Derivatives hintline, methods for their preparation, containing pharmaceutical composition, the method of achieving antiangiogenic and/or the effect of reducing the permeability of the blood vessels of warm-blooded animal

 

(57) Abstract:

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims. The invention also relates to methods for their preparation, pharmaceutical compositions containing the compound of formula I or its pharmaceutically acceptable salt as an active ingredient. The compounds of formula I or their pharmaceutically acceptable salts inhibit the effect of SAR, an important property in the treatment of several diseases, including cancer and rheumatoid arthritis. In addition, the invention relates to a method of achieving antiangiogenic and/or the effect of reducing the permeability of the blood vessels of warm-blooded animal. 7 C. and 23 C.p. f-crystals.

The invention relates to the derivatives of hintline, methods for their preparation, pharmaceutical compositions containing them as AK the blood vessels, for their use as medicaments and to their use in pharmaceuticals production to achieve the antiangiogenic effect and/or the effect of reducing the permeability of the blood vessels of warm-blooded animals such as man.

Normal angiogenesis (development of blood vessels) plays an important role in many processes, including embryonic development, wound healing, and some components of female reproductive function. Undesirable or pathological angiogenesis associated with a disease state, including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma (Fan et al., 1995, Trends Pharmacol. Sci. 16:57-66; Folkman, 1995, Nature Medicine 1:27-31). I believe that the change in the permeability of blood vessels plays a role in both normal and pathological physiological process (Cullinan-Bove et al., 1993, Endocrinology 133:829-837; Senger et al., 1993, Cancer and Metastasis Reviews, 12:303-324). Were transcribed some polypeptides with in vitro activity, accelerating the growth of endothelial cells, including acid and alkaline fibroblast growth factors (ARF and b) and vascular endothelial growth factor (CEFR). Due to the limited expression of the receptor activity of the growth factor of CEFR, p is Italy showed that SAR 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), as well as the permeability of blood vessels (Connolly et A1. , 1989, J. Biol. Chem., 264:20017-20024). The antagonism of the action of SAR through sequestration of SAR antibody may lead to inhibition of tumor growth (Kim et al., 1993, Nature 362:841-844).

Receptor tyrosine kinase (RTK) is important in the transmission of biochemical signals across the plasma cell membrane. These transmembrane molecules usually consist of an extracellular ligand-binding domain linked through a segment in the plasma membrane from intracellular tyrosinekinase domain. The binding of ligand to the receptor leads to stimulation of receptor-associated tyrosinekinase activity, which leads to phosphorylation of tyrosine residues as receptor and other intracellular molecules. These changes in phosphorylation of tyrosine initiate a signaling cascade leading to different cellular responses. To date, the decrypted at least nineteen obvious RTK subfamilies defined by amino acid sequence homology. One of these podselect the s receptor, KDR (also referred to as Flk-1) and another fms-like tyrosinekinase receptor, Flt4. It was shown that two of these related to RTC, Flt and KDR link safr with high affinity (De Vries et al. , 1992, Science 255:989-991; Terman et al., 1992, Biochem. Biophys. Res. Comm., 1992, 187:1579-1586). Linking safr with these receptors expressed in heterologous cells, is associated with changes in the status of tyrosine phosphorylation of cellular proteins and the revenues of calcium into the cell.

In the publication of the European Patent 0326330 describes some of quinoline, hintline and cinnoline fungicides for plants. Also States that some of these fungicides for plants possess insecticidal and miticidal activities. However, there is no description or any suggestion that any of the described compounds can be used in any order for the animal, such as man. In particular, in the publication of the European Patent did not provide guidance, in any way related to angiogenesis and/or increased permeability of blood vessels by means of growth factors, such as SAR.

In the publication of the European Patent 0566226 described anilinoquinazoline with activity against epidermal factor is illicit and/or increased vascular permeability through growth factors, such as SAR. Moreover, the compounds according to EP 0566226 that were tested showed no significant activity against safr receptor tyrosine kinase.

The present invention is based on the surprising discovery that some hintline inhibit the action of SAR, which is a valuable property in the treatment of diseases associated with angiogenesis and/or increased permeability of blood vessels, such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic neuropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with the proliferation of retinal vessels. Compounds of the present invention have good activity against safr receptor tyrosine kinase, showing some activity against EGF receptor tyrosine kinase. Moreover, some compounds of the present invention have significantly higher activity against safr receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase. Thus, certain compounds according to the invention that have been tested and are active against safr receptance safr receptor tyrosine kinase, without showing any appreciable activity against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase. Not being tied to any theoretical reasoning, such compounds can, for example, be of interest in the treatment of tumors associated with SAR, especially those tumors whose growth depends on SAR.

Other compounds according to the invention exhibit good activity against both SAR and against EGF receptor tyrosinekinase. Indeed, some compounds are essentially equal activity against safr and EGF receptor tyrosinekinase. It is assumed that these connections may be of interest in the treatment of tumors associated with SAR and EGF, especially when the patient suffers from a condition in which the growth of existing tumors depends on CEFR and EGF.

According to one aspect of the present invention proposed a derived hintline formula I

< / BR>
[where m is an integer from 1 to 2;

R1represents hydrogen, hydroxy, halogen, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio or-NR5R6(where R5and R6that may be the same or different, methoxy, amino or nitro;

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

X1represents-O-, -CH2-, -S-, -SO-, -SO2-, -NR7CO-, -CONR8-, -SO2NR9, -NR10SO2- or-NR11- (where R7, R8, R9, R10and R11each independently represent hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl);

R4selected from one of the following eight groups:

1) WITH THE1-5alkyl, R12(where R12represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, this heterocyclic group is linked WITH1-3the alkyl via a carbon atom, and this heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N,N-di(C1-4alkyl)carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl) or (C1-5alkyl, R13(where R13represents a group selected from pyrrolidin-1 hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N, N-di(C1-4alkyl) carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

2)2-5alkenyl R14(where R14represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, this heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N,N-di (C1-4alkyl)carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

3)2-5quinil R15(where R15represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, this heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are bonyl);

4)1-5alkyl X2C1-5alkyl X3R16(where X2and X3that may be the same or different, are each-O-, -S-, -SO-, -SO2-, -NR17CO-, -CONR18-, -SO2NR19, -NR20SO2- or-NR21- (where R17, R18, R19, R20and R21each independently represent hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl) and R16represents hydrogen or C1-3alkyl), provided that X1can't be-CH2- when R4represents C1-5alkyl X2WITH1-5alkyl3R16;

5)1-5alkyl X4COR22(where X4represents-O - or-NR23- (where R23represents hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl) and R22is-NR24R25or26(where R24, R25and R26that may be the same or different, each represent hydrogen, C1-4alkyl or C1-3alkoxy WITH2-3alkyl));

6)1-5alkyl X5R27(where X5represents-O-, -S-, -SO-, -SO2-, -OCO-, -NR28CO-, -CONR29-, -SO2NR30, -NR31SO2- or-NR32- (where Ror1-3alkoxy WITH2-3alkyl), or X5represents carbarnoyl, and R27is cyclopentyl, cyclohexyl or a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified cyclopentyl, cyclohexyl or heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N,N-di(C1-4alkyl)carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl, or R27represents a C1-3alkyl, provided that when R27represents a C1-3alkyl, X5is-S-, -SO-, -SO2-, -SO2NR30or-NR31SO2-, and X1is not-CH2-);

7)1-3alkoxy WITH2-4alkyl, provided that X1represents-S-, or X1is-SO - or-SO2-; and

8)1-3alkoxy WITH2-4alkyl or C1-4alkyl, provided that X1represents-O-; and optionally R4can be selected from the following five groups:

9)1-5alkyl X6NR36, -NR37SO2- or-NR38- (where R34, R35, R36, R37and R38each independently represent hydrogen, C1-3alkyl or C1-3alkoxy WITH2-3alkyl), and R33is cyclopentyl, cyclohexyl or a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified cyclopentyl, cyclohexyl or heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, carbamoyl, C1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

10) R39(where R39is a group selected from pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-Il, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

11)1-5alkyl, R40(where R40represents piperazine-1-yl, which has at IU is-CONR41R42(where R41and R42each independently represent hydrogen or C1-4alkyl);

12)1-5alkyl, R43(where R43represents morpholino that has one or two substituent selected from oxo, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl), provided that when R4represents a C1-3alkyl, R43X1represents-S-, -SO-, -SO2-, -SO2NR9or-NR10SO2-; and

13)1-5alkyl, R44(where R44is morpholino having at least one and optionally two substituent selected from oxo, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

with the additional proviso that when R4selected from the group 8), R1and/or R2is/are a nitro or at least one of R3represents a C1-3alkanoyloxy;]

and its salts.

Preferably m is 2.

R1represents, mainly, Fodor who respectfully, represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, more preferably hydrogen, methyl or methoxy, most preferably hydrogen or methoxy, but especially methoxy.

R2preferably represents hydrogen, fluorine, amino or nitro, but especially hydrogen.

In one embodiment of the present invention R3represents hydroxy, halogen, C1-2alkyl, C1-2alkoxy, trifluoromethyl, cyano, amino or nitro.

Mainly, in another embodiment of the present invention, one substituent R3represents Metagalaxy, and the other is selected from halogen and methyl.

In another embodiment of the invention the phenyl group, with (R3)mpreferably has the formula II:

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

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

Rcrepresents hydrogen or hydroxy;

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

In a particular aspect of this izaberete-hydroxyphenyl group or 4-chloro-2-florfenicol group, or 4-bromo-2-florfenicol group, especially 4-chloro-2-florfenicol group or 4-bromo-2-florfenicol group, more preferably 4-chloro-2-florfenicol group.

Mainly, X1represents-O-, -S-, -NR7CO-, -NR10SO2- or-NR11- (where R7, R10and R11each independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably X1represents-O-, -S-, -NR7CO - or-NR10SO2- (where R7and R10each independently represent hydrogen or C1-2alkyl).

More preferably, X1represents-O-, -S-, -NR7CO- (where R7represents hydrogen or methyl).

In particular, X1represents-O -, or-NHCO-, or-S-, especially-O - or-S-, more especially-O-.

Usually, the X2and X3that may be the same or different, each represent-O-, -S-, -SO-, -SO2-, -NR17CO - or-NR21- (where R17and R21each independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Mainly, X2and X3that may be the same or different, each represent xitil).

Preferably, X2and X3that may be the same or different, each represent-O-, -S - or-NR21- (where R21represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

In the private aspect of the present invention X3represents-O-, and X2represents-NR17CO- (where R17represents hydrogen or methyl).

Mainly, X4represents-O - or-NR23- (where R23represents hydrogen, C1-3alkyl or C1-2alkoxyethyl).

Mainly, X5represents-O-, -S-, -SO-, -SO2-, -NR28CO-, -NR31SO2- or-NR32- (where R28, R31and R32each independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl) or X5represents a carbonyl.

Preferably, X5represents-O-, -S-, -SO-, -SO2-, or-NR32- (where R32represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).

More preferably, X5represents-O - or-NR32(where R32represents hydrogen or C1-2alkyl).

Mainly, X6submitted each independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl).

Preferably X6represents-O-.

Usually R4selected from one of the following eight groups:

1) WITH THE14alkyl, R12(where R12is a group selected from 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-Il, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, and additional possible substituents are carbarnoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbarnoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or (C2-5alkyl, R45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-3hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl,1-4allylcarbamate, N, N-di(C1-4alkyl)carbarnoyl,1-4alkanoyl the th saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, this heterocyclic group attached to C3-5alkenyl through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl,1-4allylcarbamate, N, N-di(C1-4alkyl)carbarnoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or (C4-5alkenyl R47(where R47represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, one of which represents N and the other is selected independently from O, S and N, this heterocyclic group attached to C4-5alkenyl through the nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl and C1-4alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N,N-di(C1-4alkyl)carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

3)3-5quinil R48(where R48is Simo from Oh, S and N specified heterocyclic group is linked WITH3=5alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, and additional possible substituents are carbarnoyl,1-4allylcarbamate, N, N-di(C1-4alkyl)carbarnoyl, C1-4alkanoyl and C1-4alkoxycarbonyl) or (C4-5quinil R49(where R49represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, the specified heterocyclic group attached to alkenylphenol group through the nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N, N-di(C1-4alkyl)carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

4) C2-3alkyl X2C2-3alkyl X3R16(where X2and X3, the X1can't be-CH2- when R4is2-3alkyl X2C2-3alkyl X3R16;

5)2-3alkyl X4COR22(where X4is the same as defined above, and R22is-NR24R25or26(where R24, R25and R26that may be the same or different, each represent hydrogen, C1-4alkyl or C1-2alkoxyethyl));

6) C2-4alkyl X5R27(where X5is the same as defined above, and R27is cyclopentyl, cyclohexyl or a 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified cyclopentamine, tsiklogeksilnogo or heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-4allylcarbamate, N,N-di(C1-4alkyl)carbarnoyl,1-4alkanoyl and C1-4alkoxycarbonyl, or R27represents a C1-3alkyl, provided that when R27represents a C1-3the I-CH2-);

7)1-3alkoxy WITH2-4alkyl, provided that X1represents-S-, or X1is-SO - or-SO2-; and

8)1-3alkoxy WITH2-4alkyl or C1-4alkyl, provided that X1represents-O-; and optionally R4usually can be chosen from the following four groups:

9)2-4alkyl X6WITH2-4alkyl, R33(where X6is the same as defined above, and R33represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-4of alkyl, C1-4hydroxyalkyl,1-4alkoxy, carbamoyl, C1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl);

10)2-4alkyl, R40(where R40represents piperazine-1-yl, having at least one Deputy, selected from C2-3alkanoyl, C1-3alkoxycarbonyl, C1-3hydroxyalkyl and CONR41R42(where R41and R42each independently represent hydrogen or C1-3alkyl);

11) With the El, selected from oxo, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl), provided that when R4represents a C2-4alkyl, R43X1represents-S-, -SO-, -SO2-, -SO2NR9or-NR10SO2-; and

12)2-4alkyl, R44(where R44represents morpholino having at least one and optionally two substituent selected from oxo, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbamoyl, C2-3alkanoyl and C1-3alkoxycarbonyl);

with the additional proviso that when R4selected from the group 8), R1and/or R2is/are a nitro or at least one of R3represents a C1-3alkanoyloxy.

Additional suitable value of R4is2-3alkyl X2methyl X3R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1can't be-CH2- when R4represents a C2-3alkyl X
1) WITH THE1-4alkyl, R12(where R12is a group selected from 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-Il, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbarnoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or (C2-4alkyl, R45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl, C2-3alkanoyl and C1-3alkoxycarbonyl);

2) 1-R46prop-1-EN-3-yl, 1-R46but-2-EN-4-yl, 1-R46but-1-EN-3-yl, 1-R46the Penta-2-EN-4-yl or 2-R46the Penta-3-EN-5-yl (where R46represents the C O S and N specified heterocyclic group attached to alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R47but-2-EN-4-yl, 1-R47the Penta-2-EN-4-yl or 2-R47the Penta-3-EN-5-yl (where R47represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, the specified heterocyclic group attached to alkenylphenol group through the nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl,2-3alkanoyl and C1-3alkoxycarbonyl);

3) 1-R48prop-1-in-3-yl, 1-R48but-2-ine-4-yl, 1 is certain saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl) carbarnoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R49but-2-ine-4-yl, 1-R49the Penta-2-in-4-yl or 2-R49the Penta-3-in-5-yl (where R49represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl,2-3alkanoyl and C1-3alkoxycarbonyl);

4) C2-3alkyl X2C1-3alkyl), provided that X1may not represent a-CH2- when R4is2-3alkyl X2C2-3alkyl X3R16;

5) C2-3alkyl X4COR22(where X4is the same as defined above, and R22is-NR24R25or26(where R24, R25and R26that may be the same or different, each represents hydrogen, C1-4alkyl or C1-2alkoxyethyl));

6)2-3alkyl X5R27(where X5is the same as defined above, and R27represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, this group is associated with X5through a carbon atom, and the group may have one Deputy, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy, and additional possible substituents are carbarnoyl, C1-2allylcarbamate, N, N-di(C1-2alkyl)carbarnoyl, acetyl and C1-2alkoxycarbonyl, or R27represents a C1-3alkyl, provided that when R27represents a C1-3alkyl, X5is-S-, -SO-, -SO22-3alkyl, provided that X1represents-S-, or X1is-SO - or-SO2-; and optionally R4can mainly be selected from the following four groups:

8) C2-3alkyl X6C2-3alkyl, R33(where X6is the same as defined above, and R33represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl);

9)2-3alkyl, R40(where R40represents piperazine-1-yl, having at least one Deputy, selected from acetyl, C1-2alkoxycarbonyl,1-2hydroxyalkyl and CONR41R42(where R41and R42each independently represents hydrogen or C1-2alkyl);

10)2-3alkyl, R43(where R43represents morpholino, which may have one or two substituent selected from oxo, C1-2alkyl is C1-2alkoxycarbonyl), provided that when R4represents a C2-5R43X1represents-S-, -SO-, -SO2-, -SO2NR9or-NR10SO2-; and

11)2-3R44(where R44represents morpholino having at least one and optionally two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl,1-2allylcarbamate, N, N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl).

Additional preferred value of R4is2-3alkyl2metalh3R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1can't be-CH2- when R4represents a C2-3alkyl2metalh3R16.

Preferably R4selected from one of the following seven groups:

1) C1-3R12(where R12is a group selected from 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-Elna, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbarnoyl, acetyl and C1-3alkoxycarbonyl) or (C2-3aR45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl, acetyl and C1-3alkoxycarbonyl);

2) 1-R46but-2-EN-4-yl (where R46represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group attached to alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate>represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, the specified heterocyclic group attached to alkenylphenol group through the nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl, acetyl and C1-3alkoxycarbonyl);

3) 1-R48but-2-ine-4-yl (where R48represents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbarnoyl, acetyl and C1-3alkoxide the group with one or two heteroatoms, one of which is N and the other is selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl and C1-3alkoxy, and additional possible substituents are carbarnoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbarnoyl, acetyl and C1-3alkoxycarbonyl);

4) C2-3alkyl2C2-3alkyl3R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1may not represent a-CH2- when R4is2-3alkyl2C1-3alkyl3R16;

5) 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-di methylcarbamoyl)propyl, 2-(N-methylcarbamoyl)ethyl, 3-(N-methylcarbamoyl)propyl, 2-(carbamoylated)ethyl, 3-(carbamoylated)propyl or 2-(1,3 .3m-trimethylamino)ethyl, 3-(1,3 .3m-trimethylamino)propyl, 2-(isopropoxycarbonyl is)propyl, 2-(tert-butoxycarbonylamino)ethyl or 3-(tert-butoxycarbonylamino)-propyl;

6) C2-3alkyl5R27(where X5is the same as defined above, and R27represents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, this group is associated with X5through a carbon atom, and the group may have one Deputy, selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy, and additional possible substituents are carbarnoyl,1-2allylcarbamate, N,N-di(C1-2alkyl)carbarnoyl, acetyl and C1-2alkoxycarbonyl, or R27represents a C1-2alkyl, provided that when R27represents a C1-2alkyl, X5is-S-, -SO-, -SO2-, -SO2NR30or-NR31SO2-, and X1is not-CH2-); and

7)1-2alkoxyl2-3alkyl, provided that X1represents-S-, or X1represents-SO - or-SO2-; and optionally R4may preferably be selected from the following three groups:

8)2-3alkyl6C2-3R33(where X6is the same as defined the by teratoma, selected independently from O, S and N, of which at least one is N, the specified heterocyclic group attached to C2-3the alkyl via the nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl,1-2alkoxy, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl);

9)2-3R43(where R43represents morpholino, which may have one or two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl), provided that when R4represents a C2-5aR43X1represents-S-, -SO-, -SO2-, -SO2NR9or-NR10SO2-); and

10)2-3R44(where R44represents morpholino having at least one and optionally two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl,1-2allylcarbamate, N, N-di(C1-2alkyl)carbamoyl, acetyl and C1-kilh2metalh3R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1can't be-CH2- when R4represents a C2-3alkyl2metalh3R16.

More preferred R4selected from one of the following five groups:

1) WITH THE1-3R12(where R12is a group selected from 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl and piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-Il, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl, C1-2alkoxy, and additional possible substituents are carbarnoyl,1-2allylcarbamate, N,N-di(C1-2alkyl) carbarnoyl, acetyl and C1-2alkoxycarbonyl) or (C2-3R45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydro is allylcarbamate, N,N-di(C1-2alkyl)carbarnoyl, acetyl and C1-2alkoxycarbonyl);

2) 1-R50but-2-EN-4-yl (where R50represents a group selected from imidazolidin-1-yl, 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, piperidine-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazine-1-Il, morpholino, thiomorpholine, and piperidino, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-3hydroxyalkyl and C1-2alkoxy, and additional possible substituents are carbarnoyl,1-2allylcarbamate, N, N-di(C1-2alkyl)carbarnoyl, acetyl and C1-2alkoxycarbonyl);

3) 1-R51but-2-ine-4-yl (where R51represents a group selected from imidazolidin-1-yl, 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, piperidine-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperazine-1-Il, morpholino, thiomorpholine, and piperidino, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-2of alkyl, C1-2hydroxyalkyl and C1-2alkoxy, and additional possible substituents are carbarnoyl,1-2allylcarbamate, N, N-di(C1-2alkyl)carb2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1may not represent a-CH2- when R4is2-3alkyl2C1-3alkyl3R16;

5)1-2alkoxyl2-3alkyl, provided that X1represents-S-, or X1represents-SO - or-SO2-; and optionally R4may be more preferably selected from the following four groups:

6) 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-di methylcarbamoyl)propyl, 2-(N-methylcarbamoyl)ethyl, 3-(N-methylcarbamoyl)propyl, 2-(carbamoylated)ethyl, 3-(carbamoylated)propyl, 2-(1,3 .3m-trimethylamino)ethyl, 3-(1,3 .3m-trimethylamino)propyl, 2-(isopropoxycarbonyl)ethyl, 3-(isopropoxycarbonyl)propyl, 2-(solutionline)ethyl, 3-(solutionline)propyl, 2-(tert-butoxycarbonylamino)ethyl or 3-(tert-butoxycarbonylamino)-propyl;

7)2-3alkyl5R27(where R27represents a C1-2alkyl, and X5is-S-, -SO-, -SO2-, -SO6
C2-3R33(where X6is the same as defined above, and R33represents a group selected from morpholino, 2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperidino, piperazine-1-yl and 4-methylpiperazin-1-yl); and

9)2-3aR43(where R43represents morpholino, which may have one or two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl), provided that when R4represents a C2-5aR43X1represents-S-, -SO-, -SO2-, -SO2NR9or-NR10SO2-.

Additional more preferred value of R4is2-3alkyl2metalh3R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1can't be-CH2- when R4represents a C2-3alkyl2metalh3R16.

Most preferably, R4selected from one of the following five groups:

1) C1-3R12(where R12performance is or piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, 1-methylpyrrolidine-2-yl, 1-methylpyrrolidine-3-yl, piperazine-2-yl, 1-methylpiperazin-2-yl, 4-methylpiperazin-2-yl, 1,4-dimethylpiperazine-2-yl, morpholine-2-yl, morpholine-3-yl, 4 methylmorpholin-2-yl or 4-methylmorpholin-3-yl) or (C2-3R45(where R45is pyrrolidin-1-yl or thiomorpholine or 1,1-dioxothiazolidine, 2-oxopyrrolidin-1-yl, 2-(N-methylcarbamoyl)pyrrolidin-1-yl, 2-(N, N-dimethylcarbamoyl)-pyrrolidin-1-yl, 2-carbamoylation-1-yl, 2-Oxymetazoline-1-yl or 3-methyl-2-Oxymetazoline-1-yl);

2) 1-R50but-2-EN-4-yl (where R50is a 2-Oxymetazoline-1-yl, 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, piperidine-4-yl, 1-methylpiperidin-4-yl, pyrrolidin-1-yl, 1-methylpyrrolidine-3-yl, piperazine-1-yl, morpholino or thiomorpholine or 4-methylpiperazin-1-yl, piperidine or 3-methyl-2-Oxymetazoline-1-yl);

3) 1-R51but-2-ine-4-yl (where R51is a 2-Oxymetazoline-1-yl, 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, piperidine-4-yl, 1-methylpiperidin-4-yl, pyrrolidin-1-yl, 1-methylpyrrolidine-3-yl, piperazine-1-yl, morpholino or thiomorpholine or 4-UP>3
R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1may not represent a-CH2- when R4represents C2-3alkyl2C1-3alkyl3R16;

5)1-2alkoxyl2-3alkyl, provided that X1represents-S-, or X1represents-SO - or-SO2-; and optionally R4can be most preferably selected from

the following three groups:

6)2-3alkyl5R27(where R27represents a C1-2alkyl and X5represents-S-, -SO-, -SO2-, -SO2NR30or-NR31SO2and provided that X1is not-CH2-);

7)2-3alkyl6C2-3R33(where X6is as defined above and R33represents a group selected from pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholino); and

8)2-3R43(where R43represents morpholino, which may have one or two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl), provided that when R4represents a CLASS="ptx2">

An additional most preferred value of R4is C2-3alkyl2metalh3R16(where X2and X3are as defined above, and R16represents hydrogen or C1-3alkyl), provided that X1can't be-CH2- when R4represents a C2-3alkyl2metalh3R16.

Especially preferred values for the groups R4-X1are 3-(methylsulphonyl)propoxy, (1 methylpiperidin-3-yl)methoxy, 4-(pyrrolidin-1-yl)but-2-EN-1-yloxy, 2-(2-methoxyethoxy)ethoxy, 3-(1,1-dioxothiazolidine)propoxy, 2-(2-(pyrrolidin-1-yl)ethoxy)ethoxy, 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 3 morpholinopropan, 2-([N-methoxyacetyl-N-methyl]amino)ethoxy, 2-(2-oxopyrrolidin-1-yl)ethoxy, 2-thiomorpholine, 3-(2-carbamoylation-1-yl)propoxy, 3-(2-oxopyrrolidin-1-yl)propoxy and 2-(2-morpholinoethoxy)-ethoxy.

Even more preferred meanings of the group R4-X1are 3-(methylsulphonyl)propoxy, 1-methylpiperidin-3-yl)methoxy and 4-(pyrrolidin-1-yl)but-2-EN-1-yloxy.

In the particular case of the present invention relates to a compound of formula Ia:

< / BR>
[where R1arepresents odor
represents 4-chloro-2-florfenicol group or 4-bromo-2-florfenicol group;

X1arepresents-O-, -S-, -NR5aCO - or-NR6aSO2- (where R5Aand R6Aeach independently represent hydrogen or C1-2alkyl);

R4selected from one of the following eleven groups:

1) WITH THE1-4R7a(where R7arepresents a group selected from 1,3-dioxolane-2-yl, 1,3-dioxane-2-yl, 1,3-ditiolan-2-yl, 1,3-dition-2-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-Il, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or C2-3aR8a(where R8arepresents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, this group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N,N-di(C1abut-2-EN-4-yl, 1-R9abut-1-EN-3-yl, 1-R9athe Penta-2-EN-4-yl or 2-R9athe Penta-3-EN-5-yl (where R9arepresents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R10abut-2-EN-4-yl, 1-R10athe Penta-2-EN-4-yl or 2-R10athe Penta-3-EN-5-yl (where R10arepresents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbs is-R11abut-1-in-3-yl, 1-R11athe Penta-2-in-4-yl or 2-R11athe Penta-3-in-5-yl (where R11arepresents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a carbon atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or 1-R12abut-2-ine-4-yl, 1-R12athe Penta-2-in-4-yl or 2-R12athe Penta-3-in-5-yl (where R12arepresents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, of which one is N and the other is selected independently from O, S and N, the specified heterocyclic group is linked to alkenylphenol group through a nitrogen atom, the heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3
2aand X3athat may be the same or different, are each-O-, -S-, -SO-, -SO2-, -NR14aCO - or-NR15a- (where R14aand R15aeach independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl), and R13arepresents hydrogen or C1-3alkyl);

5)2-3alkyl4aR16a(where X4arepresents-O - or-NR17a- (where R17arepresents hydrogen, C1-3alkyl or C1-2alkoxyethyl) and R16ais-NR18aR19aor20a(where R18a, R19aand R20athat may be the same or different, each represent hydrogen, C1-4alkyl or C1-2alkoxyethyl));

6) C2-3alkyl5aR21a(where X5arepresents a carbonyl, -O-, -S-, -SO-, -SO2-, -NR22aCO-, -NR23aSO2- or-NR24a- (where R22a, R23aand R24aeach independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl), and R21arepresents a group selected from cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, this group is associated with X5athrough a carbon atom, and the group may have one Deputy, SEL is SUB>1-2allylcarbamate, N, N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl, or R21arepresents a C1-3alkyl, provided that when R21arepresents a C1-3alkyl, X5ais-S-, -SO-, -SO2- or-NR23aSO2-); and

7)1-2alkoxyl2-3alkyl, provided that X1arepresents-S-;

8)2-3alkyl6aWITH2-3R25a(where X6arepresents-O-, -S-, -SO-, -SO2-, -NR26aCO-, -NR27aSO2- or-NR28a- (where R26a, R27aand R28aeach independently represent hydrogen, C1-2alkyl or C1-2alkoxyethyl), and R25arepresents 5 - or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, the specified heterocyclic group may have one or two substituent selected from oxo, hydroxy, halogen, C1-3of alkyl, C1-3hydroxyalkyl, C1-3alkoxy, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl);

9)2-3R29a(where R29arepresents piperazine-1-yl, having at least on the 1a (where R30aand R31aeach independently represent hydrogen or C1-2alkyl);

10) C2-3aR32a(where R32arepresents morpholino, which may have one or two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl), provided that when R4arepresents a C1-5R32aX1Arepresents-S - or-NR6aSO2- (where R6ais the same as defined above); and

11) C2-3aR33a(where R33arepresents morpholino having at least one and optionally two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl,1-2allylcarbamate, N, N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl);

and the additional value of R4is C2-3alkyl2ametalh3aR13a(where X2aand X3aare as defined above, and R13arepresents hydrogen or C1-3alkyl);]

and its salts.

Preferred compounds of the present invention with regard to their equivalen-2-ylethoxy)-6-methoxyquinazoline,

4-(4-chloro-2-foronline)-6-methoxy-7-(4-morpholino-2-in-1 yloxy)hinzelin,

(E)-4-(4-chloro-2-foronline)-6-methoxy-7-(4-morpholino-2-EN-1-yloxy)hinzelin,

4-(4-chloro-2-foronline)-7-(3-(2,6-dimethylmorpholine)propoxy)-6-methoxyquinazoline,

4-(4-chloro-2-foronline)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl] amino)propoxy)hinzelin,

7-(2-N-tert-butoxycarbonylamino] ethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline,

4-(4-bromo-2-foronline)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl] amino)propoxy)hinzelin,

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

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-oxaprotiline)ethoxy)hinzelin and

4-(4-bromo-2-foronline)-6-methoxy-7-(2-(3-oxaprotiline)ethoxy)hinzelin

and their salts, especially their cleaners containing hydrochloride salt.

More preferred compounds of the present invention with regard to their equivalent activity against WAR and EGF receptor tyrosinekinase include:

4-(4-chloro-2-foronline)-6-methoxy-7-(2-thiomorpholine)hinzelin,

(S)-4-(4-bromo-2-foronline)-7-(3-(2-carbamoylation-1-yl)propoxy)-6-methoxyquinazoline,

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

4-(4-kopacsi-4-(4-chloro-2-foronline)-6-methoxyquinazoline,

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

4-(4-bromo-2-foronline)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)hinzelin

and their salts, especially their cleaners containing hydrochloride salt.

Especially preferred compounds in terms of their essentially equivalent activity against WAR and EGF receptor tyrosinekinase receptors include:

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

4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline

and their salts, in particular their cleaners containing hydrochloride salt.

More especially preferred compounds of the present invention with regard to their equivalent activity against WAR and EGF receptor tyrosinekinase include:

4-(4-bromo-2-foronline)-7-(3-(1,1-dioxothiazolidine)propoxy)-6-methoxyquinazoline,

4-(4-bromo-2-foronline)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)hinzelin,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-pyrrolidin-1 ylethoxy)ethoxy)hinzelin,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl] ethoxy)ethoxy)hinzelin,

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

4-(4-chloro-2-foronline)-6-methoxy-7-(2-([N-methyl-N-metox is in

and their salts, especially their cleaners containing hydrochloride salt.

In particular, the compounds of the present invention with regard to their equivalent activity against WAR and EGF receptor tyrosinekinase include:

(E)-4-(4-chloro-2-foronline)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-EN-1-yloxy)hinzelin,

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

(S)-4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline and

(R)-4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline and

(4-chloro-2-foronline)-6-methoxy-7-(3-methylsulphonyl)propoxy) hinzelin and its salts, in particular, cleaners containing hydrochloride salt, are preferred.

In the particular case of the present invention, the preferred compounds are:

4-(3-acetoxy-4-methylaniline)-6-methoxy-7-(2-methoxyethoxy)hinzelin,

4-(4-chloro-2-foronline)-7-(2-(1,3-dioxolane-2-yl)ethoxy)-6-methoxyquinazoline,

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

4-(4-chloro-2-foronline)-6-methoxy-7-(3-9-pyrrolidin-1-yl)propoxy)hinzelin,

4-(4-chloro-2-foronline)-7-(1,3-dioxolane-2-ylethoxy)-6-methoxyquinazoline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-thiomorpholine, when in this description of the group qualifies as "above" or "defined above," then this group encompasses the first occurring and the most broad definition, as well as each of all preferred definitions of the group.

In this description, unless otherwise stated, the term "alkyl" includes both linear and alkyl groups, branched-chain, but references to individual alkyl groups such as "propyl" are specific only for the case of linear chains. A similar condition applies to other General terms. Unless otherwise stated, the term "alkyl" mainly refers to the chain with 1-6 carbon atoms, preferably 1-4 carbon atoms. The term "alkoxy", as used here, unless otherwise stated, includes "alkyl"-O-groups in which "alkyl" is as defined above. The term "aryl", as defined here, unless otherwise stated, includes a reference to a6-10aryl group, which may, if desirable, to have one or more substituents selected from halogen, alkyl, alkoxy, nitro, trifloromethyl and cyano (where the alkyl and alkoxy are as defined above). The term "aryloxy" as it is used here, if not Loxi", as it is used here, refers to alkylsulfonate, arylsulfonate groups in which "alkyl" and "aryl" are as defined above. The term "alkanoyl" as it is used here, unless otherwise stated, includes formyl and alkyl C=O groups in which "alkyl" is as defined above, for example WITH2alkanoyl is ethanol and belongs to the CH3C=O, C1alkanoyl represents formyl, and refers to the SNO. In this description, unless otherwise stated, the term "alkenyl includes alkeneamine groups with linear or branched chains, but references to individual alkeneamine groups such as 2-butenyl, characteristic only for the case of a linear chain. Unless otherwise stated, the term "alkenyl" mainly relates to circuits with 2-5 carbon atoms, preferably 3-5 carbon atoms. In this description, unless otherwise stated, the term "quinil includes alkyline groups with linear or branched chain, but references to individual alkyline groups such as 2-butynyl are characteristic only for the case with linear chain. Unless otherwise stated, the term "quinil" mainly relates to circuits with 2-5 carbon atoms, przepasniak 2 and 8 khinazolinov group.

In the framework of the present invention should be considered that the compound of formula I or its salt can be tautomerism and that the drawings formulas within this specification can represent only one of the possible tautomeric forms. Note that the invention encompasses any tautomeric form which inhibits the activity of SAR receptor tyrosine kinase and is not to be limited to any one tautomeric form, used to display formulas.

You should also be aware that the compounds of formula I and their salts may exist in the form of a solvate and in resolutiony forms, such as, for example, hydrated forms. Note that the invention encompasses all such solvate form, which inhibit the activity of SAR receptor tyrosine kinase.

To eliminate any doubt, note that when X1for example, is a group of the formula-NR7CO-, it represents a nitrogen atom, R7the group, which is associated with hinazolinam ring and the carbonyl (CO) group is associated with R4where X1represents, for example, a group of the formula-CONR8- it represents a carbonyl group associated with the Chi is them two atoms X1linking groups such as-NR10SO2- and-SO2NR9-. When X1represents-NR11- he is a nitrogen atom with R11the group, which is attached to hinazolinam ring and R4. The same caveat applies to other groups, therefore, when R4is, for example, a group of the formula C1-5alkyl5R27and X5the group is-NR28CO-, a nitrogen atom with R28group attached to the alkyl chain associated with chinadaily ring, and a carbonyl group (CO) attached to R27where X5for example, is a group of formula-CONR29- this is a carbonyl group attached to the alkyl chain, which is associated with hinazolinam ring, and the nitrogen atom bearing R29group attached to R27. Next, note that when X1represents-NR11-, and R11is C1-3alkoxyl2-3the alkyl, then this is the group WITH2-3alkyl attached to the nitrogen atom of X1a similar condition applies to other groups.

To eliminate any doubt it should be considered that in the compound of formula I, when R4is, for example, a group of the formula CF> similarly, when R4for example, represents a group of the formula C2-5R14WITH2-5Alchemilla group is associated with X1and the same applies to other groups. When R4is a group 1-R33prop-1-EN-3-yl, R33attached to the first carbon, and the third carbon associated with1similarly, when R4represents a group 2-R33the Penta-3-EN-5-yl, R33attached to the second carbon, and the fifth carbon associated with1a similar condition applies to other groups.

The present invention relates to compounds of formula I, as defined above, and their salts. Salts for use in pharmaceutical compositions are pharmaceutically acceptable salts, but when the compounds of formula I and their pharmaceutically acceptable salts can be used, and other salts. Pharmaceutically acceptable salts according to the invention can, for example, include salts of joining acids to compounds of formula I, above, which are quite essential for the formation of such salts. Such salts accession acids include, for example, salts with inorganic or organic acids, giving a pharmaceutically what that florodora acid is especially preferred), or sulfuric or phosphoric acid, or triperoxonane, citric or maleic acid. In addition, when the compounds of formula I are sufficiently acid, pharmaceutically acceptable salts can be formed with inorganic or organic base, which gives a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include, for example, salt of an alkali metal such as sodium or potassium salt, a salt of alkaline earth metal such as calcium or magnesium salt, ammonium salt or salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

The compound of formula I or its salt and other compounds according to the invention (as defined above) can be obtained by any method used to obtain chemically related compounds. Such methods include, for example, illustrated in applications to the European patent publication 0520722, 0566226, 0602851 and 0635498. Such methods are proposed as the next object of the invention and described hereinafter. The necessary starting materials may be obtained by conventional methods of organic chemistry. The receipt of such starting compounds are described within the attached neogenequaternary, which well-known experts in organic chemistry.

Thus, the following methods (a)-(g) and (i) to(v) are also features 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 coupling of compounds of formula III

< / BR>
(where R1, R2X1and R4are as defined above, a L1represents a substitutable group, with a compound of formula IV:

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

The interaction is mainly carried out in the presence or acids, or bases. This acid is, for example, anhydrous inorganic acid, such as for example, hydrogen chloride. Such a base is, for example, an organic amine, such as, for example, pyridine, 2,6-lutidine, kallidin, 4-dimethylaminopyridine, triethylamine, morpholine, N-metalmorph inogo metal, for example, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Alternatively, such a base is, for example, 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. The interaction is mainly carried out in the presence of an inert solvent or diluent, for example, alcohol or a complex ether, such as methanol, ethanol, 2-propanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, simple ether such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from 10 to 150oWith, preferably in the range of from 20 to 80oC.

The connection according to the invention can be obtained in this way in the form of free base or alternatively it may be obtained in the form of a salt with the acid of the formula H-L1where L1treated base, as defined above, in the usual way.

(b) When a group of formula IIA

< / BR>
(where R3and m are as defined above) represents a phenyl group containing one or more hydroxyl groups, the compound of the formula I and salts thereof can be obtained by removing the protective groups of the compounds of formula (V):

< / BR>
(where X1, m, R1, R2, R3and R4are as defined above, P represents a protective group for hydroxyl phenol and P1 is an integer from 1 to 5 equal to the number of protected hydroxy groups, such that m-p1 is equal to the number of the substituents R3that are unprotected hydroxy groups). The choice hydroxyamino group of phenol is well known to chemists organikum, for example, the groups included in the standard descriptions, such as "Protective Groups in Organic Synthesis" ("Protective groups in organic synthesis") T. W. Greene and R. G. M. Wuts, 2ndEd. Wiley 1991, include ethers (e.g., methyl, methoxymethyl, allyl and benzyl, and benzyl, with up to two substituents selected from C1-4alkoxy and nitro), Silovye esters (for example, tert-butyldiphenylsilyl and tert-butyldimethylsilyloxy), esters (e.g. acetate, alkoxy and nitro). Removal of such hydroxyamine groups of the phenol can be carried out by any methods known for such a transformation, including the reaction conditions specified in the standard descriptions, such as those mentioned above, or similar techniques. The reaction conditions are preferably such that the hydroxy formed without adverse reactions by other provisions of the source or target substances. For example, when the protective group R represents an acetate, a transformation can be usually carried out by treating chineselanguage derived base, as defined above, including ammonia, 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. Such interaction can be carried out in the presence of an additional inert solvent or diluent as defined above, and at a temperature of from 0 to 50oUsually at about 20oC.

(C) Obtaining those compounds of formula I and their salts, in which the Deputy X1represents-O-, -S - or-NR11- or-SO2-, -CONR8or-SO2NR9- can be carried out by the interaction, usually in p , R3and R4are as defined above) with the compound of the formula VII:

R4-L1, (VII)

(where R4and L1are as defined above); L1is a substituted group, for example halogen or sulfonyloxy, such as bromine or methysulfonylmethane. Usually L1represents the group O-+P(R52)3(where R52represents a butyl or phenyl), and in such cases, the compound of formula VII is usually formed in situ. The interaction is preferably carried out in the presence of a base (as defined above in method (a)) and, mainly, in the presence of an inert solvent or diluent (as defined above in method (a)), mainly at a temperature in the range of, for example, from 10 to 150oUsually at about 50oC.

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

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

R4-X1-H, (IX)

(where L1, R1, R2, R3, R4, m and X1are as defined above). The reaction can usually be carried out in the presence of a base (as defined above in method (a)) and, mainly, in Pris is the temperature in the range for example, from 10 to 150oUsually about 100oC.

(e) Compounds of the formula I and salts thereof, where R4represents a C1-5R53[where R53choose from one of the following three groups:

1) X7R27(where X7represents-O-, -S-, -SO2-, -NR54CO-, -NR56SO2- or-NR56- (where R54, R55and R56each independently represent hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl) and R27is the same as defined above);

2) X8C1-5alkyl3R16(where X8represents-O-, -S-, -SO2-, -NR57CO-, -NR58SO2- or-NR59- (where R57, R58and R59each independently represent hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and X3and R16are as defined above); and

3) X9C1-5R33(where X9represents-O-, -S-, -SO2-, -NR60CO-, -NR61SO2- or-NR62- (where R60, R61and R62each independently represent hydrogen, C1-3alkyl or C1-3alkoxyl2-3alkyl), and R33is the same as defined above);],

can be populeuse such as defined above, and R63is1-5alkyl) with a compound of formula XI:

R53-H (XI)

(where R53is the same as defined above) to obtain the compounds of formula I. Interaction can usually be done in the presence of a base (as defined above in method (a)) and, mainly, in the presence of an inert solvent or diluent (as defined above in method (a)), and, mainly, at a temperature in the range of, for example, from 0 to 150oUsually at about 50oC.

The compounds of formula I, where R4is2-5aR45(where R45is the same as defined above, can be obtained by the coupling of compounds of formula (X) (where R63represents a C2-5alkyl) with a compound of the formula Chi:

R45-H, (XIa)

(where R45is the same as defined above) to obtain the compounds of formula I. Interaction can usually be done in the presence of a base (as defined above in method (a)) and, mainly, in the presence of an inert solvent or diluent (as defined above in method (a)), and, mainly, at a temperature in the range of, for example, from 0 to 150oUsually at about 505R6where one or both of R5and R6are C1-3the alkyl can be obtained by the interaction of the compounds of formula I, where the substituent R1represents an amino group, alkylating agent, preferably in the presence of a base as defined above.

Such alkylating agents are C1-3fragments having a substituted group, as defined above, such as C1-3alkylhalogenide, for example, C1-3alkylchloride, -bromide or iodide. The reaction is preferably carried out in the presence of an inert solvent or diluent (as defined above in method (a)) and at a temperature in the range of, for example, from 10 to 100oUsually at about ambient temperature.

(g) obtaining the compounds of formula I and their salts, where one or more substituents R1, R2or R3represents the amino group, can be obtained by reduction of corresponding compounds of formula I, where the substituent(s) in the appropriate(their) position(s) chineselanguage and/or aniline ring is/are a nitro-group(s). Recovery usually can be performed as described in method (i) next. Obtaining the compounds of formula I and its salts, where is agropol(groups), can be done by the methods described above and further in the methods (a-e) and (i-v), using chineselanguage compounds selected from compounds of formulas (I-XXVII) in which the substituent(s) in the appropriate(their) position(s) chineselanguage and/or aniline ring is/are a nitro-group(or groups).

Synthesis of intermediate compounds

(i) the compounds of formula III and their salts constitute another object of the present invention. Such compounds in which L1is a halogen, can be obtained by halogenoalkanes the compounds of formula XII:

< / BR>
(where R1, R2, R4and X1are as defined above).

Suitable halogenation agents include halides of inorganic acids, for example, thionyl chloride, phosphorus(III)chloride, phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenation reaction is usually carried out in the presence of an inert solvent or diluent, such as, for example, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. Communication is usually carried out at a temperature in the range, and their salts, which constitute another object of the present invention can be obtained by the coupling of compounds of formula XIII:

< / BR>
(where R1, R2and L1are as defined above) with a compound of formula IX, as defined above. Interaction usually can be carried out in the presence of a base (as defined above in method (a)) and, mainly, in the presence of an inert solvent or diluent (as defined above in method (a)), and, mainly, at a temperature in the range of, for example, from 10 to 150oUsually about 100oC.

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

< / BR>
(where R1, R2, R4and X1are as defined above, and1represents a hydroxy, alkoxy (preferably C1-4alkoxy or amino group) obtaining thus the compounds of formula XII or salts thereof. The cyclization can be accomplished by the coupling of compounds of formula XIV, where a1represents hydroxy or alkoxy group, with formamide or its equivalent, can cause cyclization with the formation of compounds of formula XII or its salts, such as chloride [3-(dimethylamino)-2-isoprop-2 is risotti inert solvent or diluent, such as a simple ether, for example, 1,4-dioxane. The cyclization is usually carried out at elevated temperature, preferably in the range from 80 to 200oC. the compounds of formula XII can be obtained by cyclization of the compounds of formula XIV, where a1represents the amino group, with formic acid or its equivalent, can cause cyclization, in which is formed a compound of the formula XII or salt. Equivalents of formic acid, which can cause a cyclization include, for example, three1-4alkoxylated, for example, triethoxysilane or trimethoxymethane. The cyclization is usually carried out in the presence of catalytic amount of anhydrous acid, such as sulfonic acid, e.g. p-toluensulfonate acid and in the presence of an inert solvent or diluent, such as, for example, a halogenated solvent such as methylene chloride, chloroform 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 in the range of, for example, from 10 to 100oWith, preferably in the range from 20 to 50oC.

The compounds of formula XIV obtained by reduction of the nitro group in the compound of formula XV:

< / BR>
(where R1, R2, R4X1and1are as defined above) to obtain the compounds of formula XIV as defined above. The restoration of the nitro group can usually be accomplished by any means known for such a transformation. The recovery may, for example, be carried out by hydrogenation of a solution of the nitro compounds in the presence of an inert solvent or diluent as defined above in the presence of a metal effective for the catalysis of hydrogenation reactions, such as palladium or platinum. Other recovery agents are, for example, activated metal, such as activated iron (obtained, for example, washing the iron powder diluted aqueous acid, such as hydrochloric acid). Thus, for example, the recovery may be carried out by heating the nitro compounds, and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, at a temperature in the range of, for example, from 50 to 150oUsually at about 70oC.

The compounds of formula XV and salts, which are another object of the present invention, can UP>1are as defined above) with a compound of formula IX, as defined above, to obtain compounds of formula XV. The interaction of compounds of formulas XVI and IX is usually carried out under the conditions described for process (d) above.

The compounds of formula XV and salts may, for example, also be obtained by the coupling of compounds of formula XVII:

< / BR>
(where R1, R2X1and1are as defined above, provided that X1is not-CH2-) with a compound of formula VII, as defined above, to obtain compounds of formula XV as defined above. The interaction of compounds of formulas XVII and VII usually carried out under the conditions described for process (C) above.

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

< / BR>
(where R1, R2and X1are as defined above, provided that X1is not-CH2and L2represents a substituted protective group) with a compound of formula VII, as defined above, obtaining thus the compounds of formula III, where L1presents L2.

Usually used as a compound of formula XVIII, where L2is phenoxyl from halogen, nitro and cyano. The reaction can usually be carried out under conditions described above for the method (s).

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

< / BR>
(where R1, R2, P, X1and L2are as defined above, provided that X1is not-CH2-). Removing the protective groups can be carried out by methods well known in the literature, for example, when R represents a benzyl group, removing the protective group may be carried out by hydrogenation or by treatment triperoxonane

the acid.

One compound of the formula III can, if desired, be converted into another compound of formula III with a different fragment of the L1. Thus, for example, the compound of formula III in which L1is other than halogen, for example, optionally substituted, phenoxy, can be converted to the compound of formula III in which L1is a halogen, by hydrolysis of the compounds of formula III (in which L1other than halogen) to give the compounds of formula XII as defined above with the subsequent introduction of the halogen in the compound of formula XII, psobj halogen.

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

< / BR>
(where R3, m, P1 and R are as defined above). The interaction may be, for example, carried out as described in method (a) above.

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

< / BR>
(where R1, R2L1, R3, m, P1 and R are as defined above) with a compound of formula IX, as defined above. The interaction may, for example, be carried out as described for the method (d) above.

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

< / BR>
(where R1, R2L1, R3, m, P1 and R are as defined above, provided that X1is not-CH2-) with the compound of the formula VII, as defined above. The interaction may, for example, be carried out as described for the method (C) above.

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

< / BR>
the same or different) with a compound of formula XX, as defined above. The interaction may, for example, be carried out as described for the method (a) above.

The compounds of formula XXII and their salts can be obtained by the interaction of the compounds of formulas XIX and XX, as defined above, under conditions described above in (a), obtaining the compounds of formula XXIV:

< / BR>
(where R1, R2, R3, P, X1, R1 and m are as defined above, provided that X1is not-CH2-), and then removing the protection in the compound of formula XXIV, for example, as described in (i) above.

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

< / BR>
(where R1, R2, R3, P, X1and m are as defined above), for example, by the method described in (i) above.

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

(iv) the compounds of formula VIII and their salts, as defined above, can be obtained by the interaction of the compounds of formulas XXIII and IV, as defined above, the reaction of, for example, carried out according to the method described in (deistvie the compounds of formula VI, as defined above, with a compound of formula XXVI:

L1-R63-L1, (XXVI)

(where L1and R63are as defined above), to obtain compounds of formula X. the Interaction may, for example, be carried out as described for the method (C) above.

The compounds of formula X and their salts can also be obtained, for example, removing the protective groups in the compound of formula XXVII:

< / BR>
(where L1, R63X1, R1, R2, R3, P, m and R1 are as defined above), for example, as described in (b) above.

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

When you want pharmaceutically acceptable salt of the compounds of formula I, it can be obtained, for example, the interaction of the compounds, for example, with the acid in the usual method, and acid gives a pharmaceutically acceptable anion.

Many of these intermediates are novel, for example, having the formula III, V, XII, XIV and XV, and it is another object of the invention.

Intermediate compounds of formulas VIII, X, XXI, Choi, which strongly inhibit the tyrosine kinase activity associated with SAR receptors such as Flt and/or KDR, and which inhibit angiogenesis and/or increased permeability of blood vessels, which is the subject of the present invention. These properties can be estimated, for example, using one or more methods presented below.

(a) study of the inhibition of receptor tyrosine kinase in vitro

This analysis allows to determine the ability of test compounds to inhibit the activity of tyrosine kinase. DNA encoding safr or epidermal growth factor (EGF) receptor cytoplasmic domains, can be obtained from the total gene synthesis (M. Edwards, International Biotechnology lab 5(3), 19-25, 1987) or by cloning. Then they can be expressed in expressing appropriate system to obtain a polypeptide with tyrosinekinase activity. For example, it was found that SAR and EGF receptor cytoplasmic domains, obtained by expression of recombinant protein in insect cells, have their own tyrosinekinase activity. If safr receptor Flt (sequence number in the Gene Bank H), 1.7, etc., N. (thousands of base pairs) DNA fragment code al. (Oncogene, 1990, 5:519-524), was isolated from cDNA and cloned in baculovirus permutation vector (for example, pAcYMl (see The Baculovirus Expression System: A Laboratory Guide (Baculovirus expression system: a laboratory guide), L. A. King and R. D. Possee, Chapman and Hall, 1992) or RAS or pBlueBacHis (available from Invitrogen Corporation)). This recombinant construct was also cotransfection in insect cells (for example, Spodoptera fruigiperda 21 (Sf21)) with viral DNA (e.g., Pharmingen BaculoGold) preparation of recombinant baculovirus. (Details of the methods of recombinant DNA molecules and the receipt and use of baculovirus can be found in standard reference books, for example, Sambrook et al. , 1989, Molecular cloning - A Laboratory Manual (Molecular cloning - a laboratory manual), 2ndedition, Cold Spring Harbour Laboratory Press and O'reilly et al., 1992, Baculovirus Expression Vectors - A Laboratory Manual (Expression baculovirus vectors - a laboratory manual), W. H. Freeman and Co, New York). For other tyrosinekinase for use in the analysis can be cloned and expressed in the usual way cytoplasmic fragments, starting with methionine 806 (KDR, the sequence number in the Gene Bank L04947) and methionine 668 (EGF receptor, the sequence number in the Gene Bank H).

For expression cF1t activity tyrosinasean and harvestore (collection of cells) 48 hours later. Harvestingand cells were washed in ice-cold phosphate buffered saline (PBS) (10 mm phosphate, pH 7.4, 138 mm sodium chloride, 2.7 mm potassium chloride), then resuspendable in ice cold HNTG/PMSF (20 mm Hepes, pH 7.5, 150 mm sodium chloride, 10% vol./about. glycerol, 1% vol./about. Triton X100, 1.5 mm magnesium chloride, 1 mm ethylene glycol-bis-(-aminoethylamide ether) N,N, N, N'-tetraoxane acid (EGTC), 1 mm PMSF (phenylmethylsulfonyl); PMSF was added immediately before application of 100 mm solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. The suspension was centrifuged for 10 minutes at 13,000 rpm at 4oS, supernatant (enzyme biomass) was removed and stored in aliquot at -70oC. Each new batch of enzyme biomass was titrated in the analysis by dilution with enzyme diluent (100 mm Hepes, pH 7.4, 0.2 mm of orthovanadate sodium, 0,1% vol./about. Triton X100, 0.2 mm of dithiothreitol). For a typical load of enzymatic biomass is diluted 1 in 2000 enzyme diluent and 50 ál of diluted enzyme is used for each well in the assay.

The mass of substrate solution prepared from a statistical copolymer containing tyrosine, for example Poly (Glu, Ala, Tight) 6:3:1 (Sigma P3899), stored as 1 mg/ml weight in PBS at -20othe ora of the substrate was made to all wells tablet assay (96-well immunoplate Nunc maxisorp), which was closed and left overnight at 4oC.

On the day of analysis, the substrate solution was decanted and the wells tablets for analysis were washed once with PBST (PBS. Containing 0.05% vol./about. Tween20) and once with 50 mm s, pH 7.4.

The compounds were diluted in 10% dimethyl sulfoxide (DMSO) and 25 µl of the diluted compounds were introduced into the wells washed tablets for analysis. Wells General control contained 10% DMSO instead of compound. Twenty-five microlitres 40 mm chloride manganese (II), containing 8 μm adenosine-5'-triphosphate (ATP), was added to all test wells except wells "empty" control, which contained chloride manganese (II), but without ATP. To start interaction 50 ál swierzbinski enzyme was added to each well and the plates were incubated at room temperature for 20 minutes. The liquid is then decanted and the wells washed twice in PBST. One hundred microlitres mouse IgG antiphosphotyrosine antibodies (Upstate Biotechnology Inc.product 05-321), diluted 1 in 6000 in PBST containing 0.5% of bovine serum albumin (BSA) was added to each well and the plates were incubated for 1 hour at room temperature before draining the liquid and washing the wells twice with PBST. Dobavlenoj 1 in 500 in PBST, containing 0.5% of BSA and the plates were incubated for 1 hour at room temperature before draining the fluid and washing tablets twice PBST. To each well was added a hundred microlitres solution of 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS), freshly prepared using one tablet ABTS (Boehringer 1204 521) in 50 ml of freshly prepared 50 mm phosphate-citrate buffer, pH 5.0 + 0.03% sodium perborate (received 1 capsule (Sigma R) phosphate-citrate buffer with perborate sodium (PCSB) in 100 ml of distilled water. The tablets then were incubated for 20-60 minutes at room temperature as long as the value of optical density of the wells "total" control, measured at 405 nm using a spectrophotometer to read the tablets, not reached approximately 1.0. "Empty" (without ATP) and General (without connections) of the control values used to determine the degree of dilution of the test compound which gave 50% inhibition of enzyme activity.

(b) in vitro proliferation of HUVEC

This study allows to determine the ability of the compounds to inhibit stimulated by growth factor proliferation of human endothelial the serum (FTS) and were sown on wells (re-sowing 2 to 8) in MCDB 131 + 2% vol./about. FCS + 3 mg/ml heparin + 1 mg/ml hydrocortisone, at a concentration of 1000 cells/well on 96-well pad. Through at least 4 hours, thereto was added a suitable growth factor (i.e. safr 3 ng/ml, EGF 3 ng/ml or b-FGF 0.3 ng/ml) and connection. Culture then inhibited for 4 days at 37oWith 7.5% carbon dioxide. On the 4th day of culture was sprayed 1 mccoury/well-thymidine labeled with tritium (product of Amersham TRA 61), and incubated for 4 hours. The cells were harvestable using harvester 96-hole tablet (Tomtek) and then analyzed for the introduction of tritium using a tablet counter beta radiation. The introduction of radioactivity into the cells, expressed in CPM (counts per minute) was used to measure inhibition of compounds cell proliferation stimulated by the growth factor.

(C) in vivo swelling of the uterus in rats

This test measures the ability of compounds to reduce the sharp increase in the weight of the uterus in rats, which occurs in the first 4-6 hours after estrogen stimulation. It was long known that this early increase in weight of the uterus is due to edema caused by increased permeability of the blood vessels of the uterus, and recently the cullian-Bove and s (Endocrinology, 1993, 133:829-837) showed is established, that pre-treatment of rats neutralizing monoclonal antibody to safr significantly reduces acute increase in weight of the uterus, confirming that the increase in weight is essentially mediated SAR.

Groups of rats age 20-22 days were injected subcutaneously with a single dose of estradiol benzoate (2.5 µg/rat) in a solvent or solvent. The latter acted as nelinumeroisia control. Compound was administered orally at different times before the introduction of estradiol benzoate. Five hours after injection of estradiol benzoate in rats was slaughtered in a humane manner, dissected them the uterus, dried with absorbent paper and weighed. Comparing the increase in weight of the uterus in the groups receiving test compound and benzoate estradiol or estradiol benzoate, using T-test t-test. The inhibition of estradiol benzoate considered significant at p<0,05.

The composition may be received in the form, is UCA intravenous, subcutaneous, intramuscular, intravascular or infusion), for example, in the form of a sterile solution, suspension or emulsion, for topical use, for example, in the form of ointment or cream or for rectal administration, for example, in the form of suppositories. Typically, these compositions can be manufactured by conventional methods with the use of well-known excipients.

Compositions of the present invention, mainly presented in the form of a standard dosage forms. The connection usually will be introduced warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body of the animal, i.e. approximately 0.1-100 mg/kg of the Planned unit dose is in the range of, for example, 1-100 mg/kg, preferably 1-50 mg/kg, and this is usually therapeutically effective dose. Standard dosage form such as a tablet or capsule will usually contain, for example, about 1-250 mg of the active ingredient.

According to another aspect of the present invention proposed a compound of formula I or its pharmaceutically acceptable salt as defined above, for use according to the method of therapeutic treatment of the human or animal.

Was ustanovlenno, are of interest due to their antiangiogenic effects and/or their ability to cause a decrease in permeability of the blood vessels.

The next object of the present invention is a compound of formula I or its pharmaceutically acceptable salt for use as a medicinal product, i.e. compound of formula I or its pharmaceutically acceptable salt for use as a drug to achieve the antiangiogenic effect and/or the effect of reducing the permeability of the blood vessels of warm-blooded animals such as man.

Thus, according to further aspect of the invention proposed the use of the compounds of formula I or its pharmaceutically acceptable salts in the manufacture of drugs used to achieve the antiangiogenic effect and/or the effect of reducing the permeability of the blood vessels of warm-blooded animal such as man.

According to the next invention, a method of achieving antiangiogenic effect and/or the effect of reducing the permeability of the blood vessels of warm-blooded animal, such as man, in need of such treatment, which includes introduced and, as specified above.

As mentioned above, the size of the dose needed for treatment or prevention of a specific disease conditions, will be required to change depending on the exposed treatment of the subject, route of administration and the extent of disease. Preferably, the applied daily dose in the range of 1-50 mg/kg, However, the dose will need to vary, depending on the exposed treatment of the subject, the specific route of administration and the extent of disease. Accordingly, the optimal dose can be determined by the consultant, which treats the individual patient.

Antiangiogenic or reducing the permeability of blood vessels treatment specified above, can be applied as a sole therapy or may involve, in addition to the connection according to the invention, one or more other substances and/or treatments. Such joint treatment can be achieved by simultaneous, sequential or separate introduction of the individual components of the treatment. In the field of medical Oncology is normal practice to use a combination of various forms of treatment to cure the patient of cancer. In medical Oncology the other component(s) V treatment, defined earlier, may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may include three main categories of therapeutic agent:

(I) other antiangiogenic agents, mechanism of action which is different from the mechanism of action of the agents described above (for example, linomide, inhibitors of integrinV3function, angiostatin, retuxin, thalidomide);

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, idoxifene), POCs (for example, megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, varsol, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bikalutamid, cyproterone acetate), agonists and antagonists of LH-releasing factor (e.g., goserelin acetate, leuprolide), inhibitors of testosterone 5-dihydroorotase (for example, finasteride), antiinvasive agents (for example, inhibitors of metalloproteinases, as marimastat and inhibitors activator receptor function urokinase plasminogen) and inhibitors of the functions of growth factors (such growth factors include for example platelet-derived growth factor and hepatocytic growth factor (growth factor in liver cells), such bitory serine/trionychinae); and

(iii) antiproliferative/antineoplastic drugs and their combinations used in medical Oncology, such as antimetabolites (for example antifolates type of methotrexate, ftorpirimidinu type 5-fluorouracil, purine analogues, and adenosine, cytosine arabinoside); antitumour antibiotics (for example anthracyclines type of doxorubicin, daunomycin, epirubicin and idarubitsina, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosamine, thiotepa (thiotepa); antimitoticescoe agents (for example Vinca alkaloids type vincristine and taxaide type Taxol, Taxotere); inhibitors topoisomerase (for example, epipodophyllotoxin type of etoposide and teniposide, amsacrine, topotecan).

As indicated above, the compounds defined in the present invention, are of interest due to their antiangiogenic effects and/or the effect of reducing the permeability of blood vessels. It is assumed that such compounds can be used in a wide range of painful conditions, including cancer, diabetes, psoriasis, Revos, autoimmune diseases, acute inflammation and ocular diseases with the proliferation of retinal vessels. In particular, it is assumed that such compounds according to the invention will be primarily to slow the growth of primary and recurrent solid tumours of, for example, rectum, breast, prostate, lung and skin. More specifically, it is assumed that such compounds according to the invention will inhibit the growth of those primary and recurrent solid tumours which are associated with SAR, especially those tumors, growth and development which are significantly dependent on SAR, including, for example, some tumors of the rectum, breast, prostate, lung, vulva and skin.

In addition to the use in therapeutic medicine, the compounds of formula I and their pharmaceutically acceptable salts can also be used as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the impact of inhibitors WAR receptor tyrosinekinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

Note that the term "ether" as used anywhere in this description is ichigaya examples in which, unless otherwise stated:

[(i) evaporation was carried out by evaporation on a rotary evaporator in vacuo, and the processing was carried out after removal by filtration, the remaining solid matter, such as dehumidifiers;

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

(iii) column chromatography (flash method) and liquid chromatography medium pressure (SGH) was performed on silica Merck Kieselgel (Art. 9385) or silicon dioxide with reversed phase Merck Lichroprep RP-18 (Art. 9303) obtained from E. Merck, Darmstadt, Germany;

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

(v) the melting temperature was not adjusted and was determined using an automatic device to determine the melting temperature Mettler SP62, the device with oil bath or device Koffler (Koffler) with a hot disk;

(vi) the structures of the final products of the formula I were confirmed by the methods of nuclear (generally proton) magnetic resonance (NMR) and by mass spectroscopy; the values of chemical shifts of proton magnetic resonance measured on a scale Delta and multipletness peaks in the (vii) intermediate compounds were fully characterized and their purity was assessed by thin layer chromatography (TLC), liquid chromatography high performance (HPLC), infrared (IR) or NMR spectra;

(viii) we used the following abbreviations

DMF - N,N-dimethylformamide,

DMSO - dimethyl sulfoxide,

THF is tetrahydrofuran,

TFUC - triperoxonane acid,

NMP is 1-methyl-2-pyrrolidone.

Example 1

Potassium carbonate (2.2 g, 16 mmol) was added to a solution of 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (1.51 g, 4 mmol) in DMF (30 ml) and the mixture was stirred for 15 minutes, then was added dropwise 2-bromatology ester (667 mg, 4.8 mmol). The mixture was stirred for 1 hour at room temperature, then was heated at 60oC for 17 hours, and finally cooled. Insoluble products were removed by filtration and the filter cake washed with DMF. The filtrate was distributed between ethyl acetate and water, the organic layer was separated, washed with saturated salt solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by the method of column chromatography, elwira methylene chloride/methanol (95/5, then 93/7). The purified product was washed with ether, receiving 4-(3-acetoxy-4-methylaniline)-6-methoxy-7-(2-methoxyethoxy)hinzelin (1,34 g, 84%) as a white powder.

Mass spectrum ESI: 420 [MNa]+.

Elemental analysis:

Found: From 63.1, N, 6,1, N 10.4 Percent.

C21H23N3O5.

Required: From 63.5, N, 5,8, N 10,6%.

The product was received as follows:

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) was stirred and heated at the boil under reflux for 24 hours. To the reaction mixture were added sodium acetate (3,02 g 0,037 mol) and acetic acid (1.65 ml, 0,029 mol) and was heated for another 3 hours. The mixture was evaporated and to the residue was added water, the solid products were filtered off, washed with water and dried (MgSO4). 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) was stirred and heated at the boil under reflux for 1 hour. The mixture was evaporated, the residue was treated with toluene and evaporated to dryness, obtaining 7-benzyloxy-4-chloro-6-methoxyquinazoline (3,45 g).

To a mixture of 2-methyl-5-nitrified (1.9 ml, 20.3 mmol). The mixture was stirred for 40 minutes, the solids were removed by filtration and the filtrate was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride, dried (gS4) and was evaporated, obtaining 2-acetoxy-4-nitrotoluene (3.1 g, 100%). A mixture of this substance (3.1 g, 15.9 mmol) and (0.12 g) of the catalyst is 10% palladium-on-coal in ethyl acetate (50 ml) was stirred at room temperature under hydrogen pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated, getting 3-acetoxy-4-methylaniline (2,45 g, 94%).

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (2,18 g of 7.25 mmol), 3-acetoxy-4-methylaniline (1,32 g, 8 mmol) and 2-propanol (50 ml) was stirred and heated at the boil under reflux for 1 hour. The mixture was cooled to room temperature. The precipitate was collected by filtration, washed with 2-propanol and ether, receiving 4-(3-acetoxy-4-methylaniline)-7-benzyloxy-6-methoxyquinazoline. A mixture of 4-(3-acetoxy-4-methylaniline)-7-benzyloxy-6-methoxyquinazoline (2,68 g of 5.75 mmol), catalyst (10% palladium-on-coal (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at room temperature under a pressure of 1.5 ATM of hydrogen for 30 minutes. The cat is, what was harvested by filtration and dried in vacuum at 50oWith getting 4-(3-acetoxy-4-methylaniline)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).

Example 2

A solution of 2-(2-bromacil)-1,3-dioxolane (258 mg, 1.4 mmol) in DMF (0.5 ml) was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (329 mg, of 1.02 mmol) and potassium carbonate (264 mg, 2 mmol) in DMF (2 ml). The mixture was heated at 100oC for 3 hours and left to cool. Volatile components were removed by evaporation, the residue was distributed between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic phase was separated and passed through futuresplash paper. The solvent was removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol (95/5) to give 4-(4-chloro-2-foronline)-7-(2-(1,3-dioxolane-2-yl)ethoxy-6-methoxyquinazoline (71 mg, 17%).

1H NMR spectrum: (DMSO-d6) 2,1 (m, 2H); and 3.8 (m, 3H); 3,95 (m, 5H); of 4.25 (t, 2H); of 5.05 (t, 1H); 7.18 in (s, 1H) ; and 7.3 (m, 1H); at 7.55 (m, 2H); 7,8 (s, 1H); 8,35 (s, 1H); and 9.5 (s, 1H).

Mass spectrum ESI: 420 [MN]+.

Elemental analysis:

Found: 57,4, N. 4,7, N 9,1%.

WITH20H19H3O4lF.

Required: 57,2, N, 5,6, N, 10,0%.

The original product polucha for the parent compound in Example 1) and 4-chloro-2-ftoranila (444 μl, 4 mmol) in 2-propanol (40 ml) was boiled for 1.5 hours. After cooling, the precipitate was filtered off, washed with 2-propanol, then with ether, and dried in vacuum, obtaining the hydrochloride of 7-benzyloxy-4-(4-chloro-2-foronline)-6-methoxyquinazoline (1.13 g, 64%). So pl. 239-242oC.

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

Mass spectrum ESI: 410 [MN]+.

Elemental analysis:

Found: 59,2, N 4,3, N 9.4 Per Cent.

C22H17N3O2ClF1HCl.

Required: 59,2, H 4,1, N 9,41%.

A solution of the hydrochloride of 7-benzyloxy-4-(4-chloro-2-foronline)-6-methoxyquinazoline (892 mg, 2 mmol) in TFOC (10 ml) was boiled for 50 minutes. After cooling, the mixture was poured on ice. The precipitate was filtered, dissolved in methanol (10 ml) and podslushivaet to pH 11 aqueous ammonia. After concentration by evaporation, the solid was filtered, washed with water, then with ether, and dried in vacuum, obtaining 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline in the form of a yellow solid product (460 mg, 72%).

So pl. 141-143oC.

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

Mass spectrum ESI: 320-322 [MN]oWith and periodically after 4 hours was added an additional portion of the hydrochloride of 1-(2-chloroethyl)pyrrolidine (total 800 mg), maintaining the temperature of the reaction mixture at 100oC. Then the reaction mixture was allowed to cool and the volatiles were removed by evaporation. The residue was distributed between methylene chloride and water were separated and the organic phase was passed through futuresplash paper. By column chromatography with elution methylene chloride/methanol (95/5) was obtained 4-(4-chloro-2-foronline)-6-methoxy-7-(2-pyrrolidin-1-yl)ethoxy)hinzelin (50 mg, 10%).

1H NMR spectrum: (DMSO-d6) 1,8-2,1 (m, 4H); 3,1 (m, 2H); 3,55 to 3.7 (m, 4H); of 4.05 (s, 3H); 4,6 (t, 2H); to 7.4 (m, 2H); 7,58 (d, 1H); the 7.65 (dt, 1H); and 8.5 (s, 1H); of 8.8 (s, 1H).

Mass spectrum ESI: 417 [MH]+.

Elemental analysis:

Found: 60,2, N. 5,4, N 12,3%.

C21H22N4O2ClF.

Required: 60,5, N 5,3, N 13,4%.

Example 4

A solution of 1-(3-chlorpropyl)pyrrolidine (230 mg, 0.96 mmol) was added to 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (295 mg, of 0.92 mmol) (obtained as described DL for 90 minutes and left to cool. Volatile components were removed by evaporation and the residue was distributed between methylene chloride and water were separated and the organic phase was passed through futuresplash paper and the solvent was removed under reduced pressure. The residue was dissolved in acetone and was added hydrogen chloride in ether (2 ml of 1M solution, 2 mmol). The mixture was stirred at room temperature for 30 minutes and the resulting precipitate was filtered and dried, obtaining the hydrochloride hydrate of 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)hintline (320 mg, 67%).

1H NMR spectrum: (DMSO-d6) of 1.8-2.0 (m, 6N); 3-3,6 (m, 6N); of 4.05 (s, 3H); 4,3 (t, 2H); to 7.4 (m, 2H); at 7.55 (d, 1H); 7,6 (m, 1H); and 8.4 (s, 1H); of 8.8 (s, 1H).

Mass spectrum ESI: 431 [MN]+.

Elemental analysis:

Found: 51,0, N 5,9, N 10,6%.

C22H24N4O2C1F1.8 H2O1.5 Hcl.

Required: 51,0, N. 5,7, N 10,8%.

The product was received as follows:

Pyrrolidin (3 g, 42 mmol) was added to a solution of 1-bromo-3-chloropropane (3.2 g, 20 mmol) in toluene (20 ml). The mixture was stirred at room temperature overnight, and then heated at 60oC for 4 hours. The mixture was cooled and the precipitate was removed by filtration. The volume of toluene was removed upari ropyl)pyrrolidine. This substance was used without further purification.

1H NMR spectrum: (Dl3) a 1.75 (m, 4H); 2.0 (q, 2H); to 2.35 (s, 3H, toluene); 2,45-2,6 (m, 6N); and 3.6 (t, 2H); 7,15-to 7.3 (m, 5H, toluene).

Example 5

A solution of 2-(2-methoxyethoxy)ethanol (90 mg, 0.75 mmol) in methylene chloride (1 ml) was added to tributylphosphine (320 mg, was 1.58 mmol) and 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (200 mg, to 0.63 mmol) (obtained as described for the initial substance in Example 2) in methylene chloride (6 ml) at 0oWith argon. To the resulting mixture portions was added 1,1' -(azodicarbon)piperidine (400 mg, 1.6 mmol). The mixture was left to warm to ambient temperature and stirred under argon for 2 hours. Added diethyl ether (5 ml) and precipitated in the sludge solids were removed by filtration. Volatile components were removed from the filtrate by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol (90/10). Finite partially purified product was dissolved in acetone and was added hydrogen chloride in ether (0.6 ml of 1 M solution, 0.6 mmol). The obtained precipitated precipitated product was filtered and dried, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy) hin is (t, 2H); and 7.4 (s, 1H); was 7.45 (DD, 1H); 7,55 to 7.7 (m, 2H); to 8.3 (s, 1H); is 8.75 (s, 1H); 11,5 (ush.s, 1H).

Mass spectrum ESI: 422 [MN]+.

Elemental analysis:

Found: 52,3, N. 4,7, N 9,1%.

C20H21N3O4ClF1HCl.

Required: 52,4, N 4,8, N 9,2%.

Example 6

A solution of 2-(bromomethyl)-1,3-dioxolane (190 mg, 1.1 mmol) in DMF (1 ml) was added to 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (258 mg, 0.81 mmol) (obtained as described for the initial substance in Example 2) and potassium carbonate (200 mg, 1.5 mmol) in DMF (2 ml). The mixture was heated at 100oC for 4 hours and then left to cool. Volatile components were removed by evaporation and the residue was distributed between water and methylene chloride. The organic phase was separated, passed through futuresplash paper and was purified by column chromatography, elwira methylene chloride/methanol (95/5) to give 4-(4-chloro-2-foronline)-7-(1,3-dioxolane-2-ylethoxy)-6-methoxyquinazoline (130 mg, 38%).

1H NMR spectrum: (DMSO-d6) of 3.8-4.1 (m, 7H); 4,15 (d, 2H); and 5.30 (t, 1H); 7,22 (s, 1H); 7,30 (m, 1H); at 7.55 (m, 2H); 7,80 (s, 1H); 8,35 (s, 1H); of 9.55 (s, 1H). Also contains 0.3 methanol.

Mass spectrum ESI: 406 [MN]+.

Elemental analysis:

Found: 55,1, N, 4,5, N Of 9.5%.

Example 7

A mixture of 6,7-dimethoxy-5-nitro-3,4-dihydroquinazolin-4-it (1,75 g, 7.0 mmol) and thionyl chloride (25 ml) and DMF (3 drops) was heated at the boil under reflux for 2 hours. The excess thionyl chloride was removed by evaporation and the residue was treated with azeotropic distillation with toluene. To the residue was added 3-hydroxy-4-methylaniline (0,94 g, 7.6 mmol) in 2-propanol (40 ml) and the mixture was heated at the boil under reflux for 2 hours. The mixture was left to cool, the precipitate was filtered off, washed with 2-propanol and dried, obtaining hydrochloride 6,7-dimethoxy-4-(3-hydroxy-4-methylamino)-5-nitroquinazoline (2,02 g, 81%).

So pl. 206-208oC.

1H NMR spectrum: (DMSO-d6) 3,90 (s, 3H); of 4.05 (s, 1H); of 6.65 (s, 1H); 6,97 (d, 1H); EUR 7.57 (s, 1H); 8,15 (s, 1H).

Mass spectrum ESI: 357 [MN]+.

Elemental analysis:

Found: 52,0, N 4,3, N 13.9 Per Cent.

C17H16N4O51HCl.

Required: 52,0, N 4,3, N 14,3%.

The product was received as follows:

A mixture of 4,5-dimethoxyaniline acid (19.7 g) and formamide (10 ml) was stirred and heated at 190oC for 5 hours. The mixture was left to cool to approximately 80oWith and added water (50 ml). A mixture of you who methoxy-3,4-dihydroquinazolin-4-one (3,65 g).

To 6,7-dimethoxy-3,4-dihydroquinazolin-4-ONU (10 g, 48 mmol) in water (40 ml) was added fuming nitric acid (47 ml). The reaction mixture was heated at 120oC for 1 hour, then cooled and diluted with water. The precipitate was filtered off, washed with water and dried, obtaining 6,7-dimethoxy-5-nitro-3,4-dihydroquinazolin-4-one (3.9 g, 32%).

1H NMR spectrum: (DMSO-d6) a 3.87 (s, 3H); of 4.05 (s, 1H); 7,42 (s, 1H); 8,13 (s, 1H).

Mass spectrum ESI: 251 [MN]+.

Example 8

2-methoxyethanol (10 ml) was added sodium (148 mg, 6.4 mmol), the mixture was stirred for 15 minutes, getting the final solution, and volatile components were removed by evaporation. The residue was dissolved in DMSO (5 ml) was added the hydrochloride of 7-chloro-4- (4-chloro-2-foronline)-6-nitroquinazoline (500 mg, 1.3 mmol). The mixture was stirred at room temperature for 18 hours, then diluted solution of acetic acid (1 ml) in water (20 ml). The precipitation was filtered, washed with water, dried and purified by column chromatography, elwira methylene chloride/methanol (96/4). The purified product was recrystallized from methylene chloride/isohexane, receiving 4-(4-chloro-2-foronline)-7-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as Tverdov 8,42 (s, 1H); 9,03 (s, 1H).

Mass spectrum ESI: 393 [MN]+.

Elemental analysis:

Found: From 51.8, N. 3,7, N 14,1%.

C17H14N4O4ClF.

Required: 52,0, N 3,6, N 14,3%.

The product was received as follows:

A mixture of 7-chloro-6-nitro-3,4-dihydroquinazolin-4-it (40 g, 0.18 mol) (J. Org. Chem., 1975, 40, 356), phosphorus oxychloride (50 ml) and DMF (1 ml) in chloride tionale (300 ml) was heated at the boil under reflux for 4 hours. The reaction mixture was allowed to cool and the volatiles were removed by evaporation and azeotropic distillation with toluene. The precipitate was podslushivaet aqueous solution of sodium bicarbonate and was extracted with methylene chloride (4100 ml). The extracts were combined, washed with saturated saline and filtered through futuresplash paper. The solvent was removed by evaporation and the residue triturated with ether/isohexane getting 4,7-dichloro-6-nitroquinazoline (35.2 g, 81%) as a pale yellow solid.

A mixture of 4,7-dichloro-6-nitroquinazoline (24.4 g, 0.1 mol), 4-chloro-2-foronline and hydrogen chloride in diethyl ether (100 ml of 1M solution) in 2-propanol (600 ml) was heated at the boil under reflux for 1.5 hours. The mixture was left ohla the rat 7-chloro-4-(4-chloro-2-foronline)-6-nitroquinazoline (35.0 g, 90%) as a yellow powder.

Mass spectrum ESI: 353 [MN]+.

Example 9

Triphenylphosphine (410 mg, 1.5 mmol) and 1-methyl-3-pyrrolidino (0,128 ml, 1.5 mmol) was added to a solution of 4-(chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol) (obtained as described for the original product in Example 2) in methylene chloride (4 ml). Was bury diethylazodicarboxylate (0,246 ml, 1.5 mmol) and the reaction mixture was stirred for 1 hour at room

temperature. Additionally added triphenylphosphine (61 mg, 0.23 mmol), after which diethylazodicarboxylate (37 μl, 0.23 mmol) and the mixture was stirred for 15 minutes at room temperature. The solvent was removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol (80/20), then methylene chloride/methanol/triethylamine (80/20/0/5). The purified product was dissolved in methylene chloride/methanol and the insoluble impurities were removed by filtration. To the filtrate was added a solution of hydrogen chloride in 2-propanol (0.5 ml of a 5M solution), and volatile components were removed by evaporation. The residue is triturated with 2-propanol and ether, was filtered and dried, obtaining a hydrate of the hydrochloride of 4-(4-chloro-2-foronline)-6-IU COOD) 2,13-and 2.83 (m, 2H); 2,92 (s, 3H); 2,99 (s, 3H); 3,20-of 3.32 (m, 1H); 3,44-3,59 (m, 1H); 3.72 points-3,81 (m, 1H); 3.96 points-to 4.14 (m, 2H); 4,01 (s, 3H); 5,35-5,43 (m, 1H); 7,42-7,47 (m, 2H); 7,58-7,63 (m, 2H); 8,21 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 403 [MN]+.

Elemental analysis:

Found: From 48.8, N 5,2, N 11,0%.

C20H20N4O2ClF 1H2O2HCl.

Required: 48,7, N Is 4.9, N 11,4%.

Example 10

4-(Chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol) (obtained as described for starting compound in Example 2) and triphenylphosphine (512 mg, 1.9 mmol) was added to a stirred solution of 4-morpholino-2-buten-1-ol (182 mg, 1.1 mmol) (J. Am. Chem. Soc., 1957, 79, 6184) in methylene chloride (4 ml) under argon. Was added dropwise diethylazodicarboxylate (0,307 ml, 1.9 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. Additionally added 4-morpholino-2-buten-1-ol (60 mg, 0,39 mmol), triphenylphosphine (102 mg, 0,39 mmol), after which diethylazodicarboxylate (61 μl, 0,39 mmol) and the mixture was stirred additionally for 15 minutes at room temperature. The solvent was removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/acetonitrile/methanol (60/37/3, then 60/35/5 and 55/37/8). Purified the RA). Volatile components were removed by evaporation, the solid residue suspended in ether and was filtered. The product was recrystallized from 2-propanol/methanol/diethyl ether, collecting by filtration, washed with 2-propanol and ether and dried, obtaining a hydrate of the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(4-morpholino-2-in-1 yloxy)hintline (75 mg, 18%).

So pl. 175-178oC.

1H NMR spectrum: (DMSO-d6; CF3COOD) 3,10 (m, 2H); 3.46 in (m, 2H); and 3.72 (m, 2H); 3,99 (m, 2H); is 4.03 (s, 3H); the 4.29 (s, 2H); 7,47 (DD, 2H); A 7.62 (S, 1H); a 7.62 (t, 1H); of 7.69 (DD, 1H); 8,29 (s, 1H); 8,89 (s, 1H).

Mass spectrum ESI: 457 [MN]+.

Elemental analysis:

Found: From 50.8, H Is 4.9, N, Or 10.3%.

WITH23H22N4O3lF1H2O2HCl.

Required: From 50.4, N. 4,7, N 10,2%.

Example 11

To a stirred solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(tripterocalyx)hintline (180 mg, 0.4 mmol) in THF (2 ml) and benzene (2 ml) under argon was added tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), after which the solution triisopropylsilyl sodium (102 mg, 0.48 mmol). The reaction mixture was heated at the boil under reflux for 2 hours and then left to cool. Was added dropwise 2-bromothymol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated saline solution, dried (MgSO4), and volatile components were removed by evaporation. The residue was purified by column chromatography on neutral aluminium oxide, elwira methylene chloride/acetone (95/5). The purified product was washed with ether, was filtered and dissolved in methylene chloride (4 ml). Was added hydrogen chloride in diethyl ether (0.4 ml of a 3M solution), the solution was diluted with ether and the resulting precipitate was filtered and dried, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methoxyacetyl)hintline (80 mg, 46%).

1H NMR spectrum: (DMSO-d6; CF3COOD) to 3.33 (t, 2H); to 3.34 (s, 3H); 3,71 (t, 2H); 4,07 (s, 3H); of 7.48 (DD, 1H); to 7.64 (t, 1H); of 7.69 (DD, 1H); 7,73 (s, 1H); 8,10 (s, 1H); 8,89 (s, 1H).

Mass spectrum ESI: 394 [MN]+.

Elemental analysis:

Found: 50,1, H 4,3, N 9,8, S To 7.3%.

C18H17N3O2ClFS1HCl.

Required: 50,2, H 4.2, N 9,8, S 7,4%.

The product was received as follows:

Triftormetilfullerenov anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-foronline)-7-hydroxy-6-IU is (2.2 ml) and pyridine (2.2 ml) under argon at 0oC. the Reaction mixture was stirred for 1 hour at 0oFrom left to warm to room temperature and stirred for further 1.5 hours. Volatile components were removed by evaporation, the residue was dissolved in ethyl acetate, washed with diluted hydrochloric acid and saturated saline solution, dried (gSO4) and the solvent was removed by evaporation. The residue is triturated with ether/petroleum ether, receiving 4-(4-chloro-2-foronline)-6-methoxy-7-(tripterocalyx)hinzelin (270 mg, 60%) as a beige solid product.

1H NMR spectrum: (DMSO-d6) 4,07 (s, 3H); 7,39 (DD, 1H); EUR 7.57 to 7.62 (m, 2H); a 7.92 (s, 1H); 8,21 (s, 1H); 8,49 (s, 1H).

Mass spectrum ESI: 452 [MN]+.

Example 12

To a stirred solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (225 mg, 0.70 mmol) (obtained as described for the original product in Example 2) and tributylphosphine (0.51 ml, of 2.08 mmol) in methylene chloride (10 ml) under nitrogen was added 4-(2-hydroxyethyl)thiomorpholine (114 mg, 0.78 mmol) (J. Am. Chem. Soc. 1934, 56, 1720) in methylene chloride (1 ml), then was added 1,1'-(azodicarbon)dipiperidino (525 mg, of 2.08 mmol). The mixture was stirred for 3.5 hours and left an additional 18 hours. Added ether (8 ml), the precipitate was removed felt hydrogen in ether (2.5 ml 1M solution). The precipitated product was filtered and was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was washed with ether, receiving 4-(4-chloro-2-foronline)-6-methoxy-7-(2-thiomorpholine)hinzelin (70 mg, 22%) as a pale-yellow solid product.

So pl. 181-182oC.

1H NMR spectrum: (DMSO-d6) to 3.56 (t, 2H); to 3.92 (s, 3H); 4,59 (t, 2H); 7,31 (DD, 1H); to 7.35 (s, 1H); 7,46 (d, 1H); 7,53 (DD, 1H); with 8.33 (s, 1H); 8,68 (s, 1H); 11,7 (ush.s, 1H).

Mass spectrum ESI: 449 [MN]+.

Elemental analysis:

Found: From 56.4, N, 5,1, N 12,3%.

C21H22N4O2ClFS.

Required: 56,2, N Is 4.9, N 12,5%.

Example 13

To a stirred mixture of 4-(chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (4.0 g, 12.5 mmol) (obtained as described for the original product in Example 2) and triphenylphosphine (9.81 g, 37.5 mmol) in methylene chloride (200 ml) was added a solution of (R)-(1-methylpiperidin-3-yl)methanol (to 2.29 g, 18 mmol) in methylene chloride (10 ml). Was added dropwise diethylazodicarboxylate (by 5.87 ml, 37 mmol) and the reaction mixture was stirred for 18 hours at room temperature. Volatile components were removed by evaporation and the residue was purified using the number of the i.i.d. product triturated with ethyl acetate, was filtered, washed with ethyl acetate, obtaining (R)-4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline (2,78 g, 52%).

[]D+ 11.7o.

1H NMR spectrum: (DMSO-d6) a 1.08 (m, 1H); 1,50 (m, 1H); of 1.64 (m, 1H); of 1.80 (m, 3H); 2,07 (m, 1H); of 2.16 (s, 3H); 2,62 (d, 1H); 2,81 (d, 1H); to 3.92 (s, 3H); was 4.02 (d, 2H); 7.18 in (s, 1H); to 7.32 (d, 1H); at 7.55 (m, 2H); 7,79 (s, 1H); a 8.34 (s, 1H); 9,50 (s, 1H).

Mass spectrum ESI: 431 [MN]+.

Elemental analysis:

Found: 60,7, N. 5,4, N, 13.3 Per Cent.

C22H24N4O2ClFS

Required: With 61.3, N, 5,6, N, 13,0%.

The product was received as follows:

(R)-Eternitate (5.7 g, 365 mmol) (obtained by division of telnperature by L(+)-tartaric acid as described in J. Org. Chem. , 1991, (56), 1168) was dissolved in 38.5% of aqueous solution of formaldehyde (45 ml) and formic acid (90 ml) and the mixture was heated at the boil under reflux for 18 hours. The mixture was left to cool and was added dropwise to a cooled saturated aqueous solution of sodium bicarbonate. The mixture was brought to pH 12 using sodium hydroxide, and the mixture was extracted with methylene chloride. The organic extract was washed with saturated saline solution, dried (MgSO4and the race.

Mass spectrum ESI: 172 [MN]+.

A solution of (R)-ethyl 1-methylpiperidine-3-carboxylate (5,69 g, 33 mmol) in ether (20 ml) was bury to stir the solution sociallyengaged (36,6 ml of 1M solution in THF, 36.6 mmol) in ether (85 ml) under cooling to maintain the reaction temperature at 20oC. the Mixture was stirred for 1.5 hours at room temperature, and then added water (1.4 ml), 15% aqueous sodium hydroxide solution (1.4 ml) and then water (4.3 ml). Insolubles were removed by filtration and the volatiles removed from the filtrate by evaporation, obtaining (R)-(1-methylpiperidin-3-yl)methanol (as 4.02 g, 94%) as a colourless oil.

1H NMR spectrum: (DMSO-d6) 1,06 (K, 1H); 1,51-of 1.94 (m, 5H); 2,04 (s, 3H); 2,34 (ush.s, 1H); 2,62 (m, 1H); 2,78 (d, 1H); to 3.49 (m, 1H); 3,59 (m, 1H).

Mass spectrum ESI: 130 [MN]+.

Example 14

Using a method similar to the method of Example 13, (S)-(1-methylpiperidin-3-yl)methanol (185 g, 1.1 mmol) (obtained as described for starting compound in Example 13, but when the separation D(-)-tartaric acid) was treated with 4-(chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319 mg, 1 mmol) (obtained as described for starting compound in Example 2), triphenylphosphine (785 mg, 3 mmol) and is-7-(1-methylpiperidin-3-yl)methoxyquinazoline (187 mg, 44%).

Example 15

The final compounds in Examples 13 and 14 can be mixed in any relative proportions, for example, to obtain a racemic mixture.

Alternatively, the racemate can be obtained in the following way:

1,1'-(Azodicarbon)dipiperidino (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fernilee)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol) (obtained as described for the original product in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the precipitate was removed by filtration. Volatile components were removed from the filtrate by evaporation and the residue was dissolved in acetone and was added hydrogen chloride in ether (1.5 ml, 1M solution, 1.5 mmol). The precipitated product was filtered and was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was washed with ether, collecting by filtration, and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-ylethoxy)hinzelin (105 mg, 33%).

So pl. 211-212oC.

1H NMR spectrum: (DMSO-d6) a 1.08 (m, 1H); 1,50 (m (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 431 [MN]+.

Elemental analysis:

Found: From 59.9, N, 5,5, N Is 12.9%.

C22H24N4O2C1F0,5H2O.

Required: 60,0, N. 5,7, N 12.7 Per Cent.

Example 16

To a stirred solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (1.5 g, 4.7 mmol) (obtained as described for the initial substance in Example 2) and tributylphosphine (4.0 ml, 16 mmol) in methylene chloride (50 ml) under nitrogen was added 3-(methylsulphonyl)propan-1-ol (0.6 g, 4.3 mmol), and then portions of 1,1'-(azodicarbon)dipiperidino (4,2 g, 16 mmol). The mixture was stirred for 18 hours, the final precipitate was filtered and dried, obtaining the crude product (1,36 g). The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol (gradient from 100/0 to 90/10). Paleoceanic product is triturated with acetone and the solid product was filtered, receiving additional crude product (0,53 g). The filtrate after grinding was purified by column chromatography, as previously, receiving additional crude product (0,23 g). The crude products were combined and dissolved in acetone/methanol/methylene chloride and was added to chloride of odor the La/methylene chloride/hexane, getting hydrochloride 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(methylsulphonyl)propoxy)hintline (640 mg, 29%).

So pl. >250oC.

1H NMR spectrum: (DMSO-d6) 2,25 (K, 2N); to 3.02 (s, 3H); to 3.36 (t, 2H); 4,00 (s, 3H); 4,30 (t, 2H); to 7.35 (s, 1H); 7,42 (d, 1H); of 7.60 (t, 1H); the 7.65 (d, 1H); of 8.25 (s, 1H); 8,78 (s, 1H); 11.5 (ush.s, 1H).

Mass spectrum ESI: 440 [MH]+.

Elemental analysis:

Found: 47,8, N 4,2, N, 8,8, S Of 6.7%.

C19H19N3O4ClFS1HCl.

Required: 47,4, N 4,2, N, 9,0, S To 6.8%.

The product was received as follows:

A solution of 3-(methylthio)propan-1-ol (5.3 g, 50 mmol) in methanol (500 ml) was added to a solution of OXONE (trade mark of E. I. du Pont de Nemours&Co., Inc.) (30 g) in water and the mixture was stirred at room temperature for 24 hours. The precipitated solid product was removed by filtration, and methanol was removed from the filtrate by evaporation. The aqueous residue was saturated with sodium chloride and was extracted with methylene chloride (425 ml). The aqueous residue was then saturated ammonium chloride and was extracted with ethyl acetate (425 ml). The extracts were combined, dried (gSO4) and the solvent was removed by evaporation, getting 3-(methylsulphonyl)propan-1-ol (610 mg, 9%) as oil.

1H NMR spectrum (CDCl3) of 2.10 (m, 2H); 2.9 kilat (5.91 ml, 37 mmol) was bury to stir a mixture of (E)-4-(pyrrolidin-1-yl)but-2-EN-1-ol (of 3.97 g, 28 mmol), 4-(chloro-2-foronline-7-hydroxy-6-methoxyquinazoline (3.0 g, 9 mmol) (obtained as described for the initial substance in Example 2) and triphenylphosphine (9,84 g, 38 mmol) in methylene chloride (300 ml). The reaction mixture was stirred for 18 hours at room temperature. Volatile components were removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol, was added a 1M solution of hydrogen chloride in ether. The precipitated product was filtered, washed with ether, and dried, obtaining hydrochloride (E)-4-(4-chloro-2-foronline)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-EN-1-yloxy)hintline (1,62 g, 33%).

1H NMR spectrum: (DMSO-d6; CF3D) 1,85-of 1.95 (m, 2H); 2.0 to to 2.15 (m, 2H); 3,0-3,1 (m, 2H); 3,5-3,6 (m, 2H); 3,95 (d, 2H); to 4.1 (s, 3H); 4,95 (d, 2H); 6,1 (TD, 1H); 6,35 (TD, 1H); 7.4 (s, 1H); was 7.45 (DD, 1H); of 7.6 to 7.7 (m, 2H); 8,15 (s, 1H); of 8.90 (s, 1H).

Mass spectrum ESI: 443 [MN]+.

Elemental analysis:

Found:From 52.7%, N 5,3, N 10,8%.

C21H24N4O2ClF0.6N2O1.85 Hcl.

Required: 53,0, N 5,2, N 10,7%.

The product was received as follows:

Thionyl chloride (9.3 ml, 128 mmol) of p is the resultant to 0oC. the Mixture was stirred for 3.5 hours at room temperature and poured into ice-cold water. The mixture was extracted with ether, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution, dried (MgSO4), and volatile components were removed by evaporation. The residue was purified by column chromatography, elwira petroleum ether/ether (7/3) to give 4-hlorbutin-2-in-1-ol (4,74 g, 39%).

1H NMR spectrum (CDCl3) 1,68 (t, 1H); 4,18 (d, 2H), 4,33 (d, 2H).

Pyrrolidin (7.8 ml, 94 mmol) was added dropwise to a solution of 4-hlorbutin-2-in-1-ol (4,74 g, 45 mmol) in toluene (40 ml) and the mixture was stirred and heated at 60oC for 1 hour. Volatile components were removed by evaporation and the residue was purified chromatographically, elwira methylene chloride/methanol (96/4) to give 4-(pyrrolidin-1-yl)but-2-in-1-ol (4.3 g, 69%).

1H NMR spectrum: (Dl3) 1,82 (t, 4H); 2.63 in (t, 4H); 3,44 (t, 2H), 4,29 (t, 2H).

A solution of 4-(pyrrolidin-1-yl)but-2-in-1-ol (4.3 g, 31 mmol) in THF (20 ml) was added dropwise to a suspension of sociallyengaged (2.35 g, 62 mmol) in absolute THF (8 ml) and the mixture was stirred and heated at 60oC for 2 hours. The mixture was cooled to 5oAnd dropwise and from the filtrate by evaporation. The residue was dissolved in a mixture of methylene chloride/ethyl acetate, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on aluminium oxide, elwira methylene chloride/methanol (97/3) to give (E)-4-(pyrrolidin-1-yl)but-2-EN-1-ol (3,09 g, 70%).

1H NMR spectrum (CDCl3) to 1.82 (m, 4H); 2,61 (m, 4H); 3,17 (m, 2H); 4,13 (s, 2H); of 5.84 (m, 2H).

Example 18

A solution of 4-(4-bromo-2-foronline)-7-(3-chloropropoxy)-6-methoxyquinazoline (150 mg, 0.34 mmol) in 1-(2-hydroxyethyl)piperazine (5 ml) was heated at 100oC for 30 minutes. The reaction mixture was allowed to cool and was podslushivaet aqueous solution of sodium bicarbonate, and extracted with ethyl acetate (350 ml). The extracts were combined, washed twice with water, then with saturated salt solution and dried (MgS4). Volatile components were removed by evaporation and the residue was dissolved in acetone/methanol (10/1) (50 ml) and the solution was added Hcl in ether. The precipitate was filtered off, washed with ether and hexane and dried in vacuum, obtaining the hydrochloride of 4-(bromo-2-foronline)-7-3-[4-(2-hydroxyethyl)piperazinil]propoxy)-6-methoxyquinazoline (180 mg, 80%).

1H NMR spectrum: (DMSO-d6) 2,35 (ush.t, 2H); 3,2-3,8 (ush.m, N); of 3.80 (t, 2H); was 4.02 (s, 3H); 4.35 the (t,UP>.

The product was received as follows:

A mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3 mmol) (obtained as described for the original product in Example 48), 1-bromo-3-chloropropane (1.6 ml, 16 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (25 ml) was heated at 45oC for 3 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (370 ml). The organic extracts were combined, washed with water and saturated saline solution, dried (MgSO4), and volatile components were removed by evaporation. The residue is triturated with hexane/ethyl acetate, filtered and dried in vacuum, obtaining 4-(4-bromo-2-foronline)-7-(3-chloropropoxy)-6-methoxyquinazoline (492 mg, 34%).

1H NMR spectrum: (DMSO-d6) 2,24 (m, 2H); of 3.80 (t, 2H); of 3.95 (s, 3H); 4.26 deaths (t, 2H); 7,20 (s, 1H); 7,42-of 7.55 (m, 2H); 7,63 (DD, 1H); 7,80 (s, 1H); 8,35 (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 440 [MN]+.

Example 19

A solution of OXONE (trade mark of E. I. du Pont de Nemours&Co., Inc) (390 mg) in water (2 ml) was added to a solution of 4-(chloro-2-foronline)-7-(3-(ethylthio)propoxy)-6-methoxyquinazoline (75 mg, 0.18 mmol) in methanol (10 ml) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was podslushivaet aqueous solution guide is m-saturated salt solution, dried (MgSO4) and the solvent was removed by evaporation. The solid residue was recrystallized from ethyl acetate/hexane, obtaining 4-(chloro-2-foronline)-7-(3-(ethylsulfonyl)propoxy)-6-methoxyquinazoline (35 mg, 43%).

1H NMR spectrum: (DMSO-d6) to 1.24 (t, 3H); 2,22 (m, 2H); 3.15 in (K, 2N); of 3.95 (s, 3H); 4.25 in (t, 2H); 7,20 (s, 1H); to 7.35 (DD, 1H); 7.5 to about 7.6 (m, 2H); 7,80 (s, 1H); 8,35 (s, 1H); 9,54 (s, 1H).

Mass-spectrum-am est: 454 [MN]+.

Elemental analysis:

Found: 51,7, H 4,6, N 9,2%.

C20H21N3O4ClFS0,5H2O.

Required: From 51.9, N 4,8, N 9,1%.

The product was received as follows:

A mixture of (4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (957 mg, 3 mmol) (obtained as described for the original product in Example 2), 1-bromo-3-chloropropane (2,36 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (20 ml) was heated at 40oC for 1.5 hours. The mixture was left to cool, was diluted with water and extracted with ethyl acetate (350 ml). The organic extracts were combined, washed with water and saturated saline solution, dried (MgSO4), and volatile components were removed by evaporation. The residue is triturated with hexane/ethyl acetate, filtered and dried in vacuum, obtaining 4-(4-chloro-2-ftoranila is); of 3.95 (s, 3H); 4.26 deaths (t, 2H); 7,20 (s, 1H); to 7.32 (DD, 1H); of 7.48-of 7.60 (m, 2H); 7,80 (s, 1H); 8,35 (s, 1H); 9,52 (s, 1H).

Mass-spectrum-am est: 396 [MN]+.

A mixture of Acantilado sodium (120 mg, 1.5 mmol) and 4-(4-chloro-2-foronline)-7-(3-chloropropoxy)-6-methoxyquinazoline (227 mg, or 0.57 mmol) in DMF (10 ml) was stirred and heated at 70oC for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (35 ml). The extracts were combined, washed with water (x2), and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallized from ethyl acetate/hexane. Getting 4-(chloro-2-foronline)-7-(3-(ethylthio)propoxy)-6-methoxyquinazoline (86 mg, 40%).

1H NMR spectrum: (DMSO-d6) of 1.20 (t, 3H); 2,03 (m, 2H); to 2.66 (t, 2H); of 3.95 (s, 3H); 4,20 (t, 2H); 7.18 in (s, 1H); 7,33 (DD, 1H); 7.5 to about 7.6 (m, 2H); for 7.78 (s, 1H); 8,35 (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 422 [MN]+.

Example 20

A mixture of (4-(chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (3.28 g, 10 mmol) (obtained as described for the original product in Example 2), 1-bromo-3-tetrahydropyranyloxy (2.5 g, 11 mmol) and potassium carbonate (5.0 g, 36 mmol) in DMF (50 ml) was stirred and heated at 90oC for 3 hours. The reaction mixture gave ohla is 3), and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography, elwira with ethyl acetate. The purified product was recrystallized from ethyl acetate/hexane, obtaining 4-(chloro-2-foronline)-6-methoxy-7-(3-tetrahydropyran-2-roxyroxy)hinzelin (2.25 g, 49%).

So pl. 184-185oC.

1H NMR spectrum: (DMSO-d6) 1,35-and 1.54 (m, 4H); 1,55-1,75 (m, 2H); is 2.05 (m, 2H); 3,35 is-3.45 (m, 1H); 3,66-a-3.84 (m, 2H); of 3.95 (s, 3H); to 4.23 (t, 2H); 4,60 (s, 1H); 7.18 in (s, 1H); to 7.32 (DD, 1H); 7.5 to about 7.6 (m, 2H); for 7.78 (s, 1H); 8,35 (s, 1H); at 9.53 (s, 1H).

Mass spectrum ESI: 462 [MN]+.

Elemental analysis:

Found: 59,6, N 5,3, N 9,1%.

C23H25N3O4ClF.

Required: From 59.9, N. 5,4, N 9.4 Per Cent.

Example 21

A mixture of methanolate sodium (70 mg, 1 mmol) and 4-(4-chloro-2-foronline)-7-(3-chloropropoxy)-6-methoxyquinazoline (200 mg, 0.5 mmol) (obtained as described for the original product in Example 19) in DMF (10 ml) was stirred and heated at 70oC for 1 hour. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate (325 ml). The extracts were combined, washed with water (x2), and then saturated saline solution and dried (MgSO4). The solvent of udale-7-(3-methylthiopropionate)hinzelin (143 mg, 35%).

So pl. 169-170oC.

1H NMR spectrum: (DMSO-d6) 2,0-2,12 (m, 2H); of 2.08 (s, 3H); of 2.64 (t, 2H); 3,93 (s, 3H); is 4.21 (t, 2H); 7.18 in (s, 1H); 7,33 (d, 1H); 7,50-to 7.61 (m, 2H); for 7.78 (s, 1H); 8.34 per (s, 1H); at 9.53 (s, 1H).

Mass spectrum ESI: 408 [MN]+.

Example 22

A mixture of 4-(bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.7 mmol) (obtained as described for the original product in Example 48), 2-chloroethylnitrosourea (0.1 ml, 1 mmol) and potassium carbonate (1.0 g, 7 mmol) in DMF (10 ml) was stirred and heated at 50oC for 4 hours. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate (325 ml). The extracts were combined, washed with water (x2), and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography, elwira with ethyl acetate. The purified product was recrystallized from ethyl acetate/hexane, obtaining 4-(4-bromo-2-foronline)-6-methoxy-7-(2-methylthiouracil)hinzelin (100 mg, 34%).

1H NMR spectrum: (DMSO-d6) of 2.20 (s, 3H); 2,90 (t, 2H); to 3.92 (s, 3H); 4,30 (t, 2H); 7,20 (s, 1H); 7,42-rate of 7.54 (m, 2H); a 7.62 (DD, 1H); 7,80 (s, 1H); at 8.36 (s, 1H); 9,54 (s, 1H).

Mass spectrum ESI: 438 [MN]+.

Elemental analysis:

Found: FROM 48.8, N. 3,9, of 9.8 N, S 7,3% 23

A solution of 7-(2-bromoethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (130 mg, 0.36 mmol) (obtained as described for the original product in Example 62) in 1-toxicirritative (1.5 ml) was stirred and heated at 100oC for 2 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate (325 ml). The extracts were combined, washed with water (x2), and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation, the residue was dissolved in acetone and added a 1M solution of hydrogen chloride in ether (2 ml). The obtained precipitate was filtered, and then purified using column chromatography, elwira methylene chloride/methanol/aqueous ammonia (94/5/1). The purified product was dissolved in acetone and added a 1M solution of hydrogen chloride in ether (2 ml). The precipitate was filtered off, washed with ether, and dried, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-7-(2-(4-etoxycarbonyl-piperazine-1-yl)ethoxy)-6-methoxyquinazoline (85 mg, 46%).

1H NMR spectrum: (DMSO-d6) of 1.20 (t, 3H); 3.1 to 3.6V (m, 8H); 3,66 (ush.s, 2H); 4,00 (s, 3H); 4,08 (K, 2N); 4,65 (ush.s, 2H); 7,40 (m, 2H); of 7.90 (t, 1H); the 7.65 (DD, 1H); to 8.40 (s, 1H); 8,80 (s, 1H); 11,66 (ush.s, 1H).

Mass spectrum ESI: 504 [MN]+.

Elemental analysis:

Found:,8%.

Example 24

A mixture of 4-(bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (306 mg, 0.84 mmol) (obtained as described for the original product in Example 48), 2-chloroethylthiomethyl (0.15 ml, 1.3 mmol) and potassium carbonate (0.5 g, 3.6 mmol) in DMF (10 ml) was stirred and heated at 50oC for 1 hour. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (325 ml). The extracts were combined, washed with water (x2), and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography, elwira with ethyl acetate. The purified product was recrystallized from ethyl acetate/hexane, obtaining 4-(4-bromo-2-foronline)-7-(2-utiltiies)-6-methoxyquinazoline (221 mg, 58%).

1H NMR spectrum: (DMSO-d6) to 1.24 (t, 3H); 2.66 per (K, 2N); to 2.94 (t, 2H); of 3.95 (s, 3H); 4,30 (t, 2H); 7,20 (s, 1H); was 7.45 (t, 1H); 7,52 (d, 1H); the 7.65 (DD, 1H); 7,80 (s, 1H); of 9.55 (s, 1H).

Mass spectrum ESI: 452 [MN]+.

Example 25

A solution of OXONE (trade mark of E. I. du Pont de Nemours&Co., Inc) (150 mg) in water (2 ml) was added to a solution of 4-(4-bromo-2-foronline)-7-(2-utiltiies)-6-methoxyquinazoline (125 mg, 0.28 mmol) (obtained as described in Example 24) in methanol (10 ml). The reaction mixture was stirred during the course is the PR of sodium bicarbonate and was extracted with ethyl acetate (330ml). The extracts were combined, washed with water (x2), and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography, elwira with ethyl acetate, and then methylene chloride/methanol (9/1) to give 4-(4-bromo-2-foronline)-7-(2-(ethylsulfinyl)-6-methoxyquinazoline (32 mg, 31%).

1H NMR spectrum: (DMSO-d6) to 1.21 (t, 3H); 2,72-2,84 (m, 1H); 2,86-2,96 (m, 1H); 3.04 from-of 3.12 (m, 1H); of 3.94 (s, 3H); 4,42-4,56 (m, 2H); 7.26 (s, 1H); 7,42-of 7.55 (m, 2H); to 7.64 (DD, 1H); of 7.82 (s, 1H); 8,35 (s, 1H); of 9.55 (s, 1H).

Mass spectrum ESI: 468 [MN]+.

Example 26

Using a technique similar to Example 25, 4-(4-chloro-2-foronline)-6-methoxy-7-(3-methylthiopropionate)hinzelin (250 mg, 0.6 mmol) (obtained as described in Example 21) was treated with OXONE (trade mark of E. I. du Pont de Nemours& Co. Inc) (84 mg), the product was purified and identified, receiving 4-(4-chloro-2-foronline)-6-methoxy-7-(3-methylsulfinylpropyl)hinzelin (75 mg, 29%).

1H NMR spectrum: (DMSO-d6) to 2.18 (t, 2H); 2,60 (s, 3H); 2,78 are 2.98 (m, 2H); of 3.95 (s, 3H); 4.25 in (t, 2H); 7,20 (s, 1H); to 7.35 (DD, 1H); 7,50-to 7.61 (m, 2H); 7,80 (s, 1H); 8,53 (s, 1H); of 9.55 (s, 1H).

Mass spectrum ESI: 424 [MN]+.

Elemental analysis:

Found: From 53.4, N, 4,5, N 9,8%.

C19H19N5O4ClFS.

1H NMR spectrum: (DMSO-d6) of 1.28 (t, 3H); 3.25 to (K, 2N); 3,74 (t, 2H); 4,00 (s, 3H); of 4.54 (t, 2H); the 7.43 (s, 1H); rate of 7.54 (m, 1H); 7,56 (s, 1H); of 7.75 (d, 1H); at 8.36 (s, 1H); 8,78 (s, 1H); to 11.61 (ush.s, 1H).

Mass spectrum ESI: 484 [MN]+.

Example 28

A solution of OXONE (trade mark of E. I. du Pont de Nemours&Co., Inc) (800 mg) in water (3 ml) was added to a solution of 4-(4-chloro-2-foronline)-7-(2-utiltiies)-6-methoxyquinazoline (220 mg, 0,56 mmol) in methanol (10 ml). The reaction mixture was stirred for 20 hours at room temperature, the methanol was removed by evaporation, aq is Aravali with ethyl acetate (350ml). The extracts were combined, dried (MgSO4) and the solvent was removed by evaporation. The residue was dissolved in acetone/methanol and was added 1M solution of hydrogen chloride in ether (2 ml). Volatile components were removed by evaporation, the residue is triturated with 2-propanol, filtered and dried, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-7-(2-(ethylsulfonyl-ethoxy)-6-methoxyquinazoline (24 mg, 9%).

1H NMR spectrum: (DMSO-d6) to 1.25 (t, 3H); 3,30 (K, 2N); a 3.75 (t, 2H); 4,00 (s, 3H); 4,55 (t, 2H); of 7.36 (s, 1H); 7,41 (DD, 1H); 7,58 (t, 1H); to 7.64 (DD, 1H); by 8.22 (s, 1H); 8,78 (s, 1H).

Mass spectrum ESI: 440 [MN]+.

The product was received as follows:

A mixture of 4-(chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (450 mg, 1.4 mmol) (obtained as described for the original product in Example 2), 2-chloroethyl-ethylsulfate (0.2 ml, 1.7 mmol) and potassium carbonate (1.5 g, 11 mmol) in DMF (10 ml) was heated under stirring at 50oC for 2 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (350 ml). The extracts were combined, washed with 0.1 M sodium hydroxide solution (x2), water and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation, to give crude 4-(4-chloro-2-foronline)-7-(2-ethylthio(chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (400 mg, 1.3 mmol) (obtained as described for the original product in Example 2), 2-chloroethylnitrosourea (has 0.168 ml, 1.7 mmol) and potassium carbonate (347 mg, 2.5 mmol) in NMP (10 ml) was heated under stirring at 90oC for 1 hour, then allowed to cool and was stirred for 16 hours at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined, washed with water and then saturated saline solution and dried (MgSO4). The solvent was removed by evaporation, the residue is triturated with ethyl acetate/hexane and was filtered, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylthiouracil)hinzelin (220 mg, 44%).

So pl. 174-176oC.

1H NMR spectrum: (DMSO-d6) of 2.20 (s, 3H); of 2.92 (t, 2H); of 3.94 (s, 3H); 4,32 (t, 2H); 7,20 (s, 1H); to 7.32 (d, 1H); 7,49 and 7.6 (m, 2H); 7,80 (s, 1H); at 8.36 (s, 1H); of 9.55 (s, 1H).

Mass spectrum ESI: 452 [MN]+.

Example 30

A solution of OXONE (trade mark of E. I. du Pont de Nemours&Co., Inc) (652 mg) in water (1.6 ml) was added to a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylthiouracil)hintline (200 mg, 0.5 mmol) (obtained as described in Example 29) in methanol (10 ml) and the mixture was stirred for 18 hours at room temperature. The mixture was diluted with methylene chloride, washed Irali with ethyl acetate/hexane, was filtered and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylsulfonylmethane)hinzelin (172 mg, 80%).

So pl. 227-230oC.

1H NMR spectrum: (DMSO-d6) 3,18 (s, 3H); 3,70 (t, 2H); to 3.92 (s, 3H); 4,50 (t, 2H); 7,22-7,38 (m, 2H); 7,42 (s, 1H); of 7.48-of 7.60 (m, 2H); of 8.37 (s, 1H); of 9.55 (s, 1H).

Mass spectrum-ESl: 426 [MN]+.

Elemental analysis:

Found: 46,0, N 3,6, N 8.7 Percent.

C18H17N3O4ClFS2,2 H2O.

Required: From 46.4, N 4,1, N 9,0%.

Example 31

To a mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol) (obtained as described for starting compound in Example 48) and tributylphosphine (1,42 ml, 6.1 mmol) in methylene chloride (20 ml) at 5oWith added 1,1'-(azodicarbon)dipiperidino (1.56 g, 6.2 mmol) then 3-(methylthio)-1-propanol (of 0.32 ml, 3 mmol). The mixture was stirred at 5oC for 1 hour, and then 18 hours at room temperature. Insolubles were removed by filtration and volatiles from the filtrate was removed by evaporation. The residue was purified by column chromatography, elwira with ethyl acetate/methanol (100/0 increasing to 95/5) to give 4-(4-bromo-2-foronline)-6-methoxy-7-(3-methylthiopropionate)hinzelin (400 mg, 50%).

Mass spectrum ESI: 452 [MH]+.

Example 32

A solution of OXONE (trade mark of E. I. du Pont de Nemours&Co., Inc) (800 mg) in water (4.5 ml) was added to a solution of 4-(4-bromo-2-foronline)-6-methoxy-7-(3-methylthiopropionate)hintline (300 mg, 0.66 mmol) (obtained as described in Example 31) in methanol (15 ml) and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with methylene chloride, washed with aqueous sodium hydrogen carbonate solution, dried (MgSO4) and the solvent was removed by evaporation. The residue is triturated with ethyl acetate/hexane, filtered and dried, obtaining 4-(4-bromo-2-foronline)-6-methoxy-7-(3-methyl-sulfanilamide)hinzelin (235 mg, 73%).

So pl. >250oC.

1H NMR spectrum: (DMSO-d6) 2,30 (t, 2H); 3,20 (s, 3H); 3,30 (t, 2H); 4,10 (s, 3H); 4,30 (t, 2H); 7,38 (s, 1H); 7.5 to about 7.6 (m, 2H); for 7.78 (d, 1H); 8.30 to (s, 1H); 8,80 (s, 1H).

Mass spectrum ESI: 484 [MH]+.

Elemental analysis:

Found: From 42.8, N 3,8, N Of 7.8%.

C19H19N3O4BrFS0,5 H2O.

Required: 43.1, N. 3,9, N Is 7.9%.

Example 33

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (150 mg, 0.47 mmol) (obtained as described for the original productitem the methylene (6 ml) at 0oWith added portions of 1,1'-(azodicarbon)dipiperidino (355 mg, 1.4 mmol). The mixture was allowed to warm to room temperature and was stirred for 3.5 hours. Added ether (3 ml) and the insolubles were removed by filtration and volatiles from the filtrate was removed by evaporation. The residue was dissolved in acetone and added a 1M solution of hydrogen chloride in ether. The mixture was left for 60 hours, after which the precipitate was filtered, washed with acetone and dried, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-7-(2-cyclopentylacetyl)-6-hintline (130 mg, 60%).

1H NMR spectrum: (DMSO-d6) of 1.4 to 1.8 (m, 8H); of 3.75 (t, 2H); 4,00 (s, 4H); 4,30 (t, 2H); 7,37 (s, 1H); 7,42 (DD, 1H); of 7.60 (t, 1H); to 7.64 (DD, 1H); of 8.25 (s, 1H); 8,78 (s, 1H).

Mass spectrum ESI: 432 [MN]+.

Elemental analysis:

Found: 55,8, N, 5,0, N 8,8%.

C22H23N3O3C1F1H2O1HCl.

Required: 56,0, N 5,2, N 8,9%.

Example 34

To a mixture of triphenylphosphine (of 1.57 g, 6 mmol), 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol) (obtained as described for the original product in Example 2) and N-(tert-butoxycarbonyl)ethanolamine (0,354 g, 2.2 mmol) in methylene chloride (20 ml) at 0oWith added dropwise will diethylazodicarboxylate the mixture was diluted with methylene chloride, washed with an aqueous solution of sodium bicarbonate, water and then saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (100/8/1). The product was recrystallized from acetonitrile, filtered off, washed with ethyl acetate and dried, obtaining 7-(2-[N-tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (235 mg, 25%).

So pl. 190-191oC.

1H NMR spectrum: (DMSO-d6) of 1.36 (s, N); 3.34 (K, 2N); 3,91 (s, 3H); 4,15 (t, 2H); 6,98 (t, 1H); 7,19 (s, 1H); 7,33 (DD, 1H); 7,56 (m, 2H); for 7.78 (s, 1H); 8.34 per (s, 1H); 9,51 (s, 1H).

Mass spectrum ESI: 463 [MN]+.

Elemental analysis:

Found: 57,0, N, 5,1, N 12,5%.

C22H24N4O4ClF.

Required: 57,1, N, 5,1, N 12,1%.

Example 35

Sodium hydride (55 mg, 60% dispersion in mineral oil, 1.1 mmol) was added to a solution of glutarimide (120 mg, 1.06 mmol) in DMF (5 ml) at room temperature in an argon atmosphere and the mixture was stirred for 30 minutes. Added 7-(2-bromoethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (428 mg, 1 mmol) (obtained as described for the original product in Example 62) in DMF ucie components were removed by evaporation and the residue was distributed between water and ethyl acetate. The organic phase was separated, washed with water and then dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography, elwira with ethyl acetate, then ethyl acetate/methanol (9/1). The purified product was recrystallized from ethyl acetate and hexane, was filtered and was washed with ether, receiving 4-(4-chloro-2-foronline)-7-(2-(2,6-dioxopiperidin)-6-methoxyquinazoline (252 mg, 55%).

So pl. 202-203oC.

1H NMR spectrum: (DMSO-d6) of 1.84 (m, 2H); 2.63 in (t, 4H); 3,91 (s, 3H); 4,08 (t, 2H); to 4.17 (t, 2H); 7,10 (s, 1H); 7,34 (DD, 1H); at 7.55 (m, 2H); 7,79 (s, 1H); 8.34 per (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 459 [MN]+.

Elemental analysis:

Found: 57,2, N 4,2, N 11.9 Per Cent.

WITH22H20N4O4lF.

Required: From 57.6, N 4,3, N 12,2%.

Example 36

To a stirred solution of triptoreline 7-(3-aminopropoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (151 mg, 0.4 mmol) and triethylamine (0.2 ml, 1.4 mmol) in THF (15 ml) was added isobutylparaben (88 mg, 5.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the volatile components were removed by evaporation. The residue was dissolved in methylene chloride, the solution was washed with an aqueous solution of hydram. The residue was recrystallized from acetonitrile, receiving 4-(4-chloro-2-foronline)-7-(3-[N-solutionline] propoxy)-6-methoxyquinazoline (41,2 mg, 20%) as a white solid product.

So pl. 136-137oC.

1H NMR spectrum: (DMSO-d6) of 0.87 (d, 6N); of 1.80 (m, 1H); 1.93 and (t, 2H); 3,16 (K, 2N); 3,71 (d, 2H); of 3.94 (s, 3H); 4,15 (t, 2H); 7,16 (s, 2H); to 7.32 (DD, 1H); at 7.55 (m, 2H); 7,79 (s, 1H); 8.34 per (s, 1H); 9,50 (s, 1H).

Mass spectrum ESI: 477 [MN]+.

Elemental analysis:

Found: 57,1, N Is 4.9, N Of 11.6%.

C23H26N4O4ClF.

Required: 57,1, N, 5,5, N Of 11.6%.

The product was received as follows:

A solution of di-tert-BUTYLCARBAMATE (32 g, 143 mmol) in methylene chloride (70 ml) was added dropwise to a stirred solution of 3-amino-1-propanol (10.1 g, 134 mmol) in methylene chloride (100 ml). The reaction mixture was stirred overnight and then washed with a saturated aqueous solution of sodium bicarbonate, water and then saturated saline solution. The organic layer was dried (gS4), and volatile components were removed by evaporation, getting 3-(N-tert-butoxycarbonylamino)-1-propanol (23.3 g, 100%) as a colourless oil.

1H NMR spectrum: (Dl3) to 1.48 (s, N); by 1.68 (m, 2H); 2,90 (ush.with droxy-6-methoxyquinazoline (1.0 g, 3.1 mmol) (obtained as described for starting compound in Example 2) in methylene chloride (25 ml) was added triphenylphosphine (2,46 g, 9.3 mmol) and the suspension was stirred at 0oC for 30 minutes. Was added a solution of 3-(N-tert-butoxycarbonylamino)-1-propanol (0.65 g, 3.7 mmol) in methylene chloride (3 ml) and then dropwise added diethylazodicarboxylate (1,47 ml, 7.6 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction mixture was diluted with methylene chloride and washed with an aqueous solution of sodium bicarbonate, water and then saturated

saline solution. The resulting solution was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol/triethylamine (100/0/0, and then 95/4/1) to give 7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (620 mg, 42%).

1H NMR spectrum: (DMSO-d6) of 1.36 (s, N); 1,89 (t, 2H); 3,11 (K, 2N); 3,91 (s, 3H); to 4.14 (t, 2H); 6.89 in (m, 1H); 7,16 (s, 1H); 7,31 (DD, 1H); 7,56 (m, 2H); to 7.77 (s, 1H); 8,32 (s, 1H); 9,51 (s, 1H).

Mass spectrum ESI: 477 [MN]+.

7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4-chloro-2-foronline)-6-methoxypyrazine 2 hours and the volatile components were removed by evaporation and azeotropic distillation with toluene, getting triptorelin 7-(3-aminopropoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (455 mg, 94%) as oil.

Example 37

A mixture of 7-(2-bromoethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (425 mg, 1 mmol) (obtained as described for the original product in Example 62) and 1-methyl-4-(methylamino)piperidine (128 mg, 1 mmol) in N,N-dimethylacetamide (2 ml) was stirred at 65oC for 3 hours. Volatile components were removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (75/8/1). The purified product triturated with ether, filtered off, washed with ether, and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(2-([N-methyl-N-(1-methylpiperidin-4-yl] amino)ethoxy)hinzelin (180 mg, 38%) as a pale yellow powder.

So pl. 191-192oC.

1H NMR spectrum: (DMSO-d6) of 1.44 (m, 2H); to 1.70 (m, 2H); to 1.86 (m, 2H); of 2.15 (s, 3H); 2,30 (s, 3H); 2,78 (m, 2H); is 2.88 (t, 2H); of 3.94 (s, 3H); 4,18 (t, 2H); 7,19 (s, 1H); 7,33 (m, 1H); 7,52 (m, 1H); 7,58 (t, 1H); for 7.78 (s, 1H); a 8.34 (s, 1H); 9,48 (s, 1H).

Mass spectrum ESI: 474 [MN]+.

Elemental analysis:

Found: 60,9, H 6,3, N 14,7%.

C24H29N5O2ClF.

Required: 60,8, N. 6,2, N 14.8 Per Cent.

Example 38

To the mixture oduct in Example 2), tetrahydro-3-furanmethanol (90 mg, 0.88 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (12 ml) portions was added 1,1'-(azodicarbon)dipiperidino (560 mg, 2.2 mmol) and the reaction mixture was stirred for 18 hours. The mixture was diluted with ether and the precipitate was removed by filtration. The solvent of the filtrate was removed by evaporation, the residue was dissolved in acetone and the solution was added hydrogen chloride in ether (0.75 ml of 1 M solution, 0.75 mmol). The mixture was diluted with ether and the precipitate was collected by filtration. The solid was purified by column chromatography, elwira methylene chloride/acetonitrile/methanol (gradient from 50/50/1 to 50/50/2). The purified product triturated with ether, filtered and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(tetrahydrofuran-3-ylethoxy) hinzelin (93 mg, 31%).

So pl. 201-202oC.

1H NMR spectrum: (DMSO-d6) to 1.70 (m, 1H); is 2.05 (m, 1H); 2,72 (m, 1H); of 3.56 (m, 1H); 3,66 (K, 1H); with 3.79 (m, 2H); of 3.94 (s, 3H); 4,08 (m, 2H); 7,20 (s, 1H); 7,32 (m, 1H); 7,52 (DD, 1H); 7,58 (t, 1H); for 7.78 (t, 1H); 8,35 (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 404 [MN]+.

Elemental analysis:

Found: 59,2, N, 4,6, N 10,6.

WITH20H19H3ABOUT3lF.

Required: 59,5, N is received, as described for the original product in Example 2), tributylphosphine (4.4 g, 22 mmol) and 1-(2-hydroxyethyl)-2-pyrrolidinone (1.1 g, 8.5 mmol) in methylene chloride (105 ml) portions was added 1,1'-(azodicarbon)dipiperidino (5.6 g, 22 mmol). The mixture was stirred for 18 hours, diluted with ether (100 ml) and the precipitate was removed by filtration. Volatile components of the filtrate was removed by evaporation and the residue was dissolved in acetone and the solution was added hydrogen chloride in ether (15 ml of 1 M solution, 15 mmol). The solid was filtered and was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was dissolved in acetone and the solution was added hydrogen chloride in ether (15 ml of 1M solution, 15 mmol). The precipitate was filtered off, washed with ether, and dried, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)hintline (2.1 g, 60%).

So pl. 250-252oC.

1H NMR spectrum: (DMSO-d6) of 1.92 (m, 2H); 2,22 (t, 2H); to 3.52 (t, 2H); 3,68 (t, 2H); was 4.02 (s, 3H); 4,30 (t, 2H); 7,38 (s, 1H); 7,42 (m, 1H); 7,58 (t, 1H); 7,66 (DD, 1H); 8,35 (s, 1H); 8,79 (s, 1H); of 11.69 (ush.s, 1H)

Mass spectrum ESI: 431 [MN]+.

Elemental analysis:

Found: From 53.5, N, 4,4, N 12,2%.


To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol) (obtained as described for the initial substance in Example 2), tributylphosphine (420 g, 2.1 mmol) and 1-(2-hydroxyethyl)-2-imidazolidinone (100 mg, 7.7 mmol) in methylene chloride (10 ml) portions was added 1,1'-(azodicarbon)dipiperidino (525 mg, 2.1 mmol). The mixture was stirred for 18 hours, diluted with ether and the precipitate was removed by filtration. Volatile components of the filtrate was removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product triturated with ether, filtered off, washed with ether, and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-Oxymetazoline-1-yl)ethoxy)hinzelin (19 mg, 6%).

So pl. > 250oC.

1H NMR spectrum: (DMSO-d6) with 3.27 (t, 2H); of 3.53 (m, 4H); of 3.97 (s, 3H); 4,27 (t, 2H); to 6.39 (s, 1H); 7,26 (s, 1H); 7,35 (m, 1H); EUR 7.57 (DD, 1H); to 7.61 (t, 1H); of 7.82 (s, 1H); scored 8.38 (s, 1H); of 9.55 (c, 1H).

Mass spectrum ESI: 432 [MN]+.

Elemental analysis:

Found: 53,7, N, 4,4, N 15.4 Per Cent.

C20H19N5O3ClF1H2O.

Required: From 53.4, N. 4,7, N 15.6 Per Cent.

Example 41

To a mixture of 4-(4-chloro-2-foronline)-7-hydroc is spina (420 g, 2.1 mmol) and 4-(2-hydroxyethyl)-1,1-dioxothiazolidine (140 mg, 7.8 mmol) in methylene chloride (10 ml) portions was added 1,1'-(azodicarbon)dipiperidino (525 mg, 2.1 mmol). The mixture was stirred for 18 hours, diluted with ether and the precipitate was removed by filtration. Volatile components of the filtrate was removed by evaporation and the residue was dissolved in acetone, was added a solution of hydrogen chloride in ether (14 ml of 1M solution, 14 mmol) and the precipitate was collected by filtration. The residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product triturated with ether/methylene chloride, was filtered and dried, obtaining 4-(4-chloro-2-foronline)-7-(2-(1,1-dioxothiazolidine)ethoxy)-6-methoxyquinazoline (120 mg, 36%).

So pl. 246-249oC.

1H NMR spectrum: (DMSO-d6) 3,03 (t, 2H); 3,10 (ush.s, 8H); of 3.95 (s, 3H); 4,27 (t, 2H); from 7.24 (s, 1H); 7,38 (m, 1H); 7,53 (DD, 1H); 7,58 (t, 1H); 7,80 (s, 1H); 8,35 (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 481 [MN]+.

Elemental analysis:

Found: 52,0, N, 4,6, N 11,9, 's 6.6 Percent.

C21H22N4O4ClFS.

Required: 52,4, H 4,6, N 11,6, S Of 6.7%.

Example 42

Hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (94 mg, Polina (0.11 g, of 1.26 mmol) and 4-dimethylaminopyridine (200 mg, of 1.64 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 24 hours and the volatile components were removed by evaporation. To the residue was added water and the aqueous mixture was extracted with methylene chloride (330 ml). The extracts were combined and the solvent was removed by evaporation. The residue is triturated with ether and the precipitate was filtered. The solid was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was washed with acetone, filtered and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(3-morpholinosydnonimine)hinzelin (88 mg, 46%)

So pl. 216-217oC.

1H NMR spectrum: (DMSO-d6) 2,02 (m, 2H); 2,5 (m, 2H); to 3.45 (m, 4H); 3,55 (m, 4H); to 3.92 (s, 3H); 4,15 (t, 2H); 7.18 in (s, 1H); to 7.32 (d, 1H); at 7.55 (m, 2H); for 7.78 (s, 1H); 8.34 per (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 475 [MN]+.

Elemental analysis:

Found: 58,2, N 5,2, N 12,2%.

C23H24N4O4ClF.

Required: 58,2, N, 5,1, N 11,8%.

The original compound was prepared as follows:

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319,5 mg, 1 mmol) (obtained as described for the original product mmol). The mixture was stirred and heated at 105oC for 4 hours, then left to cool. The mixture was diluted with methylene chloride and the insoluble impurities were removed by filtration. The solvent of the filtrate was removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product triturated with ether, filtered and dried, obtaining 4-(4-chloro-2-foronline)-7-(3-ethoxycarbonylmethoxy)-6-methoxyquinazoline (230 mg, 53%).

1H NMR spectrum: (DMSO-d6) of 1.18 (t, 3H); 2,02 (m, 2H); 2,48 (m, 2H); of 3.94 (s, 3H); 4,06 (K, 2N); 4,15 (t, 2H); 7.18 in (s, 1H); 7,32 (m, 1H); rate of 7.54 (m, 2H); FOR 7.78 (S, 1H); 8.34 per (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 434 [MN]+.

Elemental analysis:

Found: 58,0, N 4,8, N 9,8%.

C21H21N3O4ClF.

Required: 58,1, N Is 4.9, N 9.7 Per Cent.

A mixture of 4-(4-chloro-2-foronline)-7-(3-ethoxycarbonylmethoxy)-6-methoxyquinazoline (220 mg, 0.5 mmol) in aqueous sodium hydroxide solution (4 ml, 2M solution, 8 mmol), water (2 ml) and methanol (0.5 ml) was stirred and heated at 40oC for 3 hours. The mixture was left to cool, and then was acidified using 2M hydrochloric acid. The obtained white precipitate was filtered and washed Example 43

Hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (145 mg, 0.75 mmol) was added to a mixture of 7-(3-carboxypropyl)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (250 mg, of 0.62 mmol) (obtained as described for the original product in Example 42), 1-methylpiperazine (of 0.21 ml, 2.32 mmol) and 4-dimethylaminopyridine (300 mg, 2,46 mol) in DMF (7.5 ml). The reaction mixture was stirred at room temperature for 24 hours and the volatile components were removed by evaporation. To the residue was added water and the aqueous mixture was extracted with methylene chloride (330 ml). The combined organic extracts were washed with saturated brine and the solvent was removed by evaporation. The residue is triturated with ether and the precipitate was filtered. The solid was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product triturated with ether, filtered and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)-propoxy)hinzelin (133 mg, 44%).

So pl. 248-250oC.

1H NMR spectrum: (DMSO-d6) 2,00 (t, 2H); of 2.15 (s, 3H); to 2.25 (m, 4H); of 2.45 (m, 2H); to 3.45 (m, 4H); to 3.92 (s, 3H); 4,15 (t, 2H); 7.18 in (s, 1H); 7,30 (d, 1H); at 7.55 (m, 2H); for 7.78 (s, 1H); 8.34 per (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 488 [MN]UB>3lF0,2H2O.

Required: 58,6, N, 5,6, N 14,3%.

Example 44

To a suspension of 7-(3-carboxypropyl)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (260 mg, 0.64 mmol) (obtained as described for the original product in Example 42) in methylene chloride (25 ml) was added oxalicacid (0.4 ml, 2.2 mmol), and then 1 drop of DMF. The mixture was stirred at room temperature for 2.5 hours and the volatile components were removed by evaporation. The solid residue was added a solution of pyrrolidine made (0.13 ml, 2.1 mmol) in N,N-dimethylacetamide (8 ml) and the mixture was stirred at room temperature for 2 hours. Volatile components were removed by evaporation and the residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was washed with acetone, collected by filtration and dried, obtaining 4-(4-chloro-2-foronline)-6-methoxy-7-(3-pyrrolidin-1 incorporporated)hinzelin (206 mg, 70%).

So pl. 254-256oC.

1H NMR spectrum: (DMSO-d6) to 1.76 (m, 2H); of 1.85 (m, 2H); 2,02 (m, 2H); to 2.41 (t, 2H); 3,26 (t, 2H); to 3.38 (t, 2H); of 3.95 (s, 3H); 4,15 (t, 2H); 7.18 in (s, 1H); to 7.32 (d, 1H); at 7.55 (m, 2H); for 7.78 (s, 1H); 8.34 per (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 459 [MN]+.

Elemental analysis:

Found: 5P> Example 45

A mixture of 4-(4-chloro-2-foronline)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline (210 mg, 0.52 mmol), water (5 ml) and TFOC (5 ml) was stirred at room temperature for 3 hours and then was heated at 60oC for 1 hour. The solution was allowed to cool, then diluted with water and the resulting precipitate was filtered and dried. The solid was dissolved in methanol (10 ml) and cyclopentylamine (0,057 ml, or 0.57 mmol) was added to the dried molecular sieves . The mixture was stirred for 30 minutes, was added glacial acetic acid (0,20 ml, 3.2 mmol) and cyanoborohydride sodium (150 mg, 2.4 mmol) and the reaction mixture was stirred for 4 hours and then left for 18 hours. Insolubles were removed by filtration and the solvent from the filtrate was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product triturated with ether/hexane, filtered and dried, obtaining 4-(4-chloro-2-foronline)-7-(2-cyclopentyloxy)-6-methoxyquinazoline (80 mg, 36%).

So pl. 171-173oC.

1H NMR spectrum: (DMSO-d6) of 1.55 (m, 8H); to 2.94 (t, 2H); is 3.08 (m, 1H); of 3.94 (s, 3H); 4,19 (t, 2H); 7,19 (s, 1H); 7,33 (m, 1H); 7,52 (DD, 1H); to 7.59 (t, 1H); for 7.78 (s, 1H); 8.34 per (s, 1 is ω:

Dimethylacetal of bromoacetaldehyde (0,74 ml, 3.1 mmol) was added to a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (1.0 g, 3,13 mmol) (obtained as described for the original product in Example 2) and anhydrous potassium carbonate (2.16 g, 15.6 mmol) in DMF (30 ml). The mixture was stirred and heated at 110oC for 4 hours, then left to cool and the volatiles were removed by evaporation. To the residue was added water and the aqueous mixture was extracted with methylene chloride (x4). The extracts were combined, washed with saturated saline and was dried by filtration through footclaws paper. Volatile components were removed by evaporation, the residue is triturated with ether, collected by filtration and dried, obtaining 4-(4-chloro-2-foronline)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline (440 mg, 35%).

1H NMR spectrum: (DMSO-d6) to 3.36 (s, 6N); of 3.94 (s, 3H); of 4.05 (d, 2H); 4.75 V (t, 1H); 7,22 (s, 1H); 7,32 (m, 1H); 7,52 (m, 1H); 7,58 (t, 1H); 7,80 (t, 1H); 8,35 (s, 1H); 9,52 (s, 1H).

Mass spectrum ESI: 408 [MN]+.

Example 46

Diethylazodicarboxylate (1,55 ml of 9.89 mmol), 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3 mmol) (obtained as described for starting compound in Example 48) and a solution of (E)-4-(pyrrolidin-1-yl)but-2-EN-1-ol (697 mg, 4,9 IMO is consequently to a solution of triphenylphosphine (2,59 g, of 9.89 mmol) in methylene chloride (150 ml), cooled to 5oC. the Mixture was stirred at room temperature for 10 minutes, then was added methylene chloride (100 ml), then successively triphenylphosphine (432 mg, 1.6 mmol), (E)-4-pyrrolidin-1-yl)but-2-EN-1-ol (232 mg, 1.6 mmol) and diethylazodicarboxylate (246 μl, 1.6 mmol). The mixture was stirred at room temperature for 30 minutes and then the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol (8/2, then 7/3 and 6/4). Paleoceanic product was re-purified column chromatography, elwira methylene chloride/methanol (8/2, then 7,5/2,5). The purified product was dissolved in methylene chloride, was added 3.7 M solution of hydrogen chloride in ether (3 ml) and the volatile components were removed by evaporation. The residue is triturated with ether, filtered and dried in vacuum, obtaining hydrochloride (E)-4-(4-bromo-2-foronline)-6-methoxy-7-(4-pyrrolidin-1-albut-2-EN-1-yloxy)hintline (600 mg, 32%).

1H NMR spectrum: (DMSO-d6, CF3COOD) as 1.8-1.9 (m, 2H); 2,0-2,1 (m, 2H); 3,0-3,1 (m, 2H); 3,45-3,55 (m, 2H); 3,88 (d, 2H); 4,01 (s, 3H) and 4.9 (d, 2H); 6,0 (TD, 1H); 6,3 (TD, 1H); 7,41 (s, 1H); 7.5 to the 7.65 (m, 2H); of 7.82 (d, 1H); 8,13 (s, 1H); 8,88 (s, 1H).

Mass spectrum(EI): 487 [MN]BrF0,5H2O2HCl.

Required: From 48.5, N 4,8, N 9,8%.

Example 47

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol) (obtained as described for the original product in Example 2), triphenylphosphine (393 mg, 1.5 mmol) and 1-(3-hydroxypropyl)-2-pyrrolidone (107 mg, 0.75 mmol) in methylene chloride (5 ml) under nitrogen atmosphere was bury diethylazodicarboxylate (261 mg, 1.5 mmol). The mixture was stirred at room temperature for 20 minutes, and then purified, pouring directly into the column with silica, elwira methylene chloride/ethyl acetate/methanol (60/35/5, then 60/30/10). The purified product was washed with ether and was filtered. The solid was dissolved in ethyl acetate and treated 3M hydrogen chloride in ethyl acetate (0.4 ml). The precipitate was filtered, washed with ethyl acetate and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)hintline (170 mg, 70%).

1H NMR spectrum: (DMSO-d6, CF3COOD) 1,9-2,0 (m, 2H); 2,0-2,1 (m, 2H); of 2.21 (t, 2H); 3,4-3,5 (m, 4H); was 4.02 (s, 3H); 4,20 (s, 3H); 4,20 (t, 2H); to 7.32 (s, 1H); 7,46 (DD, 1H); 7,63 (t, 1H); 7,71 (DD, 1H); 8,17 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 445 [MN]+.

Elemental analysis:

Found the 4,9, N of 11.6%.

The product was received as follows:

Solution-butyrolactone (8.6 g, 0.1 mol) and 3-amino-1-propanol (9 g, 0.12 mol) was heated at the boil under reflux for 18 hours. The crude reaction mixture was distilled under reduced pressure, obtaining 1-(3-hydroxypropyl)-2-pyrrolidone (2.5 g, 17%).

so Kip.~ 130oWith ~ 0.05 mm RT.article.

1H NMR spectrum: (Dl3) a 1.7-1.8 (m, 3H); 2.0 to to 2.15 (m, 2H); 2,44 (t, 2H); 3,4-3,5 (m, 4H); of 3.54 (t, 2H).

Mass spectrum(EI): 143 [MN]+.

Example 48

Using a technique similar to Example 47, 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (146 mg) in methylene chloride (5 ml) was treated with 1-(3-hydroxypropyl)-2-pyrrolidone (86 mg, 0.6 mmol), triphenylphosphine (314 mg, 1.2 mmol) and diethylazodicarboxylate (209 mg, 1.2 mmol), was purified and isolated by obtaining the hydrochloride of 4-(4-bromo-2-foronline)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)hintline (140 mg, 67%).

1H NMR spectrum: (DMSO-d6, CF3COOD) 1,9-2,0 (m, 2H); 2,0-2,1 (m, 2H); of 2.21 (t, 2H); 3,4-3,5 (m, 4H); was 4.02 (s, 3H); 4,20 (t, 2H); to 7.32 (s, 1H); 7.5 to the 7.65 (m, 2H); of 7.82 (d, 1H); 8,15 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 490 [MH]+.

Elemental analysis:

Found: From 49.9, N, 4,4, N 10,5%.

C22H was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (8,35 g, 27.8 mmol) (obtained as described for the original product in Example 1) and 4-bromo-2-foronline (5,65 g, 29.7 mmol) in 2-propanol (200 ml) was heated at the boil under reflux for 4 hours. The precipitate was filtered off, washed with 2-propanol and then with ether, and dried in vacuum, obtaining the hydrochloride of 7-benzyloxy-4-(4-bromo-2-foronline)-6-methoxyquinazoline (9,46 g, 78%).

1H NMR spectrum: (DMSO-d6, CF3COOD) 4,0 (s, 3H); lower than the 5.37 (s, 2H); of 7.35-7.5 (m, 4H); 7,52 to 7.62 (m, 4H); 7,8 (d, 1H); 8,14 (9s, 1H); 8,79 (s, 1H).

Mass spectrum ESI: 456 [MN]+.

Elemental analysis:

Found: 54,0, N. 3,7, N 8.7 Percent.

WITH22H17N3O2rF0,9l.

Required: 54,2, N. 3,7, N 8,6%.

A solution of the hydrochloride of 7-benzyloxy-4-(4-bromo-2-foronline)-6-methoxyquinazoline (9.4 g, 19,1 mmol) in TFOC (90 ml) was heated at the boil under reflux for 50 minutes. The mixture was allowed to cool and poured into ice. The precipitate was collected by filtration and dissolved in methanol (70 ml). The solution was brought to pH 9-10 with concentrated aqueous ammonia solution. The mixture was concentrated, pariva to half the original volume. The precipitate from oxygenation (5,66 g, 82%).

1H NMR spectrum: (DMSO-d6, CF3COOD) of 3.95 (s, 3H); to 7.09 (s, 1H); of 7.48 (s, 1H); rate of 7.54 (t, 1H); to 7.64 (d, 1H); 7,79 (s, 1H); 8,31 (s, 1H).

Mass spectrum ESI: 366 [MN]+.

Elemental analysis:

Found: 49,5, N 3,1, N 11.3 Per Cent.

C15H11N3O2BrF.

Required: 49,5, N, 3,0, N 11,5%.

Example 49

To a mixture of 4-(4-bromo-2-foronline)-6-methoxy-7-(3-methylaminopropane)hintline (109 mg, 0.25 mmol) and triethylamine (30 mg, 0.3 mmol) in methylene chloride (3 ml), cooled to 0oWith, bury methanesulfonanilide (32 mg, 0,275 mmol). The solution was stirred for 2 hours at 0oWith and volatile components were removed by evaporation. The residue was distributed between ethyl acetate and water, the organic layer was separated, washed with saturated salt solution, dried (gS4) and the solvent was removed by evaporation. The solid is triturated with ether and was filtered. The solid was dissolved in methylene chloride containing methanol (0.5 ml), and added 3M hydrogen chloride in ethyl acetate (0.3 ml). The suspension was diluted with ethyl acetate and concentrated by evaporation. The final solid product was filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-bromo-2-ftoranila the CO-d6, CF3COOD) 2,1-2,2 (m, 2H); 2.82 from (s, 3H); 2,89 (s, 3H); 3,29 (t, 2H); was 4.02 (s, 3H); 4,27 (t, 2H); to 7.35 (s, 1H); 7,55-the 7.65 (m, 2H); 7,79 (d, 1H); to 8.12 (s, 1H); 8,88 (s, 1H).

Mass spectrum(EI): 512 [MN]+.

Elemental analysis:

Found: From 43.5, N 4,2, N 10,0%.

C20H22N4O4BrFS0,6N2O0,75l.

Required: From 43.5, N, 4,4, N 10,2%.

The product was received as follows:

To a suspension of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (364 mg, 1 mmol) (obtained as described for the original product in Example 48), triphenylphosphine (786 kg, 3 mmol) and 3-methylamino-1-propanol (178 mg, 2 mmol) (J. Am. Chem. Soc., 1954, 76, 2789) in methylene chloride (4 ml) under nitrogen atmosphere was added dropwise diethylazodicarboxylate (522 mg, 3 mmol). The mixture was stirred for 1 hour at room temperature, the reaction mixture was added neutral alumina (~20 g) and the solvent was removed by evaporation. The powder is poured into a column of neutral aluminum oxide and suirable a mixture of methylene chloride/methanol (95/5, then 90/10 and 80/20). The purified product triturated with ether, filtered, washed with ether and dried in vacuum, obtaining 4-(4-bromo-2-foronline)-6-methoxy-7-(3-methylaminopropane)hinzelin (220 mg, 50%).

is described for starting compound in Example 48), triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml) under nitrogen atmosphere was bury solution diethylazodicarboxylate (209 mg, 1.2 mmol) in methylene chloride (1 ml), and then (S)-1-(3-hydroxypropyl)-pyrrolidin-2-carboxamide (97 mg, 0,56 mmol). The mixture was stirred for 1 hour at room temperature and then was further added triphenylphosphine (109 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidin-2-carboxamide (34 mg, 0,56 mmol). After that, the mixture was stirred for 2 hours at room temperature and was purified reaction mixture, pouring directly on a column with silica and elwira methylene chloride/ethyl acetate/methanol (60/35/5). The purified product triturated with ether, filtered, washed with ether and dried in vacuum. The solid was dissolved in methylene chloride and was added 3M hydrogen chloride in ethyl acetate (0.4 ml). The obtained precipitate was filtered, washed with ethyl acetate and dried in vacuum, obtaining hydrochloride (S)-4-(4-bromo-2-foronline)-7-(3-(2-carbamoylation-1-yl)propoxy)-6-methoxyquinazoline (110 mg, 47%).

1H NMR spectrum: (DMSO-d6; CF3D; 60oC) 1,9-2,0 (m, 2H); 2,0-2,1 (m, 2H); 2,15 was 2.25 (m, 2H); 3,2-3,3 (m, 1H); 3,3-3,5 (m, 2H); of 3.7-3.8 (m, 1H); was 4.02 (s, 3H); 4,15-4,2 (m, 1H); from 4.3 to 4.4 (m, 2H); to 7.4 (s, 1H); 7.5 to about 7.6 (m, 2H); of 7.75 (d, 1H) H 4,9, N of 11.2%.

C23H25N5O3BrF0,8H2O1,9l.

Required: 45,9, N 4,8, N Of 11.6%.

The product was received as follows:

3-bromo-1-propanol (584 mg, 4.2 mmol) was added to a mixture of (S)-pyrrolidin-2-carboxamide (399 mg, 3.5 mmol) and potassium carbonate (966 mg, 7 mmol) in acetonitrile (10 ml). The mixture was heated at the boil under reflux for 5 hours and the reaction mixture was stirred for 18 hours at room temperature. Insoluble products were removed by filtration and the solvent from the filtrate was removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/methanol (9/1, then 8/2) to give (S)-1-(3-hydroxypropyl)-pyrrolidin-2-carboxamid (365 mg, 60%).

Mass spectrum(EI): 173 [MN]+.

Example 51

To a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylaminorex)hintline (113 mg, 0.3 mmol) (obtained as described for starting compound in Example 60) and triethylamine (33 mg, 0.33 mmol) in methylene chloride (3 ml) were added methoxyacetanilide (34 mg, 0.31 mmol). The mixture was stirred for 18 hours at room temperature, and then was distributed between ethyl acetate and saturated ) was purified by chromatography on silica, elwira methylene chloride/acetonitrile/methanol (6/3/1). The purified solid product was washed with methylene chloride and ether, was filtered, washed with ether and dried in vacuum. The solid product was dissolved in a mixture of methylene chloride/methanol (1/1) was added 2M hydrogen chloride in ethyl acetate (0.5 ml). The mixture was diluted with ether and the resulting precipitate was filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-([N-methyl-N-methoxyacetyl]amino)ethoxy)hintline (62 mg, 42%).

1H NMR spectrum: (DMSO-d6; CF3COOD; 80oC) 2,9-3,2 (ush.s, 3H); at 3.35 (s, 3H); 3,8-3,9 (ush.s, 2H); of 4.05 (s, 3H); 4,0-4,3 (m, 2H); 4,4 (t, 2H); to 7.4 (s, 1H); was 7.45 (d, 1H); of 7.6 to 7.7 (m, 2H); 8,1 (s, 1H); of 8.8 (s, 1H).

Mass spectrum(ESI): 449 [MN]+.

Elemental analysis:

Found: From 48.8, N, 4,6, N 10,7%.

C21H22N4O4ClF0,N2O1,35l.

Required: 49,0, N Is 4.9, N 10,9%.

Example 52

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol) (obtained as described for the original product in Example 2), triphenylphosphine (615 mg, 2.3 mmol) and 4-(2-hydroxyethyl)-3-research (170 mg, 1,17 mmol) (EP 580402 A2) in methylene chloride (5 ml) under nitrogen atmosphere was bury deli methylene chloride (5 ml) and continued stirring for 18 hours at room temperature. Was added THF (5 ml), 4-(2-hydroxyethyl)-3-morpholine (113 mg, 0.78 mmol), triphenylphosphine (204 mg, 0.78 mmol), and then bury diethylazodicarboxylate (136 mg, 0.78 mmol). The mixture was stirred 5 minutes at room temperature and was purified, pouring directly on a column with silica, elwira methylene chloride/ethyl acetate/methanol (5/4/1). The purified solid product was dissolved in methylene chloride and was added 2M solution of hydrogen chloride in methanol (0.5 ml). The mixture was concentrated by evaporation and then diluted with ether. The precipitate was filtered off, washed with ether, and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-oxaprotiline)ethoxy)hintline (150 mg, 39%).

1H NMR spectrum: (DMSO-d6; CF3COOD) to 3.6 (t, 2H); 3,8-3,9 (m, 4H); of 4.05 (s, 3H); to 4.1 (s, 3H); 4,4 (t, 2H); and 7.3 (s, 1H); was 7.45 (d, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); 8,1 (s, 1H); 8,9 (c, 1H).

Mass spectrum ESI: 469 [MN]+.

Elemental analysis:

Found: From 51.6, N, 4,4, N 11,8%.

C21H20N4O4ClF0,35H2O0,95l.

Required: 51,7, N, 4,5, N 11,5%.

Example 53

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol) (obtained as described for the original product in Use is tmosphere nitrogen was bury diethylazodicarboxylate (209 mg, 1.2 mmol). The mixture was stirred for 1 hour at room temperature, was added triphenylphosphine (105 mg, 0.4 mmol), 2-(2-morpholinoethoxy)ethanol (49 mg, 0.28 mmol) and diethylazodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 1 hour at room temperature and was purified, pouring directly on a column with silica, elwira methylene chloride/acetonitrile/methanol (6/3/1). The purified product was washed with ether, was filtered and dissolved in methylene chloride. Added 2M ethereal hydrogen chloride (0.5 ml) and the precipitate was filtered off, washed with ether, and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)hintline (100 mg, 45%).

1H NMR spectrum: (DMSO-d6; CF3D)) 3,1-3,2 (m, 2H); 3,3-3,5 (m, 5H); of 3.7-3.8 (m, 2H); 3,9-4,0 (m, 5H); was 4.02 (s, 3H); 4,4 (ush.s, 2H); 7,46 (s, 1H); of 7.48 (d, 1H); to 7.6 (t, 1H); 7.7 (d, 1H); of 8.25 (s, 1H); 8,89 (s, 1H).

Mass spectrum ESI: 477 [MH]+.

Elemental analysis:

Found: From 48.8, N, 5,6, N, 9,9.

C23H26N4O4ClF1H2O1,95HCl.

Required: From 48.8, N 5,3, N 9,9%.

The original compound was prepared as follows:

To a mixture of the research (2.58 g, 30 mmol) and potassium carbonate (5.5 g, 40 mmol) in ACET what linecom and then was stirred for 18 hours at room temperature. Insoluble products were removed by filtration and volatiles from the filtrate was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol (95/5, then 90/10 then 80/20) to give 2-(2-morpholinoethoxy)ethanol (600 mg, 34%).

1H NMR spectrum (CDCl3) 2,5 (ush.c, 4H); at 2.59 (t, 2H); 3,6-of 3.85 (m, 10H).

Mass spectrum(EI): 175 [M]+.

Example 54

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol) (obtained as described for the original product in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0,56 mmol) (obtained as described for starting compound in Example 50) in methylene chloride (4 ml) was bury diethylazodicarboxylate (209 mg, 1.2 mmol). The mixture was stirred for 2 hours at room temperature and in addition was added triphenylphosphine (105 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidin-2-carboxamide (49 mg, 0.28 mmol) followed by precapitalism of diethylazodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 1 hour at room temperature and was purified, pouring directly on a column with silica and elwira methylene chloride/ACET is dried in vacuum. The solid product was dissolved in methylene chloride and was added 2M solution of hydrogen chloride in diethyl ether (0.5 ml). The mixture was diluted with ether and the resulting precipitate was filtered, washed with ether and dried in vacuum, obtaining hydrochloride (S)-7-(3-(2-carbamoylation-1-yl)propoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (70 mg, 32%).

1H NMR spectrum: (DMSO-d6; CF3COOD) of 1.8-2.0 (m, 2H); 2,05-of 2.15 (m, 2H); about 2.2-2.3 (m, 2H); about 3.1 to 3.5 (m, 2H); of 3.7-3.8 (m, 1H); was 4.02 (s, 3H); 4,05-4,2 (m, 2H); 4,3 (m, 2H);? 7.04 baby mortality (s, 1H); was 7.45 (d, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); by 8.22 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 474 [MN]+.

Elemental analysis:

Found: 49,4, N 12,4, N 5.3%.

WITH23H25N5O3lF1,5H2O1 55l.

Required: 49,5, N 12,6, N 5.3%.

Example 55

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol) (obtained as described for the original product in Example 2), CIS-3-(2,6-dimethylmorpholine)-1-propanol (97 mg, 0,56 mmol) and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml) under nitrogen atmosphere was bury diethylazodicarboxylate (209 mg, 1.2 mmol). The mixture was stirred 1 hour at room temperature and the solvent was removed by evaporation. The residue was purified using column chromium is Lena and added 2M hydrogen chloride in ether. The solution was diluted with ether and left to interact. The precipitate was filtered off, washed with ether, and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-7-(3-(2,6-dimethyl-morpholino)propoxy)-6-methoxyquinazoline (130 mg, 59%).

1H NMR spectrum: (DMSO-d6; CF3COOD) of 1.17 (d, 6N); 2.3 to 2.4 (m, 2H); and 2.7 (t, 2H); of 3.25 to 3.35 (m, 2H); 3,55 (d, 2H); 3,9-4,0 (m, 2H); is 4.03 (s, 3H); of 4.35 (t, 2H); the 7.43 (s, 1H); was 7.45 (d, 1H); 7,63 (t, 1H); of 7.70 (d, 1H); of 8.25 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 475 [MN]+.

Elemental analysis:

Found: 51,7, N, 6,0, N 9.7 Per Cent.

C24H28N4O3ClF0,6N2O1,95l.

Required: From 51.8, N, 5,6, N, 10,0%.

The product was received as follows:

To a solution of 2,6-dimethylmorpholine (1,15 g, 10 mmol) (supplied by Aldrich Chemical Company Limited in the form of a mixture of isomers) in acetonitrile (15 ml) was added 3-chloro-1-propanol (1.04 g, 11 mmol), and then potassium carbonate (2,07 g, 15 mmol). The mixture was boiled under reflux during the night and left to cool, insoluble products were removed by filtration and volatiles from the filtrate was removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/acetonitrile/methanol/SUB>) to 1.16 (d, 6N); a 1.7-1.8 (m, 4H); 2,61 (t, 2H); 2.91 in (d, 2H); 3,6-3,7 (m, 2H); 3,81 (t, 2H)

Mass spectrum ESI: 173 [MN]+< / BR>
Example 56

Through a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(tripterocalyx)hintline (180 mg, 0.4 mmol) in absolute THF (2 ml) and benzene (2 ml) was barbotirovany oxygen and the reaction mixture is placed in a nitrogen atmosphere. Added tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), and then the solution triisopropylsilyl sodium (102 mg, 0.48 mmol) (Tetrahedron Lett., 1994, 35, 3221) in THF (2 ml) and the mixture is boiled under reflux for 2 hours. The mixture was allowed to cool to room temperature and was sequentially added 4-(3-chloropropyl)morpholine (98 mg, 0.6 mmol) (J. Am. Chem. Soc., 1945, 67, 736), DMF (2 ml) and tetrabutylammonium fluoride (0.5 ml of 1M solution in THF, 0.5 mmol). The mixture was stirred for 1 hour at room temperature, the volatile components were removed by evaporation and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated salt solution, dried (gSO4) and the solvent was removed by evaporation. The residue was purified on neutral alumina, elwira methylene chloride/acetone (90/10 then 80/20). The purified product was rubbed with a mixture of diethyl ether and hexane, tfilter is propylthio)hintline (65 mg, 30%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 2,1-2,2 (m, 2H); 3,1-3,2 (m, 2H); up 3.22 (t, 2H); 3,3-3,4 (m, 2H); 3,47 (d, 2H); 3,74 (t, 2H); 4.0 a (d, 2H); 4,08 (s, 3H); of 7.48 (d, 1H); to 7.64 (t, 2H); to 7.68 (d, 1H); 7,86 (s, 1H); 8,19 (s, 1H); 8,91 (s, 1H).

Mass spectrum ESI: 463 [MN]+.

Elemental analysis:

Found: 47,6, N 5,16, N 47,6%.

WITH22H24N4O2lFS1,2H2O1,85l.

Required: 47,8, N 5,16, N 47,8%.

Example 57

3-Chlorobenzoyl acid (188 mg, 1.05 mmol) was added in portions to a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methoxyacetyl)hintline (275 mg, 0.7 mmol) (obtained as described in Example 11) in methylene chloride (6 ml). The mixture was stirred for 30 minutes at room temperature, diluted with methylene chloride (20 ml), washed with aqueous sodium hydrogen carbonate solution and then with saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/acetone (8/2, then 7/3 and 6/4). The purified product was dissolved in methylene chloride and was added 3M hydrogen chloride in ether (0.5 ml). The mixture was diluted with ether and the resulting precipitate was filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-SUB>6; CF3D) 3,05 (TD, 1H); 3.24 in (s, 3H); 3,5-3,6 (m, 1H); of 3.7-3.8 (m, 2H); to 4.1 (s, 3H); 7.5 (d, 1H); the 7.65 (t, 1H); of 7.75 (d, 1H); or 8.2 (s, 1H); and 8.4 (s, 1H); and 9.0 (s, 1H).

Mass spectrum ESI: 410 [MN]+.

Elemental analysis:

Found: From 47.9, N 4,2, N 9,3%.

C18H17N3O3ClFS0,5H2O0,85l.

Required: 48,0, N 4,2, N 9,3%.

Example 58

To a solution of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (159 mg, 0.5 mmol) (obtained as described for starting compound in Example 2), 4-hydroxy-1-methylpiperidine (115 mg, 1 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in methylene chloride (5 ml), cooled to -5oC. in the nitrogen atmosphere was bury diethylazodicarboxylate (218 mg, 1.25 mmol). The mixture was stirred 1 hour at room temperature, the solvent was removed by evaporation and the residue was distributed between 2M hydrochloric acid and ether. The aqueous layer was separated, brought to pH 9 with an aqueous solution of sodium bicarbonate and was extracted with methylene chloride. Methylenchloride layer was washed with saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified on neutral alumina, elwira methylene chloride/methanol (97/3). The purified product was washed with ether, about the.

1H NMR spectrum: (DMSO-d6; CF3COOD) 1,9-2,0 (m, 1H); 2,05-of 2.15 (m, 2H); 2,35 at 2.45 (m, 1H); 2,85 and 2,90 (2s, 3H); 3,05-of 3.25 (m, 2H); to 3.45 (m, 1H); 3,6 (d, 1H); to 4.1 and 4.12 (2s, 3H); 4,8-4,9 (m, 0.5 H); 5-5,05 (m, 0.5 H); of 7.4 to 7.7 (m, 4H); of 8.2 (d, 1H); 8,9 (s, 1H).

Mass spectrum ESI: 417 [MN]+.

Example 59

To a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(3-methylaminopropane)hintline (170 mg, 0.43 mmol) and triethylamine (67 μl, 0.48 mmol) in methylene chloride (3 ml) was bury methanesulfonanilide (35 μl, 0.46 mmol). The mixture was stirred 5 hours at room temperature, the volatile components were removed by evaporation and the residue was distributed between ethyl acetate and water. The organic layer was separated, washed with water and then saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/acetonitrile/methanol (70/28/2). The purified product was dissolved in a mixture of methylene chloride/methanol (1/1) was added 2M hydrogen chloride in ether (1 ml). Volatile components were removed by evaporation and the residue triturated with ether, filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)p is 89 (s, 3H); 3,3 (t, 2H); was 4.02 (s, 3H); 4,27 (t, 2H); of 7.36 (s, 1H); 7,46 (d, 1H); of 7.6 to 7.7 (m, 2H); to 8.14 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 469 [MN]+.

Elemental analysis:

Found: From 48.1, N. 4,7, N 10,8%.

C20H28N4O4ClFS0,9l.

Required: From 47.9, N, 4,6, N 11.2 Per Cent.

The original compound was prepared as follows:

A solution of di-tert-BUTYLCARBAMATE (4.9 g, 22 mmol) in THF (12 ml) was bury to a solution of 3-methylamino-1-propanol (2 g, 22 mmol) (J. Am. Chem. Soc. , 1954, 76, 2789) in a mixture of THF (12 ml) and water (12 ml). The mixture was stirred for 18 hours at room temperature, THF was removed by evaporation. The aqueous residue was extracted with ether. The extracts were combined, washed with 0.1 M hydrochloric acid and then with saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation, getting 3-([N-(tert-butylcarbamoyl)-N-methyl]amino-1-propanol (3,95 g, 95%).

1H NMR spectrum (CDCI3) of 1.46 (s, N); of 1.6-1.8 (m, 2H); and 2.83 (s, 3H); 3,3-3,4 (ush.s, 2H); 3,5-3,6 (ush.s, 2H)

Mass spectrum(EI): 190 [MN]+< / BR>
To a solution of 3-([N-(tert-butylcarbamoyl)-N-methyl]amino-1-propanol (1.77 g, 9.4 mmol), 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (2 g, 6.26 mmol) (obtained as described for the original product in Example 2) and triphenylphosphine (4.1 g, ment and the mixture was stirred 1 hour at room temperature and in addition was added 3-([N-(tert-butylcarbamoyl)-N-methyl] amino-1-propanol (236 mg, 1.2 mmol), triphenylphosphine (820 mg, 3.1 mmol) and diethylazodicarboxylate (492 μl, 3.1 mmol). The solution was stirred 1 hour at room temperature and was concentrated by evaporation. The residue was purified by column chromatography, elwira acetonitrile. The purified product was washed with ether, was filtered and was re-purified by column chromatography, elwira methylene chloride/methanol (97/3) to give 7-(3-([N-(tert-butylcarbamoyl)-N-methyl] amino)propoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (2.2 g, 72%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 1,3 (, N); 2,0-2,1 (m, 2H); 2,8-2,9 (ush. s, 3H); 3,4-3,5 (m, 2H); 4.0 a (s, 3H); 4.25 in (t, 2H); and 7.3 (s, 1H); was 7.45 (d, 1H); of 7.6 to 7.7 (m, 2H); 8,08 (s, 1H); 8,88 (c, 1H).

Mass spectrum(El): 491 [MN]+.

Elemental analysis:

Found: 58,6, N, 5,8, N 11.3 Per Cent.

C24H28N4O4ClF.

Required: From 58.7 N 5,7, N 11,4%.

A solution of 7-(3-([N-(tert-butylcarbamoyl)-N-methyl] amino)-propoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (2.1 g, 4.3 mmol) in a mixture of methylene chloride (6 ml) and TFOC (5 ml) was stirred at room temperature for 1 hour. Was added to the toluene and volatile components were removed by evaporation. The residue was dissolved in water and the solution was brought to pH 7-8 feast upon the eating of the filtrate and the solid product was carefully washed with water. The solid product was recrystallized from methylene chloride/methanol, the product was filtered, washed with water and then with ether, and dried in vacuum over pjatiokisi phosphorus, receiving 4-(4-chloro-2-foronline)-6-methoxy-7-(3-methylaminopropane) hinzelin (1.4 g, 83%)

1H NMR spectrum: (DMSO-d6; CF3COOD) to 2.2-2.3 (m, 2H); to 2.65 (s, 3H), 3.1 to 3.2 (m, 2H); of 4.05 (s, 3H); 4,32 (t, 2H); 7,37 (s, 1H); of 7.48 (d, 1H); to 7.64 (t, 1H); to 7.67 (d, 1H); 8,11 (s, 1H); 8,9 (s, 1H).

Mass spectrum(EI): 391 [MN]+.

Example 60

To a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylaminorex)hintline (100 mg, 0.26 mmol) in acetone (2.5 ml), heated to 50oC in nitrogen was bury the triethylamine (44 μl, 0.32 mmol), and then a solution of 2-pomatoleios ether. The mixture was stirred for 7 hours at 50oWith, then left to cool and was distributed between ethyl acetate and water. The organic layer was separated, washed with saturated salt solution, dried (MgSO4), and volatile components were removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol (92/8). The purified product was dissolved in methylene chloride, the insoluble impurities were removed by filtration and to the filtrate was added 2.2 M hydrogen chloride in ether (0.5 ml). Flying is rochloride 4-(4-chloro-2-([N-(2-methoxyethyl)-N-methyl]amino)ethoxy)hintline (22 mg, 16%).

1H NMR spectrum: (DMSO-d6; CF3COOD) of 3.0 (s, 3H); at 3.35 (s, 3H); 3,4-3,6 (m, 2H); 3,65-of 3.85 (m, 4H); a 4.03 (s, 3H); with 4.64 (t, 2H); 7,45 (s, 1H); 7,47 (d, 1H); 7,63 (t, 1H); of 7.69 (d, 1H); 8,23 (s, 1H); 8,9 (s, 1H).

Mass spectrum ESI: 435 [MN]+.

Elemental analysis:

Found: Compared To 48.9, N 5,3, N 10.4 Percent.

C21H24N4O3ClF0,8H2O1,85l.

Required:From 48.8, N 5,3, N 10,8%.

The product was received as follows:

To a suspension of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (2,56 mg, 8 mmol) (obtained as described for starting compound in Example 2), 2-([N-(tert-butylcarbamoyl)-N-methyl] amino)ethanol (2.1 g, 1.2 mmol) (Synth. Commun. 1993, 23, 2443) and triphenylphosphine (6.3 g, 24 mmol) in methylene chloride (50 ml) under nitrogen atmosphere was bury diethylazodicarboxylate (3.13 g, 24 mmol). The reaction mixture was stirred for 1.5 hours at room temperature and in addition was added 2-([N-(tert-butylcarbamoyl)-N-methyl] amino)ethanol (0.21 g, 1.2 mmol), triphenylphosphine (630 mg, 2.4 mmol) and diethylazodicarboxylate (0.31 g, 2.4 mmol). The mixture was stirred for 1 hour; the mixture was purified, pouring directly on a column with silica and elwira methylene chloride/ether/methanol (60/30/10) to give 7-(2-([N-(tert-butylcarbamoyl)bonil)-N-methyl] amino)-ethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (2.38 g, 5 mmol) in methylene chloride (5 ml) and TFOC (10 ml) was stirred at room temperature for 1 hour. Was added to the toluene and volatile components were removed by evaporation. The residue was distributed between 2M hydrochloric acid and ethyl acetate. The aqueous layer was brought to pH 8 with sodium bicarbonate and was extracted with ethyl acetate. The organic extracts were combined, washed with saturated salt solution, dried (MgSO4) and the solvent was removed by evaporation, receiving 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylaminorex)hinzelin (700 mg, 37%).

1H NMR spectrum: (DMSO-d6; CF3COOD) of 2.75 (s, 3H); 3,5-3,6 (m, 2H); of 4.05 (s, 3H); to 4.5 (t, 2H); of 7.4-7.5 (m, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); 8,15 (s, 1H); of 8.8 (s, 1H).

Example 61

To a solution of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylaminorex)hintline (150 mg, 0.4 mmol) (obtained as described for starting compound in Example 60) and triethylamine (61 μl, 0.44 mmol) in methylene chloride (4 ml) was added dimethylcarbamoyl (38 μl, 0.42 mmol). The mixture was stirred 2.5 hours at room temperature, the precipitate was filtered and washed with ether. The solid product was purified by column chromatography, elwira methylene chloride/methanol (92/8). The purified product was dissolved in chloride methylene. The residue is triturated with ether and the solid product was filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-N, N, N-trimethylamino)ethoxy)hintline (80 mg, 41%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 2,73 (C, 6N); only 2.91 (s, 3H); 3,59 (t, 2H); 4.0 a (s, 3H); 4,34 (t, 2H); of 7.36 (s, 1H); 7.5 (d, 1H); 7,63 (t, 1H); to 7.68 (d, 1H); 8,1 (s, 1H); 8,9 (s, 1H).

Mass spectrum(EI): 447 [M]+.

Elemental analysis:

Found: 51,2, N, 5,1, N 13.9 Per Cent.

WITH21H23N5ABOUT3lF0,5H2O1l.

Required: 51,1, N, 5,1, N 14,2%.

Example 62

7-(2-Bromoethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (150 mg, 0.35 mmol) and 1-acetylpiperidine (135 mg, 1 mmol) were heated together at 140oC for 10 minutes. The mixture was allowed to cool and dissolved in a mixture of methylene chloride/ethyl acetate. The solution was washed with water and then saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol (9/1). The purified product was dissolved in methylene chloride and was added 2.9 M hydrogen chloride in ether. The precipitate was filtered, washed with ether and dried in vacuum, obtaining the Hydra is P>H NMR spectrum: (DMSO-d6; CF3COOD; 50oC) 2,07 (s, 3H); 3,3-3,7 (ush.s, 8H); of 3.75 (t, 2H); of 4.05 (s, 3H); with 4.65 (t, 2H); 7,45 (ush.s, 2H); about 7.6 to 7.7 (m, 2H); 8,15 (s, 1H); 8,9 (s, 1H).

Mass spectrum(EI): 473 [M]+.

Elemental analysis:

Found: 49,8, N, 5,0, N 12,5%.

C23H25N5O3ClF0,5H2O1 9l.

Required: 50,0, N, 5,1, N 12.7 Per Cent.

The product was received as follows:

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (5 g, 15.6 mmol) (obtained as described for starting compound in Example 2) and potassium carbonate (8.6 g, 62 mmol) in DMF (50 ml) was added 1,2-dibromoethane (5,4 ml, 62 mmol) and the mixture was stirred 18 hours at room temperature. Added water and the resulting precipitate was filtered. The solid product was purified chromatography on neutral aluminium oxide, elwira methylene chloride/methanol (95/5). Paleoceanic product was purified again by chromatography on silica, elwira methylene chloride/methanol (97/3). The purified product triturated with ether, filtered, washed with ether and dried in vacuum, obtaining 7-(2-bromoethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (3.5 g, 54%).

1H NMR spectrum: (DMSO-d6) of 3.28 (s, 3H); of 3.96 (s, 3H); 4,48 (t is toxi)ethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (150 mg, 0.32 mmol) in 1-methylpiperazine (2 ml) was heated at 100oC for 1 hour. The mixture was left to cool and was distributed between ethyl acetate and water. The organic layer was separated and washed with water and then saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/methanol (85/15, then 80/20). The purified product was dissolved in methylene chloride/methanol (1/1) and was added 2.9 M hydrogen chloride in ether. Volatile components were removed by evaporation and the solid is triturated with ether, filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)hintline (54 mg, 28%).

1H NMR spectrum: (DMSO-d6; CF3COOD; 50oC) a 2.9 (s, 3H); 3.5 to 3.8 (m, 10H); 3,95 (ush.s, 4H); a 4.03 (s, 3H); 4,4 (m, 2H); 7,40 was 7.45 (m, 1H); 7,42 (s, 1H); 7,55-the 7.65 (m, 2H); 8,15 (s, 1H); of 8.8 (s, 1H).

Mass spectrum ESI: 490 [MN]+.

Elemental analysis:

Found: 46,0, N, 5,6, N 10,9%.

C24H29N5O3ClF1,5H22,9 Hcl.

Required: 46,3, N, 5,6, N 11.2 Per Cent.

The product was received as follows:

To a mixture of 4-(4-CHL is I in Example 2) and potassium carbonate (1.73 g, 12 mmol) in DMF (10 ml) was added 2-bromatology ether (of 1.57 ml, 12 mmol). The mixture was stirred 18 hours at room temperature and distributed between ethyl acetate and water. The organic layer was separated, washed with water and then saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/acetonitrile/methanol (60/38/2). The purified product triturated with ether, filtered, washed with ether and dried in vacuum, obtaining 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-foronline)-6-methoxy-hinzelin (762 mg, 52%).

1H NMR spectrum (CDCl3) a 3.5 (t, 2H); 3.9 to (t, 2H); of 3.95 (t, 2H); is 4.03 (s, 3H); of 4.35 (t, 2H); 7.03 is (s, 1H); 7,2-7,4 (m, 4H); 8,55 (t, 1H); to 8.7 (s, 1H)

Mass spectrum ESI: 472 [MN]+< / BR>
Example 64

A solution of 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline (150 mg, 0.32 mmol) (obtained as described for the original product in Example 63) in pyrrolidine (2 ml) was heated at 80oC for 5 hours. The mixture was allowed to cool and was distributed between ethyl acetate and water. The organic layer was washed with water and then saturated saline solution, dried (MgSO4) and the solvent was removed by evaporation. The Remainder Aluminum (80/20/0, then 80/20/1). The purified product was dissolved in methylene chloride and was added 2.9 M hydrogen chloride in ether (1 ml). Volatile components were removed by evaporation, the residue is triturated with ether, filtered and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-pyrrolidin-1 ylethoxy)-ethoxy)hintline (35 mg, 20%).

1H NMR spectrum: (DMSO-d6; CF3D) as 1.8-1.9 (m, 2H); 1,95-2,1 (m, 2H); 3,05 is 3.15 (m, 2H); of 3.45 (t, 2H); 3,55-the 3.65 (m, 2H); 3,8-of 3.85 (m, 2H); 3.95 to 4.0 a (m, 2H); 4,01 (s, 3H); 4,4 (ush.c, 2H); 7.39 (s, 1H); of 7.48 (d, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); 8,11 (s, 1H); 8,89 (s, 1H).

Mass spectrum ESI: 461 [MN]+.

Elemental analysis:

Found: 49,4, N. 5,4, N 10.1 Per Cent.

WITH23H26H4O3lF1,2H22hcl.

Required: 49,7, N, 5,5, N 10.1 Per Cent.

Example 65

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol) (obtained as described for the original product in Example 2) and potassium carbonate (324 mg, 2.3 mmol) in DMF (5 ml) was added 1-(2-(2-bromacil)ethoxy-2-pyrrolidinone (272 mg, 1.1 mmol) and the mixture was stirred 4 hours at room temperature. The mixture was distributed between ethyl acetate and water, the organic layer was separated, washed with water and then saturated saline solution, dried (MgSO4) luira methylene chloride/acetonitrile/methanol (60/37/3). Paleoceanic product was re-purified column chromatography on silica, elwira methylene chloride/methanol (95/5). The purified product was dissolved in methylene chloride and was added 2.9 M hydrogen chloride in ether (1 ml). Volatile components were removed by evaporation, the residue is triturated with ether, filtered and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-[2-oxopyrrolidin-1-yl]ethoxy)ethoxy)hintline (63 mg, 16%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 1,85-of 1.95 (m, 2H); 2,2 (t, 2H); 3,35 is-3.45 (m, 4H); the 3.65 (t, 2H); 3.9 to (ush.s, 2H); was 4.02 (s, 3H); 4,35 (ush.s, 2H); to 7.35 (s, 1H); was 7.45 (d, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); 8,15 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 475 [MN]+.

Elemental analysis:

Found: 53,2, N, 5,0, N 11,1%.

C23H24N4O4ClF0,6N2O0,85l.

Required: From 53.5, N, 5,1, N 10,8%.

The product was received as follows:

A solution of 2-pyrrolidinone (1.5 g, 17.6 mmol) in anhydrous toluene (8 ml) was bury to a suspension of sodium hydride (741 mg, 18 mmol, prewashed with pentane) in anhydrous toluene (60 ml) and the mixture was stirred at 100oC for 1.5 hours. The mixture was allowed to cool to room temperature and was added bromide tetrol temperature, insoluble products were removed by filtration and the solid product was washed with ether. Volatile components were removed from the filtrate by evaporation and the residue was purified by column chromatography on silica, elwira methylene chloride/acetonitrile/ methanol (60/38/2) to give 1-(2-(2-bromacil)ethoxy)-2-pyrrolidinone (971 mg, 23%).

1H NMR spectrum: (Dl3) 2,0-2,1 (m, 2H); 2,4 (t, 2H); 3,4-3,5 (m, 4H); to 3.52 (t, 2H); the 3.65 (t, 1H); of 3.78 (t, 2H).

Mass spectrum(EI): 237 [M]+.

Example 66

To a mixture of (E)-4-morpholino-2-EN-1-ol (151 mg, 0.96 mmol) (J. Med. Chem. , 1972, 15, 110-112), 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (220 mg, 0,688 mol) (obtained as described for starting compound in Example 2) and triphenylphosphine (541 mg, 2 mmol) in methylene chloride (4 ml) was bury diethylazodicarboxylate (325 μl, 2 mmol). The mixture was stirred for 30 minutes at room temperature and in addition was added (E)-4-morpholino-2-EN-1-ol (10 mg, 0.06 mmol), triphenylphosphine (36 mg, 0,137 mol) and diethylazodicarboxylate (22 μl, 0.14 mmol). The mixture was stirred for 20 minutes and the volatile components were removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/methanol (92/8). The purified solid is ranged by evaporation and the solid product was washed with ether, was filtered, washed with ether and dried in vacuum, obtaining hydrochloride (E)-4-(4-chloro-2-foronline)-6-methoxy-7-(4-morpholino-2-EN-1-yloxy)hintline (165 mg, 45%).

1H NMR spectrum: (DMSO-d6; CF3COOD) of 3.1-3.15 in (m, 2H); 3,35 is-3.45 (m, 2H); 3.75 to (t, 2H); 3.9 to (d, 2H); 4.0 a (d, 2H); is 4.03 (s, 3H); 4,95 (d, 2H); 6,05 (TD, 1H); 6,3 (TD, 1H); 7,45 (s, 1H); 7,47 (d, 1H); a 7.62 (t, 1H); 7.7 (d, 1H); of 8.25 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 459 [MN]+.

Elemental analysis:

Found: 50,3, N 5,3, N 10.1 Per Cent.

C23H24N4O3ClF1,4H2O1 8l.

Required: 50,2, N 5,2, N 10,2%.

Example 67

To a mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (284 mg, 0.78 mmol) (obtained as described for the original product in Example 48), triphenylphosphine (613 mg, 2.34 mmol) and 4-(2-hydroxyethyl)-3-morpholino (170 mg, 1,17 mmol) (EP 580402 A2) in methylene chloride (10 ml) under nitrogen was bury diethylazodicarboxylate (368 μl, 2.34 mmol). The mixture was stirred 2.5 hours at room temperature, insoluble products were removed by filtration. The filtrate was purified, pouring it directly on a column with silica and elwira methylene chloride/ethyl acetate/ methanol (60/35/5). The purified product was washed with ether and was filtered. Solid is dared in ether (0.5 ml). Volatile components were removed by evaporation and the residue triturated with ether, filtered and dried in vacuum, obtaining the hydrochloride of 4-(4-bromo-2-foronline)-6-methoxy-7-(2-(3-oxaprotiline)ethoxy)-hintline (108 mg, 26%).

1H NMR spectrum: (DMSO-d6; CF3COOD) to 3.56 (t, 2H); 3,8-3,9 (m, 4H); 4,06 (s, 3H); 4,06 (s, 2H); 4,4 (t, 2H); to 7.35 (s, 1H); 7.5 to about 7.6 (m, 2H); 7,8 (d, 1H); 8,13 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 491 [MH]+.

Elemental analysis:

Found: 47,1, N 4,1, N 10,5%.

C21H20N4O4BrF0,3H2O0,95l.

Required: From 47.5, N 4,1, N 10,5%.

Example 68

To a mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (218 mg, 0.6 mmol) (obtained as described for the original product in Example 48), triphenylphosphine (95 μl, 0.84 mmol) and 1-(2-hydroxyethyl)-2-pyrrolidinone (95 μl, 0.84 mmol) in methylene chloride (8 ml) under nitrogen was bury diethylazodicarboxylate (283 μl, 1.8 mmol). The mixture was stirred 4 hours at room temperature and then purified, pouring directly on a column with silica and elwira methylene chloride/acetonitrile/methanol (60/32,5/7,5). The purified product was washed with ether and was filtered. The solid product was dissolved in methylene chloride/methanol (1/1) and DOB was filtered and dried in vacuum, getting hydrochloride 4-(4-bromo-2-foronline)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)hintline (182 mg, 60%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 1,9-2,0 (m, 2H); 2,24 (t, 2H); of 3.53 (t, 2H); 3,7 (t, 2H); 4,01 (s, 3H); 4,34 (t, 2H); of 7.36 (s, 1H); 7.5 to about 7.6 (m, 2H); of 7.75 (d, 1H); is 8.16 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 477 [MN]+.

Elemental analysis:

Found: 50,2, N 4,3, N 10,9%.

WITH21H20N4ABOUT3rF0,8l.

Required: 50,0, N 4,2, N 11,1%.

Example 69

To a mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (182 mg, 0.5 mmol) (obtained as described for starting compound in Example 48), triphenylphosphine (393 mg, 1.5 mmol) and 2-(2-methoxyethoxy)ethanol (84 μl, 0.7 mmol) in methylene chloride (7 ml) under nitrogen was bury diethylazodicarboxylate (236 μl, 1.5 mmol). The mixture was stirred 4 hours at room temperature, the reaction mixture was purified, pouring directly on a column with silica and elwira with ethyl acetate/petroleum ether (9/1, then 10/0). The purified product was washed with ether and was filtered. The solid product was dissolved in methylene chloride/methanol and was added 2M hydrogen chloride in ether (1 ml). The mixture was concentrated by evaporation and the precipitate was filtered, prominately (84 mg, 34%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 3,26 (s, 3H); 3,47 (m, 2H); to 3.64 (m, 2H); of 3.85 (m, 2H); was 4.02 (s, 3H); of 4.35 (m, 2H); to 7.35 (s, 1H); of 7.5 to 7.7 (m, 2H); of 7.82 (d, 1H); to 8.12 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 468 [MN]+.

Elemental analysis:

Found: From 47.5, N, 4,4, N 8.7 Percent.

C20H21N3O4BrF0,N2O0,65l.

Required: From 47.9, N, 4,6, N 8,3%.

Example 70

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (383 mg, 1.2 mmol) (obtained as described for starting compound in Example 2), 4-(3-hydroxypropyl)-3,5-dioxaborolane (291 mg, 1,68 mmol) and triphenylphosphine (944 mg, 3.6 mmol) in methylene chloride (10 ml) under nitrogen was bury diethylazodicarboxylate (567 μl, 3.6 mmol). The mixture was stirred 6 hours at room temperature, and insoluble products were removed by filtration. The filtrate was purified, pouring it directly on a column with silica and elwira methylene chloride/acetonitrile /methanol (60/34/6, then 60/24/16 and 60/16/24). Paleoceanic product was re-purified column chromatography, elwira methylene chloride/acetonitrile/methanol (5/4/1). The purified product was dissolved in methylene chloride/methanol, was added 2M hydrogen chloride in ether (1 ml) and letoacouela, getting hydrochloride 4-(4-chloro-2-foronline)-7-(3-(3,5-dioxaborolane)propoxy)-6-methoxyquinazoline (56 mg, 10%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 2,0-2,1 (m, 2H); at 3.35 (t, 2H); 3,98 (s, 2H); 4,01 (s, 3H); 4,24 (t, 2H); 7,33 (s, 1H); was 7.45 (d, 1H); a 7.62 (t, 1H); to 7.68 (d, 1H); 8,13 (s, 1H); 8,87 (c, 1H).

Mass spectrum ESI: 475 [MN]+.

Elemental analysis:

Found: Compared To 48.9, N. 4,4%.

C22H20N4O5ClF1,4H2O1HCl.

Required: 49,2, N 4,5%.

The product was received as follows:

The solution diglycolic acid (2,32 g, 20 mmol) 3-amino-1-propanol (6 ml) was boiled under reflux at 180oC for 3 hours. Volatile components were removed by evaporation and the residue was purified by column chromatography on silica, elwira methylene chloride/methanol (8/2) to give 4-(3-hydroxypropyl)-3,5-dioxaborolan (of 3.46 g, 99%).

1H NMR spectrum: (Dl3) of 2.75 to 2.8 (m, 2H); 3,1 (ush.s, 1H); 3.45 points to 3.5 (m, 2H); 3.75 to (t, 2H); Android 4.04 (s, 2H)

Mass spectrum(EI): 174 [M]+< / BR>
Example 71

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (319,5 mg, 1 mmol) (obtained as described for starting compound in Example 2), triphenylphosphine (786 mg, 3 mmol) and 4-(2-hydroxyethyl)-3,5-D3 mmol). The mixture was stirred for 4.5 hours at room temperature, and insoluble products were removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography on silica, elwira methylene chloride/acetonitrile /methanol (85/12,5/2,5). The purified product was dissolved in methylene chloride, was added 2M hydrogen chloride in ether (1 ml) and the mixture was diluted with ether. The precipitate was filtered off, washed with ether, and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-7-(2-(3,5-dioxaborolane)ethoxy)-6-methoxyquinazoline (97 mg, 20%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 4,0 (s, 3H); 4,19 (d, 2H); 4,39 (t, 2H); of 4.45 (s, 4H); to 7.35 (s, 1H); was 7.45 (d, 1H); to 7.67 (t, 1H); of 7.69 (d, 1H); to 8.12 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 461 [MN]+.

Elemental analysis:

Found: From 49.9, N. 3,9, N 11,1%.

C21H18N4O5ClF0,5H2O0,9l.

Required: 50,2, N, 4,0, N 11,1%.

The product was received as follows:

To a solution of diglycolic anhydride (2,32 g, 20 mmol) in pyridine (10 ml) was bury ethanolamine (2,44 g, 40 mmol). The mixture was stirred for 5 minutes at room temperature and then boiled to reverse the internal chromatography elwira methylene chloride/methanol (9/1) to give 4-(2-hydroxyethyl)-3,5-dioxaborolan (400 mg, 12.5 per cent).

1H NMR spectrum (CDCI3) 1,6 (ush.s, 1H); and 3.8 (t, 2H); of 4.05 (t, 2H); 4,4 (s, 4H).

Mass spectrum (EI: 160 [MN]+.

Example 72

To a mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (292 mg, 0.8 mmol) (obtained as described for the original product in Example 48), triphenylphosphine (629 mg, 2.4 mmol) and 2-(2-morpholinoethoxy)ethanol (196 mg, 1.12 mmol) (obtained as described for the original product in Example 53) in methylene chloride (10 ml) under nitrogen atmosphere was bury diethylazodicarboxylate (378 μl, 2.4 mmol). The mixture was stirred 3.5 hours at room temperature, and the reaction mixture was purified, pouring directly on a column with silica and elwira methylene chloride/ acetonitrile/methanol (6/3/1). The purified product was dissolved in methylene chloride/methanol and the insoluble impurities were removed by filtration. To the filtrate was added 2M hydrogen chloride in ether (1 ml) and the volatile components were removed by evaporation. The residue is triturated with ether, filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-bromo-2-foronline)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)hintline (232 MGM, 6N); was 4.02 (s, 3H); 4,4 (ush.s, 2H); 7,45 (s, 1H); 7.5 to about 7.6 (m, 2H); 7,8 (m, 1H); by 8.22 (s, 1H); 8,87 (s, 1H).

Mass spectrum ESI: 523 [MN]+.

Elemental analysis:

Found: 46,3, N Is 4.9, N 9,2%.

WITH23H26N4O4rF0,5H2O1,8l.

Required: 46,3, N Is 4.9, N 9.4 Per Cent.

Example 73

To a mixture of 4-(4-bromo-2-foronline)-7-hydroxy-6-methoxyquinazoline (170 mg, 0.46 mmol) (obtained as described for the original product in Example 48), triphenylphosphine (367 mg, 1.4 mmol) and 3-(1,1-dioxothiazolidine)-1-propanol (135 mg, 0.7 mmol) in methylene chloride (4 ml) under nitrogen atmosphere was bury diethylazodicarboxylate (220 μl, 1.4 mmol). The mixture was stirred for 1 hour at room temperature and added additional triphenylphosphine (61 mg, 0.23 mmol), 3-(1,1-dioxothiazolidine)-1-propanol (30 mg, 0.23 mmol) and diethylazodicarboxylate (37 μl, 0.23 mmol). The mixture was stirred for 1 hour at room temperature and the mixture was purified, pouring directly on a column with silica and elwira methylene chloride/methanol (95/5). The purified product was dissolved in methylene chloride/methanol, was added 2.2 M hydrogen chloride in diethyl ether (1 ml) and the volatile components were removed by evaporation. The residue is triturated with ether, Otti is holino)propoxy)-6-methoxyquinazoline (138 mg, 47%).

1H NMR spectrum: (DMSO-d6; CF3D) 2.3 to 2.4 (m, 2H); 3,5 (t, 2H); 3,7-3,8 (ush. s, 4H); 3,85 (ush.s, 4H); a 4.03 (s, 3H); of 4.35 (t, 2H); to 7.4 (s, 1H); 7.5 to about 7.6 (m, 2H); 7,8 (d, 1H); 8,21 (s, 1H); 8,88 (c, 1H).

Mass spectrum ESI: 539 [MN]+.

Elemental analysis:

Found: 42,1, N, 4,6, N 8,6%.

C22H24N4O4BrFS1,1H2O1,85l.

Required: 42,2, N, 4,5, N 8,9%.

The original compound was prepared as follows:

A mixture of 3-amino-1-propanol (650 μl, 8.4 mmol) and vinylsulfonic (1 g, 8.4 mmol) was heated at 110oC for 45 minutes. The mixture was left to cool and was purified by column chromatography, elwira methylene chloride/methanol (95/5) to give 3-(1,1-dioxothiazolidine)-1-propanol (800 mg, 90%).

1H NMR spectrum (CDCl3) a 1.7-1.8 (m, 2H); by 2.73 (t, 2H); 3,06 (ush.s, 8H); 3,25 (s, 1H); of 3.78 (t, 2H)

Mass spectrum ESI: 194 [MN]+< / BR>
Example 74

A solution of 2-methoxyethylamine (42 mg, 0.26 mmol) (J. Am. Chem. Soc. , 1992, 114, 1743-1749) in acetonitrile (1 ml) was added to a mixture of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylaminorex)hintline (94 mg, 0.25 mmol) (obtained as described for starting compound in Example 60) and triethylamine (80 μl, 0.5 mmol) in acetonitrile (15 ml). The mixture was stirred 10 mi the m methylene and water. The organic layer was separated, washed with saturated salt solution, dried (gSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol (97/3). The purified product was dissolved in methylene chloride (5 ml) was added 2.2 M hydrogen chloride in ether (2 ml), and volatile components were removed by evaporation. The residue is triturated with ether, filtered, washed with ether and dried in vacuum, obtaining the hydrochloride of 4-(4-chloro-2-foronline)-7-(2-([N-methyl-N-(2-methoxycarbonyl)] amino)ethoxy-6-methoxyquinazoline (86 mg, 64%).

1H NMR spectrum: (DMSO-d6; CF3COOD) 2,96 (s, 3H); or 3.28 (s, 3H); 3,47 (t, 2H); up 3.6-3.7 (m, 4H); was 4.02 (s, 3H); 4,37 (t, 2H); 7,37 (s, 1H); 7,46 (d, 1H); to 7.64 (t, 1H); 7.7 (d, 1H); 8,15 (s, 1H); 8,88 (s, 1H).

Mass spectrum ESI: 499 [MH]+.

Elemental analysis:

Found: 47,2, N Is 4.9, N 10,2%.

C21H24N4O5ClFS1HCl.

Required: 47,1, N. 4,7, N 10,5%.

Example 75

Using a technique similar to the method of Example 74, a mixture of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-methylenedioxy)-hintline (102 mg, 0.27 mmol) (obtained as described for starting compound in Example 60) and triethylamine (0.1 ml, to 0.72 mmol) in acetonitrile (17 ml) clicks ochloride hydrochloride salt of 4-(4-chloro-2-foronline)-6-methoxy-7-(2-([N-methyl-N-[3-morpholinepropanesulfonic] amino)ethoxy)hintline (96 mg, 54%).

1H NMR spectrum: (DMSO-d6; CF3D) 2,1-2,2 (m, 2H); 3,0 (s, 3H); 3,05 is 3.15 (m, 2H); 3,2 and 3.3 (m, 2H); 3,3-3,4 (m, 2H); of 3.45 (d, 2H); 3,65 to 3.8 (m, 4H); 3,95 (d, 2H); is 4.03 (s, 3H); 4,39 (t, 2H); 7,42 (s, 1H); was 7.45 (d, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); or 8.2 (s, 1H); 8,9 (s, 1H).

Mass spectrum ESI: 568 [MN]+.

Example 76

To a mixture of 4-(4-chloro-2-foronline)-7-hydroxy-6-methoxyquinazoline (111 mg, 0.35 mmol) (obtained as described for the original product in Example 2), triphenylphosphine (312 mg, 1,19 mmol) and (S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidine (84 mg, 0.42 mmol) in methylene chloride (10 ml), cooled to 0oC. in the nitrogen atmosphere was bury diethylazodicarboxylate (of 0.18 ml, to 1.14 mmol). The mixture was stirred for 15 minutes at 0oS, was allowed to warm to ambient temperature and then was stirred for 22 hours. Addition was added (S)-1-(3-hydroxypropyl)-2-(N, N-dimethylcarbamoyl)pyrrolidin (10 mg, 0.05 mmol), triphenylphosphine (35 mg, 0.13 mmol) and diethylazodicarboxylate (20 μl, 0.13 mmol) and the mixture is then stirred for another 2 hours. The mixture was distributed between water and methylene chloride and the aqueous phase is brought to pH 2 2M hydrochloric acid. The aqueous layer was separated, brought to pH 9 with sodium bicarbonate and was extracted with methylene chloride. Objectwriter was removed by evaporation. The residue was purified by column chromatography on silica, elwira methylene chloride/methanol (85/15, then 75/25 and 60/40). The purified product was dissolved in methylene chloride (5 ml) and methanol (1 ml), was added 3.9 M hydrogen chloride in ether (0.5 ml) and the mixture was diluted with ether. The precipitate was filtered off, washed with ether, and dried in vacuum, obtaining hydrochloride (S)-4-(4-chloro-2-foronline)-7-(3-(2-(N, N-dimethylcarbamoyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazoline (86 mg, 32%).

1H NMR spectrum: (DMSO-d6; CF3OD) 1,8-of 1.95 (m, 2H); to 2.1-2.3 (m, 4H); 2,92 (c, 3H); 3,0 (s, 3H); 3,2 is-3.45 (m, 3H); 3.75 to of 3.85 (m, 1H); 4.0 a (s, 3H); 4,32 (t, 2H); 4.75 V (t, 1H); 7.4 in (c, 1H); was 7.45 (d, 1H); the 7.65 (t, 1H); 7.7 (d, 1H); of 8.25 (s, 1H); 8,9 (s, 1H).

Mass spectrum ESI: 502 [MH]+.

Elemental analysis:

Found: 50,2, N, 5,5, N Of 11.6%.

WITH25H29N5O3lF1H2O2HCl.

Required: 50,6, N, 5,6, N 11,8%.

The product was received as follows:

A mixture of (S)-2-(N, N-dimethylcarbamoyl)pyrrolidine (426 mg, 3 mmol (Chem. Pharrr. Bull, 1973, 21, 2112-2116), 3-bromo-1-propanol (0,41 ml, 4.5 mmol) and potassium carbonate (829 mg, 6 mmol) in acetonitrile (6 ml) was boiled under reflux for 8 hours. The mixture was left to cool and distributed between x>) and the solvent was removed by evaporation. The residue was purified by column chromatography, elwira methylene chloride/methanol (gradient from 90/10 to 60/40) to give (S)-1-(3-hydroxypropyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin (290 mg, 48%).

1H NMR spectrum (CDCl3; CD3COOD) 1,8-2,1 (m, 4H); about 2.2-2.3 (m, 1H); 2,6-2,7 (m, 1H); 3,0 (s, 3H); 3,10 (s, 3H); 3,4-3,6 (m, 3H); 3.75 to of 3.85 (m, 3H); of 5.05 (m, 1H)

Mass spectrum ESI: 223 [MNa]+< / BR>
Example 77

The following representatives of standard dosage forms containing the compound of formula Ia or pharmaceutically acceptable salt (hereafter compound X), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet

Compound X - 100

Lactose Ph. Eur. - 182,75

Croscarmellose sodium to 12.0

Pasta corn starch (5% wt./about. paste) was 2.25

Magnesium stearate - 3,0

(b) Tablet II, mg/tablet

Compound X - 50

Lactose Ph. Eur. - 223,75

Croscarmellose sodium is 6.0

Corn starch - 15,0

Polyvinylpyrrolidone (5% wt./about. paste) was 2.25

Magnesium stearate - 3,0

(c) Tablet III mg/tablet

Compound X - 1,0

Lactose Ph. Eur. - 93,25

Croscarmellose sodium is 4.0

Pasta corn starch (5% wt./BR>
Magnesium stearate and 1.5

(e) Injection I (50 mg/ml)

Compound X to 5.0% wt./about.

1H. the sodium hydroxide solution to 15.0% wt./about.

0.1 N. hydrochloric acid (to establish a pH of 7.6)

The polyethylene glycol 400 - 4.5% wt./about.

Water for injection to 100%

(f) Injection II (10 mg/ml)

Compound X 1.0% wt./about.

Sodium phosphate BF - 3,6% wt./about.

of 0.1 n sodium hydroxide solution to 15.0% wt./about.

Water for injection to 100%

(g) Injection III (1 mg/ml, buffered to pH 6)

Compound X 0.1% wt./about.

Sodium phosphate BF - of 2.26% wt./about.

Citric acid - 0,38% wt./about.

The polyethylene glycol 400 and 3.5% wt./about.

Water for injection to 100%

Note

The above compositions can be obtained by conventional means, well known in the pharmaceutical practice. The tablets (a)-(C) can be covered by conventional means, for example, covered with acetamitaphen cellulose.

1. Derived hintline formula I

< / BR>
where m is an integer 1 or 2;

R1represents hydrogen, nitro or C1-3alkoxy;

R2represents hydrogen or nitro;

R3represents hydroxy, Gal, S-, -SO - or-SO2-;

R4selected from one of the following thirteen groups: 1)1-5R12(where R12represents 5 - or 6-membered saturated heterocyclic group selected from DIOXOLANYL, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiomorpholine, imidazolidinyl, morpholinyl, piperazinil and tetrahydropyranyl, and this heterocyclic group is linked WITH1-5the alkyl via a carbon atom, and this heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl) or (C1-5R13(where R13represents a group selected from pyrrolidin-1-yl, imidazolidin-1-yl, thiomorpholine, and this group may have one or two substituent selected from oxo, hydroxy, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N, N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl); 2)2-5R14(where R14is pyrrolidinyl or morpholinyl); 3)2-5a is SUP>16(where X2represents-O-, -NR17CO-, -NR20SO2- or-NR21- (where R17, R20and R21each independently represents a C1-3alkyl), X3represents-O -, and R16represents hydrogen or C1-3alkyl); 5) C1-5alkyl4CR22(where X4represents-NR23(where R23represents hydrogen or C1-3alkyl) and R22represents-NR24R25or26(where R24, R25and R26represent1-4alkyl)); 6)1-5alkyl5R27(where X5represents-O-, carbonyl or-NR32- (where R32represents hydrogen or C1-3alkyl) and R27is cyclopentyl or 5 - or 6-membered saturated heterocyclic group selected from piperidinyl, morpholinyl, piperazinil, pyrrolidinyl and tetrahydropyranyl, and the specified cyclopentyl or heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl, or R27predstavljaet a-S-, -SO-, -SO2- or-NR31SO2- (where R31represents hydrogen or C1-3alkyl)); 7)1-3alkoxyl2-4alkyl, provided that X1represents-S-, -SO - or-SO2-; 8)1-3alkoxyl2-4alkyl or C1-4alkyl, provided that X1represents-O-; 9)1-5alkyl6C1-5R33(where X6represents-O-, -NR37SO2- (where R37represents hydrogen or C1-3alkyl) and R33represents 5 - or 6-membered saturated heterocyclic group selected from pyrrolidinyl, morpholinyl and piperazinil, and this heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N, N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl); 10) R39(where R39is a group selected from pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl, and this group may have one or two substituent selected from oxo, hydroxy, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-41-4alkanoyl,1-4alkoxycarbonyl and C1-4hydroxyalkyl); 12)1-5R43(where R43represents morpholino, which may have one or two substituent selected from oxo, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl)carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl), provided that, when R4represents a C1-5R43X1represents-S-, -SO - or-SO2-; and 13) WITH1-5R44(where R44represents morpholino, which has at least one and optionally two substituent selected from oxo, C1-4of alkyl, C1-4hydroxyalkyl, carbamoyl,1-4allylcarbamate, N,N-di(C1-4alkyl) carbamoyl,1-4alkanoyl and C1-4alkoxycarbonyl); with the additional proviso that, when R4choose from group 8), R1and/or R2is/are a nitro or at least one of R3represents a C1-3alkanoyloxy,

and its salts.

2. Derived hintline under item 1, where R1represents hydrogen, nitro, methoxy Jerusalem.

4. Derived hintline according to any one of paragraphs.1-3, where R2represents hydrogen.

5. Derived hintline on any one of the preceding paragraphs, where the phenyl group-containing (R3)mhas the formula II

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

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

Rcrepresents hydrogen or hydroxy;

Rdrepresents hydrogen, fluorine or chlorine.

6. Derived hintline on any one of the preceding paragraphs, where m is equal to 2.

7. Derived hintline on any one of the preceding paragraphs, where the phenyl group, with (R3)mthe Deputy is 4-chloro-2-forfamilies group or 4-bromo-2-forfamilies group.

8. Derived hintline on any one of the preceding paragraphs, where X1represents-O - or-S-.

9. Derived hintline on any one of the preceding paragraphs, where X1represents-O-.

10. Derived hintline according to any one of paragraphs.1-7, where4selected from one of the following eleven groups: 1)1-4RDIN-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-yl, and this group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or (C2-4aR45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, and this group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl); 2) 1-R46prop-1-EN-3-yl, 1-R46but-2-EN-4-yl, 1-R46but-1-EN-3-yl, 1-R46the Penta-2-EN-4-yl or 2-R46the Penta-3-EN-5-yl (where R46is pyrrolidinyl or morpholinyl, and specified heterocyclic group is linked to alkenylphenol group through a carbon atom), or 1-R47but-2-EN-4-yl, 1-R47the Penta-2-EN-4-yl or 2-R47the Penta-3-EN-5-yl (where R47is pyrrolidinyl or morpholinyl, and specified heterocyclic group is linked to alkenylphenol-2-in-4-yl or 2-R48the Penta-3-in-5-yl (where R48is morpholinyl, and specified heterocyclic group is linked to alkenylphenol group through a carbon atom), or 1-R49but-2-ine-4-yl, 1-R49the Penta-2-in-4-yl or 2-R49the Penta-3-in-5-yl (where R49is morpholinyl, and specified heterocyclic group is linked to alkenylphenol group through a nitrogen atom); 4)2-3alkyl2C1-3alkyl3R16(where X2and X3are as defined in paragraph 1, and R16represents hydrogen or C1-3alkyl); 5)2-3alkyl4CR22(where X4is as defined in paragraph 1, and R22represents-NR24R25or26(where R24, R25and R26represent hydrogen or C1-4alkyl); 6) C2-3alkyl5R27(where X5the same as that defined in paragraph 1, and R27represents a group selected from cyclopentyl, pyrrolidinyl and piperidinyl, and this group is associated with X5through the carbon atom and the group may have one Deputy, selected from oxo, hydroxy, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl,1-2allylcarbamate, N,N-di(C1-2alkyl)ka is then, if R27represents a C1-3alkyl, X5represents-S-, -SO-, -SO2- or-NR31SO2- (where R31represents hydrogen or C1-3alkyl))); 7)1-2alkoxyl2-3alkyl, provided that X1represents-S-, -SO - or-SO2-; 8) C2-3alkyl6C2-3aR33(where X6the same as that defined in paragraph 1, and R33represents 5 - or 6-membered saturated heterocyclic group selected from pyrrolidinyl, morpholinyl and piperazinil, and this heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl); 9)2-3R40(where R40represents piperazine-1-yl having one Deputy, selected from acetyl, C1-2alkoxycarbonyl and C1-2hydroxyalkyl); 10)2-3R43(where R43represents morpholino may have one or two substituent selected from oxo, C1-3of alkyl, C1-2hydroxyalkyl, carbamoyl,1-2allylcarbamate, N, N-di(C1-2alkyl)carbs which R43then X1represents-S-, -SO - or-SO2-; and (11)2-3R44(where R44represents morpholino having at least one and optionally two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N, N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl).

11. Derived hintline under item 10, where R4selected from one of the following nine groups: 1)1-3R12(where R12is a group selected from 1,3-dioxolane-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-yl, and this group may have one or two substituent selected from oxo, hydroxy, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl,1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl) or (C2-3R45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, and this group may have one or two substituent selected from oxo, hydroxy, C1-2of alkyl, C1-2hydroxyalkyl, carbama
but-2-EN-4-yl (where R50represents a group selected from pyrrolidin-1-yl, pyrrolidin-3-yl, morpholino); 3) 1-R51but-2-ine-4-yl (where R51represents morpholino); 4) C2-3alkyl2C1-3alkyl3R16(where X2and X3are as defined in paragraph 1, and R16represents hydrogen or C1-3alkyl); 5)1-2alkoxyl2-3alkyl, provided that X1represents-S-, -SO - or-SO2-; 6) 2-(3,3-dimethylurea)ethyl, 3-(3,3-dimethylurea)propyl, 2-(1,3 .3m-trimethylamino)ethyl, 3-(1,3 .3m-trimethylamino)propyl, 2-(isopropoxycarbonyl)ethyl, 3-(isopropoxycarbonyl)propyl, 2-(solutionline) ethyl, 3-(solutionline)propyl, 2-(tert.-butoxycarbonylamino)ethyl or 3-(tert.-butoxycarbonylamino)cut; 7)2-3alkyl5R27(where R27represents a C1-2alkyl and X5represents-S-, -SO-, -SO2- or-NR31SO2- (where R31represents hydrogen or C1-3alkyl)); 8) C2-3alkyl6C2-3aR33(where X6such, as defined in paragraph 1, and R33represents a group selected from morpholino, 2-oxopyrrolidin-1-yl, pyrrolidin-1-yl, piperaz the first may have one or two substituent, selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N, N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl), provided that, if R4represents a C2-3R43then X1represents-S-, -SO - or-SO2-.

12. Derived hintline under item 10 or 11, where R4selected from one of the following eight groups: 1)1-3R12(where R12represents a 1,3-dioxolane-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 1-methylpiperidin-2-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, 1-methyl-pyrrolidin-2-yl, 1-methylpyrrolidine-3-yl, piperazine-2-yl, 1-methylpiperazin-2-yl, 4-methylpiperazin-2-yl, 1,4-dimethylpiperazine-2-yl, morpholine-2-yl, morpholine-3-yl, 4-methylmorpholin-2-yl or 4-methylmorpholin-3-yl) or (C2-3R45(where R45is pyrrolidinyl-1-yl, thiomorpholine, 1,1-dioxothiazolidine, 2-oxopyrrolidin-1-yl, 2-(N-methylcarbamoyl)pyrrolidin-1-yl, 2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl, 2-carbamoylation-1-yl, 2-Oxymetazoline-1-yl or 3-methyl-2-Oxymetazoline-1-yl); 2) 1-R50but-2-EN-4-yl (where R50is pyrrolidin-1-yl or morpholino); 3) 1-R< 3R16(where X2and X3are as defined in paragraph 1, and R16represents hydrogen or C1-3alkyl); 5)1-2alkoxyl2-3alkyl, provided that X1represents-S-, -SO - or-SO2-; 6) C2-3alkyl5R27(where R27represents a C1-2alkyl and X5represents-S-, -SO-, -SO2or NR31SO2- (where R31represents hydrogen or C1-3alkyl)); 7)2-3alkyl6C2-3R33(where X6such, as defined in paragraph 1, and R33represents a group selected from pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholino); and 8)2-3R43(where R43represents morpholino, which may have one or two substituent selected from oxo, C1-2the alkyl and C1-2hydroxyalkyl), provided that, if R4represents a C2-3R43then X1represents-S-, -SO - or-SO2-.

13. Derived hintline under item 1 of the formula Ia

< / BR>
where R1arepresents hydrogen or methoxy;

R2arepresents hydrogen;

phenyl group containing (R3a)mArepresents 4-chloro-2-ftorfyenil from one of the following eleven groups: 1)1-4R7a(where R7ais a group selected from 1,3-dioxolane-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl piperazine-2-yl, and this group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl) or C2-4aR8a(where R8arepresents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, and this group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl); 2) 1-R9aprop-l-EN-3-yl, 1-R9abut-2-EN-4-yl, 1-R9abut-1-EN-3-yl, 1-R9athe Penta-2-EN-4-yl or 2-R9athe Penta-3-EN-5-yl (where R9ais pyrrolidinyl or morpholinyl, and specified heterocyclic group is linked to alkenylphenol group through a carbon atom), or 1-R10abut-2-EN-4-yl, 1-R10athe Penta-2-EN-4-yl or 2-Rl0athe Penta-3-EN-5-is connected with alkenylphenol group through a nitrogen atom); 3) 1-R11aprop-1-in-3-yl, 1-R11abut-2-ine-4-yl, 1-R11abut-1-in-3-yl, 1-R11athe Penta-2-in-4-yl or 2-R11athe Penta-3-in-5-yl (where Rllais morpholinyl, and specified heterocyclic group is linked to alkenylphenol group through a carbon atom), or 1-R12abut-2-ine-4-yl, 1-R12athe Penta-2-in-4-yl or 2-R12athe Penta-3-in-5-yl (where R12ais morpholinyl, and specified heterocyclic group is linked to alkenylphenol group through a nitrogen atom); 4) C2-3alkyl2aCl-3alkyl3aR13a(where X2arepresents-O-, -NR14aCO - or-NR15a(where R14aand R15aeach independently represents a C1-2alkyl), X3represents-O -, and R13arepresents hydrogen or C1-3alkyl); 5) C2-3alkyl4aCOR16a(where X4arepresents-NR17a- (where R17arepresents hydrogen or C1-3alkyl) and R16arepresent-NR18aR19aor20a(where R18a, R19aand R20arepresent1-4alkyl)); 6) C2-3alkyl5aR21a(where X5arepresents a carbonyl, -O - or-NR24a- (where R24arepresents hydrogen or C1-ICAM this group is associated with X5athrough the carbon atom and the group may have one Deputy, selected from oxo, hydroxy, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl, or R21arepresents a C1-3alkyl, provided that when R21Arepresents a C1-3alkyl, X5arepresents-S-, -SO-, -SO2- or-NR23aSO2- (where R23arepresents hydrogen or C1-2alkyl))); 7)1-2alkoxyl2-3of alkyl, provided that X13represents-S-; 8) C2-3alkyl6aC2-3aR25a(where X6arepresents-O - or-NR23aSO2- (where R27arepresents hydrogen or C1-2alkyl) and R25arepresents 5 - or 6-membered saturated heterocyclic group selected from pyrrolidinyl, morpholinyl and piperazinil, and this heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N,N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl); 9) C2-3aR29a1-2hydroxyalkyl); 10)2-3R32a(where R32arepresents morpholino, which may have one or two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl), provided that, if R4arepresents a C2-3aR32athen X1arepresents-S-; and (11) C2-3aR33a(where R33arepresents morpholino having at least one and optionally two substituent selected from oxo, C1-2of alkyl, C1-2hydroxyalkyl, carbamoyl, C1-2allylcarbamate, N,N-di(C1-2alkyl)carbamoyl, acetyl and C1-2alkoxycarbonyl);

and its salts.

14. Derived hintline under item 1, chosen from:

4-(4-chloro-2-foronline)-7-(1,3-dioxolane-2-ylethoxy)-6-methoxyquinazoline,

4-(4-chloro-2-foronline)-6-methoxy-7-(4-morpholino-2-in-1 yloxy)hintline,

(E)-4-(4-chloro-2-foronline)-6-methoxy-7-(4-morpholino-2-EN-1-yloxy)hintline,

4-(4-chloro-2-foronline)-7-(3-(2,6-dimethylmorpholine)propoxy)-6-methoxyquinazoline,

4-(4-chloro-2-foronline)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl] amino)propoxy)geom-2-foronline)-6-methoxy-7-(3-([N-methyl-N-methylsulphonyl]amino)propoxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-Oxymetazoline-1-yl)ethoxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(3-oxaprotiline)ethoxy)hintline,

4-(4-bromo-2-foronline)-6-methoxy-7-(2-(3-oxaprotiline)ethoxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-thiomorpholine)hintline,

(S)-4-(4-bromo-2-foronline)-7-(3-(2-carbamoylation-1-yl)propoxy)-6-methoxyquinazoline,

(4-chloro-2-foronline)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)hintline,

(S)-7-(3-(2-carbamoylation-1-yl)propoxy)-4-(4-chloro-2-foronline)-6-methoxyquinazoline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)hintline and

4-(4-bromo-2-foronline)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)hintline,

and its salts.

15. Derived hintline under item 1, chosen from:

4-(4-chloro-2-foronline)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline,

4-(4-bromo-2-foronline)-7-(3-(1,1-dioxothiazolidine)propoxy)-6-methoxyquinazoline,

4-(4-bromo-2-foronline)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)hintline,

the hydroxy-7-(2-(2-[4-methylpiperazin-1-yl] ethoxy)ethoxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(3-morpholinopropan)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(2-([N-methyl-N-methoxyacetyl] amino)ethoxy)hintline and

4-(4-bromo-2-foronline)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)hintline,

and its salts.

16. Derived hintline under item 1, chosen from:

(E)-4-(4-chloro-2-foronline)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-EN-1-yloxy)hintline,

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(methylsulphonyl)propoxy)hintline,

(S)-4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline and

(R)-4-(4-chloro-2-foronline)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline,

and its salts.

17. Derived hintline under item 1, chosen from:

4-(4-chloro-2-foronline)-6-methoxy-7-(3-(methylsulphonyl)propoxy)hintline and its salts.

18. Derived hintline under item 1 of the formula I

< / BR>
where m is an integer 1 or 2;

R1represents hydrogen, nitro or C1-3alkoxy;

R2represents hydrogen or nitro;

R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano;

X1represents-O-, -S-, -SO - or-SO1-5the alkyl via a carbon atom and the heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-4the alkyl and C1-4hydroxyalkyl) or (C1-5R13(where R13represents a group selected from pyrrolidin-1-yl, imidazolidin-1-yl, thiomorpholine, and this group may have one or two substituent selected from oxo, hydroxy, C1-4the alkyl and C1-4hydroxyalkyl); 2)2-5aR14(where R14is pyrrolidinyl or morpholinyl); 3)2-5R15(where R15is morpholinyl); 4)1-5alkyl2C1-5-alkyl3R16(where X2represents-O-, -NR17CO-, -NR20SO2- or-NR21- (where R17, R20and R21each independently represents a C1-3alkyl), X3represents-O -, and R16represents hydrogen or C1-3alkyl); 5)1-5alkyl4CR22(where X4play a-NR24R25or26(where R24, R25and R26represent1-4alkyl)); 6)1-5alkyl5R27(where X5represents-O - or-NR32- (where R32represents hydrogen or C1-3alkyl) and R27is cyclopentyl or 5 - or 6-membered saturated heterocyclic group selected from piperidinyl, morpholinyl, piperazinil, pyrrolidinyl and tetrahydropyranyl, and the specified cyclopentyl or heterocyclic group may have one or two substituent selected from oxo, hydroxy, C1-4the alkyl and C1-4hydroxyalkyl); 7)1-3alkoxyl2-4of alkyl, provided that X1represents-S-; and 8)1-3alkoxyl2-4the alkyl or C1-4of alkyl, provided that X1represents-O-; with the additional proviso that, when R4choose from group 8), R1and/or R2is/are a nitro or at least one of R3represents a C1-3alkanoyloxy;

and its salts.

19. Derived hintline on p. 18, where R1represents methoxy.

20. Derived hintline under item 18 or 19, where R2represents UB>mhas the formula II

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

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

Rcrepresents hydrogen or hydroxy;

Rdrepresents hydrogen, fluorine or chlorine.

22. Derived hintline according to any one of paragraphs.18-21, where X1represents-O-.

23. Derived hintline on any one of the preceding paragraphs in the form of pharmaceutically acceptable salts.

24. The method of obtaining the derived hintline formula I or its salt as defined in paragraph 1, including the interaction of the compounds of formula III

< / BR>
where R1, R2X1and R4are as defined in paragraph 1;

L1represents a substitutable group,

with the compound of the formula IV

< / BR>
where R3and m are as defined in paragraph 1,

obtaining the compounds of formula I and their salts, and, when required pharmaceutically acceptable salt derived hintline formula I, the interaction of the compounds with an acid or a base, to obtain the desired pharmaceutically acceptable salt.

25. How about getting the j-O-, -S - or-SO2that includes the interaction of the compounds of formula VI

< / BR>
where X1, m, R1, R2and R3are as defined in paragraph 1,

with the compound of the formula VII

R4-L1(VII)

where R4is as defined in paragraph 1, and L1defined in paragraph 24,

and when you want pharmaceutically acceptable salt derived hintline formula I, the interaction of the compounds with an acid or a base, to obtain the desired pharmaceutically acceptable salt.

26. The method of obtaining the derived hintline formula I or its salt as defined in paragraph 1, including the interaction of the compounds of formula VIII

< / BR>
with the compound of the formula IX

R4-X1-H (VII)

where R1, R2, R3, R4, m and X1are as defined in paragraph 1;

L1defined in paragraph 24,

and when you want pharmaceutically acceptable salt derived chinaonline formula I, the interaction of the compounds with an acid or a base, to obtain the desired pharmaceutically acceptable salt.

27. The method of obtaining the derived hintline formula I or its salt as defined in paragraph 1, and where R4is the way the>represents-O - or-NR56(where R56represents hydrogen or C1-3alkyl) and R27is as defined in paragraph (1); 2) X8C1-5alkyl3R16(where X8represents-O-, -NR57CO-, -NR58SO2- or-NR59(where R57, R58and R59represents a C1-3alkyl) and X3and R16are as defined in paragraph (1); and (3) X9C1-5R33(where X9represents-O - or-NR61SO2- (where R61represents hydrogen or C1-3alkyl) and R33is as defined in paragraph (1); ] , or where R4represents a C2-5aR45(where R45represents a group selected from imidazolidin-1-yl, pyrrolidin-1-yl, thiomorpholine, and this group may have one or two substituent selected from oxo, hydroxy, C1-3of alkyl, C1-3hydroxyalkyl, carbamoyl, C1-3allylcarbamate, N, N-di(C1-3alkyl)carbamoyl,2-3alkanoyl and C1-3alkoxycarbonyl);

including the interaction of the compounds of formula X

< / BR>
where X1, R1, R2, R3, R4m are as defined in paragraph 1;

L1The R>
where R53is the same as defined above,

or with the compound of the formula Chi

R45-H (XIa)

where R45is as defined above;

R63in the compound X represents a C2-5alkyl,

obtaining the compounds of formula I; and, when required pharmaceutically acceptable salt derived hintline formula I, the interaction of the compounds with an acid or a base, to obtain the desired pharmaceutically acceptable salt.

28. Pharmaceutical composition for achieving antiangiogenic and/or the effect of reducing the permeability of the blood vessels of warm-blooded animal, comprising as active ingredient a compound of formula I, as defined in paragraph 1, or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable excipient or the media.

29. The way to achieve antiangiogenic and/or the effect of reducing the permeability of the blood vessels of warm-blooded animal in need of such treatment, comprising the introduction of a specified animal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt as defined in paragraph 1.

30. The compound of formula I, as Apparate to achieve antiangiogenic and/or the effect of reducing the permeability of the blood vessels of warm-blooded animals, such as people.

Priorities for items:

09.05.1997 - PP.1-13, 16-17, 24-30;

23.09.1997 on PP.14-15;

25.09.1996 on PP.18-22;

25.09.1996, 09.05.1996 and 23.09.1977 on p. 23 depending on its subordination.

 

Same patents:

The invention relates to an improved process for the preparation of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione used as antifibrillatory and antiarrhythmic agent, the General formula

< / BR>
incorporating the following stages: a) interaction 1- [[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-2,4-imidazolidinedione formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane and their mixtures, in the presence of a weak base selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione 4-methylpiperazine education 1-[[[5-(4-chlorophenyl)-2-furanyl] the methylene]amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione

The invention relates to an improved process for the preparation of 1,3-disubstituted 4-oxocyclohexa ureas used as antifibrillatory and antiarrhythmic agents, the General formula

< / BR>
where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy; R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and a represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen; incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichloro is tons of potash, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia

The invention relates to a new crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane hydrofolate, method thereof, pharmaceutical compositions on the basis and method of reducing or preventing the rarefaction of bone, including the introduction to the patient an effective amount of the specified new connection

The invention relates to a new method of producing compounds of the formula I

< / BR>
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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

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

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The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH
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