue is purified by chromatography on a column using as eluent increasingly polar mixtures of methylene chloride and ethyl acetate, giving 4-chloro-6,7-dimethoxyquinazolin (0.6 g, 27%).

Example 2

To melt 2,4-dihydroxytoluene (0.6 g, 4.8 mmol) at a temperature of 140oTo add solid hydroxy who in example 1). The resulting mixture is stirred at a temperature of 140oC for 15 minutes and leave to cool, then diluted with water, acidified to pH 4 and extracted with ethyl acetate. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and the solvent evaporated. The crude product was first purified flash chromatography, elwira a mixture of petroleum ether: ethyl acetate (1:9), and then the absorption HPLC, elwira a mixture trichlormethane: acetonitrile (85:15), which gives 6,7-dimethoxy-4-(3-hydroxy-4-methylphenoxy)hinzelin (116 mg, 34%).

So pl. 213-216oC.

Range1H NMR: (Dl3) 2,22 (s, 3H); of 4.05 (s, 6H); and 6.6 (s, 1H); 6,69 (dd, 1H); to 7.2 (d, 1H); and 7.3 (s, 1H); 7,52 (s, 1H); 8,35 (br s, 1H); 8,65 (s, 1H).

MS-ESI: 313 [MN]+.

Elemental analysis: C17H16N2O4.

Found, %: C 65,36; N. Of 5.53; N 8,92.

Calculated, %: C, Compared With 65.38; H 5,16; N 8,97.

The original substance is obtained in the following way:

To a solution of 2,4-dimethoxytoluene (1 g, 6.5 mmol) in pentane (10 ml) at -70oTo add trichromacy boron (3.1 ml, 3.2 mmol). The reaction mixture was left to warm to room temperature and stirred for further 2 hours. Then add a mixture of ice water and ethyl acetate, the aqueous layer was alkalinized layer is separated and the aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with a saturated solution of salt, dried (MgSO4) and the solvent evaporated. The residue is purified flash chromatography, elwira a mixture of methylene chloride: ethyl acetate (9:1), which gives 2,4-dihydroxytoluene (759 mg, 94%) as a white solid.

Example 3

In accordance with the procedure described in example 2, during the execution of the absorption HPLC extracted with a second connection, elwira a mixture trichlormethane: acetonitrile (75: 25), which gives 6,7-dimethoxy-4-(5-hydroxy-2-methylphenoxy)hinzelin (123 mg, 36%).

So pl. 231-239oC.

Range1H NMR: (Dl3) 2,1 (s, 3H); of 4.05 (s, 6H); and 6.6 (s, 1H); 6,72 (dd, 1H); to 7.15 (d, 1H); to 7.32 (s, 1H); 7,58 (s, 1H); 8,65 (s, 1H).

MS-ESI: 313 [MH]+.

Elemental analysis: C17H16N2O40.1 G2O.

Found, %: C 65,05; N. Of 5.68; N 8,6.

Calculated, %: C 65,00; N 5,20; N 8,92.

Example 4

A mixture of 4-(4-chloro-2-pertenece)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), 2-pomatoleios ester (83 mg, 0.6 mmol) and potassium carbonate (207 mg, 1.5 mmol) in DMF (3 ml) is heated to 180oC for 45 minutes. The reaction mixture is allowed to cool, diluted with water and acidified to pH 3.5. The resulting aqueous mixture extrathyroidal solvent. The residue is purified flash chromatography, elwira a mixture of methylene chloride: ether (7:3), giving 4-(4-chloro-2-pertenece)-7-(2-methoxyethoxy)-6-methoxyquinazoline (130 mg, 68%).

So pl. 167-168oC.

Range1H NMR: (DMSO d6) 3,76 (t, 2H); 3,99 (s, 3H); 4,34 (t, 2H); to 7.4 (d, 1H); 7,44 (s, 1H); 7,56 (t, 1H); EUR 7.57 (s, 1H); of 7.70 (dd, 1H); 8,56 (s, 1H).

MS-ESI: 379 [MH]+.

Elemental analysis: C18H16FClN2O40.1 G2O.

Found, %: 57,03; N A 4.53; N 7,41.

Calculated, %: C 56,81; N 4,29; N Of 7.36.

The original substance is obtained in the following way:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med. Chem. 1977, vol. 20, 146-149, 10 g, 0.04 mol) and reagent Golda (7,4 g, 0.05 mol) in dioxane (100 ml) is stirred and heated under reflux for 24 hours. To the reaction mixture is added sodium acetate (3,02 g 0,037 mol) and acetic acid (1.65 ml, 0,029 mol) and heated for another 3 hours. The mixture is evaporated, to the residue water is added, the solid is filtered off, washed with water and dried. Recrystallization from acetic acid gives 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) is stirred and heated for about hydrochlorid 7-benzyloxy-4-chloro-6-methoxy-hintline (3,45 g).

To a solution of the hydrochloride of 7-benzyloxy-4-chloro-6-methoxyquinazoline (506 mg, 1.5 mmol) in pyridine (8 ml) is added 4-chloro-2-terfenol (264 mg, 1.8 mmol) and heat the mixture under reflux for 45 minutes. The solvent is evaporated and the residue distributed between ethyl acetate and water. The organic layer was washed with 0.1 M Hcl solution, water and saturated salt solution, dried (MgSO4) and the solvent evaporated. The solid residue is ground into powder with petroleum ether, the crude product is collected by filtration and purified flash chromatography, elwira a mixture of methylene chloride:ether (9:1), giving 7-benzyloxy-4-(4-chloro-2-pertenece)-6-methoxyquinazoline (474 mg, 77%) as a cream solid.

So pl. 179-189oC.

Range1H NMR: (DMSOd6) to 3.99 (s, 3H); are 5.36 (s, 2H); 7,35-7,5 (m, 4H); 7,55-the 7.65 (m, 5H); 7,72 (d, 1H); and 8.6 (s, 1H).

MS-ESI: 411 [MN]+.

Elemental analysis: C22H16lFN2O30,06 N2O0,SN2CL2.

Found, %: C 63,38; N 4,07; N Is 6.78.

Calculated, %: 63,64; N 3,93; N Of 6.73.

A solution of 7-benzyloxy-4-(4-chloro-2-pertenece)-6-methoxyquinazoline (451 mg, 1.1 mmol) in TFU (4,5 ml) is heated under reflux for 3 hours. The mixture is diluted with toluene and volatile the rum and dried in vacuum to obtain 4-(4-chloro-2-pertenece)-7-hydroxy-6-methoxyquinazoline (320 mg, 90%).

Range1H NMR: (DMSO d6) 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).

MS-ESI: 321 [MN]+.

Example 5

To a solution of 3-hydroxybenzamide (168 mg, 1.3 mmol) and N,N-diisopropylethylamine (233 μl, 1.3 mmol) in DMF (5 ml) is added 4-chloro-6,7-dimethoxyquinazolin (200 mg, 0.89 mmol) (obtained similarly to the original substance in example 1). The reaction mixture is heated at a temperature of 40oC for 10 minutes, after which it is allowed to cool, diluted with water, acidified to pH 3 and extracted with ethyl acetate. The organic extract was washed with saturated salt solution, dried (gSO4) and the solvent evaporated. The residue is recrystallized from a mixture of ethanol / ether to obtain 6,7-dimethoxy-4-(3-hydroxyphenyl)hintline (259 mg, 93%) as a white solid.

So pl. 221-230oC.

Range1H NMR: (DMSO d6) 4,0 (2s, 6H); and 6.9 (dd, 1H); 7,05 (s, 1H); 7,07 (d, 1H); 7,34 (t, 1H); 7/35 (s, 1H); 7,38 (s, 1H); to 8.7 (s, 1H); of 9.8 (br s, 1H).

MS-ESI: 315 [MH]+.

Elemental analysis: C16H14N2O3S.

Found, %: C 61,06; N Br4.61; N 8,95.

Calculated, %: C 61,13; N. Of 4.49; N 8,91.

The original substance is obtained in the following way:

To a solution of 3-meth Reaction mixture is left to warm to

room temperature and stirred for further 60 minutes, after which it was diluted with ethyl acetate and water and alkalinized water 2 M sodium hydroxide solution to pH 9. The mixture is then extracted with ethyl acetate, the combined extract was washed with saturated salt solution, dried (gSO4) and the solvent evaporated. The residue is purified flash chromatography, elwira a mixture of petroleum ether: ethyl acetate (8:2), which gives 3-hydroxybenzoyl (819 mg, 91%).

Range1H NMR: (Dl3) 3,42 (s, 1H); 4,85 (br s, 1H); and 6.6 (d, 1H); 6.75 in (s, 1H); 6,85 (d, 1H); and 7.1 (t, 1H).

Example 6

To a solution of 4-(5-acetoxy-4-chloro-2-foronline)-6-methoxy-7-(2-methoxyethoxy)hintline (180 mg, 0.4 mmol) in methanol (50 ml) is added concentrated aqueous ammonia solution (5 ml). The mixture is stirred at room temperature for 3 hours and diluted with water. A large part of the methanol is evaporated, the precipitate is collected by filtration, washed with water and dried to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-methoxyethoxy)hintline (73 mg, 45%).

So pl.>250oC.

Range1H NMR: (DMSO d6) 3,29 (s, 3H); 3,74 (t, 2H); of 3.94 (s, 3H); to 4.28 (t, 2H); to 7.15 (d, 1H); 7,19 (s, 1H); 7,38 (d, 1H); to 7.77 (s, 1H); at 8.36 (s, 1H); 9,40 (s, 1H).

MS-ESI: 394 [MN]+.

Elemedicine, %: 51,2; N 4,8; N 9,9.

The original substance is obtained in the following way:

A mixture of 4-chloro-2-fluoro-5-hydroxyanisole (2.5 g, 15 mmol) (described in European patent 61741 A2) and 7-benzyloxy-4-chloro-6-methoxyquinazoline (4,2 g, 14 mmol) (obtained similarly to the original substance in example 4, but with a water treatment) in isopropanol is heated under reflux for 2 hours. The mixture is then allowed to cool, the solid product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxyquinazoline (4.8 g/ 81%).

Range1H NMR: (DMSO d6) 3,98 (s, 3H); by 5.18 (s, 2H); 7,05 (d, 1H); 7.18 in-7,27 (m, 7H); of 8.06 (s, 1H); scored 8.38 (s, 1H).

To a stirred suspension of the hydrochloride of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxyquinazoline (600 mg, 1.4 mmol) in methylene chloride (7 ml), add triethylamine (216 ml, 1.5 mmol) and acetic anhydride (133 ml, 1.4 mmol). The mixture is stirred at room temperature for 3 hours and the insoluble matter is removed by filtration, the filtrate is evaporated volatiles and the residue purified flash chromatography, elwira a mixture of methylene chloride: methanol (100:0 increasing in polarity to 97:3), giving 4-(5-ACETex is 1H NMR: (DMSO d6) was 2.34 (s, 3H); of 3.94 (s, 3H); 5,28 (s, 2H); 7,28 (s, 1H); 7,35-7,44 (m, 2H); 7,50 (d, 2H); 7,58 (d, 1H); of 7.70 (d, 1H); 7,80 (s, 1H); of 8.37 (s, 1H); of 9.30 (s, 1H).

MS-ESI: 468 [MN]+.

A solution of 4-(5-acetoxy-4-chloro-2-foronline)-7-benzyloxy-6-methoxyquinazoline (250 mg, 0.54 mmol) in methanol (5 ml), trichloromethane (5 ml) and DMF (1 ml) is stirred for 4 hours in an atmosphere of hydrogen under a pressure of 1 ATM with such a catalyst, such as 5% palladium on coal (100 mg). The catalyst was removed by filtration through diatomaceous earth and the solvent is evaporated. The residue is dissolved in ethyl acetate, washed with water and saturated salt solution and dried (gSO4). A large part of the solvent is evaporated, the mixture is cooled and add hexane to obtain a solid product, which is collected by filtration, washed with hexane/ethyl acetate and dried, giving 4-(5-acetoxy-4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (170 mg, 45%).

Range1H NMR: (DMSO d6) is 2.37 (s, 3H); of 3.95 (s, 3H); was 7.08 (s, 1H); to 7.59 (d, 1H); to 7.68 (d, 1H); for 7.78 (s, 1H); 8.34 per (s, 1H); 9,48 (s, 1H).

To a stirred mixture of 4-(5-acetoxy-4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.66 mmol), 2-methoxyethanol (63 ml, 0.8 mol) and tributylphosphine (405 ml, 1.6 mmol) in methylene chloride at 0oWith portions add 1-1'-(asociat within 2 hours. The precipitated solid is removed by filtration, and then from the filtrate the solvent is evaporated and the residue purified flash chromatography, elwira a mixture of acetonitrile:methylene chloride (1:9 with increasing polarity to 4: 6), giving 4-(5-acetoxy-4-chloro-2-foronline)-6-methoxy-7-(2-methoxyethoxy)hinzelin (180 mg, 62%) as a solid.

Range1H NMR: (DMSO d6) to 2.35 (s, 3H); to 3.33 (s, 3H); 3.75 to (t, 2H); 3/95 (s, 3H); to 4.28 (t, 2H); 7,22 (s, 1H); of 7.60 (d, 1H); 7,72 (d, 1H); 7,80 (s, 1H); 8,39 (s, 1H); 9,60 (s, 1H).

MS-ESI: 436 [MN]+.

Example 7

A mixture of the hydrochloride of 4-chloro-6,7-dimethoxyquinazoline (2.1 g, 8 mmol) (obtained similarly to the original substance in example 1, but without water treatment) and 4-chloro-2-fluoro-5-hydroxyanisole (1,43 g, 8.9 mmol) (described in European patent 61741 A2) in isopropanol (150 ml) is heated under reflux for 2 hours. The reaction mixture is allowed to cool, the solid product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(4-chloro-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazoline (1.45 g, 47%).

So pl. >250oC.

Range1H NMR: (DMSO d6) 4,0 (s, 6H); 7,17 (d, 1H); 7,34 (s, 1H); 7,50 (d, 1H); by 8.22 (s, 1H); 8,80 (s, 1H).

MS-ESI: 350 [MH]+.

Elemental AU 49,7; N 3,6; N 10,9.

Example 8

A mixture of the hydrochloride of 4-chloro-6,7-dimethoxyquinazoline (2.5 g, 9.6 mmol) (obtained similarly to the original substance in example 1, but without water treatment) and 2-fluoro-5-hydroxy-4-methylaniline (1.48 g, 10.5 mmol) in isopropanol (150 ml) is heated under reflux for 2 hours. The reaction mixture is allowed to cool, the solid product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazoline (2.2 g, 71%).

So pl. >250oC.

Range1H NMR: (DMSO d6) to 2.15 (s, 3H); 3,99 (s, 6H); to 6.88 (d, 1H); 7,10 (d, 1H); to 7.32 (s, 1H); to 8.20 (s, 1H); 8,78 (s, 1H); to 9.66 (s, 1H).

Elemental analysis: C17H16N3FO31l0,65S3H8O.

Found, %: From 56.3; H 5,4; N 10,4.

Calculated, %: From 56.3; H 5,5; N 10,4.

The original substance is obtained in the following way:

To a solution of 4-fluoro-2-METHYLPHENOL (10 g, 79 mmol) in 6% aqueous sodium hydroxide solution at 0oC for 30 minutes add methylchloroform (6.8 ml, 88 mmol). The mixture is stirred for 2 hours and extracted with ethyl acetate (100 ml). An ethyl acetate extract is washed with water (100 ml) and dried (gSO4), the solvent is evaporated from the floor is (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) is added slowly a mixture of concentrated nitric acid (6 ml) and concentrated sulfuric acid (6 ml) so that the temperature of the reaction mixture was below the 50oC. the resulting mixture was stirred for 2 hours, then add a mixture of ice water and the precipitated product collected by filtration. The crude product is purified by chromatography on silica gel, elwira mixtures of methylene chloride: hexane, gradually increasing the polarity, and then a mixture of methanol:methylene chloride (1:19), which gives 4-fluoro-2-methyl-5-NITROPHENOL (2.5 g, 22%) as a solid.

Range1H NMR: (DMSO d6, CD3CO2D) 2,31 (s, 3H); 7,38 (d, 1H); 7,58 (d, 1H).

MS-ESI: 171 [MN]+.

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) is heated under reflux for 4 hours. The reaction mixture is allowed to cool, neutralized with 2 M aqueous sodium hydroxide solution and extracted with ethyl acetate (100 ml). An ethyl acetate extract is dried (MgSO4) and the solvent is evaporated to obtain 2-ft N); of 4.67 (s, 2H); from 6.22 (d, 1H); of 6.65 (d, 1H); 8,68 (s, 1H).

MS-ESI: 142 [MN]+.

Example 9

A mixture of 4-chloro-6-methoxy-7-(2-methoxyethoxy)hintline (76 mg, 0.28 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (40 mg, 0.28 mmol) (obtained similarly to the original substance in example 8) in isopropanol (2.5 ml) is stirred and heated under reflux for 7 hours. The reaction mixture is allowed to cool, after which the precipitated product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-methoxyethoxy)hintline (79 mg, 66%) as a white solid.

So PL >275oC.

Range 1H NMR: (DMSO d6) 2,19 (s, 3H); to 3.36 (s, 3H); of 3.80 (m, 2H); 4,00 (s, 3H); 4,33 (m, 2H); 6.90 to (d, 1H); 7,10 (d, 1H); 7,37 (s, 1H); to 8.20 (s, 1H); is 8.75 (s, 1H); 9,65 (br s, 1H); at 11.25 (br s, 1H).

MS-ESI: 374 [MH]+.

Elemental analysis: C19H20N3FO41HCl.

Found, %: C 55,7; N 4,8; N 10,1.

Calculated, %: C 55,7; H 5,2; N 10,3.

The original substance is obtained in the following way:

A mixture of ethyl 4-hydroxy-3-methoxybenzoate (9.8 g, 50 mmol), 2-pomatoleios ether (8,46 ml, 90 mmol) and potassium carbonate (12,42 g, 90 mmol) in acetone (60 ml) is heated with reverse holodilnie which is evaporated from the filtrate volatiles and the residue is ground to powder with hexane, that gives ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (11.3 g, 89%) as a white solid.

So pl. 57-60oC.

Range1H NMR: (DMSO d6) is 1.31 (t, 3H); 3,29 (s, 3H); of 3.32 (s, 3H); 3,68 (m, 2H); 4.16 the (m, 2H); to 4.28 (q, 2H); 7,06 (d, 1H); was 7.45 (d, 1H); 7,56 (dd, 1H).

MS-FAB: 255 [MN]+.

To mix concentrated nitric acid (75 ml) at 0oWith added in several portions of ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (9.5 g, 37 mmol). The resulting mixture was left to warm to room temperature and stirred for further 90 minutes, then diluted with water, extracted with methylene chloride, dried (gSO4) and the solvent evaporated. The residue is ground to powder with hexane, giving ethyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (10.6 g, 95%) as an orange solid.

So pl. 68-69oC.

Range1H NMR: (DMSO d6) of 1.27 (t, 3H); 3,30 (s, 3H); of 3.69 (m, 2H); to 3.92 (s, 3H); 4.25 in (m, 2H); the 4.29 (q, 2H); 7,30 (s, 1H); the 7.65 (s, 1H).

MS-CI: 300 [MH]+.

A mixture of ethyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate 10,24 g, 34 mmol), cyclohexene (30 ml) and the catalyst, such as 10% palladium on coal (2.0 g) in methanol (150 ml) is heated under reflux for 5 hours. The reaction mixture is allowed to cool and diluted with females is recrystallized from a mixture of ethyl acetate/hexane to obtain ethyl 2-amino-5-methoxy-4-(2-methoxyethoxy)benzoate (8.0 g) as a yellowish brown solid. To this product add formamide (80 ml) and heat the mixture at a temperature of 170oC for 18 hours. Approximately half of the solvent is evaporated in a high vacuum and the residue is left on overnight for maturation. The solid product is collected by filtration, washed with ether and dried to obtain 6-methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-it (5,3 g, 62% as a result of executing two steps) as a gray solid.

Range1H NMR: (DMSO d6) to 3.35 (s, 3H); 3,74 (m, 2H); to 3.89 (s, 3H); 4.26 deaths (m, 2H); to 7.15 (s, 1H); 7,47 (s, 1H); 7,98 (s, 1H); a 12.03 (br s, 1H).

MS-CI: 251 [MN]+.

To a mixture of 6-methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-it (of 5.1 g, 20 mmol) in thionyl chloride (50 ml) is added DMF (0.5 ml). The mixture is stirred and heated under reflux for 3 hours, allowed to cool and evaporated the excess thionyl chloride. The residue is suspended in methylene chloride and washed with aqueous sodium bicarbonate solution. The aqueous phase is extracted with methylene chloride and the combined extracts dried (MgSO4). The crude product is recrystallized from a mixture of methylene chloride/hexane to obtain 4-chloro-6-methoxy-7-(2-methoxyethoxy)hintline (2.8 g, 51%) as a fine white solid.

Range

Example 10

A mixture of the hydrochloride of 4-chloro-6,7-dimethoxyquinazoline (152 mg, 0.6 mmol) (obtained similarly to the original substance in example 1, but without water treatment) and 4-bromo-2,6-diferencia (121 mg, 0.6 mmol) in isopropanol (7 ml) is heated under reflux for 2 hours. The resulting mixture is allowed to cool, after which the solid product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(4-bromo-2,6-diptiranjan)-6,7-dimethoxyquinazoline (81 mg, 35%).

Range1H NMR: (DMSO d6) 4,0 (s2, 3H each); to 7.2 (s, 1H); to 7.35 (d, 2H); or 8.2 (s, 1H); 8,9 (s, 1H); to 11.8 (br s, 1H).

MS-ESI: 396 [MN]+.

Example 11

Hydrochloride 4-chloro-6,7-dimethoxyquinazoline (300 mg, 1.15 mmol) (obtained similarly to the original substance in example 1, but without water treatment) and 2,4-debtor-5-hydroxyanisol (184 mg, 0.90 mmol) in isopropanol (10 ml) is heated under reflux for 2 hours. The reaction mixture is allowed to cool, after which the precipitated product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(2,4-debtor-5-hydroxyimino)-6,7-dimethoxyquinazoline (250 mg, 65%).

Range1H NMR: (DMSO d6) to 3.99 (s, 6H); 7,05 (dd, 1H); 7,17 (s, 1H); 7,40 (dd, 1H); 8,10 (s, 1H); 8,68 (s, 1l.

Found, %: From 51.8; H 3,9; N 11,3.

Calculated, %: From 52.0; H 3,8; N 11,4.

The original substance is obtained in the following way:

To a solution of 2,4-differenoe (25 g, 0,192 mol) and sodium hydroxide (8.1 g, 0,203 mol) in water (140 ml) add methylchloroform (16,35 ml, 0,173 mol). The resulting mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and evaporated volatile substance that gives 2,4-debtor-1-methoxycarbonylamino (32 g, 89%).

Range1H NMR: (DMSO d6) 3,85 (s, 3H); to 7.64 (d, 2H); 7,72 (d, 1H).

To a chilled mixture of 2,4-debtor-1-methoxycarbonylbenzyl (5.0 g, or 0.027 mol) in concentrated sulfuric acid (4 ml) is added slowly a mixture of concentrated nitric acid (4 ml) and concentrated sulfuric acid (4 ml) so that the reaction temperature was below 30oC. the resulting mixture was stirred for further 3 hours and then diluted with a mixture of water with ice, after which the precipitated product is collected by filtration, washed with water and dried to obtain 2,4-debtor-5-methoxycarbonylamino-1-nitrobenzene (2.8 g, 45%).

Range1H NMR: (DMSO d6) 3,85 (s, 3H); of 7.97 (dd, 1H); 8,44 (dd, 1H).

A mixture of 2,4-debtor-5-methoxycarbonylamino-1 nitrobenzo is of 4 hours is stirred in hydrogen atmosphere under a pressure of 1 ATM. The catalyst was removed by filtration through diatomaceous earth and the solvent is evaporated to obtain 2,4-debtor-5-methoxycarbonylmethylene (2.3 g, 97%).

Range1H NMR: (DMSO d6) is 3.82 (s, 3H); 5,20 (s, 2H); of 6.65 (dd, 1H); 7,20 (dd, 1H).

MS-ESI: 204 [MN]+.

To a solution of 2,4-debtor-5-methoxycarbonylmethylene (2.0 g, 9,85 mmol) in ethanol (100 ml) is added concentrated aqueous ammonia (20 ml) and stirred the mixture at room temperature for 3 hours. The reaction mixture was diluted with water and evaporated major part of organic volatiles. The aqueous residue is neutralized to pH 7 and extracted with ethyl acetate. The extracts washed with water, dried (MgSO4) and the solvent evaporated, giving 2,4-debtor-5-hydroxyanisol (1.2 g, 85%).

Range1H NMR: (DMSO d6) 4,78 (s, 2H); 6,34 (t, 1H); 6.87 in (t, 1H); 9,23 (s, 1H).

MS-ESI: 145 [MN]+.

Example 12

6-Methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (200 mg, 0.8 mmol) (obtained similarly to the original substance in example 9) and DMF (0.1 ml) in thionyl chloride (20 ml) is heated under reflux for 2 hours. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. The residue is dissolved in isopropyl the least 11) and heat the mixture under reflux for 2 hours. Then the reaction mixture is allowed to cool, the precipitated product is collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(2,4-debtor-5-hydroxyimino)-6-methoxy-7-(2-methoxyethoxy)hintline (83 mg, 28%).

Range1H NMR: (DMSO d6) to 3.35 (s, 3H); of 3.77 (t, 2H); 4,00 (s, 3H); 4,30 (t, 2H); 7,10 (dd, 1H); of 7.36 (s, 1H); 7,40 (t, 2H); to 8.20 (s, 1H); 8,78 (d, 2H).

MS-ESI: 378 [MH]+.

Elemental analysis: C18H17N3O4F21HCl.

Found, %: From 51.8; H 4,2; N 10,1.

Calculated, %: From 52.2; H 4,4; N 10,2.

Example 13

A mixture of 7-(2-acetoacetate)-4-(5-benzyloxy-2-fluoro-4-methylaniline)-6-methoxyquinazoline (133 mg, 0.27 mmol) and catalyst, such as 10% palladium on coal (50 mg) in ethyl acetate (8 ml) is stirred in hydrogen atmosphere under a pressure of 1 ATM at room temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth, the greater part of the solvent is evaporated and to the residue add hexane. The precipitated product is collected by filtration and dried to obtain 7-(2-acetoacetate)-4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxyquinazoline (16 mg, 15%).

Range1H NMR: (DMSO d6) was 2.05 (s, 3H); 2.13 and (s, 3H); 3,91 (s, 3H); from 4.3 to 4.4 (m, 4H); make 6.90 (d, 1H); 6,98 (d, 1H); 7.18 in (s, 1H); 7,79 (s, 1H); 8.30 to mesh 4-fluoro-2-methyl-5-NITROPHENOL (4,69 g, 27 mmol) (obtained similarly to the original substance in example 8), benzylbromide (3,59 ml, 30 mmol) and potassium carbonate (7,58 g, 55 mmol) in DMF (100 ml) is heated at a temperature of 80oC for 4 hours. The reaction mixture is allowed to cool, diluted with water and stirred for 15 minutes. The precipitated product is collected by filtration, washed with water and dried to obtain 5-benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (6.4 g, 89%).

Range1H NMR: (DMSO d6) of 2.28 (s, 3H); 5,22 (s, 2H); 7,3-7,5 (m, 6H); of 7.70 (s, 1H).

To a suspension of Nickel Raney catalyst (75 mg) and hydrazine hydrate is added (465 ml, 9.5 mmol) in methanol (10 ml) add 5-benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (500 mg, 1.9 mmol) in methanol (10 ml) and heated under reflux. The mixture is left at the boiling point under reflux for 15 minutes, after which insoluble substances are removed by filtration through diatomaceous earth. The filter is washed with methanol and from the filtrate the solvent is evaporated, giving 5-benzyloxy-2-fluoro-4-methylaniline (440 mg, 99%).

Range1H NMR: (DMSO d6) 2,02 (s, 3H); 4,88 (s, 2H); to 4.98 (s, 2H); 6,44 (d, 1H); 6,76 (d, 1H); 7,3-7,5 (m, 5H).

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-it (5.0 g) (obtained similarly to the original prophetic is,5 g), in toluene (100 ml) is stirred under hydrogen atmosphere for 3 hours. The resulting mixture was filtered and the filtrate evaporated. The residue is partitioned between a mixture of ethyl acetate (500 ml), methanol (20 ml) and water (300 ml). The organic phase is separated, dried (MgSO4) and the solvent evaporated. The residue is ground to powder with hexane, giving 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1.1 g, 27%).

Range1H NMR: (DMSO d6) to 2.29 (s, 3H); of 3.84 (s, 3H); 7,42 (s, 1H); a 7.62 (s, 1H); 8,1 (br s, 1H).

MS-ESI: 235 [MN]+.

A mixture of 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-it (1,69 g, 7.2 mmol), thionyl chloride (50 ml) and DMF (3 drops) is heated under reflux for 2 hours. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. The residue is distributed between methylene chloride and saturated aqueous sodium bicarbonate. The organic phase is separated, dried (MgSO4) and the solvent evaporated. To the residue add 5-benzyloxy-2-fluoro-4-methylaniline (1.8 g, 7.8 mmol) in isopropanol (50 ml) and the resulting mixture heated under reflux for 2 hours. The mixture is allowed to cool, add hexane and the precipitated product collected by filtration, giving 7-acetoxy-4-(5-benzyloxy-2-fluoro-what); at 5.10 (s, 2H); 7,1-7,5 (m, 7H); of 7.75 (s, 1H); 8,39 (s, 1H); 8,77 (s, 1H).

To a solution of 7-acetoxy-4-(5-benzyloxy-2-fluoro-4-methylaniline)-6-methoxyquinazoline (1.5 g, 3.4 mmol) in methanol (100 ml) is added concentrated aqueous ammonia solution (25 ml). The mixture is stirred at room temperature for 30 minutes to evaporate the greater part of organic volatiles. Add water, after which the precipitate is collected by filtration, washed with water and dried to obtain 4-(5-benzyloxy-2-fluoro-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (1.2 g, 89%), which is used without further research.

A mixture of 4-(5-benzyloxy-2-fluoro-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (440 mg, 1 mmol), 2-bromoethanol (77 ml, 1 mmol) and potassium carbonate (150 mg, 1.1 mmol) in DMF (5 ml) is heated at a temperature of 50oC for 1 hour, add an additional amount of 2-bromoethanol (42 ml, 0.6 mmol) and potassium carbonate (150 mg, 1.1 mmol) and incubated the mixture at a temperature of 50oC for 2 hours. The reaction mixture is diluted with water, neutralized with 2 M hydrochloric acid and extracted with ethyl acetate. The extracts are dried (gSO4), the solvent is evaporated and the residue is ground to powder with ether and hexane, giving 4-(5-benzyloxy-2-fluoro-4-m, 3H); of 3.80 (t, 2H); of 3.94 (s, 3H); to 4.14 (t, 2H); 4,90 (s, 1H); 5,10 (s, 2H); 7,05 to 7.2 (m, 2H); 7,25 was 7.45 (m, 5H); 7,79 (s, 1H); 8.30 to (s, 1H); 9,20 (s, 1H).

To a mixture of 4-(5-benzyloxy-2-fluoro-4-methylaniline)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (233 mg, 0.52 mmol), triethylamine (80 ml, or 0.57 mmol) and 4-(N,N-dimethylamino)pyridine (5 mg) in ethyl acetate (50 ml) is added acetic anhydride (55 ml of 0.58 mmol). The mixture is stirred for 2 hours at room temperature and add water, then the organic layer was separated, washed with water and saturated salt solution and dried (MgSO4). A large part of the solvent is evaporated and add hexane. The precipitated product is collected by filtration to obtain 7-(2-acetoacetate)-4-(5-benzyloxy-2-fluoro-4-methylaniline)-6-methoxyquinazoline (110 mg, 43%).

Range1H NMR: (DMSO d6) 2,03 (s, 3H); 2,22 (s, 3H); to 3.92 (s, 3H); from 4.3 to 4.4 (m, 4H); to 5.08 (s, 2H); 7,13 (d, 1H); 7.18 in (d, 1H); 7,3 was 7.45 (m, 5H); 7,80 (s, 1H); 8.30 to (s, 1H); 9,42 (s, 1H).

Example 14

A mixture of 4-(5-benzyloxy-2-fluoro-4-methylaniline)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (150 mg, 0.33 mmol) (obtained similarly to the original substance in example 13) and a catalyst such as 10% palladium on coal (20 mg) in ethyl acetate (8 ml) was stirred at room temperature in hydrogen atmosphere under a pressure of 1 ATM for 18 hours. The catalyst Udal. The precipitate is collected by filtration and dried to obtain 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (50 mg, 41%).

Range1H NMR: (DMSO d6) and 2.14 (s, 3H); of 3.80 (q, 2H); of 3.94 (s, 3H); 4,15 (t, 2H); of 4.90 (t, 1H); 6.90 to (d, 1H); 7,00 (d, 1H); 7,17 (s, 1H); 7,80 (s, 1H); with 8.33 (s, 1H); to 9.32 (s, 1H); 9,37 (s, 1H).

MS-ESI: 360 [MN]+.

Example 15

Hydrochloride 4-chloro-6,7-dimethoxyquinazoline (210 mg, 0.8 mmol) (obtained similarly to the original substance in example 1, but without water treatment) and hydrochloride 4-chloro-2,6-diferencia (177 mg, 0.89 mmol) in isopropanol (8 ml) is heated under reflux for 2 hours. Then the reaction mixture is allowed to cool, add hexane and the precipitated product collected by filtration, washed with isopropanol and dried to obtain hydrochloride of 4-(4-chloro-2,6-diptiranjan)-6,7-dimethoxyquinazoline (45 mg, 16%).

So pl. >250oC.

Range1H NMR: (DMSO d6) 4,00 (s, 3H); 4,01 (s, 3H); to 7.35 (s, 1H); 7,63 (d, 2H); by 8.22 (s, 1H); 8,81 (s, 1H).

MS-ESI: 352 [MH]+.

The original substance is obtained in the following way:

To tert-butyl potassium (31.8 g, 283 mmol) in DMF (500 ml) at a temperature of -25oC for 30 minutes, add a solution of 3,5-deformirovannoe (20 g, 126 mmol) and atidal the Ute in a mixture of ice (600 g) and 2 M hydrochloric acid (500 ml). The aqueous mixture is extracted with ethyl acetate, the combined extracts washed with water and sodium bicarbonate solution and dried (MgSO4), after which the solvent is evaporated to obtain ethyl 2-chloro-2-(2,6-debtor-4-nitrophenyl)ethanoate (34 g, 97%).

Range1H NMR: (DMSO d6) to 1.15 (t, 3H); 4,1-4,3 (m, 2H); 6,44 (s, 1H); 8.17 and (d, 2H).

To a solution of ethyl 2-chloro-2-(2,6-debtor-4-nitrophenyl)ethanoate (34,86 g, 125 mmol) in ethanol (300 ml) and 5oC for 5 minutes add 2.5 M aqueous sodium hydroxide solution (300 ml) so that the reaction temperature was below the 25oC. the Mixture is cooled to 18oC and add 30% hydrogen peroxide (40 ml). The resulting mixture is stirred at a temperature of 20oC for 2.5 hours and add sodium sulfite until the test peroxide does not become negative, then it is acidified to pH 1 6M hydrochloric acid and extracted with ethyl acetate. The organic extracts are again shaken out with saturated aqueous sodium bicarbonate, aqueous extracts acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are dried (MgSO4) and the solvent is evaporated to obtain 2,6-debtor-4-nitrobenzoic acid (4,89 g, 19%).

Range1is anyone as 10% palladium on coal (500 mg), in ethanol (150 ml) was stirred at room temperature in hydrogen atmosphere under a pressure of 1 ATM for 3 hours. The catalyst was removed by filtration through diatomaceous earth, the filter is washed with ethanol and the solvent is evaporated to obtain 4-amino-2,6-diferential acid (3.8 g, 91%).

Range1H NMR: (DMSO d6) 6,12 (d, 2H); 6,28 (s, 2H).

MS-ESI: 174 [MN]+.

To a suspension of 4-amino-2,6-diferential acid (550 mg, 3,18 mmol) in acetic acid (6 ml) at a temperature of 15oC for 15 minutes, add a solution of sodium nitrite (220 mg, 3,18 mmol) in concentrated sulfuric acid (2 ml). The mixture is stirred at a temperature of 15oC for 1 hour, heated to 90oC and poured into a solution of copper chloride (I) (800 mg) in concentrated hydrochloric acid (11 ml) at a temperature of 95oC. the resulting mixture is heated at a temperature of 95oC for 45 minutes and leave to cool, then diluted with water and extracted with ethyl acetate, the organic extracts dried (MgSO4) and the solvent evaporated, giving 4-chloro-2,6-differentyou acid (600 mg, 98%).

Range1H NMR: (DMSO d6) to 7.50 (d, 2H).

MS-ESI: 192 [MN]+.

To a solution of difene shall triethylamine (477 ml, 6 mmol) and the resulting mixture heated under reflux for 2 hours. The reaction mixture is allowed to cool and the solvent is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried (MgSO4) and purified by chromatography on columns, elwira increasingly polar mixtures telengard:hexane:methanol (1:1:0 to 95:0:5), which gives N-tert-butoxycarbonyl-4-chloro-2,6-diptiranjan (170 mg, 25%).

Range1H NMR: (DMSO d6) of 1.41 (s, N); 7,39 (d, 2H); 8,86 (s, 1H).

To N-tert-butoxycarbonyl-4-chloro-2,6-diptiranjan (330 mg, 1.3 mmol) is added a saturated solution of hydrogen chloride in ethyl acetate (4 ml) and stirred the mixture at room temperature for 2 hours. The precipitate is collected by filtration to obtain hydrochloride of 4-chloro-2,6-diferencia (140 mg, 56%).

Range1H NMR: (DMSO d6) 6,12 (s, 2H); was 7.08 (d, 2H).

Example 16

A mixture of 6-methoxy-7-(3-morpholinopropan)-3,4-dihydroquinazolin-4-it (370 mg, of 1.16 mmol), thionyl chloride (5 ml) and DMF (3 drops) is heated under reflux for 2 hours and allowed to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. To the solid residue is added a solution of 2-fluoro-5-hydroxy-4-methylaniline (220 mg, 1,56't cool. The precipitate is collected by filtration, washed with methylene chloride and dried. The crude solid product is treated with an aqueous sodium bicarbonate solution to obtain a suspension, after which the product is again collected by filtration and purified by chromatography on columns, elwira a mixture of methylene chloride:methanol (9:1), giving 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(3-morpholinopropan)hinzelin (140 mg, 27%).

Range1H NMR: (DMSO d6) 2,0 (m, 2H); of 2.15 (s, 3H); 2,35 is 2.55 (m, 6H); 3,55 (br t, 4H); 3,90 (s, 3H); 4,20 (t, 2H); 6,85-to 6.95 (m, 2H); 7,10 (s, 1H); of 7.75 (s, 1H); of 8.25 (s, 1H); 9,20 (s, 2H).

Elemental analysis: C23H27N4O4F.

Found, %: C 62,2; N 6,1; N 12,4.

Calculated, %: From 62.4; H 6,2; N 12,7.

The original substance is obtained in the following way:

To a solution of phenol (1.26 g, 13.3 mmol) in dry 1-methyl-2-pyrrolidinone (20 ml) is added sodium hydride (400 mg, 80% suspension in paraffin oil, 13.3 mmol) and the resulting mixture is stirred for 10 minutes. Then add 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.6 g, 5.3 mmol) (obtained similarly to the original substance in example 4, but with a water treatment) and the reaction mixture is heated at a temperature of 110oC for 2 hours. The mixture is allowed to cool, add the water and a saturated salt solution. Removal of the solvent under reduced pressure to give 7-benzyloxy-6-methoxy-4-phenoxybenzoic (1.6 g, 84%) as a yellowish solid.

Range1H NMR: (DMSO d6) 3,98 (s, 3H); lower than the 5.37 (s, 2H); 7,25-to 7.6 (m, 11H); of 7.60 (s, 1H); 8,54 (s, 1H).

MS-ESI: 300 [MN]+.

7-Benzyloxy-6-methoxy-4-phenoxybenzoic (160 mg, 0.44 mmol) in TFU (3 ml) is heated under reflux for 30 minutes. The solvent is evaporated and the residue treated with an aqueous sodium bicarbonate solution. The precipitated product is collected by filtration, washed with water and dried to obtain 7-hydroxy-6-methoxy-4-phenoxybenzamide (105 mg, 88%).

Range1H NMR: (DMSO 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).

MS-ESI: 269 [MN]+.

To 7-hydroxy-6-methoxy-4-phenoxybenzamide (1.0 g, 3.7 mmol) and potassium carbonate (2.6 g, an 18.8 mmol) in DMF (30 ml) is added 4-(3-chloropropyl)morpholine (0.9 g, 4.5 mmol) (J. Am. Chem. Soc. 1945, 67, 736). The mixture is heated at a temperature of 110oC for 4 hours and allowed to cool. Solids are removed by filtration, the filtrate is evaporated volatile substances. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride: methanol (96:4), which gives 6-methoxy-7-(3-Mor s, 4H); of 3.95 (s, 3H); 4.25 in (t, 2H); 7,25-7,35 (m, 3H); 7,40 (s, 1H), 7,45-of 7.55 (m, 2H), 7,55 (s, 1H); and 8.50 (s, 1H).

MS-ESI: 396 [MN]+.

A mixture of 6-methoxy-7-(3-morpholinoethoxy)-4-phenoxybenzamide (980 mg, 2.48 mmol) and 2 M hydrochloric acid (25 ml) is heated at a temperature of 100oC for 2 hours and allowed to cool. The solution is alkalinized with solid sodium bicarbonate and the product extracted with methylene chloride. The organic phase is passed through footclaws paper and the solvent is evaporated, giving 6-methoxy-7-(3-morpholinopropan)-3,4-dihydroquinazolin-4-one (750 mg, 95%) as a pale brown solid which is used without further purification.

MS-ESI: 320 [MN]+.

Example 17

A mixture of 6-methoxy-7-(3-morpholinopropan)-3,4-dihydroquinazolin-4-it (370 mg, of 1.16 mmol) (obtained similarly to the original substance in example 16), thionyl chloride (5 ml) and DMF (3 drops) is heated under reflux for 2 hours and allowed to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. To the solid residue is added a solution of 4-chloro-2-fluoro-5-hydroxyanisole (210 mg, of 1.30 mmol) (described in European patent 61741 A2), in isopropanol (10 ml). Poluchayut acetone and the precipitate collected by filtration. The crude solid product is suspended in aqueous sodium bicarbonate solution, again collected by filtration and purified by chromatography on columns, elwira a mixture of methylene chloride: methanol: ammonia (100:10:1), giving 4-(4-chloro-2-fluoro-5-hydroxyanisol)-6-methoxy-7-(3-morpholinopropan)hinzelin (160 mg, 30%).

Range1H NMR: (DMSO d6) 2,0 (m, 2H); 2,35 is 2.55 (m, 6H); 3.6 (t, 4H); of 3.95 (s, 3H); 4,15 (t, 2H); to 7.15 (m, 2H); to 7.35 (d, 1H); of 7.75 (s, 1H); 8,35 (s, 1H); 9,35 (s, 1H); 10,15 (s, 1H).

MS-ESI: 463 [MH]+.

Elemental analysis: C22H24N4O4FCl.

Found, %: 57,1; N Is 5.3; N, 12,0.

Calculated, %: 57,1; H 5,2; N 12,1.

Example 18

To 4-chloro-6-methoxy-7-(2-methylthiouracil)hintline (0.8 g, 2.8 mmol) and 2-fluoro-5-hydroxy-4-methyl-aniline production (0,44 g of 3.12 mmol) (obtained similarly to the original substance in example 8) in isopropanol (25 ml) was added 1 M ethereal solution of hydrogen chloride (3.1 ml, 3.1 mmol). The mixture is heated under reflux for 2 hours and allowed to cool. The resulting suspension is diluted with acetone, the precipitate is collected by filtration and purified by chromatography on columns, elwira a mixture of methylene chloride:methanol:ammonia (100:8: 1), giving 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-methylthiouracil)hinzelin (580 mg, 52%).

MS-ESI: 390 [MN]+.

Elemental analysis: C19H20N3O3FS0,5H2O.

Found, %: With 57.4; H 5,1; N 10,5.

Calculated, %: C 57,3; N 5,3; N 10,5.

The original substance is obtained in the following way:

To 7-hydroxy-6-methoxy-4-phenoxybenzamide (2.25 g, 8.4 mmol) (obtained similarly to the original substance in example 16) and potassium carbonate (6.0 g, a 43.4 mmol) in DMF (70 ml) is added 2-chloroethylnitrosourea (1.2 g, 10.9 mmol). The mixture is heated at a temperature of 110oC and allowed to cool, after which it is filtered and is evaporated from the filtrate volatile substances. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride: methanol (96: 4), which gives 6-methoxy-7-(2-methylthiouracil)-4-phenoxybenzoic (1.55 g, 54%).

A mixture of 6-methoxy-7-(2-methylthiouracil)-4-phenoxybenzamide (1.5 g, 4.4 mmol) and 2 M hydrochloric acid (25 ml) is heated at a temperature of 100oC for 2 hours. The mixture is allowed to cool, stirring, add methylene chloride, giving a white precipitate. The precipitate is collected by filtration, washed with water and methylene chloride and dried to obtain hydrochloride of 6-methoxy-7-(2-methylthiouracil)-3,4-dihydroquinazolin-4-it (1.1 g, 83%).

+.

Elemental analysis: C12H14N2O3S1HCl.

Found, %: From 46.4; H 5,2; N 8,8.

Calculated, %: From 47.6; H 5,0; N 9,3.

A mixture of 6-methoxy-7-(2-methylthiouracil)-3,4-dihydroquinazolin-4-it (1.07 g, 4.0 mmol), thionyl chloride (20 ml) and DMF (4 drops) is heated under reflux for 2 hours and allowed to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. The solid residue partitioned between aqueous sodium bicarbonate solution and methylene chloride, the organic phase is separated and washed with a saturated solution of salt. Then the organic phase is passed through footclaws paper and the solvent is evaporated to obtain 4-chloro-6-methoxy-7-(2-methylthiouracil)hintline (810 mg, 71%).

MS-ESI: 285 [MN]+.

Examples 19 and 20

To a solution of 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-methylthiouracil)hintline (485 mg, 1.2 mmol) (obtained as described in example 18) in methylene chloride (90 ml) and DMA (6 ml) is added 3-chloroperoxybenzoic acid (wet, 50-60%, 500 mg). After 2 hours, add 2 servings 3-chloroperoxybenzoic acid (total 160 mg). Check to see if there were any in the mixture of the oxidant and evaporated volatile substances. the-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-(methylsulphonyl)ethoxy)hinzelin (94 mg, 19%).

Range1H NMR: (DMSO d6) to 2.15 (s, 3H); 3,18 (s, 3H); 3,70 (t, 2H); of 3.95 (s, 3H); 4,50 (t, 2H); 6,92 (d, 1H); 6,97 (d, 1H); to 7.25 (s, 1H); 7,83 (s, 1H); with 8.33 (s, 1H); 9,27 (s, 1H); of 9.30 (s, 1H).

MS-ESI: 422 [MN]+.

Elemental analysis: C19H20N3O5SF0,5H2O.

Found, %: 53,0; N Is 4.9; N 9,7.

Calculated, %: 53,0; N IS 4.9; N 9,8

and 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-(2-(methylsulfinyl)ethoxy)hinzelin (120 mg, 25%).

Range1H NMR: (DMSO d6) of 2.16 (s, 3H); 2,69 (s, 3H); 3.15 in (m, 1H); 3,37 (m, 1H); of 3.94 (s, 3H); 4.53-in (m, 2H); 6,92 (d, 1H); 6,97 (d, 1H); 7,83 (s, 1H); 8,32 (s, 1H); 9,27 (s, 1H); of 9.30 (s, 1H).

MS-ESI: 406 [MN]+.

Elemental analysis: C19H20N3O4F.

Found, %: C Of 55.5; H 5,0; 10,0 N.

Calculated, %: 56,0; N. Of 5.4; N 10,3.

Example 21

A mixture of 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy-3,4-dihydroquinazolin-4-it (260 mg, 0.90 mmol), thionyl chloride (5 ml) and DMF (2 drops) is heated under reflux for 45 minutes and leave to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. To the residue is added a solution of 4-chloro-2-fluoro-5-hydroxyanisole (160 mg, 1.0 mmol) (described in European patent 61741 A2) in isopropanol (5 ml), after which the resulting mixture nagrody collected by filtration, washed with acetone and dried to obtain hydrochloride of 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hintline (381 mg, 83%).

Range1H NMR: (DMSO d6) 1,85-of 2.15 (br m, 4H); 3,20 (br s, 2H); of 3.5-3.7 (br m, 4H); of 4.05 (s, 3H); with 4.65 (t, 2H); then 7.20 (d, 1H); 7.5 (a m, 2H); to 8.45 (s, 1H); 8,80 (s, 1H); to 10.5 (br s, 1H); 11,35 (br s, 1H); of 11.75 (br s, 1H).

MS-ESI: 433 [MN]+.

Elemental analysis: C21H22N4O3ClF2HCl0,17 isopropanol.

Found, %: With 49.7; H 5,0; N 10,6.

Calculated, %: From 50.1; H 5,0; N 10,9.

The original substance is obtained in the following way:

To 7-hydroxy-6-methoxy-4-phenoxybenzamide (1.0 g, 3.7 mmol) (obtained similarly to the original substance in example 16) and potassium carbonate (3.9 g, 28.3 mmol) in DMF (30 ml) was added 1-(2-chloroethyl)pyrrolidinedione (1.27 g, 7.5 mmol). The mixture is heated at a temperature of 110oC for 4 hours and allowed to cool, after which it is filtered and is evaporated from the filtrate volatile substances. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol:ammonia (100:8:1), to obtain the oil, which is pounded into powder with ethyl acetate, giving 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hinzelin (200 mg, 15%) as a white solid.

Range

MS-ESI: 366 [MN]+.

A mixture of 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy) hintline (565 mg, 1.55 mmol) and 2 M hydrochloric acid (5 ml) is heated at a temperature of 90oC for 90 minutes and leave to cool. The resulting solution was neutralized with an aqueous solution of sodium bicarbonate and evaporated water. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol: ammonia (100:8:1), giving 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (480 mg). This substance is used without further research.

Example 22

To 4-chloro-6-methoxy-7-(2-morpholinoethoxy)hintline (210 mg, of 0.65 mmol) and 4-chloro-2-fluoro-5-hydroxyanisole (115 mg, 0.71 mmol) (described in European patent 61741 A2) in isopropanol (5 ml) was added 1 M ethereal solution of hydrogen chloride (0,72 ml, to 0.72 mmol). The resulting mixture was heated under reflux for 2 hours and allowed to cool, after which it is diluted with acetone and the precipitated product collected by filtration. The crude product is dissolved in a mixture of methylene chloride: ammonia (100:1) and methanol, insoluble materials are removed by filtration and evaporated from the filtrate volatile substances. The solid residue washed with water and dried with1H NMR: (DMSO d6) 2,45-2,60 (m, 4H); 2,78 (t, 2H); to 3.58 (t, 4H); of 3.94 (s, 3H); 4.26 deaths (t, 2H); 7,17 (d, 1H); 7.23 percent (s, 1H); 7,38 (d, 1H); 7,79 (s, 1H); of 8.37 (s, 1H); 9,43 (s, 1H); 10,17 (s, 1H).

MS-ESI: 449 [MN]+.

Elemental analysis: C21H22N4O4ClF1,25H2O.

Found, %: From 53.5; H 5,2; N 11,6.

Calculated, %: From 53.5; H 5,3; N 11,9.

The original substance is obtained in the following way:

To 7-hydroxy-6-methoxy-4-phenoxybenzamide (0.5 g, of 1.86 mmol) (obtained similarly to the original substance in example 16) and potassium carbonate (1.2 g, 8,7 mmol) in DMF (60 ml) is added 1,2-dibromoethane (1.6 ml, of 18.6 mmol). The resulting mixture is heated at a temperature of 85oC for 2 hours and allowed to cool. Insoluble substances are removed by filtration and evaporated from the filtrate volatile substances with obtaining balance,

which is purified by chromatography on columns, elwira a mixture of methylene chloride: methanol (97:3), which gives 7-(2-bromoethoxy)-6-methoxy-4-phenoxybenzoic (440 mg, 63%).

MS-ESI: 375 [MN]+.

The mixture of the research (8 ml) and 7-(2-bromoethoxy)-6-methoxy-4-phenoxybenzamide (450 mg, 1.2 mmol) was stirred at room temperature for 3 hours. The excess of the research is evaporated and the residue partitioned between an aqueous solution of bicarbonate natorial. Rubbing the rest into powder with isohexane gives a solid which is collected by filtration and dried to obtain 6-methoxy-7-(2-morpholinoethoxy)-4-phenoxybenzamide (410 mg, 90%).

MS-ESI: 382 [MN]+.

A mixture of 6-methoxy-7-(2-morpholinoethoxy)-4-phenoxybenzamide (400 mg, 1.05 mmol) and 2 M hydrochloric acid (10 ml) is heated at a temperature of 100oC for 2 hours and allowed to cool. The resulting mixture was neutralized with solid sodium bicarbonate. Adding methylene chloride gives a white precipitate, which is collected by filtration, washed with acetone and dried to obtain 6-methoxy-7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-it (320 mg, 100%).

MS-ESI: 306 [MN]+.

A mixture of 6-methoxy-7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-she (310 mg, of 1.02 mmol), thionyl chloride (10 ml) and DMF (2 drops) is heated under reflux for 4 hours and allowed to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. The residue is partitioned between aqueous sodium bicarbonate solution and methylene chloride. The organic layer is separated, washed with saturated salt solution and filtered through footclaws paper. Volatile matter is evaporated the XI-7-(2-morpholinoethoxy)hinzelin (225 mg, 68%).

MS-ESI: 324 [MN]+.

Example 23

To 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)hintline (115 mg, 0.34 mmol) and 4-chloro-2-fluoro-5-hydroxyanisole (61 mg, 0.38 mmol) (described in European patent 61741 A2) in isopropanol (5 ml) was added 1 M ethereal solution of hydrogen chloride (to 0.34 ml, 0.34 mmol). The resulting mixture was heated under reflux for 90 minutes and leave to cool, then diluted with acetone and the solid product collected by filtration. The crude solid is treated with a mixture of methylene chloride: methanol: ammonia (100: 8:1) (5 ml). add the water. The precipitated product is collected by filtration and dried to obtain 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)hintline (32%).

Range1H NMR: (DMSO d6) of 2.28 (s, 3H); 2,53 (m, 4H); 2,60 (m, 4H); of 2.81 (t, 2H); of 3.95 (s, 3H); 4.25 in (t, 2H); 7.18 in (d, 1H); 7,20 (s, 1H); of 7.36 (d, 1H); 7,80 (s, 1H); 8,35 (s, 1H); 9,43 (s, 1H); 10,18 (br s, 1H)

MS-ESI: 462 [MN]+.

Elemental analysis: C22H25N5O3lF1,3H2O.

Found, %: C 54,1; N 5,3; N 14,0.

Calculated, %: C To 54.4; H 5,7; N 14,4.

The original substance is obtained in the following way:

A mixture of 1-methylpiperazine (7 ml) and 7-(2-bromoethoxy)-6-methoxy-4-phenoxybenzamide (1,0 is for 5 hours. The excess 1-methylpiperazine is evaporated and the residue partitioned between aqueous sodium bicarbonate solution and methylene chloride. The organic phase is separated, passed through footclaws paper and evaporated volatiles to obtain 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-phenoxybenzamide (970 mg, 92%).

Range1H NMR: (DMSO d6) of 2.21 (s, 3H); of 2.38 (m, 4H); of 2.58 (m, 4H); to 2.85 (t, 2H); was 4.02 (s, 3H); of 4.35 (t, 2H); 7,39 (m, 3H); 7,46 (s, 1H); at 7.55 (m, 2H); to 7.61 (s, 1H); 8,59 (s, 1H).

A mixture of 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-phenoxybenzamide (960 mg, 2.4 mmol) and 2 M hydrochloric acid (20 ml) is heated at a temperature of 95oC for 2 hours and allowed to cool. The solution is alkalinized with solid sodium bicarbonate, water is evaporated and the residue is subjected to the azeotropic distillation with toluene. The residue is thoroughly washed with methylene chloride, washing combine water, insoluble materials are removed by filtration and the solvent is evaporated to obtain 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-it (500 mg, 66%).

MS-ESI: 319 [MH]+.

A mixture of 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-it (500 mg, 1.57 mmol), thionyl chloride (20 ml) and DMF (3 drops) is heated aboutnight the azeotropic distillation with toluene. The residue is treated with an aqueous solution of sodium bicarbonate and extracted the product with methylene chloride. The combined extracts washed with saturated salt solution, is passed through footclaws paper and the solvent is evaporated to obtain 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)hintline (120 mg, 23%).

MS-ESI: 337 [MN]+.

Example 24

A mixture of 6-methoxy-7-(2-piperidinoethyl)-3,4-dihydroquinazolin-4-she (440 mg, 1,45 mmol), thionyl chloride (15 ml) and DMF (3 drops) is heated under reflux for 3 hours and allowed to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene, giving crude hydrochloride 4-chloro-6-methoxy-7-(2-piperidinoethyl) hintline (640 mg).

The sample (320 mg, 0.89 mmol) of the substance added to a solution of 4-chloro-2-fluoro-5-hydroxyquinazoline (130 mg, 0.8 mmol) (described in European patent 61741 A2), in isopropanol (10 ml). The resulting mixture was heated under reflux for 90 minutes and leave to cool, then diluted with acetone, the precipitated product is collected by filtration and dried. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol:ammonia (100:8:1). The purified product by rastovaniem and dried to obtain hydrochloride of 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-piperidinoethyl)hintline (137 mg, 32%).

Range1H NMR: (DMSO d6) a 1.75 (br m, 6H); 4,00 (s, 3H); with 4.65 (t, 2H); to 7.15 (d, 1H); to 7.35 (s, 1H); 7,42 (d, 1H); 8,15 (s, 1H); at 8.60 (s, 1H); 10,4 (s, 1H); to 10.6 (br s, 2H).

MS-ESI: 447 [MN]+.

Elemental analysis: C22H24N4O3ClF2HCl.

Found, %: From 51.0; H 5,4; N 10,6.

Calculated, %: From 50.8; H 5,0; N 10,8.

The original substance is obtained in the following way:

To 7-hydroxy-6-methoxy-4-phenoxybenzamide (1.0 g, 3.73 mmol) (obtained similarly to the original substance in example 16) and potassium carbonate (2.6 g, an 18.8 mmol) in DMF (30 ml) was added 1-(2-chloroethyl)piperidinedione (0,83 g, 4.5 mmol).

The resulting mixture is heated at a temperature of 110oC for 2.5 hours and allowed to cool. Insoluble substances are removed by filtration and evaporated from the filtrate volatile substances. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol (9:1), giving 6-methoxy-4-phenoxy-7-(2-piperidinoethyl)hinzelin (1/2 g, 85%).

Range1H NMR: (DMSO d6) to 1.38 (m, 2H); 1,50 (m, 4H); 2,4-2,5 (m, 4H); a 2.75 (t, 2H); of 3.95 (s, 3H); 4,27 (t, 2H); 7,30 (m, 3H); 7,40 (s, 1H); 7,46 (m, 2H); rate of 7.54 (s, 1H); charged 8.52 (s, 1H).

MS-ESI: 380 [MN]+.

A mixture of 6-methoxy-4-phenoxy-7-(2-piperidinoethyl)hintline (1,15 g, 3.0 mmol) and 2 M solution of chloride is obtained mixture is neutralized with solid sodium bicarbonate and extracted with methylene chloride. The organic phase is separated, passed through footclaws paper and evaporated volatile substances with obtaining solid product (230 mg). The aqueous phase is brought to pH 10, the precipitate is collected by filtration, washed with water and dried, giving the second portion of the product (220 mg). The products combine with obtaining 6-methoxy-7-(2-piperidinoethyl)-3,4-dihydroquinazolin-4-it (450 mg, 50%).

MS-ESI: 304 [MN]+.

Example 25

A mixture of 7-(2-cyclopentylacetyl)-6-methoxy-3,4-dihydroquinazolin-4-it (260 mg, 0.85 mmol), thionyl chloride (5 ml) and DMF (2 drops) is heated under reflux for 2 hours and allowed to cool. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. To the residue is added a solution of 4-chloro-2-fluoro-5-hydroxyanisole (140 mg, 0.87 mmol) (described in European patent 61741 A2) in isopropanol (5 ml), the mixture was heated under reflux for 1 hour and allowed to cool. The suspension is diluted with acetone and collect the precipitate by filtration. The crude product is dissolved in a mixture of methylene chloride:methanol:ammonia (100:8:1.2 ml), the insoluble matter is removed by filtration and evaporated from the filtrate the solvent. The residue is dissolved in acetone, addition of the hydrochloride of 4-(4-chloro-2-fluoro-5-hydroxyimino)-7-(2-cyclopentylacetyl)-6-methoxyquinazoline (50 mg, 12%).

Range1H NMR: (DMSO d6) of 1.5 to 1.75 (m, 8H); of 3.75 (m,2H); 3,9-4,1 (m, 1H); 4,00 (s, 3H); 4.80 to (t, 2H); 7,20 (m, 1H); to 7.35 (s, 1H); 7,50 (d, 1H); of 8.25 (s, 1H); is 8.75 (s, 1H); to 10.5 (br s, 1H); 11,4 (br s, 1H).

MS-ESI: 448 [MH]+.

Elemental analysis: C22H23N3O4ClF1HCl0,1H2O.

Found, %: C 54,1; N 4,8; N 8,5.

Calculated, %: C To 54.4; H 5,0; N 8, 6.

The original substance is obtained in the following way:

To a solution of 3-toluensulfonate (6.8 g, 35,7 mmol) in pyridine (27 ml) at a temperature of 5oWith added dropwise 2-cyclopentylacetyl (4.3 g, up 33.1 mmol) in pyridine (18 ml). The resulting mixture was left to warm to room temperature and stirred overnight, then poured onto ice containing concentrated hydrochloric acid (46 ml), and extracted the product with ether. The organic phase is washed with 2 M hydrochloric acid solution, dried (gSO4) and the solvent evaporated to obtain 2-cyclopentylacetyl 4-toluensulfonate (6,9 g, 73%), which is used without further purification.

To a suspension of sodium hydride (184 mg, 60% suspension in oil, 4.6 mmol) in DMF (3 ml) is added 7-hydroxy-6-methoxy-4-phenoxybenzoic (1,11 g, 4.2 mmol) (obtained similarly to the original substance in precapitalistic 4-toluensulfonate (1.25 g, of 4.45 mmol) in DMF (3 ml). The resulting mixture was stirred at room temperature for 30 minutes, heated for 2 hours at a temperature of 60oWith, then another 4 hours at a temperature of 80oWith and leave to cool. The mixture is poured onto ice and extracted with methylene chloride. The combined extracts washed with saturated salt solution, is passed through photodeluxe paper and the solvent is evaporated. The residue is purified by chromatography on columns, elwira with ethyl acetate. The purified product is grinded into powder with isohexane that gives 7-(2-cyclopentylacetyl)-6-methoxy-4-phenoxybenzoic (480 mg, 28%).

Range1H NMR: (DMSO d6) 1,2-1,7 (m, 8H); of 3.77 (m, 2H); of 3.95 (s, 3H); 4.0 a (m, 1H); 4.25 in (m, 2H); 7,30 (m, 3H); 7,38 (s, 1H); was 7.45 (m, 2H); at 7.55 (s, 1H); and 8.50 (s, 1H).

MS-ESI: 381 [MN]+.

A mixture of 7-(2-cyclopentylacetyl)-6-methoxy-4-phenoxybenzamide (470 mg, 1.2 mmol) and 2 M hydrochloric acid (6 ml) is heated at a temperature of 90oC for 2 hours and allowed to cool. Add water and extracted the product with methylene chloride. The combined extracts are washed with aqueous sodium bicarbonate solution, passed through footclaws paper and the solvent is evaporated. Kneading the powder with ethyl acetate to give 7-(2-cyclopent is/BR> To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (820 mg, 2.2 mmol) in methanol (20 ml) was added 1 M aqueous sodium hydroxide solution (4 ml, 4 mmol) and stirred the mixture for 1 hour at room temperature. Then add concentrated hydrochloric acid (0.8 ml), the volatiles evaporated and the residue purified by chromatography on columns, elwira a mixture of methylene chloride:methanol (60: 40), giving 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (313 mg, 45%).

So pl. 276-278oC.

Range1H NMR: (DMSO d6; CF3COOD) to 2.18 (s, 3H); 4.0 a (s, 3H); to 6.88 (d, 1H); for 7.12 (d, 1H); 7,26 (s, 1H); 8,08 (s, 1H); 8,76 (s, 1H).

MS-ESI: 316 [MH]+.

Elemental analysis: C16H14N3O3FlHCl0,1H2O.

Found, %: C To 54.4; H 4,4; N 11,5.

Calculated, %: C To 54.4; H 4,3; N 11,9.

The original substance is obtained in the following way:

A solution of (4-fluoro-2-methyl-5-nitrophenyl)methylcarbamate (3 g, 13 mmol) (obtained as described in European patent 0307777 A2) in ethanol (60 ml) containing platinum oxide(IV) (300 mg), stirred in a hydrogen atmosphere under a pressure of 0.3 psi for 1 hour. After filtration of the mixture and evaporation of the solvent extraction is>) 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-methoxyquinazoline (800 mg, 2.6 mmol) (obtained similarly to the original substance in example 4, but with a water treatment) and 2-fluoro-5-methoxycarbonylamino-4-methylaniline (570 mg, 2.89 mmol) in isopropanol (20 ml) is heated under reflux for 2 hours. The solution is cooled to room temperature, the solid is filtered, washed with isopropanol and dried in vacuo to obtain 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxyquinazoline (1.0 g, 77%).

Range1H NMR: (DMSO d6; CF3OD) 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).

MS-ESI: 464 [MN]+.

A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxyquinazoline (700 mg, 1.4 mmol) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) containing 10% palladium on coal (100 mg), stirred in an atmosphere of hydrogen under a pressure of 1 ATM for 1 hour. The solution is filtered and the solvent is evaporated, then the residue is ground to powder with ether, filtered and dried in vacuum to obtain 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (570 mg, 98%).

Range1H A: 374 [MN]+.

Example 27

A solution of the hydrochloride of 4-chloro-7-(2-methoxyethoxy)hintline (275 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (170 mg, 1.2 mmol) (obtained similarly to the original substance in example 8) in 2-pentanol (5 ml) is heated under reflux for 2 hours. The mixture is allowed to cool, the precipitate is collected by filtration, washed with isopropanol and ether and dried in vacuum at a temperature of 70oWith that gives the hydrochloride of 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethoxy)hintline (295 mg, 78%) as a cream solid.

So pl. 217 to 220oC.

Range1H NMR: (DMSO d6) 2,17 (s, 3H); to 3.36 (s, 3H); 3.75 to (t, 2H); 4,34 (t, 2H); 6.89 in (d, 1H); 7,11 (d, 1H); 7,30 (d, 1H); 7,52 (dd, 1H); 8,66 (d, 1H); 8,82 (s, 1H); 9,68 (s, 1H); 11,40 (s, 1H).

MS-ESI: 344 [MH]+.

Elemental analysis: C18H18N3O3F1HCl.

Found, %: From 56.8; H 5,2; N 11,1.

Calculated, %: C 56,9; N 5,0; N 11,1.

The original substance is obtained in the following way:

A solution of 2-amino-4-fermenting acid (3 g, and 19.3 mmol) in formamide (30 ml) is heated at a temperature of 150oC for 6 hours. The reaction mixture was poured into a mixture of ice water (1:1) (250 ml). The precipitated solid is collected by filtration, washed in the on add sodium (400 mg, 17 mmol) and heat the mixture under reflux for 30 minutes. To the resulting solution was added 7-fluoro-3,4-dihydroquinazolin-4-one (750 mg, of 4.57 mmol) and heat the mixture under reflux for 15 hours. The resulting mixture is cooled and poured into water (250 ml), after which it is acidified to pH 4 with concentrated hydrochloric acid. The obtained solid product is collected by filtration, washed with water and ether and dried in vacuo to obtain 7- (2-methoxyethoxy)-3,4-dihydroquinazolin-4-she (580 mg, 58%).

A solution of 7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-it (500 mg, 2.2 mmol) in thionyl chloride (15 ml) and DMF (0.1 ml) is heated under reflux for 3 hours. Volatile matter is evaporated to obtain hydrochloride of 4-chloro-7-(2-methoxyethoxy)hintline in the form of a cream solid (520 mg, 83%).

Example 28

A solution of the hydrochloride of 4-chloro-7-(2-methoxyethoxy)hintline (275 mg, 1.0 mmol) (obtained similarly to the original substance in example 27) and 4-chloro-2-fluoro-5-hydroxyanisole (193 mg, 1.2 mmol) (described in European patent 61741 A2) 2-pentanol (5 ml) is heated under reflux for 2 hours. The mixture is allowed to cool, the precipitate is collected by filtration, washed with isopropanol-7-(2-methoxyethoxy)hintline (178 mg, 45%) as a cream solid.

So pl. 224-227oC.

Range1H NMR: (DMSO d6) to 3.36 (s, 3H); 3,76 (t, 2H); 4,34 (t, 2H); 7,14 (d, 1H); and 7.3 (d, 1H); 7,53 (m, 2H); 8,66 (d, 1H); cent to 8.85 (s, 1H); of 10.58 (s, 1H); 11,40 (s, 1H).

MS-ESI: 364 [MN]+.

Elemental analysis: C17H15N3O3FCl1HCl.

Found, %: From 50.8; H 4,1; N 10,4.

Calculated, %: From 51.0; H 4,0; N 10,5.

Example 29

A solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline) -7-methoxyacetophenone (201 mg, 0.5 mmol) in methanol (5 ml) and 2 M aqueous sodium hydroxide solution (0.5 ml) was stirred at room temperature for 1 hour. The mixture is diluted with water and adjusted to pH 6 by adding 2 M hydrochloric acid solution. The precipitated solid is collected by filtration, washed with water, dried and dissolved in a mixture of methylene chloride and methanol. Then add 5 M solution of hydrogen chloride in isopropanol (0.3 ml) and most of the solvent is evaporated. The precipitated solid is collected by filtration, washed with methylene chloride and dried in vacuum to obtain hydrochloride of 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetophenone (70 mg, 36%) as a yellow solid.

So pl. 213-215oC.

s, 1H).

MS-ESI: 357 [MH]+.

Elemental analysis: C18H17N4O3FlHCl0,5H2O.

Found, %: C Of 53.7; H Is 4.9; N 13,6.

Calculated, %: C 53,8; N 4,8; N 13,9.

The original substance is obtained in the following way:

A mixture of 7-nitro-3,4-dihydroquinazolin-4-it (5 g, 26 mmol) in thionyl chloride (50 ml) and DMF (1 ml) is heated under reflux for 1.5 hours. The excess thionyl chloride is removed by evaporation and the residue is subjected to the azeotropic distillation with toluene. The residue is suspended in ether, collected by filtration and dried in vacuum to obtain hydrochloride of 4-chloro-7-nitroquinazoline (6.4 g, 100%).

Range1H NMR: (DMSO d6) compared to 8.26 (dd, 1H); at 8.36 (d, 1H); to 8.40 (s, 1H); 8,42 (dd, 1H).

MS-ESI: 209 [MH]+.

A solution of the hydrochloride of 4-chloro-7-nitroquinazoline (2,46 g, 10 mmol) and 2-fluoro-5-methoxycarbonylamino-4-methylaniline (2.2 g, 11 mmol) (obtained similarly to the original substance in example 26) in isopropanol (25 ml) is heated at a temperature of 50oC for 1 hour. The mixture is allowed to cool, the precipitated solid is collected by filtration and recrystallized from a mixture of methylene chloride/methanol/isopropanol to obtain hydrochloride of 4-(2-fluoro-5-methoxycarbonylamino-4-metranil is 1 (s, 3H); 3,86 (s, 3H); 7,40 (d, 1H); 7,46 (d, 1H); 8,49 (dd, 1H); 8,63 (s, 1H); 8,84 (s, 1H); 8,89 (d, 1H).

MS-ESI: 373 [MH]+.

Elemental analysis: C17H13N4O5F1HCl.

Found, %: C 50,0; H 3,6; N 13,8.

Calculated, %: C 50,0; H 3,5; N 13,7.

A mixture of the hydrochloride of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-nitroquinazoline (5,3 g, 13 mmol) and catalyst, such as 10% palladium on coal (1 g) in ethanol (100 ml), 7 M solution of hydrogen chloride in ethanol (1.8 ml) and methanol (20 ml) is stirred in hydrogen atmosphere under a pressure of 1.7 ATM for 75 minutes. The catalyst was removed by filtration through diatomaceous earth, the filter is washed thoroughly with methylene chloride, methanol and ether, then from the filtrate the solvent is evaporated, giving the hydrochloride of 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)hintline (4.8 g, 97%) as a yellow solid.

Range1H NMR: (DMSO 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).

MS-ESI: 343 [MH]+.

To a suspension of the hydrochloride of 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)hintline (415 mg, 1.1 mmol) in methylene chloride (10 ml) add methoxyacetanilide (119 mg, 1.1 mmol) and triethylamine (232 mg, 2.3 mmol), PEFC is dilatatum and water. The organic layer is separated, washed with saturated salt solution, dried (gSO4) and the solvent evaporated. The obtained solid is purified by chromatography on columns, elwira a mixture of methylene chloride:acetonitrile (50:50), and then with a mixture of methylene chloride: acetonitrile: methanol (50:45:5), giving 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-methoxyacetophenone (250 mg, 60%) as a yellow solid.

Range1H NMR: (DMSO d6) to 2.18 (s, 3H); to 3.41 (s, 3H); 3,85 (s, 3H); 4.09 to (s, 2H); 7,30 (d, 1H); 7,44 (d, 1H); to 7.84 (d, 1H); by 8.22 (s, 1H); at 8.36 (d, 1H); 8,44 (s, 1H); 9,74 (s, 1H); of 10.21 (s, 1H).

MS-ESI: 437 [MPa]+.

Example 30

To a solution of the hydrochloride of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxyquinazoline (400 mg, 1.05 mmol) in methanol (10 ml) was added 1 M aqueous sodium hydroxide solution (2.1 ml, 2.1 mmol) and the resulting mixture is stirred for 50 minutes at room temperature. The solvent is evaporated, the residue is dissolved in water and adjusted to pH 7 by adding hydrochloric acid. The aqueous mixture is extracted with ethyl acetate, the extracts washed with a saturated solution of salt, dried (MgSO4) and the solvent evaporated. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride: methanol (95: 5 and 80:20). Ocie substance is evaporated and the residue is ground to powder with pentane, that gives 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-hydroxyquinazoline (149 mg, 44%) as a yellow solid.

So pl. 274-278oC.

Range1H NMR: (DMSO d6) of 2.16 (s, 3H); 6.87 in (d, 1H); 7,10 (d, 1H); 7,22 (d, 1H); 7,32 (ss, 1H); to 8.57 (d, 1H); 8,76 (s, 1H); to 9.66 (s, 1H); 11,24 (s, 1H); 11,70 (s, 1H).

MS-ESI: 285 [MN]+.

Elemental analysis: C15H12N3O2F1HCl0,3H2O0,05 NaCl.

Found, %: From 54.2; 4,1; N 12,3.

Calculated, %: From 54.6; H 4,2; N 12,7.

The original substance is obtained in the following way:

To benzyl alcohol (10 ml, 96 mmol) is added sodium (368 mg, 16 mmol) and the resulting mixture is heated at a temperature of 148oC for 30 minutes. Then add 7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol) (J. Chem. Soc., section b, 1967, 449) and incubated the mixture at a temperature of 148oWith in 24 hours. The reaction mixture is allowed to cool, the solution was poured into water (170 ml) and the aqueous mixture was adjusted to pH 3 by adding concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and ether and dried in vacuo to obtain 7-benzyloxy-3,4-dihydroquinazolin-4-it (890 mg, 89%) as a white solid.

So pl. 267-269oC.

Range1H NMR: (DMSO d615H12N2O20,04 H2O.

Found, %: From 71.4; H Is 4.9; N 10,7.

Calculated, %: From 71.2; H 4,8; N 11,1.

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

So pl. 131-132oC.

Range1H NMR: (DMSO d6; CF3COOD) 5,32 (s, 2H); 7,29 (d, 1H); 7,34-7,52 (m, 6H); to 8.12 (d, 1H); 9,03 (s, 1H).

MS-ESI: 270 [MN]+.

To a solution of the hydrochloride of 7-benzyloxy-4-chlorination (1 g, 3.7 mmol) in 2-pentanol (15 ml) at a temperature of 120oWith added 2-fluoro-5-methoxycarbonylamino-4-methylaniline (883 mg, 4.4 mmol) (obtained similarly to the original substance in example 26) and the resulting mixture heated under reflux for 4 hours. The precipitate is collected by filtration, washed with isopropanol and ether and dried in vacuum to obtain hydrochloride of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)hintline (1.65 g, 97%) as a cream solid.

s, 1H); and 11.2 (s, 1H).

MS-ESI: 434 [MN]+.

Elemental analysis: C24H20N3O4F1HCl0,5H2O.

Found, %: From 60.1; H Is 4.9; N 8,5.

Calculated, %: With A 60.2; H 4,6; N 8,8.

The hydrochloride of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)hintline (1,53 g, 3.25 mmol) and the catalyst, such as 10% palladium on coal (180 mg) in methanol/DMF/trichlormethane (75 ml, 6 ml, 30 ml) is stirred in hydrogen atmosphere under a pressure of 1.5 ATM for 45 minutes. The catalyst was removed through diatomaceous earth and evaporated from the filtrate the solvent. The residue is ground to powder with ether, the obtained solid is collected by filtration and dried in vacuum to obtain hydrochloride of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-hydroxyquinazoline (1,23 g, 84%) as an orange solid.

So pl. 205-210oC.

Range1H NMR: (DMSO 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).

MS-ESI: 344 [MH]+.

Example 31

To a suspension of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-(3-morpholinopropan)hintline (219 mg, 0.45 mmol) in methanol (6 ml) is added 2 M aqueous sodium hydroxide solution (453 μl, 0,9 mover hydrochloric acid. The precipitate is collected by filtration, washed with water and ethanol and dried. The solid is dissolved in a mixture of methylene chloride/methanol and add 5 M solution of hydrogen chloride in isopropanol (0.3 ml). Volatile matter is evaporated, the obtained solid is washed with ether and dried in vacuum to obtain 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(3-morpholinopropan)hintline (186 mg, 80%) as a yellow solid.

So pl. 228-233oC.

Range1H NMR: (DMSO d6; CF3COOD) of 2.21 (s, 3H); 3,1 (t, 2H); up 3.22 (t, 2H); 3,5-3,6 (m, 4H); and 3.8 (t, 2H); of 4.05 (d, 2H); 6,94 (d, 1H); 7,10 (d, 1H); 7,88 (d, 1H); 8,55 (s, 1H); to 8.7 (d, 1H); 8,9 (s, 1H).

MS-ESI: 426 [MH]+.

Elemental analysis: C22H24N5O3F1,9l0,6H2O0,2 isopropanol.

Found, %: C 52,1; N 5,8; N 13,4.

Calculated, %: From 52.5; H 5,6; N 13,5.

The original substance is obtained in the following way:

To a solution of methyl 3-morpholinopropan (1 g, 5.7 mmol) in ethanol (20 ml) add potassium hydroxide (485 mg, 8.6 mmol) and the resulting mixture is stirred for 2 hours at a temperature of 80oC. the Solution is allowed to cool and adjusted to pH 1 by adding 6 M hydrochloric acid solution. Insoluble matter is removed by filtration and Lipari what filtrowanie, washed with methylene chloride and dried in vacuum to obtain 3-morpholinopropan acid (993 mg, 89%) as a white solid.

Range 1H NMR: (DMSO d6; CF3COOD) and 2.83 (t, 2H); of 3.13 (t, 2H); to 3.36 (t, 2H); 3.46 in (d, 2H); to 3.73 (t, 2H); of 3.97 (d, 2H).

MS-ESI: 159 [MH]+.

To a suspension of 3-morpholinopropan acid (325 mg, 1.6 mmol) in pyridine (12 ml) is added 1,3-dicyclohexylcarbodiimide (343 mg, 1.6 mmol) and stirred the mixture for 10 minutes. Then add the hydrochloride of 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)hintline (370 mg, 0.97 mmol) (obtained similarly to the original substance in example 29) and stirred the mixture for 32 hours. Add 3-morpholinopropan acid (57 mg, 0.29 mmol) and 1,3-dicyclohexylcarbodiimide (100 mg, 0.48 mmol) and stirred the mixture for another 18 hours. The solvent is evaporated, the residue is distributed between water and ethyl acetate and the aqueous layer was brought to pH 8 by adding saturated sodium bicarbonate solution. The organic layer was separated, washed with a saturated solution of salt, dried (MgSO4) and the solvent evaporated. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol (95:5), giving 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-(3-morpholino (s, 3H); 2,4-2,5 (m, 4H); 2,5-2,6 (m, 2H); 2,62 is 2.7 (m, 2H); to 3.58 (t, 4H); 3,85 (s, 3H); 7,30 (d, 1H); 7,44 (d, 1H), and 7.7 (d, 1H); 8,13 (s, 1H); 8,35 (s, 1H); to 8.41 (s, 1H); of 9.7 (s, 1H); 10,46 (s, 1H).

Example 32

To a solution of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-(2-methoxyethylamine)hintline (304 mg, from 0.76 mmol) in methanol (8 ml) at a temperature of 5oWith added 2 M aqueous solution of sodium hydroxide (760 μl, 1.5 mmol). The resulting mixture was stirred for 30 minutes at room temperature, diluted with water and adjusted to pH 6 by adding 2 M hydrochloric acid solution. The precipitated solid is collected by filtration and suspended in a mixture of methylene chloride/methanol. Then add 5 M solution of hydrogen chloride in isopropanol (0.4 ml) and the resulting solution is evaporated volatile substances. The residue is ground to powder with ether, the solid product is collected by filtration, washed with ether and dried in vacuo, giving the hydrochloride of 4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethylamine)hintline (260 mg, 90%) as a yellow solid.

So pl. 192-197oC.

Range1H NMR: (DMSO d6) of 2.16 (s, 3H); of 3.32 (s, 3H); to 3.38 (m, 2H); to 3.58 (m, 2H); of 6.71 (bs, 1H); to 6.88 (d, 1H); and 7.1 (d, 1H); to 7.2 (d, 1H); 7,73 (m, 1H); of 8.37 (d, 1H); 8,61 (s, 1H); to 9.66 (s, 1H); 10,95 (s, 1H).

MS-ESI: 343 [MN]+.

The educt solution of hydrochloric acid (76 ml) is heated at a temperature of 50-60oC for 2 hours. The mixture is allowed to cool and adjusted to pH 7.5 by adding saturated aqueous sodium bicarbonate solution. This solution is added to a suspension of the hydrochloride of 7-amino-4-(2-fluoro-5-methoxy-carbonyloxy-4-methylaniline)hintline (400 mg, 1 mmol) (obtained similarly to the original substance in example 30) in ethanol (32 ml) and acetic acid (95 μl, 1.5 mmol). The mixture is then stirred for 5 minutes, add Lamborghini sodium (133 mg, 2 mmol) and bring the solution to pH 5.5 by adding glacial acetic acid. The mixture is stirred for 18 hours, the organic solvent is evaporated and the resulting aqueous mixture is distributed between ethyl acetate and water. The organic layer is separated, washed with saturated salt solution, dried (gSO4) and the solvent evaporated. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol (96:4 and 12:8), giving 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-7-(2-methoxyethylamine)hinzelin (308 mg, 77%) as a yellow foam.

Range1H NMR: (DMSO d6); CF3COOD) 2,22 (s, 3H); to 3.33 (s, 3H); to 3.41 (t, 2H); of 3.60 (t, 2H); a 3.87 (s, 3H); of 6.68 (br s, 1H); 7,22 (dd, 1H); 7,37 (d, 1H); the 7.43 (d, 1H); 8.30 to (d, 1H); to 8.7 (s, 1H).

Example 33

To a suspension of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-IU Aut 2 M aqueous solution of sodium hydroxide (620 μl) and stirred the mixture for 90 minutes at room temperature. The reaction mixture was diluted with water and adjusted to pH 7 by adding 2 M hydrochloric acid solution. The precipitated solid is collected by filtration, again suspended in ethanol and add 5 M solution of hydrogen chloride in isopropanol (0.3 ml). From the resulting solution is evaporated volatile substances, the solid is washed with ether, collected by filtration and dried in vacuum to obtain hydrochloride of 4-(2-fluoro-5-hydroxy-4-methylaniline)-6-methoxy-7-methoxyacetophenone (216 mg, 82%).

So pl. 300-306oC.

Range1H NMR: (DMSO d6) to 2.18 (s, 3H); 3,47 (s, 2H); 4,13 (s, 3H); is 4.21 (s, 3H); 6,92 (d, 1H); 7,13 (d, 1H); to 8.41 (s, 1H); 8,80 (s, 1H); of 8.90 (s, 1H); 9,54 (s, 1H); 9,72 (s, 1H); 11,49 (s, 1H).

MS-ESI: 387 [MN]+.

Elemental analysis: C19H19N4O4F1HCl0,6N2O.

Found, %: C 52,3; N 4,8; N 12,7.

Calculated, %: From 52.6; H Is 4.9; N 12,9.

The original substance is obtained in the following way:

To a solution of 4-methoxy-2-methylaniline (49,7 g, 360 mmol) in DMA (200 ml) at a temperature of 5oWith added dropwise acetic anhydride (50 ml) and stirred for 4.5 hours at room temperature. The solvent is evaporated, the obtained solid is washed with water and dried in vacuum, giving N-(4-methods, H); 7,42 (d, 1H).

To a solution of N-(4-methoxy-2-were) ndimethylacetamide (28 g, 0.14 mol) in methylene chloride (500 ml), cooled and maintained at a temperature of -30oWith that added dropwise a mixture of tin chloride (IV) (19.3 ml) and 69.5% nitric acid (10.3 ml) in methylene chloride (140 ml). The reaction mixture is stirred at a temperature of -30oC for 1.5 hours, allowed to warm to room temperature and poured into a mixture of ice water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The combined extracts dried (MgSO4), the solvent is evaporated and the residue purified by chromatography on columns, elwira a mixture of petroleum ether:ethyl acetate (2:8), which gives N-(4-methoxy-2-methyl-5-nitrophenyl)ndimethylacetamide (17.8 g, 51%).

Range1H NMR: (DMSO d6) to 2.06 (s, 3H); to 2.29 (s, 3H); of 3.9 (s, 3H); from 7.24 (s, 1H); to 7.99 (s, 1H); 9,41 (s, 1H).

To a solution of N-(4-methoxy-2-methyl-5-nitrophenyl)ndimethylacetamide (35 g, 0,156 mol) and magnesium sulfate (38,5 g) in water (2.3 l) at a temperature of 75oWith portions add the potassium permanganate (68 g). The mixture was incubated at a temperature of 75oWith over 3.5 hours, add an additional amount of magnesium sulfate (4 g) and potassium permanganate (12 g) and continue to stir the mixture for another 30 minutes at the temperature the earth, the filtrate is cooled and acidified to pH 1 with concentrated hydrochloric acid. The precipitated solid is collected by filtration and washed with water, then aqueous filtrate is extracted with ethyl acetate. Solid product and an ethyl acetate extracts are combined and extracted with 2 M aqueous solution of sodium hydroxide. The basic aqueous layer was separated, washed with ethyl acetate, acidified with concentrated hydrochloric acid and again extracted with ethyl acetate. An ethyl acetate extract is washed with saturated salt solution, dried (gSO4) and the solvent evaporated to obtain 2-acetamido-5-methoxy-4-nitrobenzoic acid (21,6 g, 54%) as a yellow solid.

Range 1H NMR: (DMSO d6) a 2.12 (s, 3H); 3,93 (s, 3H); 7,74 (s, 1H); is 8.75 (s, 1H).

A solution of 2-acetamido-5-methoxy-4-nitrobenzoic acid (21,6 g, 85 mmol) in water (76 ml) and concentrated hydrochloric acid (30,5 ml) is heated under reflux for 3 hours. The reaction mixture was cooled to 0oWith the obtained solid is collected by filtration, washed with water and dried in vacuum to obtain 2-amino-5-methoxy-4-nitrobenzoic acid (16.6 g, 92%).

Range1H NMR: (DMSO d6) 3,79 (s is amide (250 ml) is heated under reflux for 4.5 hours. The reaction mixture was cooled to 0oWith and diluted with water, the precipitate is collected by filtration, washed with water and dried in vacuo to obtain 6-methoxy-7-nitro-3,4-dihydroquinazolin-4-it (to 11.56 g, 67%).

Range1H NMR: (DMSO d6; CF3D) was 4.02 (s, 3H); 7,8 (s, 1H); to 8.12 (s, 1H); 8,18 (s, 1H).

A suspension of 6-methoxy-7-nitro-3,4-dihydroquinazolin-4-it (8 g, 36 mmol) in thionyl chloride (150 ml) and DMF (0.8 ml) is heated under reflux for 3 hours. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. The obtained solid is ground to powder with ether, collected by filtration and dried in vacuum to obtain hydrochloride of 4-chloro-6-methoxy-7-nitroquinazoline (7.5 g, 75%).

Range1H NMR: (DMSO d6) 4,13 (s, 3H); 7,8 (s, 1H); to 8.7 (s, 1H); 9,13 (s, 1H).

A mixture of the hydrochloride of 4-chloro-6-methoxy-7-nitroquinazoline (784 mg, 2.8 mmol) and 2-fluoro-5-methoxycarbonylamino-4-methylaniline (621 mg, 3.1 mmol) (obtained similarly to the original substance in example 26) in isopropanol (10 ml) is heated under reflux for 2 hours. The mixture is allowed to cool, the precipitated product is collected by filtration, washed with isopropanol and ether and dried in vacuum to obtain hydrochlo/SUP>H NMR: (DMSO d6) 2,22 (s, 3H); 3,86 (s, 3H); 4,10 (s, 3H); 7,41 (d, 1H); 7,46 (d, 1H); to 8.40 (s, 1H); 8,55 (s, 1H); 8,77 (s, 1H); 11,4 (br s, 1H).

MS-ESI: 403 [MH]+.

A mixture of the hydrochloride of 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxy-7-nitroquinazoline (1.1 g, 25 mmol) and catalyst, such as 10% palladium on coal (220 mg) in methanol (200 ml) and ethanol (10 ml) is stirred in hydrogen atmosphere under a pressure of 2.7 ATM for 7 hours. The catalyst was removed by filtration through diatomaceous earth and evaporated from the filtrate the solvent, the solid residue is washed with ether, collected by filtration and dried in vacuum to obtain hydrochloride of 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxyquinazoline (930 mg, 91%).

Range1H NMR: (DMSO d6) 2,22 (s, 3H); a 3.87 (s, 3H); was 4.02 (s, 3H); 6,9 (s, 1H); between 7.4 to 7.5 (m, 2H); to 7.99 (s, 1H); to 8.62 (s, 1H).

MS-ESI: 372 [MN]+.

To a solution of the hydrochloride of 7-amino-4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxyquinazoline (215 mg, 0.52 mmol) in methylene chloride (5 ml) and pyridine (1.5 ml) at 0oWith added dropwise methoxyacetanilide (62 μl, of 0.68 mmol) and stirred the mixture for 2 hours at 0oC. Then add more methoxyacetanilide (14 μl, 0.15 mmol) and stirred the mixture in the lead up to pH 9, adding saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with a saturated solution of salt, dried (MgSO4) and the solvent evaporated. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride: acetonitrile: methanol (60:38:2), giving 4-(2-fluoro-5-methoxycarbonylamino-4-methylaniline)-6-methoxy-7-methoxyacetophenone (175 mg, 75%) as a white solid.

Range1H NMR: (DMSO d6) of 2.21 (s, 3H); 3,47 (s, 2H); a 3.87 (s, 3H); 4,07 (s, 3H); 4,15 (s, 3H); to 7.35 (d, 1H); was 7.45 (d, 1H); of 7.96 (s, 1H); to 8.40 (s, 1H); 8,65 (s, 1H); 9.28 are (s,1H); 9,65 (s, 1H).

Example 34

To 4-chloro-6-methoxy-7-(2-thiomorpholine)hintline (340 mg, 1.0 mmol) and 4-chloro-2-fluoro-5-hydroxyanisole (200 mg, 1.2 mmol) (described in European patent 61741 A2) in tert-butanol (15 ml) add a solution of hydrogen chloride in ether (1.0 ml of 1.0 M solution, 1.0 mmol). The reaction mixture is heated at a temperature of 95oC for 1 hour and stirred for 18 hours at room temperature, then diluted with acetone, the precipitated product is collected by filtration, washed with acetone and dried to obtain hemihydrate 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-thiomorpholine)hintline (480 mg, 88%) as a beige powder.

Rangeptx2">

MS-ESI: 465 [MN]+.

Elemental analysis: C21H22N4ClFO3S2HCl0,5H2O.

Found, %: C 45,8; N. Of 4.4; N, 10,0.

Calculated, %: 46.1; H 4,6; N 10,2.

The original substance is obtained in the following way:

To 7-hydroxy-6-methoxy-4-phenoxybenzamide (6.0 g, 22 mmol) (obtained similarly to the original substance in example 16) and potassium carbonate (14.4 g, 107 mmol) in DMF added 1,2-dibromoethane (19.2 ml, 286 mmol). The mixture is stirred at a temperature of 85oC for 2.5 hours, allowed to cool and the insoluble matter is removed by filtration. The solvent is evaporated and the residue purified by chromatography on columns, elwira mixture elwira a mixture of methylene chloride:methanol (93:7). The product is ground to powder with ethyl acetate, which gives 7-(2-bromoethoxy)-6-methoxy-4-phenoxybenzoic (5,3 g, 63%).

A mixture of 7-(2-bromoethoxy)-6-methoxy-4-phenoxybenzamide (2.0 g, 5.3 mmol) in thiomorpholine (15 ml) was stirred at room temperature for 5 hours, then diluted with water and the precipitate collected by filtration. The solid product is dissolved in methylene chloride, washed with saturated salt solution and passed through footclaws paper. The solvent is evaporated to obtain 6-methoxy-4- [MN]+.

A mixture of 6-methoxy-4-phenoxy-7-(2-thiomorpholine)hintline (2.0 g, 5 mmol) in 2 M hydrochloric acid (25 ml) is heated at a temperature of 90oC for 1.5 hours. The resulting mixture is allowed to cool and adjusted to pH 7 by adding solid sodium bicarbonate. Then add methylene chloride, the obtained semi-solid product is separated by decanting and filtering water mixture. This product is dissolved in acetone and the insoluble matter is removed by filtration. The solvent is evaporated and the residue is subjected to the azeotropic distillation with toluene, which gives 6-methoxy-7-(2-thiomorpholine)-3,4-dihydroquinazolin-4-one (1.5 g, 92%) as a white solid.

MS-ESI: 322 [MN]+.

A mixture of 6-methoxy-7-(2-thiomorpholine)-3,4-dihydroquinazolin-4-it (1.5 g, 4.6 mmol), thionyl chloride (25 ml) and DMF (0.2 ml) is heated under reflux for 2 hours. The excess thionyl chloride is evaporated and the residue is subjected to the azeotropic distillation with toluene. The resulting resin is distributed between aqueous sodium bicarbonate solution and methylene chloride. The organic layer is separated and the aqueous layer was extracted with methylene chloride (440 ml). The combined extracts are passed through

footclaws:methanol (95:5). The purified product is grinded into powder with acetone, giving 4-chloro-6-methoxy-7-(2-thiomorpholine-ethoxy)hinzelin (400 mg, 25%) as an orange-brown solid.

MS-ESI: 342 [MN]+.

Example 35

To 4-chloro-6-methoxy-7-(2-(2-methoxyethylamine)ethoxy)hintline (110 mg, 3.5 mmol) and 4-chloro-2-fluoro-5-hydroxyanisole (72 mg, 4.5 mmol) (described in European patent 61741 A2) in tert-butanol (5 ml) add a solution of hydrogen chloride in ether (1.0 ml of 1.0 M solution, 1.0 mmol). The resulting mixture is heated at a temperature of 95oC for 1 hour, allowed to cool and diluted with acetone. The precipitated product is collected by filtration, washed with methylene chloride and acetone and dried to obtain a hydrate of the hydrochloride of 4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(2-methoxyethylamine)ethoxy)hintline (110 mg, 59%) as a beige powder.

Range1H NMR: (DMSO d6) 3,2-3,6 (m, 4H); to 3.38 (s, 3H); to 3.73 (t, 2H); 4.09 to (s, 3H); 4,58 (t, 2H); from 7.24 (d, 1H); 7,52 (d, 1H); at 7.55 (s, 1H); 8,48 (s, 1H); a 7.85 (s, 1H); a 9.35 (br s, 1H); 10,65 (br s, 1H); of 11.75 (br s, 1H).

MS-ESI: 437 [MH]+.

Elemental analysis: C20H22N4ClFO42HCl1,2H2O.

Found, %: C 45,1; N 4,6; N 10,1.

Calculated, %: From 45.2; H 5,0; N 10,5.

The original substance polychloride the original substance in example 22) in 2-methoxyethylamine (8 ml) was stirred at room temperature for 4 hours, then it is diluted with water and extracted with methylene chloride (525 ml). The combined extracts washed with saturated salt solution and passed through footclaws paper. The solvent is evaporated and the residue purified by chromatography on columns, elwira a mixture of methylene chloride:methanol:aqueous ammonia (100:8: 1), giving 6-methoxy-4-phenoxy-7-(2-(2-methoxyethylamine)ethoxy)hinzelin (760 mg, 70%) as a white solid.

MS-ESI: 370 [MN]+.

A mixture of 6-methoxy-4-phenoxy-7-(2-(2-methoxyethylamine)ethoxy)hintline (760 mg, 2 mmol) in 2 M hydrochloric acid (5 ml) is heated at a temperature of 90oC for 1.5 hours. The mixture is allowed to cool and adjusted to pH 7 by adding solid sodium bicarbonate. The water is evaporated and the residue extracted with a mixture of methylene chloride:methanol:aqueous ammonia (100:8:1). Then, the extract is evaporated volatiles, the residue is dissolved in methylene chloride, passed through footclaws paper and the solvent is evaporated to obtain 6-methoxy-7-(2-(2-methoxyethylamine)ethoxy)-3,4-dihydroquinazolin-4-it (600 mg, 99%) as a white solid.

A mixture of 6-methoxy-7-(2-(2-methoxyethylamine)ethoxy)-3,4-dihydroquinazolin-4-it (300 mg, 1 mmol), tonight and the residue is subjected to the azeotropic distillation with toluene. The resulting resin is distributed between aqueous sodium bicarbonate solution and methylene chloride. The organic layer is separated and the aqueous layer was extracted with methylene chloride (440 ml). The combined extracts are passed through footclaws paper and the solvent is evaporated to obtain 4-chloro-6-methoxy-7-(2-(2-methoxyethylamine)ethoxy)hintline (120 mg, 38%) as a yellow solid.

Example 36

A solution of 4-chloro-6-methoxy-7-(3-morpholinopropan)hintline (202 mg, 0.6 mmol) and 5 M solution of hydrogen chloride (1.5 ml) in isopropanol (5 ml) is heated at a temperature of 80oC for 18 hours. The mixture is allowed to cool and evaporated volatile substances. The residue is distributed between methylene chloride and water and the aqueous layer was adjusted to pH 6.5 by adding 0.1 M aqueous solution of sodium hydroxide. The organic layer was separated, washed with water and saturated salt solution, dried (gSO4) and the solvent evaporated. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride:methanol (95:5). The purified solid is dissolved in a mixture of methylene chloride/methanol and add 2.2 M ethereal solution of hydrogen chloride. Volatile matter is evaporated, the solid residue is suspended in ether, collected by filtration, washed with E. isolina (91 mg, 26%).

Range1H NMR: (DMSO d6; CF3COOD) 2.3 to 2.4 (m, 2H); 3,1-3,2 (m, 2H); 3,3-3,4 (m, 2H); 3,55 (d, 2H); 3.75 to (t, 2H); 4,01 (d, 2H); is 4.03 (s, 3H); of 4.35 (t, 2H); the 7.43 (s, 1H); 7,76 (d, 2H); 8,21 (s, 1H); 8,93 (s, 1H).

MS-ESI: 511 [MN]+.

Elemental analysis: C22H23N4O3rF20,3 H2O1,85l 0,09 ever,05 CH2CL2. Found, %: From 45.4; H 4,7; N 9,2.

Calculated, %: From 45.4; H 4,5; N 9,4.

The original substance is obtained in the following way:

To a solution of 3-morpholinopropan-1-ol (1.54 g, 10 mmol), 7-hydroxy-3,4-dihydro-6-methoxy-3-((pivaloyloxy)methyl)hinzelin-4-it (2.6 g, 8.5 mmol) and triphenylphosphine (4,45 g, 17 mmol) in methylene chloride (40 ml) added dropwise diethylazodicarboxylate or 2.67 ml, 17 mmol). The resulting mixture is stirred for 2 hours at room temperature, after which the volatiles evaporated. The residue is purified by chromatography on columns, elwira a mixture of methylene chloride: methanol (97: 3 and 95:5), which gives 3,4-dihydro-6-methoxy-3-((pivaloyloxy)methyl)-7-(3-morpholinopropan)hinzelin-4-one (3.6 g, 97%).

Range1H NMR: (DMSO d6; CF3COOD) of 1.12 (s, 9H); about 2.2-2.3 (m, 2H); 3,1-3,2 (m, 2H); of 3.32 (t, 2H); 3,55 (d, 2H); 3,65 of 3.75 (m, 2H); to 3.92 (s, 3H); of 4.05 (d, 2H); 4.25 in (t, 2H); to 5.93 (s, 2H); 7.23 percent (s, 1H); rate of 7.54 (s, 1H); to 8.41 (s, 1H).

A solution of 3,4-dihydro-6-methoxy-3-((pivaloyloxy) is mesilat at room temperature for 2 days. Volatile matter is evaporated. The solid residue is suspended in ether, collected by filtration, washed with ether and dried in vacuum to obtain 4-hydroxy-6-methoxy-7-(3-morpholinopropan)hintline (2,87 g, 79%).

Range1H NMR: (DMSO d6; CF3COOD) to 2.2-2.3 (m, 2H); 3.15 in (t, 2H); at 3.35 (t, 2H); 3,55 (d, 2H); 3,7 (t, 2H); of 3.94 (s, 3H); of 4.05 (d, 2H); 4.26 deaths (t, 2H); 7.29 trend (s, 1H); 7,56 (s, 1H); 8,96 (s, 1H).

A solution of 4-hydroxy-6-methoxy-7-(3-morpholinopropan)hintline (2,87 g, 9 mmol) and DMF (1 ml) in thionyl chloride (35 ml) is heated under reflux for 45 minutes. Then add toluene and evaporated volatile substances. The residue is distributed between ethyl acetate and water and the aqueous layer was brought to pH 8 by adding 2 M aqueous solution of sodium hydroxide. The organic layer is washed with water and saturated salt solution, dried (gSO4) and evaporated volatile substances. The solid residue purified by chromatography on columns, elwira a mixture of methylene chloride: acetonitrile:methanol (50:47,5:2,5), giving 4-chloro-6-methoxy-7-(3-morpholinopropan)hinzelin (2 g, 66%).

An NMR spectrum: (CDCl3) to 2.13 (m, 2H); 2,48 (br s, 4H); of 2.56 (t, 2H); and 3.72 (t, 4H); of 4.05 (s, 3H); the 4.29 (t, 2H); 7,37 (d, 2H); 8,86 (s, 1H).

Example 37 the Following are typical pharmaceutical dosage forms, containing a compound of formula I, Il and diseases in humans:

(a) Tablet I mg/tablet:

Connection X - 100

Lactose (European Pharmacopoeia) - 182,75

Crosscarmellose sodium to 12.0

Corn starch paste (5% paste in a ratio of mass to volume) was 2.25

Magnesium stearate - 3,0

(b) Tablet II, mg/tablet:

Connection X - 50

Lactose (European Pharmacopoeia) - 223,75

Crosscarmellose sodium - 6,0

Corn starch - 15,0

Polyvinylpyrrolidone (5% paste in a ratio of mass to volume) was 2.25

Magnesium stearate - 3,0

(c) Tablet III mg/tablet:

Connection X - 1,0

Lactose (European Pharmacopoeia) - 93,25

Crosscarmellose sodium - 4,0

Corn starch paste (5% paste in a ratio of mass to volume) - 0,75

Magnesium stearate - 1,0

(d) the Capsule mg/capsule:

Connection X - 10

Lactose (European Pharmacopoeia) - 488,5

Magnesium stearate and 1.5

(e) Injecting the solution I, 50 mg/ml:

Compound X (ratio of mass to volume), % - 5,0

1 N sodium hydroxide solution (volume ratio), % - 15,0

a 0.1 N solution of hydrochloric acid To a pH of 7.6

Polyethylene glycol 400 (ratio of mass to volume) - 4,5

Water for injection to 100%

(f) Injecting the solution II, 10 mg/ml

Compound X (mass ratio of the aqueous sodium hydroxide solution (volume ratio), % - 15,0

Water for injection to 100%

(g) Injecting the solution III, 1 mg/ml, buffered to pH 6:

Compound X (ratio of mass to volume), % - 0,1

Sodium phosphate (British Pharmacopoeia) (ratio of mass to volume), % - 2.26 and

Citric acid (in the ratio of mass to volume), % - 0,38

Polyethylene glycol 400 (ratio of mass to volume), % - 3,5

Water for injection to 100%

Note

The above composition can be obtained with conventional methods that are well known in the pharmaceutical business. The tablets (a)-(C) can be by known methods applied intersolubility floor, for example, from acatitla pulp.

The results are given in the table.

Notes to table

Identification of compounds

Column 1 shows the numbers of the examples of this application, the respective test compounds; 26 additional examples are numbered as A1-A26.

Column 2 shows the designation of the linker group that connects the phenyl ring at position 4 chineselanguage ring (in the description and the claims designated as Z). Column 3 shows the substituents in the 6 and 7 positions chineselanguage rings. Column 4 indicates the position and p the results are shown in micromolar ranges, within which are the values of the IC50for each connection, specifically, the concentration of a compound that reduces enzyme activity in two times compared to the difference in activity in the presence of 2 μm adenosine-5'-triphosphate (ATP) and in the absence of 2 μm ATP.

In columns 5 and 6 show the results of enzymatic analysis in relation to cFlt and cKDR, which represent the cytoplasmic domains of the receptors Flt and KDR growth factor vascular endothelial respectively.

It should be noted that the compounds of examples 13, 15, 18, 19, 20, 21, 22, 23, 24, 25, 30, 31, 32 and 33 were tested using a lower concentration of MnCl2than the concentration listed in the description of the analysis techniques in section 5 (a). Instead of 25 μl of 40 mm nl2used 25 μl of 12 mm nl2. Compounds tested in both concentrations showed no significant differences in the values of the IC50.

HUVEC analysis results in the form of micromolar ranges, within which are the values of the IC50for each test compound, specifically, the concentration of a compound that reduces by half the proliferation of endothelial cells, umbilical vein human (HUVEC), defined by the inclusion labeled with tritium thymidine is proliferation, which flows during the analysis in the absence of growth factors.

Column 7 shows the results of HUVEC analysis in relation to the growth factor vascular endothelial (VEGF).

Column 8 shows the "basal" concentration, which refers to the concentration of the compound, inhibiting stimulated by growth factor introduction labeled with tritium thymidine below observed for cells not treated with any growth factor or compound in the course of the analysis, which indicates nonspecific effects of the compounds on DNA synthesis.

Data in vitro, are presented in the table show that all the tested compounds exhibit activity, usually high activity, while inhibition tyrosinekinase activity of VEGF receptors KDR and/or Flt and that essentially all of the tested compounds exhibit good activity in vitro inhibition of VEGF-dependent injection of thymidine.

1. Derivatives hintline formula I

< / BR>
in which Z denotes-O-, -NH - or-S-;

m = 1 to 5, an integer, provided that when Z represents-NH-, m = 3 - 5;

R1is hydrogen, C1-3alkoxy;

R2is hydrogen;

R3hydroxy, halogen, C1-3alkyl, C1-3alkoxy, Cde each of R7and R8is hydrogen, C1-3alkyl;

R4choose one of the following seven groups that contain 1) hydrogen, C1-5foralkyl,1-5alkyl; 2)1-5alkyl2CR12where X2denotes-O - or-NR13- where R13is hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl, and R12- -NR14R15or16where each of R14, R15and R16that may be the same or different values, denotes hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl; 3)1-5alkyl3R17where X3denotes-O-, -S-, -SO-, -SO2-, -OCO-, -NR18CO-, -CONR19-, -SO2NR20-, -NR21SO2- or-NR22- where R18-R22independently from each other hydrogen or C1-3alkyl, R17is hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 - or 6-membered saturated heterocyclic group selected from Tetra-hydropyridine and morpholinyl, WITH1-3the alkyl group may have one or two substituent selected from oxo, hydroxy, halogen and C1-4alkoxy and a cyclic group can have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-41-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy; 5)2-5R23where R has the above meanings; 6)2-5R23where R23has the above values, and 7)1-5alkyl4WITH1-5alkyl5R24where each of X4and X5that may be the same or different values, denotes-O-, -S-, -SO-, -SO2-, -NR25CO-, -CONR26-, -SO2NR27-, -NR28SO2- or-NR29- where R25-R29independently from each other hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl, R24is hydrogen or C1-3alkyl; excluding 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazolin; 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazolin; 4-(3-chlorophenylthio)-6,7-dimethoxyquinazolin; 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin,

or their salts.

2. Derivatives hintline under item 1, in which R1is hydrogen or ethoxy, methoxy.

3. Derivatives hintline by any of the BR> in which Rais hydrogen, methyl, fluorine or chlorine;

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

Rcis hydrogen or hydroxy;

Rdis fluorine or chlorine.

4. Derivatives hintline according to any one of the preceding paragraphs, in which Z is NH.

5. Derivatives hintline according to any one of the preceding paragraphs, in which X1denotes-O-, -NR8CO-, where R8is hydrogen or C1-2alkyl, or NH.

6. Derivatives hintline according to any one of the preceding paragraphs, in which R4choose one of the following seven groups containing 1)1-5alkyl, C1-5foralkyl; 2)2-3alkyl2CR12where X2matter specified in paragraph 1, and R12refers to-NR14R15or16where each of R14, R15and R16that may be the same or different values, means1-2alkyl or C1-2alkoxyethyl; 3)2-4alkyl3R17where X3matter specified in paragraph 1, and R17is a group selected from C1-3of alkyl, cyclopentyl or cyclohexyl, WITH1-3the alkyl group may have one or two substituent selected from oxo, hydroxy, halogen and1-2
of alkyl, C1-2- hydroxyalkyl and C1-2alkoxy; 4)2-4R31where R31denotes a group selected from morpholino, thiomorpholine, pyrrolidin-1-yl, piperazine-1-yl and piperidino, which may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy; 5)3-4R31where R31has the specified values; 6)3-4R31where R31has the specified values, and 7)2-3alkyl4WITH2-3alkyl5R24where X4and X5have the values listed in paragraph 1, and R24is hydrogen or C1-3alkyl.

7. Derivatives hintline according to any one of the preceding paragraphs, in which R4choose one of the following five groups containing 1) C1-3alkyl, C1-3foralkyl; 2) 2-(3,3-dimethylurea)ethyl, 3-(3,3-dimethylurea)-propyl, 2-(3-methylurea)ethyl, 3-(3-methylurea)propyl, 2-braidouts, 3-ureidopropionic, 2-(N, N-dimethylcarbamoyl)-ethyl, 3-(N, N-dimethylcarbamoyl)propyl, 2-(N-methylcarbamoyl)ethyl, 3-(N-methylcarbamoyl)propyl, 2-(carbamoylated)ethyl, 3-(carbamoylated)propyl; 3) C2-3alkyl3R17where X3illogical, WITH1-2the alkyl group may have one or two substituent selected from hydroxy, halogen and C1-2alkoxy, and cyclopentene or tsiklogeksilnogo group may have one Deputy, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy; 4)2-3R31where R31denotes a group selected from morpholino, thiomorpholine, piperidine, piperazine-1-yl and pyrrolidin-1-yl, which may have one Deputy, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy, and 5)2-3alkyl4C2-3alkyl5R24where X4and X5have the meanings specified in paragraph 1, and R24is hydrogen or C1-2alkyl.

8. Derivatives hintline according to any one of the preceding paragraphs, in which R4is methyl, ethyl, trifluoromethyl, 2,2,2-triptorelin, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulfinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N, N-dimethylsulphamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-sulphatoethyl, 2-(N, N-dimethylamino)ethyl, 3-(N, N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropan, 2-piperidinoethyl, 3-piperidinoethyl, 2-(piperazine-1-yl)acetylamino)ethyl, 3-(2-methoxyethylamine)propyl, 3-(2-hydroxyethylamino)propyl, 2-thiomorpholine, 3-thiomorpholine, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl or 2-(2-methoxyethoxy)ethyl.

9. Derivatives hintline according to any one of the preceding paragraphs, in which R4- 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulfinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N, N-dimethylamino)ethyl, 3-(N, N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropan, 2-piperidinoethyl, 3-piperidinoethyl, 2-(piperazine-1-yl)ethyl, 3-(piperazine-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl) propyl, 2-(2-methoxyethylamine)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamine)propyl, 3-(2-hydroxyethylamino)propyl, 2-thiomorpholine, 3-thiomorpholine, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl or 2-(2-methoxyethoxy)ethyl.

10. Derivatives hintline under item 1, which is selected from the group consisting of

4-(2-fluoro-5-hydroxy-4-methylaniline)-6,7-dimethoxyquinazolin;

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

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-methoxyacetophenone;

4-(4-bromo-2,6-diptiranjan)-6-methoxy-7-(3-morpholinopropan)girasoli is 4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)hinzelin;

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

4-(4-chloro-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-6-metoxy-7-(3-morpholinopropan)hinzelin;

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

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

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

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

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethylamine)hinzelin;

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

4-(2,4-debtor-5-hydroxyimino)-6,7-dimethoxyquinazolin;

4-(2,4-debtor-5-hydroxyimino)-6-methoxy-7-2-methoxyethoxy)hinzelin,

and their salts.

12. Derivatives hintline under item 1, which is selected from the group consisting of

4-(4-bromo-2,6-diptiranjan)-6,7-dimethoxyquinazolin;

4-(4-bromo-2-fluoro-5-hydroxyimino)-6,7-dimethoxyquinazolin;

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

6,7-dimethoxy-4-(3-hydroxy-4-methylphenoxy)hinzelin;

4-(4-chloro-2-fluoro-5-hydroxydeoxyguanosine;

4-(4-chloro-2-fluoro-5-hydroxyimino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)hinzelin;

4-(2-fluoro-5-hydroxy-4-methylaniline)-7-(2-methoxyethoxy)hinzelin;

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

and their salts.

13. Derivatives hintline according to any one of the preceding paragraphs in the form of pharmaceutically acceptable salts.

14. The method of obtaining the derived hintline formula I or its salts (p. 1), which lies in the fact that the compound of formula III

< / BR>
in which R1, R2X1and R4have the values listed in paragraph 1;

L1is replaced part,

subjected to interaction with the compound of the formula IV

< / BR>
in which Z, R3and m have the meanings specified in paragraph 1,

and when you want to get a salt derived hintline formula I, the compound obtained is subjected to interaction with acid or base, which gives the desired salt.

15. The method of obtaining the derived hintline formula I or its salts (p. 1), in which the group IIA

< / BR>
in which R3and m have the meanings specified in paragraph 1,

is a phenyl group having one or more hydroxyl groups, values, specified in paragraph 1;

P represents a phenolic hydroxyamino group;

R1= 1-5, integer equal to the number of protected hydroxyl groups, with m-R1equal to the number of the substituents R3that are not protected hydroxyl groups;

and when you want to get a salt derived hintline formula I, the compound obtained is subjected to interaction with acid or base, which gives the desired salt.

16. The method of obtaining the derived hintline formula I or its salts (p. 1), in which the Deputy X1denotes-O-, -NR7- (where R7matter specified in paragraph (1), including the interaction of the compounds of formula VI

< / BR>
in which m, X1, R1, R2, R3and Z have the values listed in paragraph 1,

with the compound of the formula VII

R4-L1VII

in which R4matter specified in paragraph 1;

L1has the above values,

and when you want to get a salt derived hintline formula I, the compound obtained is subjected to interaction with acid or base, which gives the desired salt.

17. The method of obtaining the derived hintline formula I or its salts (p. Ute values, specified in paragraph 1;

L1has the above values,

with the compound of the formula IX

R4-X1-N (IX)

in which R4and X1have the values listed in paragraph 1,

and when you want to get a salt derived hintline formula I, the compound obtained is subjected to interaction with acid or base, which gives the desired salt.

18. The method of obtaining the derived hintline formula I or its salts (p. 1) in which R4- C1-5R32where R32choose one of the following four groups that contain 1) X6C1-3alkyl, where X6denotes-O-, -S-, -SO2-, -NR33CO - or-NR34SO2- where R33and R34independently from each other hydrogen or C1-3alkyl; 2) NR35R36where each of R35and R36that may be the same or different values, denotes hydrogen or C1-3alkyl; 3) X7C1-35alkyl5R24where X7denotes-O-, -S-, -SO2-, -NR37CO-, -NR38SO2- or-NR39where R37-R39independently from each other hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl, X5and R24have the values listed in paragraph (1); and (4) R is La, pyrrolidinyl, piperazinil, piperidinyl, thiomorpholine, thiazolidine and imidazolidinyl, this heterocyclic group attached to C2-5the alkyl via a nitrogen atom and has one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy,

including the interaction of the compounds of formula X:

< / BR>
in which X1, R1, R2, R3, Z and m have the meanings specified in paragraph 1;

L1has the above meanings;

R40- C1-5alkyl,

with the compound of the formula XI:

R32-N, (XI)

in which R32has the above values,

and when you want to get a salt derived hintline formula I, the compound obtained is subjected to interaction with acid or base, which gives the desired salt.

19. The pharmaceutical composition providing antiangiogenic and/or reducing vascular permeability effect in warm-blooded animals, which comprises as an active ingredient derived hintline formula I under item 1 or its pharmaceutically acceptable salt together with a pharmaceutically suitable excipient or carrier.

20. The way Inga the m treatment which is that specified the animal is administered an effective amount of the compounds of formula I or its pharmaceutically acceptable salt under item 1.

21. Derivatives hintline according to any one of paragraphs. 1-13, which are intended for use as medicines, providing antiangiogenic and/or reducing vascular permeability effect in warm-blooded animals.

Priority points:

17.12.1996 on PP. 1-9, 14-21;

10.02.1997 on PP. 10 and 11;

08.08.1996 on PP. 12 and 13.

 

Same patents:

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 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 substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

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 invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt

The invention relates to an improved process for the preparation of 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid hydrochloride which is a substance tropisetrona and is used as an antiemetic, effective for vomiting caused by anticancer chemotherapy drugs

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

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 substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts
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