Derivatives of 5-pyridyl-1,3-azole, the method of production thereof, prodrug, pharmaceutical composition, method of antagonization adenosine a3 receptor, the method of inhibiting r mar-kinase, the method of inhibiting the production of tnf-alpha and method of prevention or treatment of diseases with their use

 

(57) Abstract:

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group. The compounds of formula (I) and which have antagonistic activity against adenosine A3-receptor and therefore can be useful as a preventive or medicines for the treatment of diseases mediated by the function of the adenosine A3receptors, cytokines or R MAR-kinase. 8 N. and 30 C. p. F.-ly, 8 PL.

The technical field to which the invention relates

The present invention relates to new derivatives of 5-pyridyl-1,3-azole with excellent therapeutic effects, in particular antagonistic activity against adenosine A3-receptor, inhibitory effect on R MAR-kinase, inhibiting effect on the production of TNF and the like, the method of production thereof, to pharmaceutical compositions and so on.

Background of invention

Are known subtypes of adenosine receptor as A1AND2AAND2band a3. Adenosine has tracheostenosis effect on a patient with asthma, and theophylline, which is the treatment for asthma, by contrast, shows the antagonism of the adenosine. In addition, recently it became known that the activation AND3-receptor in rat causes degranulation of the granules of mast cells (Journal of Biological Chemistry, 268 so, 16887-16890, 1993), and a3the receptor is present on eosinophils vu calcium (Blood, so 88, 3569-3574, 1996).

In addition, cytokines such as TNF- (factor - tumor necrosis), IL-1 (interleukin-1) and the like, are biological substances produced by many cells, such as monocyte or macrophage in response to infection and other cellular stress (Koj, A., Biochim. Biophis. Acta, 1317, 84-94 (1966)). Although these cytokines play an important role in the immune response, when they are present in the right quantity, it is assumed that excessive production causes a variety of inflammatory diseases (Dinarello, C. A., Curr. Opin. Immunol., 3, 941-948 (1991)). R MAR-kinase, cloned as a homolog MAR-kinase, associated with the management of the production of these cytokines and conversion system of signals associated with the receptor, and, probably, inhibition R MAR-kinase will be a medicine for the treatment of inflammatory diseases (Stein, C., Andersen, D., Annual Report in Medicinal Chemisry, edited by Bristol, J. A., Academic Press, T. 31, pages 289-298, 1996).

As compounds exhibiting selective antagonism against adenosine AND3receptors described derivatives of xanthine in GB-A-2288733 and WO 95/11681, and in the Journal of Medicinal Chemistry, 40 so, 2596-2608, 1997 describes the following compounds:

In addition, in WO 97/33879 described antagonist of adenosine A1-C4alkyl, C1-C4alkoxy or1-C4alkylcarboxylic, or its salt, and, in particular, the described connection

As compounds with inhibitory effect on R MAR-kinase, also described imidazole derivatives in JP-T 7-50317 (WO 93/14081) and derived oxazole in JP-T 9-505055 (WO 95/13067).

On the other hand, as derivatives of thiazole following known compounds:

1) derivatives of 1,3-thiazole represented by the formula:

in which R1is cycloalkyl group, cyclic amino group, the amino group, optionally having as a substituent, 1 or 2 lower alkyl, phenyl, acetyl or lower alkoxycarbonylmethyl, alkyl group optionally having as a substituent a hydroxyl, carboxyl or lower alkoxycarbonyl, or phenyl group optionally having as a substituent carboxyl, 2-carboxyethyl or 2-carboxy-1-propenyl, R2is pyridyloxy group optionally having as a substituent a lower alkyl, R3represents a phenyl group optionally having as a substituent of lower alkoxy, lower alkyl, hydroxyl, halogen or yazvennoi activities, inhibitory activity against the enzyme that synthesizes thromboxane A3(THA2), and inhibitory activity against coagulation of platelets (JP-A 60-58981),

2) derivatives of 1,3-thiazole represented by the formula:

in which R1represents an alkyl group, alkenylphenol group, aryl group, aracelio group, cycloalkyl group, heterocyclic group with carbon as a point of joining or amino group, optionally having substituents, R2is pyridyloxy group optionally substituted alkyl group, R3represents a phenyl group optionally having substituents, or their salts, which have an analgesic, cough, anti-inflammatory, antiulcer activity, inhibitory activity against the enzyme that synthesizes TXA2and inhibitory activity against coagulation of platelets (JP-A 61-10580),

3) derivatives of 1,3-thiazole represented by the formula:

in which R1represents an alkyl group, alkenylphenol group, aryl group, aracelio group, cycloalkyl group, heterocyclic group with carbon as a point pressestelle substituted alkyl group, R3represents an aryl group optionally having substituents, or their salts, which have an analgesic, cough, anti-inflammatory, antiulcer activity, inhibitory activity against the enzyme that synthesizes TXA2and inhibitory activity against coagulation of platelets (USP 4612321),

4) imidazole derivatives represented by the formula:

which have anticancer activity and cytokinemia activity, in particular, as described (WO 97/12876) the following connections:

As we have not yet found the antagonist of adenosine A3-receptor, a means of inhibiting R MAR-kinase and a means of inhibiting the production of TNF-, with satisfactory activity and action, safety (oral), absorbability, stability (metabolism) and the like, it is desirable that a highly effective antagonist of adenosine A3-receptor, a means of inhibiting R MAR-kinase and means for inhibiting the production of TNF-, are useful for prevention or treatment of diseases associated with adenosine A3receptor, cytokine-mediated diseases and is like the s in the result of various researches new connections which can be N-oxidised and which is represented by formula (I):

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents or an acyl group,

R2represents an aromatic group optionally having substituents,

R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or their salt [more commonly referred to as the compound (I)], a structural feature of which is that the position of the 5 rings, presents f is maseno 4-peredelnoj group and in addition, it has a side chain with an aromatic group in position 2 peredelnoj group, and found that the compounds (I) possess unexpectedly superior pharmaceutical activities, such as a selective affinity for the adenosine A3-and receptor antagonistic activity against adenosine A3-receptor inhibitory activity against R MAR-kinase, and the like, based on the specific chemical structure, and that have excellent physical properties, for example, pharmaceutical, such as stability and the like, and pharmaceutically satisfactory, so found the quality described above, and became the basis for the creation of the present invention.

In accordance with the present invention include:

(1) optionally N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents or an acyl group,

R2represents an aromatic group, neosyazaemuyu deputies, or aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salt,

(2) the compound according to (1), where Z represents the divalent acyclic hydrocarbon group optionally having substituents,

(3) the compound according to (1), which is a compound represented by the formula:

in which n is 0 or 1, and other symbols, such as defined in (1), or its salt,

(4) the compound according to (1) or (3) where R1represents the

(i) a hydrogen atom,

(ii) C1-6alkyl group, a C2-6alkenylphenol group, C2-6alkylamino group3-6cycloalkyl group6-14aryl group or7-16aracelio group [kazankina, C1-3alkylenedioxy, nitro, cyano, optionally halogenated C1-6the alkyl, optionally halogenated C2-6alkenyl, carboxy2-6alkenyl, optionally halogenated C2-6the quinil, optionally halogenated C3-6cycloalkyl,6-14aryl, optionally halogenated C1-8alkoxy, C1-6alkoxycarbonyl2-6alkoxy, hydroxy, C6-14aryloxy, C7-16aralkylated, mercapto, optionally halogenated C1-6alkylthio,6-14aaltio,7-16Uralkali, amino, mono-C1-6alkylamino, mono-C6-14arylamino, di-C1-6alkylamino, di-C6-14arylamino, formyl, carboxy, C1-6alkylcarboxylic,3-6cycloalkylcarbonyl, C1-6alkoxycarbonyl,6-14arylcarbamoyl,7-16aralkylamines,6-14aryloxyalkyl, C7-16orelkinoservisa, 5 - or 6-membered heterocyclic carbonyl, carbamoyl, thiocarbamoyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate,6-14arylcarbamoyl, 5 - or 6-membered heterocyclic of carbamoyl, C1-6alkylsulfonyl,6-14arylsulfonyl, C1-6alkylsulfonyl,6-14UB>1-6alkylsulfonamides,6-14arylsulfonamides, C1-6alkylcarboxylic,6-14arylcarboxylic, C1-6alkoxycarbonyl, mono-C1-6allylcarbamate, di-C1-6allylcarbamate,6-14arylcarbamoyl, nicotinuric, 5-7-membered saturated cyclic amino, optionally having 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom in addition to one nitrogen atom and carbon atoms (indicated cyclic amino may have substituents selected from the group consisting of C1-6of alkyl, C6-14aryl, C1-6alkylcarboxylic, 5-10-membered aromatic heterocyclic group and oxo), 5-10-membered aromatic heterocyclic group containing 1-4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms, sulfo, sulfamoyl, sulfamoyl and sulfamoyl],

(iii) a 5-14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and optionally having substituents selected from group a of substituents,

(iv) ACI is or-SO2-R7(where R5represents a hydrogen atom, a C1-6alkyl group, a C2-6alkenylphenol group, C2-6alkylamino group3-6cycloalkyl group6-14aryl group or7-16aracelio group optionally having substituents selected from group a of substituents, or a 5 to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and optionally having substituents selected from group a of substituents, R6represents a hydrogen atom or a C1-6alkyl group, R7represents C1-6alkyl group, a C2-6alkenylphenol group2-6alkylamino group3-6cycloalkyl group6-14aryl group or7-16aracelio group optionally having substituents selected from group a of substituents, or a 5 to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and optionally having substituents selected from group a of substituents),

(v) an amino group (the group mgpy, WITH2-6alkenylphenol group3-6cycloalkyl group6-14aryl group or7-16aranceles group optionally having substituents selected from group a of substituents, 5 to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and optionally having substituents selected from group a of substituents), acyl group, such as defined in (iv), and C1-6alkylidene group optionally having substituents selected from group a of substituents) or

(vi) a 5-7 membered non-aromatic cyclic amino group, optionally having 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom in addition to one nitrogen atom and carbon atoms (indicated cyclic amino may have substituents selected from the group consisting of C1-6of alkyl, C6-14aryl, C1-6alkylcarboxylic, 5-10-membered aromatic heterocyclic group and oxo);

R2is6-14monocyclic or condensed polycyclic aromatic hydrocarbon group optionally having replaced the th, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and optionally having substituents selected from group a of substituents;

R3represents a hydrogen atom, pyridyloxy group optionally having substituents selected from group a of substituents, or WITH6-14monocyclic or condensed polycyclic aromatic hydrocarbon group optionally having substituents selected from group a of substituents;

X represents O, S, SO or SO2:

Y represents a bond, O, S, SO, SO2or a group represented by the formula NR4(in which R4represents a hydrogen atom, a C1-6alkyl group, a C2-6alkenylphenol group, C2-6alkylamino group3-6cycloalkyl group6-14aryl group or7-16aracelio group optionally having substituents selected from group a of substituents, or acyl group, such as defined in (iv);

Z represents a bond, C1-15alkylenes group, C2-16alkenylamine group or2-16alkynylamino group optionally having substituents selected from group a of substituents,stitely,

(6) the compound according to (1), where R1represents (i) C1-6alkyl group, (ii)6-14aryl group, optionally substituted with substituents selected from C1-6alkylthio, C1-6alkylsulfonyl and halogen atom, or (iii) amino group, optionally having 1 or 2 acyl represented by the formula -(C=O)-R5’ (in which R5’ represents C1-6alkyl group, a C6-14aryl group or a 5-14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom),

(7) the compound according to (1), where R1represents the amino group, optionally having 1 or 2 acyl groups represented by the formula -(C=O)-R5(in which R5’ is6-14aryl group or a 5-14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom),

(8) the compound according to (1), where R2is6-14aryl group optionally having substituents,

(9) the compound according to (1), where R2prolinol aromatic heterocyclic group, containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom

(10) the compound according to (1), where R2is6-14aryl group or a 5-14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom

(11) the compound according to (1), where R3is6-14aryl group optionally having substituents,

(12) the compound according to (1), where R3is6-14aryl group, optionally substituted by one or two C1-6alkilani or C1-6alkoxy,

(13) the compound according to (1), where X represents an optionally oxidized sulfur atom,

(14) the compound according to (1), where X represents a sulfur atom,

(15) the compound according to (1), where Y represents an oxygen atom or a group represented by the formula NR4(in which R4such as defined in (1)),

(16) the compound according to (1), where Y represents an oxygen atom, optionally oxidized sulfur atom or the group, as is consistent with (1), where Y represents O, NH or S

(18) the compound according to (1), where Z represents the lower alkylenes group optionally having substituents,

(19) the compound according to (1), where Z represents a bond or C1-6alkylenes group optionally having oxo,

(20) the compound according to (1), where R1represents (i) C1-6alkyl group, (ii)6-14aryl group, optionally substituted C1-6alkylthio, C1-6alkylsulfonyl and a halogen atom, or (iii) amino group, optionally having 1 or 2 acyl groups represented by the formula -(C=O)-R5’ (in which R5’ represents C2-6alkyl group, a C6-14aryl group or a 5-14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom);

R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 to 14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom;

R or C1-6alkoxy;

X represents a sulfur atom;

Y represents an oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4’ (in which R4’ represents C1-6alkyl group);

Z represents C1-6alkylenes group optionally having oxo, or C1-6alkyl or bond

(21) the compound according to (1), where R1represents the amino group, optionally having 1 or 2 acyl represented by the formula -(C=O)-R5(in which R5’ is6-14aryl group or a 5-14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom);

R2is6-14aryl group or a 5-14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom;

R3is6-14aryl group optionally substituted by 1 or 2 C1-6alkilani or C1-6alkoxy;

X represents a sulfur atom; Y represents O, NH or S; Z submitted the(3, 5dimethylphenyl)-1,3-thiazol-2-yl]ndimethylacetamide (compound example No. 9),

N-[5-(2-benzylamino-4-pyridyl)-4-(3, 5dimethylphenyl)-1,3-thiazol-2-yl]ndimethylacetamide (compound example No. 10),

N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 13),

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 14),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-phenylacetamide (compound example No. 15-2),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-phenylacetamide (compound example No. 15-3),

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-phenylacetamide (compound example No. 15-4),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 15-6),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-1),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 16-2),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide (compound example No. 16-3),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyrate (compound example No. 16-5),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-7),

N-[4-[4-(3-metalfoil)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-9),

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 16-10),

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-11),

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylpropionamide (compound example No. 16-12),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-15),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 16-16),

N-benzyl-N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 19-2),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 19-3),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 19-4),

N-benzyl-N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 19-5),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 19-6),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 19-7),

N-benzyl-N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound PR is -9),

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (the compound of example No. 19 within 10),

N-benzyl-N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 19-17),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 19-18),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 19-19),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 20),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 21-1),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 21-2),

N-benzyl-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 21-5),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 21-6),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 25-1),

N-(4-terbisil)-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl) -1,3-thiazole-5-is,

(24) the method of obtaining the compound according to (1), including:

the interaction of the compounds represented by the formula:

in which Hal represents a halogen atom, and other symbols, such as defined in (1) or its salt with a compound represented by the formula:

in which R1such as defined in (1) or its salt to obtain the compound represented by the formula:

each character, such as defined in (1) or its salts or

(ii) the interaction of the compounds represented by the formula:

in which Hal represents a halogen atom, and other symbols, such as defined in (1) or its salt with a compound represented by the formula:

each character, such as defined in (1) or its salt to obtain the compound represented by the formula:

each character, such as defined in (1), or its salt, or

(iii) the interaction of the compounds represented by the formula:

each character, such as defined in (1) or its salt with a compound represented by the formula:

in which L represents a leaving group, and other symbols">each character, such as defined in (1), or its salt, or

(iv) the interaction of the compounds represented by the formula:

each character, such as defined in (1) or its salt with peroxyketal, hydrogen peroxide or alkylhydroperoxides obtaining compounds represented by the formula:

each character, such as defined in (1), or its salt,

(25) a pharmaceutical composition which contains the compound according to (1) or its prodrug,

(26) the composition according to (25), which is an antagonist of adenosine A3receptors

(27) the composition according to (25), which is an agent for the prevention or treatment of diseases associated with adenosine A3receptor,

(28) the composition according to (25), which is an agent for the prophylaxis or treatment of asthma or allergic diseases

(29) the composition according to (25), which is an agent for the prevention or treatment of brain edema, vascular diseases of the brain or head injury,

(30) the composition according to (25), which is a means for inhibiting R MAR-kinase,(32) the composition according to (25), which is an agent for the prevention or treatment of cytokine-mediated diseases

(33) the composition according to (25), which is an agent for the prophylaxis or treatment of inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, atherosclerosis, diseases of Creutzfeldt-Jakob disease, viral infections, atopic dermatitis, systemic lupus erythematosus, encephalopathy from AIDS, meningitis, angina, heart attack, congestive heart failure, hepatitis, transplantation, hypotension on dialysis or disseminated intravascular coagulation,

(34) the method of antagonization adenosine A3receptor, comprising introducing an effective amount of optionally N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group, it is necessarily having substituents, or acyl group,

R2represents an aromatic group optionally having substituents,

R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs mammal

(35) a method of inhibiting R MAR-kinase, comprising introducing an effective amount of optionally N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents, or Acillin3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs mammal

(36) a method of inhibiting production of TNF-including the introduction of effective amounts of optional N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents or an acyl group,

R2represents an aromatic group optionally having substituents,

R3the burly group, optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs mammal

(37) a method for preventing or treating asthma, allergic diseases, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, cerebral hemorrhage, heart attack, brain, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, atherosclerosis, diseases of Creutzfeldt-Jakob disease, viral infections, atopic dermatitis, systemic lupus erythematosus, encephalopathy from AIDS, the hypotension on dialysis or disseminated intravascular coagulation, including the introduction of effective amounts of optional N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents or an acyl group,

R2represents an aromatic group optionally having substituents,

R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs mammal

(38) the use of optional N-oxidized United group, optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents or an acyl group,

R2represents an aromatic group optionally having substituents,

R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs to obtain funds to provide antagonistic action on adenosine A3-receptor

(39) the use of optional N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon g is a group, optionally having substituents or an acyl group,

R2represents an aromatic group optionally having substituents,

R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs to obtain funds for the inhibition R MAR-kinase,

(40) the use of optional N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents, or SS="ptx2">R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs for receiving means for inhibiting the production of TNF-, and

(41) the use of optional N-oxidized compound represented by the formula:

in which R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an amino group, optionally having substituents or an acyl group,

R2represents an aromatic group optionally having substituents,

R3represents the atom moderaterna having substituents,

X represents an oxygen atom or an optionally oxidized sulfur atom,

Y represents a bond, oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and

Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or its salts or prodrugs to obtain funds for the prevention or treatment of asthma, allergic diseases, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, cerebral hemorrhage, heart attack, brain, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, atherosclerosis, disease of Creutzfeldt-Jakob disease, viral infections, atopic dermatitis, systemic lupus erythematosus, encephalopathy from AIDS, meningitis, strokes, heart attacks, stagnation is soudstage clotting.

In addition, in accordance with the present invention include:

(42) the compound according to (1), where R1represents the amino group, optionally having one or two acyl groups represented by the formula: -(C=O)-R5, -(C=O)-OR5, (C=O) -NR5R6, -(C=S)-OTHER5or-SO2-R7where each of the symbols defined in (4),

(43) the compound according to (1), where R1represents C1-6alkyl group optionally having substituents,

(44) the compound according to (1), where R1is6-14aryl group optionally having a C1-6alkylsulfonyl group

(45) the compound according to (7), where R5’ represents a phenyl group or pyridyloxy group

(46) the compound according to (1), where R2is6-14aryl group optionally having substituents, or a 5 to 14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and optionally having substituents,

(47) the compound according to (1), where R2is Venelin is inuu group, optionally substituted by one or two C1-6alkilani or C1-6alkoxy.

The best way of carrying out the invention

In the above formula, R1represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or an acyl group.

“Acyl group” represented by the symbol R1for example, represents an acyl group represented by the formula: -(C=O)-R5, -(C=O)-OR5, -(C=O)-NR5R6, -(C=S)-OTHER5or-SO2-R7(where R5represents a hydrogen atom, a hydrocarbon group optionally having substituents, or a heterocyclic group optionally having substituents, R6represents a hydrogen atom or a C1-6alkyl, R7represents a hydrocarbon group optionally having substituents, or a heterocyclic group optionally having substituents), and the like.

In this formula the “hydrocarbon group” of the “hydrocarbon group optionally having substituents” represents, for example, acyclic or cyclic hydrocarbon group (for example, alkyl, alkenyl, quinil, the cycle is symbolic hydrocarbon group, having 1-16 carbon atoms.

As the “alkyl” are preferred, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) and, in particular, C1-3alkyl (e.g. methyl, ethyl, propyl and isopropyl), and the like.

As “alkenyl” are preferred, for example,2-6alkenyl (for example, vinyl, allyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, and the like) and the like.

As quinil” are preferred, for example,2-6quinil (for example, ethinyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexenyl and the like) and the like.

As cycloalkyl” are preferred, for example, WITH3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like.

As the “aryl” are preferred, for example, WITH6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-antral and the like) and the like.

As aralkyl” are preferred, for example,7-16<, -phenylbutyl, 5-fenilpentil and the like) and the like.

“Substituents” of “hydrocarbon group optionally having substituents” represented by the symbol R5for example, represent an oxo, a halogen atom (e.g. fluorine, chlorine, bromine, iodine and the like), C1-3alkylenedioxy (for example, methylenedioxy, Ethylenedioxy and the like), nitro, cyano, optionally halogenated C1-6alkyl, optionally halogenated C2-6alkenyl, carboxy-C2-6alkenyl (for example, 2-carboxyethyl, 2-carboxy-2-methylethenyl and the like), optionally halogenated C2-6quinil, optionally halogenated3-6cycloalkyl,6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-antral and the like), optionally halogenated C1-8alkoxy, C1-6alkoxycarbonyl-C1-6alkoxy (for example, ethoxycarbonylmethoxy and the like), hydroxy, C6-14aryloxy (for example, phenyloxy, 1 naphthyloxy, 2-naphthyloxy and the like), WITH7-16Arakelots (for example, benzyloxy, penetrate and the like), mercapto, optionally halogenated C1-6alkylthio,6-14aaltio (for example, phenylthio, 1-n, amino, mono-C1-6alkylamino (for example, methylamino, ethylamino and the like), mono-C6-14arylamino (for example, phenylamino, 1 naphthylamine, 2-naphthylamine and the like), di-C2-6alkylamino (for example, dimethylamino, diethylamino, ethylmethylamino and the like), di-C6-14arylamino (for example, diphenylamino and the like), formyl, carboxy, C1-6alkylsulphonyl (for example, acetyl, propionyl and the like), WITH3-6cycloalkylcarbonyl (for example, cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl and the like),1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), WITH6-14arylcarbamoyl (for example, benzoyl, 1-naphtol, 2-naphtol and the like), C7-16aralkylamines (for example, phenylacetyl, 3-phenylpropionyl and the like), WITH6-14aryloxyalkyl (for example, phenoxycarbonyl and the like), C7-16Uralelectromed (for example, benzyloxycarbonyl, ventilatsioonil and the like), 5 - or 6-membered heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinoethyl, thiomorpholine, piperazine-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl and the like),Noah), di-C1-6allylcarbamate (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino and the like), WITH6-14arylcarbamoyl (for example, phenylcarbamoyl, 1-afterburner, 2-afterburner and the like), 5 - or 6-membered heterocyclic carbarnoyl (for example, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-taylornol, 3-taylornol and the like), C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and the like), WITH6-14arylsulfonyl (for example, phenylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl and the like), C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl and the like), WITH6-14arylsulfonyl (for example, phenylsulfinyl, 1-naphthylmethyl, 2-naphthylmethyl and the like), formylamino, C1-6alkylcarboxylic (for example, acetylamino and the like),6-14arylcarboxamide (for example, benzoylamine, naphthylamine and the like), C1-6alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, butoxycarbonylamino and the like), C1-6alkylsulfonyl (for example, methylsulfonylamino, ethylsulfonyl and the like), WITH6-14arylsulfonicalkylcarboxylic (for example, acetoxy, propionyloxy and the like), WITH6-14arylcarboxylic (for example, benzoyloxy, niftycorners and the like), C1-6alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), mono-C1-6allylcarbamate (for example, methylcarbamoyl, ethylcarbamate and the like), di-C1-6allylcarbamate (for example, dimethylcarbamoyl, diethylcarbamoyl and the like), WITH6-14arylcarbamoyl (for example, phenylcarbamoyloxy, afterburners and the like), nicotinuric, 5-7-membered saturated cyclic amino, optionally having substituents, 5-10-membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), sulfo, sulfamoyl, sulfamoyl, sulfamoyl and the like.

“Hydrocarbon group” may have 1 to 5, preferably 1-3, above Deputy identical or different.

The above “optionally halogenated C1-6alkyl”, for example, represents a C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) and the like, optionally having 1-5, preferably 1-3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like). His examples are methyl, chloromethyl, deformity, trichloromethyl, trifluoromethyl, ethyl, 2-bromacil, 2,2,2-triptorelin, pentafluoroethyl, propyl, 3,3,3-cryptochromes, isopropyl, butyl, 4,4,4-tripcomputer, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tryptophanyl, hexyl, 6,6,6-triptorelin and the like.

The above “optionally halogenated C1-6alkenyl”, for example, is a1-6alkenyl (for example, vinyl, propenyl, Isopropenyl, 2-butene-1-yl, 4-penten-1-yl, 5-HEXEN-1-yl) and the like, optionally having 1-5, preferably 1-3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like).

The above “optionally halogenated C2-6quinil” represents a C2-6quinil (for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyne-1-yl and the like) and the like, is not necessarily the th above “optionally halogenated3-6cycloalkyl”, for example, represents a C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like, optionally having 1-5, preferably 1-3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like). His examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorothiophenol, 4-chlorcycloguanil and the like.

The above “optionally halogenated C1-8alkoxy”, for example, represents a C1-8alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like) and the like, optionally having 1-5, preferably 1-3, halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like). His examples are methoxy, deformedarse, triptoreline, ethoxy, 2,2,2-triptoreline, propoxy, isopropoxy, butoxy, 4,4,4-triptoreline, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.

The above “optionally halogenated C1-6alkylthio”, for example, represents a C1-6alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, batistatou halogen (for example, fluorine, chlorine, bromine, iodine and the like). His examples are methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia, pentylthio, hexylthio and the like.

“5-7-Membered saturated cyclic amino” of the above “5 to 7 membered saturated cyclic amino, optionally having substituents”, is a 5-7-membered saturated cyclic amino, optionally containing, in addition to one nitrogen atom and carbon atoms, 1-4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and examples are pyrrolidin-1-yl, piperidino, piperazine-1-yl, morpholino, thiomorpholine, hexahydro-azepin-1-yl and the like.

“Vice” “5-7-membered saturated cyclic amino, optionally having substituents”, for example, represent a 1-3 C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), WITH6-14aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-antral and the like), C1-6alkylsulphonyl (for example, acetyl, propionyl and the like), 5-10-membered aromatic the sludge, 5-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), oxo and the like.

“Heterocyclic group” of the “heterocyclic group optionally having substituents” represented by the symbol 5for example, represents a monovalent group obtained by removing one arbitrary hydrogen atom from a 5 to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, preferably (i) a 5 to 14-membered (preferably 5-to 10-membered, particularly preferably 5 to 6 membered) aromatic heterocycle, (ii) 5-10-membered (preferably 5 to 6 membered) non-aromatic heterocycle, or (iii) 7-10-membered heterocycle with bridge connection.

The above “5 to 14-membered (preferably 5-to 10-membered) aromatic heterocycle” represents an aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, oil, the urin, 4H-hemolysin, isoquinoline, quinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnoline, carbazole, carboline, phenanthridine, acridine, fenesin, thiazole, isothiazol, phenothiazines, isoxazol, furazan, phenoxazine and the like, and the ring formed by odensala these rings (preferably monocyclic) with 1 or more (preferably 1-2) aromatic rings (such as benzene ring and the like).

The above “5-to 10-membered nonaromatic a heterocycle”, for example, is pyrrolidin, imidazolin, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dixital, oxadiazolyl, thiadiazoline, triazoline, thiadiazole, dithiazole and the like.

The “7-10-membered heterocycle with bridge connection”, for example, represents Hinkley, 7-azabicyclo[2.2.2] heptane and the like.

“Heterocyclic group” is preferably a 5 to 14-membered (preferably 5-to 10-membered) (monocyclic or bicyclic) heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom. In particular, the examples of it are the aroma is INAIL, 3-chinolin, 4-chinolin, 5-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazole, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like, and non-aromatic heterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolyl, 4-imidazolyl, 2-pyrazolidone, 3-pyrazolidone, 4-pyrazolidine, piperidine, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinil, 2-piperazinil, morpholino, thiomorpholine and the like.

Of them, for example, preferred is a 5 - or 6-membered heterocyclic group containing, in addition to carbon atoms, 1-3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom. In particular, examples are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazole, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolyl, 4-imidazolyl, 2-pyrazolidone, 3-pyrazolidone, 4-pyrazolidine, piperidine, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazin, optionally having substituents”, for example, are the same “Vice” as the substituents of the “hydrocarbon group optionally having substituents”, (((a5.

“Heterocyclic group” may have 1 to 5, preferably 1-3, the aforementioned substituents at substitutable position and, when the number of substituents is 2 or more, respective substituents may be the same or different.

“C1-6By alkyl” represented by the symbol R6for example, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

“Hydrocarbon group optionally having substituents” and “heterocyclic group optionally having substituents” represented by the symbol R7for example, constitute the “hydrocarbon group optionally having substituents” and “heterocyclic group optionally having substituents” represented by the symbol R5respectively.

“Hydrocarbon group optionally having substituents” and “heterocyclic group optionally having substituents” represented by the symbol R1for example, imagine what Ino having substituents”, represented by the symbol R5respectively.

“Amino group, optionally having substituents” represented by the symbol R1for example, represents (1) an amino group, optionally having 1 or 2 substituent, and (2) cyclic amino group, optionally having substituents, and the like.

“Substituents” of the “amino group, optionally having 1 or 2 substituent” on the above (1), for example, represent a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an acyl group, alkylidene group optionally having substituents, and the like. The mentioned “hydrocarbon group optionally having substituents” and “heterocyclic group optionally having substituents”, are “hydrocarbon group optionally having substituents” and “heterocyclic group optionally having substituents”, which are respectively represented by the symbol5as explained above. “Acyl group” is the same “acyl group” represented by the symbol R1as explained above.

“Alkylidene group” “akiltopu (for example, methylidene, ethylidene, propylidene and the like) and the like. “Vice” “alkylidene group optionally having substituents” are 1-5, preferably 1-3, the same substituents as the “substituents” of the “alkylidene group optionally having substituents” represented by the symbol R5.

When the number of the above “substituents” of the “amino group, optionally having 1 or 2 substituent is 2, respective substituents may be the same or different.

“Cyclic amino group” of the “cyclic amino group, optionally having substituents” in the above paragraph (2), represents a 5-7 membered non-aromatic cyclic amino group, optionally containing, in addition to one nitrogen atom and carbon atoms, 1-4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom. In particular, the examples of it are pyrrolidin-1-yl, piperidino, piperazine-1-yl, morpholino, thiomorpholine, hexahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl, 3,4-dihydro-1(2H)-pyrimidinyl and the like. “Substituents” of the “cyclic amino, optional, we, optionally having substituents” represented by the symbol R5.

Examples 5-7-membered non-aromatic cyclic amino group having 1 oxo, are 2-Oxymetazoline-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-exoterica-1(2H)-pyrimidinyl, 2-oxo-3,6-dihydro-1(2H)-pyrimidinyl, 2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, 2-oxopyrrolidin-1-yl, 2-oxopiperidine, 2-oxopiperidin-1-yl, 3-oxopiperidin-1-yl, 2-oxo-2,3,4,5,6,7-hexahydroazepin-1-yl and the like.

For R1preferred are amino group, optionally having substituents, aryl group optionally having substituents, an alkyl group optionally having substituents, and the like.

Other preferred examples of the amino group, optionally having substituents is amino, optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5, -(C=O)-OR5, -(C=O)-NR5R6, -(C=S)-OTHER5or-SO2-R7[where the respective symbols represent the same meanings as described above]. Especially preferred is an amino group, optionally having 1 or 2 acyl represented by the formula: -C(C=O)-R5or -(C=O)-NR5R6[where appropriate the th Vice”, for example, is a preferably6-14aryl group (preferably phenyl group and the like) optionally having 1-5 substituents selected from C1-6alkylthio,6-14aaltio, C1-6alkylsulfonyl,6-14arylsulfonyl, C1-6alkylsulfonyl,6-14arylsulfonyl and carboxy.

As the “alkyl group optionally having substituents” is preferred, for example, C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like) optionally substituted by 1 to 3 substituents selected from a halogen atom, a C1-6alkoxy, hydroxy, carboxy and C1-6alkoxycarbonyl and the like, and particularly preferred is C1-3alkyl group such as methyl, ethyl and the like.

Of them for R1preferred are (i) C1-6an alkyl group (for example, C1-4alkyl group such as methyl, ethyl, propyl, butyl), (ii)6-14aryl group (e.g. phenyl group) optionally substituted by substituents selected from C1-6alkylthio (for example, methylthio), C1-6alkylsulfonyl (for example, methylsulphonyl) and the purposes of the formula -(C=O)-R5’ (in which R5’ represents C1-6alkyl group (for example, C1-3alkyl group such as methyl), C6-14aryl group (e.g. phenyl group) or a 5 to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom (for example, 5-6-membered heterocyclic group containing, in addition to carbon atoms and 1-2 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, such as Peregrina group)). For R5’ and R5’ suitable is phenyl or Peregrina group.

In the above formula, R2represents an aromatic group optionally having substituents.

“Aromatic group” of the “aromatic group optionally having substituents” represented by R2for example, represents an aromatic hydrocarbon group, aromatic heterocyclic group and the like.

Examples of the “aromatic hydrocarbon group” include6-14monocyclic or condensed polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-antral and the like, and, more preferably, FROM6-10aryl group and the like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like, preferably phenyl, and the like).

“Aromatic heterocyclic group” is a monovalent group obtained by removing one arbitrary hydrogen atom from a 5 to 14-membered (preferably 5-to 10-membered) aromatic heterocycle containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom. The above “5 to 14-membered (preferably 5-to 10-membered) aromatic heterocycle”, for example, is an aromatic heterocycle such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, oil[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-hemolysin, isoquinoline, quinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, carbazole-carboline, phenanthridine, acridine, fenesin, thiazole, isothiazol, phenothiazines, isoxazol, furazan, phenoxazine and the like, and the ring formed kineticheskimi rings (for example, the benzene ring and the like).

“Aromatic heterocyclic group” represents, preferably, 5 to 14-membered (preferably 5-to 10-membered) (monocyclic or bicyclic) aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and the like and, in particular, represents an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazole, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like.

“Substituents” of the “aromatic group optionally having substituents”, is 1-5, preferably 1-3, the same substituents as the “substituents” of “hydrocarbon group optionally having substituents” represented by the symbol R5. When the number of substituents is 2 or more, sootla (1)6-14aryl group optionally having substituents, and (2) a 5 to 14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, and which one is preferable (1)6-14aryl group (e.g. phenyl group, naftalina group), optionally substituted by halogen atom (e.g. a chlorine atom, a fluorine atom), or C1-6alkoxy (e.g. methoxy), (2) 5-14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom (for example, 5-6-membered aromatic heterocyclic group containing, in addition to carbon atoms and 1-2 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, such as Peregrina group, thienyl group and the like, and, in particular, are suitable phenyl group, Peregrina group and the like.

In the above formula, R3represents a hydrogen atom, pyridyloxy group optionally having substituents, or an aromatic hydrocarbon group optionally having zai symbol R3are the same substituents as the “substituents” of “hydrocarbon group optionally having substituents” represented by the symbol R5.

“Peregrina group” may for example be 1-5, preferably 1-3, the above substituents in substitutable positions, and when the number of substituents is 2 or more, respective substituents may be the same or different. In addition, the nitrogen atom in the cycle can be N-oxidized.

“Aromatic hydrocarbon group” of the “aromatic hydrocarbon group optionally having substituents” represented by the symbol R3represents the same aromatic hydrocarbon group as the “aromatic hydrocarbon group” of the “aromatic group optionally having substituents” represented by the symbol R2and, preferably, is a6-14aryl group and the like, such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-antral and the like, and, more preferably, FROM6-10aryl group and the like (for example, phenyl, 1-naphthyl, 2-naphthyl and the like, preferably phenyl, and the like), and the like. “Vice” “aromatase same as the substituents of the “aromatic hydrocarbon group optionally having substituents” represented by the symbol R2.

For R3WITH6-14aryl group optionally having substituents is preferred, and of these groups, preferred is a6-14aryl group, optionally substituted by 1 or 2 C1-6alkilani (for example, stands, ethyl and the like), and, in particular, is suitable phenyl group optionally substituted by 1 or 2 C1-6alkilani or C1-6alkoxy (for example, 3-methoxyphenyl, 2-were, 2,4-dimetilfenil and the like).

In the above formula X represents an oxygen atom or an optionally oxidized sulfur atom.

“Optionally oxidized sulfur atom” represented by the symbol X represents S, SO and SO2.

Preferably X represents an optionally oxidized sulfur atom. Is preferred when X is s

In the above formula, Y represents a bond, oxygen atom, optionally oxidized sulfur atom or the formula NR4(in which R4represents a hydrogen atom, a hydrocarbon group optionally having substituents, or the Oh S, SO and SO2.

“Hydrocarbon group optionally having substituents” represented by the symbol R4for example, represents the same group as the “hydrocarbon group optionally having substituents” represented by the symbol R5. Of them, preferred is a C1-6alkyl group such as methyl, ethyl and the like, and, in particular, C1-3alkyl group such as methyl and the like.

“Acyl group” represented by the symbol R4is the same group as the “acyl group” represented by the symbol R1.

For Y are preferred oxygen atom, optionally oxidized sulfur atom, a group represented by the formula NR4(in which R4represents the same meanings as described above) and the like, and of these, the preferred oxygen atom, optionally oxidized sulfur atom, a group represented by the formula NR4’ (in which R4’ is hydrogen or C1-6alkyl group), and the like, and more preferred oxygen atom, S, SO2, NH, N(CH3and the like, and particularly preferred is O or NH.

In the above formula, Z represents a bond and ntna acyclic hydrocarbon group” of the “divalent acyclic hydrocarbon group, optionally having substituents”, for example, is a1-15alkylenes group (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptameron, octamethylene and the like, preferably C1-6alkylenes group and the like), WITH2-16alkenylamine group (for example, vinile, propylen, 1-butylen, 2-butylen, 1-penttinen, 2-penttinen, 3-penttinen and the like), WITH2-16alkynylamino group (for example, ethynylene, propylen, 1-Butylin, 2-Butylin, 1-pentikinen, 2-pentikinen, 3-pentikinen and the like) and the like, preferably1-15alkylenes group, more preferably a C1-6alkylenes group and the like. “Substituents” of the “divalent acyclic hydrocarbon group optionally having substituents” represented by the symbol Z, for example, are the same as the “substituents” of “hydrocarbon group optionally having substituents” represented by the symbol R5.

For Z, it is preferable lower Allenova group, with optional C1-3alkyl (e.g. methyl), oxo and the like, (for example, C1-6Allenova group such as methylene, ethylene, propylene and the Lenovo group, optionally having oxo (e.g., C1-3Allenova group such as methylene, ethylene, propylene, in particular methylene).

In particular, for use Z-CH2-, (CH2)2-, -(CH2)3-, -CO-, -CH2CO-, -(CH2)2CO-, -CH(CH3) and the like, and particularly suitable are-CH2-, -CO -, and the like.

The nitrogen atom in the compound (I) can be N-oxidized. For example, a nitrogen atom, an atom that is part of a 4-peredelnoj group, which substituent in position 5 of the ring represented by the formula:

showing the symbol has the same meanings as described above, may be N-oxidized. For the compounds of formula (I), preferred are compounds represented by the formula:

in which n is 0 or 1, and other symbols have the same meanings as described above, or its salt.

As the compound (I) preferably uses the following compounds (A)-(F).

(A) Compound (I), where R1represents the amino group, optionally having substituents, R2represents C6-14aryl group optionally having substituents, R3is6-14aryl group is dostavlenny formula NR4(in which R4has the same meanings as described above), and/or Z represents lower alkylenes group optionally having substituents.

(C) the Compound (I), where R1represents (i) C1-6alkyl group (for example, C1-4alkyl group such as methyl, ethyl, propyl, butyl and the like),

(ii)6-14aryl group (e.g. phenyl group) optionally substituted by substituents selected from C1-6alkylthio (for example, methylthio), C1-6alkylsulfonyl (for example, methylsulphonyl) and halogen atom (e.g. chlorine atom, fluorine atom), or

(iii) amino group, optionally having 1 or 2 acyl represented by the formula -(C=O)-R5’ (in which R5’ represents C1-6alkyl group (for example, C1-3alkyl group such as methyl and the like), 6-14aryl group (e.g. phenyl group) or a 5 to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom (for example, 5-6-membered aromatic heterocyclic group containing, in addition to carbon atoms and 1-2 heteroatoms of one or two withdrawal6-14aryl group (e.g. phenyl group, naftalina group), optionally substituted by halogen atom (e.g. a chlorine atom, a fluorine atom), or C1-6alkoxy (e.g. methoxy), or a 5 to 14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom (for example, 5-6-membered aromatic heterocyclic group containing, in addition to carbon atoms and 1-2 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, such as Peregrina group, thienyl group and the like);

R3is6-14aryl group (particularly phenyl group) optionally substituted by one or two C1-6alkilani (e.g., stands) or C1-6alkoxy (e.g. methoxy);

X represents a sulfur atom;

Y represents an oxygen atom, optionally oxidized sulfur atom or a group represented by the formula NR4’ (in which R4’ represents C1-6alkyl group (particularly, an oxygen atom, S, SO2, NH, N(CH)3and the like);

Z represents C1-6alkylenes group/SUB>alkyl, such as methyl), or link.

(C) the Compound (I), where R1represents the amino group, optionally having 1 or 2 acyl represented by the formula -(C=O)-R5(in which R5’ is6-14aryl group (e.g. phenyl group) or a 5 to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom (for example, 5-6-membered aromatic heterocyclic group containing, in addition to carbon atoms and 1-2 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, such as Peregrina group);

R2is6-14aryl group (e.g. phenyl group) or a 5 to 14-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom (for example, 5-6-membered aromatic heterocyclic group containing, in addition to carbon atoms and 1-2 heteroatoms of one or two kinds selected from a nitrogen atom, sulfur atom and oxygen atom, such as Peregrina group);

R1-6alkilani (e.g., stands) or C1-6alkoxy (e.g. methoxy);

X represents a sulfur atom;

Y represents O, NH or S;

Z represents a bond or C1-6alkylenes group (in particular, C1-3alkylenes group optionally having oxo, such as methylene, ethylene and the like) optionally having oxo.

(D) Compound (I) obtained in examples 1-79.

(E) [4-(3, 5dimethylphenyl)-5-(2-phenylmethoxy-4-pyridyl)-1,3-thiazol-2-yl]amine (compound of example No. 1),

N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 2),

N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonyl)]-4-pyridyl]-1,3-thiazol-2-yl]nicotinamide (compound of example No. 3),

N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 4),

N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 5),

N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine (compound example No. 6),

N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzenedithiol (compound example No. 7),

N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylmethylamine (soedineniya No. 9),

N-(5-(2-benzylamino-4-pyridyl)-4-(3, 5dimethylphenyl)-1,3-thiazol-2-yl]ndimethylacetamide (compound example No. 10),

N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 13),

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 14),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl] phenylacetamide (compound example No. 15-2),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 15-3),

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 15-4),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 15-6),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl] benzamide (compound example No. 16-1),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl] 3-phenylpropionamide (compound example No. 16-2),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide (compound example No. 16-3),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyrate (compound example No. 16-5),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-7),

N-[4-[4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] benzamide (compound example No. 16-9),

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 16-10),

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-11),

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylpropionamide (compound example No. 16-12),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 16-15),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 16-16),

N-benzyl-N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 19-2),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 19-3),

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 19-4),

N-benzyl-N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 19-5),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 19-6),

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 19-7),

N-benzyl-N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound PR is -9),

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (the compound of example No. 19 within 10),

N-benzyl-N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 19-17),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 19-18),

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 19-19),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (compound example No. 20),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (compound example No. 21-1),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide (compound example No. 21-2),

N-benzyl-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (compound example No. 21-5),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine (compound example No. 21-6),

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (compound example No. 25-1),

N-(4-terbisil)-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazole-5-Ile ammonium, salt with organic base, salt with inorganic acid, salt with organic acid, salt with basic or acidic amino acid and the like. Suitable salt of the metal is a salt of an alkali metal such as sodium salt, potassium salt and the like; salt with alkaline earth metal such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. Suitable examples of the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N’-dibenziletilendiaminom and the like. Suitable examples of the salt with inorganic acid include salts with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of the salt with organic acid include salts with formic acid, acetic acid, triperoxonane acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, bensaali amino acid are for example, salts with arginine, lysine, ornithine and the like. Suitable examples of salts with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

Of these salts, preferred are pharmaceutically acceptable salts. For example, when the compound has an acidic functional group, there are inorganic salts such as alkali metal salt (e.g. sodium salt, potassium salt and the like), salts of alkaline earth metal (e.g. calcium salt, magnesium salt, barium salt and the like), ammonium salt and the like, and when you keep in the connection of the main functional groups are salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids, such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonate acid, p-toluensulfonate acid and the like.

Below is described the method of obtaining the compound (I). The compound (I) in the om, shown in the following schemes 1, 2, 4, and 5 reactions, and in the same way.

The corresponding characters in the compounds in schemes 1, 2, 4, and 5 reactions have the same meanings as described above. Connection diagrams reactions include their salts, for example, are the same as the salt of compound (I).

[Scheme 1 reactions]

Compounds (II), (III), (V), (VIII), (XI), (XII), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXVI) and (XXVII) can be used as such when they are commercially available or can be obtained by a method known per se or a similar method.

The compound (IV) can be obtained by condensation of compound (II) and compound (III) in the presence of a base.

The amount of compound (III) is from about 0.5 mol to about 3 mol, preferably from about 0.8 mol to about 2 mol, per 1 mol of compound (II).

The amount of base is from about 1 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (II).

“Base”, for example, is a basic salt, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate and the like, an inorganic base, such as hydroxide n is hydrated amine, such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, alkali metal hydride such as sodium hydride, potassium hydride and the like, metal amide such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium and the like, a metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, water or a mixture of two or more of them.

The reaction temperature is usually from about -5 to about 200C, preferably from about 5 to about 150C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 20 hours

Although the reaction product can be used in the next stage in the reaction solution or in the form of neo is DAMI division, such as recrystallization, distillation, chromatography and the like.

The compound (VI) can be obtained by treating compound (IV) the substrate and condensation of the resulting compound with compound (V).

In the compound (V) L is a leaving group.

“Leaving group” denoted by the symbol L represents, for example, a C1-6alkoxy (e.g. methoxy, ethoxy and the like), di-C1-6alkylamino (for example, dimethylamino, diethylamino and the like), N-C6-10aryl-N-C1-6alkylamino (for example, N-phenyl-N-methylamino and the like), 3-7-membered cyclic amino (e.g., pyrrolidino, morpholino, methylaziridine-1-yl and the like), optionally substituted C6-10the aryl and/or C1-6the alkyl, N-C1-6alkyl-N-C1-6alkoxyamino (N-methoxy-N-methylamino and the like) and the like. In addition, the “leaving group” denoted by the symbol L represents, for example, a hydroxy, a halogen atom (e.g. fluorine, chlorine, bromine, iodine and the like), optionally halogenated1-5alkylsulfonate (for example, methanesulfonate, econsultancy, trichlorocarbanilide and the like), WITH6-10arylsulfonate, optional Imier, represents a C6-10arylsulfonate (for example, phenylsulfonyl, naftiliaki and the like) optionally having 1-3 substituent selected from C1-6of alkyl, C1-6alkoxy and nitro. Examples of it are benzosulfimide, m-nitrobenzenesulfonate, p-toluensulfonate and the like.

The amount of base is from about 0.8 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (IV).

As the base used, for example, amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -78 to about 60, preferably from about -78 to about 20C. The reaction time is usually from about 5 min to about 24 h, predpochtite the reaction solution or in the form of the crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (VII) can be obtained by treating compound (VI) a halogen or metal halide. This reaction is carried out, when required, in the presence of a base or basic salt.

The amount of halogen or halide of the metal is from about 1 to about 5 mol, preferably from about 1 to about 2 mol, per 1 mol of compound (VI).

The Halogens are bromine, chlorine, iodine and the like.

“The metal halide is a halide of copper, such as copper bromide (II) chloride copper (II) and the like.

The amount of base is from about 1 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (VI).

“Base”, for example, is an inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and the like, arene is Lamin, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, NITRILES, sulfoxidov, organic acids, aromatic amines or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 to about 150, preferably from about 0 to about 100C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (Ia) can Beattie Foundation.

In the compound (VII) Hal represents halogen.

When the compound (VIII) are commercially available, it can be used as such or can be obtained in a known manner per se or a method corresponding to the known method, or the method shown in scheme 3 reactions.

The amount used of the compound (VIII) is from about 0.5 mol to about 3 mol, preferably from about 0.8 mol to about 2 mol, per 1 mol of compound (VII).

The amount of base is from about 1 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (VII).

“Base”, for example, is the basis of alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, sodium carbonate, potassium carbonate, cesium, sodium bicarbonate, and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

The above reaction it is advisable PR is jut, assuming that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, NITRILES, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -5 to about 200C, preferably from about 5 to about 150C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture of traditional ways and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (IX) can be obtained by treating compound (Ia) with an acid.

The amount of acid used is from about 1 mol to about 100 mol, preferably from about 1 mol to about 30 mol, per 1 mol of compound (Ia).

As “acid” are used, for example, mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the TA and the like.

The above reaction is carried out in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, water, mixtures of water and amides, mixtures of water and alcohols, and the like.

The reaction temperature is usually from about 20 to about 200C, preferably from about 60 to about 150C. The reaction time is usually from about 30 minutes to about 72 hours, preferably from about 1 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (X) can be obtained by treating compound (IX) halogenation agent.

The amount of halogenation agent is from about 1 mol to about 10 mol, preferably from about 1 mol to about 5 mol, per 1 mol of compound (IX).

As a halogenation agent” are used, for example, thionyl chloride, pentachloride phosphorus oxychloride phosphorus and so pastorates. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, NITRILES, sulfoxidov, organic acids, aromatic amines or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 to about 150, preferably from about 0 to about 100C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (Ib) can be obtained by condensation of compound (X) with compound (XI). The reaction is carried out, when required, in the presence of a base.

The amount of base is from about 0.8 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 my potassium carbonate, cesium carbonate and the like, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, hydrides of alkali metals, such as sodium hydride, potassium hydride and the like, amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium and the like, alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -78 to about 200C, preferably from about room temperature to about S. The reaction time is usually hundreds of reactions can be used in the next reaction as the reaction solution or in the form of the crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

[Scheme 2 reactions]

The compound (XIII) is produced from compound (XII) by the method described in Synthesis, pages 877-882, 1996 or Journal of Organic Chemistry, volume 61, pages 4810-4811, 1996.

The compound (XIV) is obtained by treating compound (XIII) the basis and odensala the obtained compound with compound (V).

The amount of base is from about 0.8 mol to about 5 mol, preferably from about 2 moles to about 2.5 mol per 1 mol of compound (XIII).

As the base used, for example, alkylate, such as n-utility and the like, and amides of metals, such as sodium amide, diisopropylamide lithium, hexamethylene-silized lithium and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more of them, and the like.

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (XV) can be obtained by treating compound (XIV) with halogen or metal halide. This reaction is carried out, when required, in the presence of a base or basic salt.

The amount of halogen or halide of the metal is from about 1 to about 5 mol, preferably from about 1 to about 2 mol, per 1 mol of compound (XIV).

The Halogens are bromine, chlorine, iodine and the like.

“The metal halide is a halide of copper, such as copper bromide (II) chloride copper (II) and the like.

The amount of base is from about 1 mol to about 10 mol, preferably from about 1 mol to about 3 mol, per 1 mol of compound (XIV).

“ what, the lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, NITRILES, sulfoxidov, organic acids, aromatic amines or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 to about 150, preferably from about 0 to about 100C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours

Although the reaction product can be used in the following reactions in si in the traditional way and can easily be purified by the methods of separation, such as recrystallization, distillation, chromatography and the like.

The compound (XVI) can be obtained by condensation of compound (XV) with the compound (VIII). This reaction is carried out, when required, in the presence of a base.

In the compound (XV) Hal represents halogen.

When the compound (VIII) are commercially available, it can be used as such or can be obtained in a known manner per se or a method corresponding to the method, or the method shown in scheme 3 reactions.

The amount used of the compound (VIII) is from about 0.5 mol to about 3 mol, preferably from about 0.8 mol to about 2 mol, per 1 mol of compound (XV).

The amount of base is from about 1 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (XV).

“Base”, for example, is a basic salt, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexylmethyl is Noah.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, NITRILES, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -5 to about 200C, preferably from about 5 to about 150C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (XVII) is obtained by removing the protecting compound (XVI) using acid or base.

The amount used of the acid or base is from about 0.1 mol to about 50 mol, preferably from about 1 mol D. the slots, such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the like, a Lewis acid such as trichloride boron, tribromide boron, and the like, a Lewis acid together with thiols or sulfides, organic acids, such as triperoxonane acid, p-toluensulfonate acid and the like.

As “base”, for example, use metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate and the like, alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, organic bases such as triethylamine, imidazole, formamidine and the like.

The above reaction it is advisable to carry out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxidov, water or a mixture of two or more of them, and the like.

The reaction time is usually from about 10 min dimanno 0 to about 200C, preferably from about 20 to about 120C.

The compound (IC) can be obtained by condensation of compound (XVII) with the compound (XVIII), optionally in the presence of a base.

The amount used of the compound (XVIII) is from about 0.8 to about 5 mol, preferably from about 1 to about 3 mol, per 1 mol of compound (XVII).

The amount of base is from about 0.1 mol to about 3 mol, preferably from about 0.3 mol to about 1.2 mol, per 1 mol of compound (XVII).

“Base”, for example, is a basic salt, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate and the like, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, hydrides of alkali metals, such as sodium hydride, potassium hydride and the like, amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide l is the similar.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -78 to about 100C, preferably from about -78 to about 70C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 0.5 to about 20 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like. Then the compounds in which R4is other than a hydrogen atom may, if necessary, can be synthesized by alkylation or acylation.

[Scheme 3 reactions]

The compound (XX) obtained by odensala compound (XIX) and amines represented by the formula, R6H.

R6predstava the compound (XIX) R5is alkoxygroup. “Alkoxygroup” represents, for example, C1-6alkoxygroup, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

The number “amines” is from about 1 to about 30 mol, preferably from about 1 to about 10 mol, per 1 mol of compound (XIX).

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, NITRILES, ketones or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -5 to about 200C, preferably from about 5 to about 120C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and may bite.

The compound (VIII) is obtained by hydrolysis of compound (XX) with the use of acid or base.

The amount used of the acid or base is from about 0.1 mol to about 50 mol, preferably from about 1 mol to about 20 mol, per 1 mol of compound (XX), respectively.

As the “acid” is used, for example, mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the like, a Lewis acid such as trichloride boron, tribromide boron, and the like, a Lewis acid together with thiols or sulfides, organic acids, such as triperoxonane acid, p-toluensulfonate acid and the like.

As “base”, for example, use metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and the like, alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, organic bases such as triethylamine, imidazole, formamidine and the like.

The above reaction it is advisable to carry out without solvent or in Pris is no, use, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxidov, water or a mixture of two or more of them, and the like.

The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 30 minutes to about 12 hours, the reaction Temperature is usually from about 0 to about 200C, preferably from about 20 to about 120C.

The compound (VIII) can be obtained by treating compound (XXI) with hydrogen sulfide in the presence of a base.

The amount of hydrogen sulfide is from about 1 to about 30 mol, per 1 mol of compound (XXI).

The amount of base is from about 1 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (XXI).

“Base”, for example, is a aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, ammonia and the like.

The specified reaction no limit, assuming that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines or a mixture of two or more of them, and the like.

This reaction is carried out at atmospheric pressure or under elevated pressure. The reaction temperature is usually from about -20 to about 80 ° C, preferably from about -10 to about 30C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (VIII) can also be obtained by treating compound (XXII) pentasulfide phosphorus or reagent Lesson (Lawesson).

The amount used pentasulfide phosphorus or reagent Lesson is from about 0.5 to about 10 mol, preferably from about 0.5 to about 3 mol, inertnogo solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons or a mixture of two or more of them, and the like.

The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 30 minutes to about 12 hours, the reaction Temperature is usually from about 0 to about 150C, preferably from about 20 to about 120C.

The product (VIII) reaction can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

When the compound (I) (including the compounds (Ia), (Ib) and (Ic) is acylaminorhodanines, the target compound can be obtained by the reaction of acylation of the corresponding amino compounds known per se.

For example, of compounds (I), the compound in which R1is allmenalp, optionally having substituents, get usamobility.

The number Alliluyeva agent is from about 1 to about 5 mol, preferably from about 1 to about 2 mol, per 1 mol of the corresponding 2-thiazoline.

“Allerease agent, for example, represents a carboxylic acid corresponding to the target acyl group, or its reactive derivative (e.g. acid halide, acid anhydride, ester and the like) and the like.

The amount of base or acid is from about 0.8 to about 5 mol, preferably from about 1 to about 2 mol, per 1 mol of the corresponding 2-thiazoline.

“Base”, for example, represents triethylamine, pyridine, 4-dimethylaminopyridine and the like.

“Acid”, for example, is methansulfonate acid, p-toluensulfonate acid, camphorsulfonic acid and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated

The reaction temperature is usually from about -20 to about 150, preferably about 0 to 100C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

Compound (Id) can also be obtained, as shown in figure 4, and corresponding method.

[Scheme 4 reaction]

Compound (Id) is produced by treating compound (I) organic percolate.

The amount of organic percolate is from about 0.8 to about 10 mol, preferably from about 1 to about 3 mol, per 1 mol of compound (I).

“Organic percolate”, for example, is a peracetic acid, cryptocercus acid, m-chloroperbenzoic acid and the like.

The above reaction is expediently carried out without solvent or in the Pris is t, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxidov, alcohols, NITRILES, ketones or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 to about 130C, preferably from about 0 to about 100C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 12 hours

Alternatively, compound (Id) is also obtained by treating compound (I) hydrogen peroxide or alkylhydroperoxides, optionally in the presence of a base, acid or metal oxide.

The amount of hydrogen peroxide or cumene alkyl is from about 0.8 to about 10 mol, preferably from about 1 to about 3 mol, per 1 mol of compound (I).

“Alkylhydroperoxide”, for example, represents a tert-butylhydroperoxide, cumonherface and the like.

The amount used of the base, acid or metal oxide is from about 0.1 to about 30 mol, preferably from about 0.8 to about 5 mol, per 1 mol of compound (I).

“Onoi the like, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and the like.

“Acid”, for example, is a mineral acid, such as hydrochloric acid, sulfuric acid, Perlina acid and the like, a Lewis acid such as boron TRIFLUORIDE, aluminium chloride, titanium tetrachloride, and the like, organic acids such as formic acid, acetic acid, and the like.

“Metal oxide”, for example, is an oxide of vanadium (V2O5), osmium tetroxide (sO4), tungsten oxide (WO3), molybdenum oxide (Moo3), selenium dioxide (SeO2), chromium oxide (SGAs3), and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxidov, alcohols, NITRILES, ketones or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 to about 130C, predpochtitelno from about 0.5 to about 12 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

Alternatively, compound (IC) is also obtained by the method shown in the following reaction scheme 5.

[Map 5 responses]

The compound (XXIII) is obtained by removing protection from compound (XIV) using acid or base.

The amount used of the acid or base is from about 0.1 to about 50 mol, preferably from about 1 to about 20 mol, per 1 mol of compound (XIV), respectively.

As the “acid” is used, for example, mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the like, a Lewis acid such as trichloride boron, tribromide boron, and the like, a Lewis acid together with thiols or sulfides, organic acids, such as triperoxonane acid, p-toluensulfonate acid and the like.

As a “founding‾mu such that basic salts such as sodium carbonate, potassium carbonate and the like, alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, organic bases such as triethylamine, imidazole, formamidine and the like.

The above reaction it is advisable to carry out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxidov, water or a mixture of two or more of them, and the like.

The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 30 minutes to about 12 hours, the reaction Temperature is usually from about 0 to about 200C, preferably from about 20 to about 120C.

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillate what EDINENIE (XVIII), not necessarily in the presence of a base.

The amount used of the compound (XVIII) is from about 0.8 to about 5 mol, preferably from about 1 to about 3 mol, per 1 mol of compound (XXIII).

The amount of base is from about 0.1 to about 3 mol, preferably from about 0.3 to about 1.2 mol, per 1 mol of compound (XXIII).

“Base”, for example, is a basic salt, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate and the like, inorganic bases such as sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, hydrides of alkali metals, such as sodium hydride, potassium hydride and the like, amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium and the like, alkoxides of metals, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like.

Specified the reactions the i.i.d. limit, assuming that the reaction proceeds, use, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -78 to about 100C, preferably from about -78 to about 70C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 0.5 to about 20 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (XXV) is obtained by treating compound (XXIV) halogen or metal halide. This reaction is carried out, when required, in the presence of a base or basic salt.

The amount of halogen or halide of the metal is from about 1 to about 5 mol, preferably from about 1 to about 2 mol, per 1 mol of compound (XXIV).

The Halogens are bromine, chlorine, iodine and the like.

the Noah.

The amount of base is about 1-10 mol, preferably about 1-3 mol, per 1 mol of compound (XXIV).

“Base”, for example, represents the hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, NITRILES, sulfoxidov, organic acids, aromatic amines or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 the h to about 24 h, preferably from about 10 minutes to about 5 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (IC) obtained by condensation of compound (XXV) with a compound (VIII). This reaction is carried out optionally in the presence of a base.

In the compound (XXV) Hal represents halogen.

The amount used of the compound (VIII) is from about 0.5 to about 3 mol, preferably about 0.8 to 2 mol, per 1 mol of compound (XXV).

The amount of base is from about 1 to about 30 mol, preferably from about 1 to about 10 mol, per 1 mol of compound (XXV).

“Base”, for example, is a basic salt, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, Triin, N-methyl-morpholine and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, NITRILES, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -5 to about 200C, preferably from about 5 to about 150C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like. Then the compounds in which R4is other than a hydrogen atom may, if necessary, can be synthesized by alkylation or acylation.

[6 reactions]

The compound (XXVII) get to (XXVI) Hal’ represents a halogen atom, such as fluorine, chlorine, bromine and iodine.

The amount of base is from about 0.8 to about 5 mol, preferably from about 1 to about 1.2 mol, per 1 mol of compound (XXVI).

As the base used, for example, alkylate, such as n-utility and the like, and amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -78 to about 60, preferably from about -78 to about 20C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 0.5 to about 3 o'clock

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can the such.

The compound (XXVIII) can be obtained by treating compound (XXVII) a halogen or metal halide. This reaction is carried out optionally in the presence of a base or basic salt.

In the compound (XXVII) l’ represents a halogen atom, such as fluorine, chlorine, bromine and iodine.

The amount of halogen or halide of the metal is from about 1 to about 5 mol, preferably from about 1 to about 2 mol, per 1 mol of compound (XXVII).

The Halogens are bromine, chlorine, iodine and the like.

“The metal halide is a halide of copper, such as copper bromide (II) chloride copper (II) and the like.

The amount of base is from about 1 mol to about 10 mol, preferably from about 1 mol to about 3 mol, per 1 mol of compound (XXVII).

“Base”, for example, represents the hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines, is lanolin, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, NITRILES, sulfoxidov, organic acids, aromatic amines or a mixture of two or more of them, and the like.

The reaction temperature is usually from about -20 to about 150, preferably from about 0 to about 100C. The reaction time is usually from about 5 minutes to about 24 hours, preferably from about 10 minutes to about 5 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

The compound (X) can be obtained by condensation of compound (XXVIII) with a compound (VIII). This Rea is ohms halogen, such as fluorine, chlorine, bromine and iodine.

The amount used of the compound (VIII) is from about 0.5 mol to about 3 mol, preferably from about 0.8 mol to about 2 mol, per 1 mol of compound (XXVIII).

The amount of base is from about 1 mol to about 30 mol, preferably from about 1 mol to about 10 mol, per 1 mol of compound (XXVIII).

“Base”, for example, is a basic salt, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like.

The above reaction is expediently carried out without solvent or in the presence of an inert solvent. Although the solvent is not particularly limited, provided that the reaction proceeds, use, for example, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, NITRILES, or a mixture of two or more is occhialino from about 5 to about 150C. The reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 30 hours

Although the reaction product can be used in the next reaction as the reaction solution or in the form of a crude product, it can be isolated from the reaction mixture in a conventional manner and can be easily cleaned partitioning methods, such as recrystallization, distillation, chromatography and the like.

In the above reactions, when the starting compound has amino, carboxy, hydroxy as substituents, these groups can be introduced protective group commonly used in the chemistry of peptides, and the like, and upon completion of the reaction, the desired compound can be obtained by removing, if necessary, the protective groups.

As a protective group for amino, for example, use a formyl or C1-6alkylsulphonyl (for example, acetyl, propionyl and the like), C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and the like), vinyloxycarbonyl,7-10Uralelectromed (for example, benzyloxycarbonyl and the like), trityl, phthaloyl and the like, which may have substituents. In CA>-6alkylsulphonyl (for example, acetyl, propionyl, valeryl and the like), nitro and the like, and the number of substituents is 1 to 3.

As a protective group for carboxy, for example, use C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, trityl, silyl and the like, which respectively may have substituents. As such alternate use halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), formyl, C1-6alkylsulphonyl (for example, acetyl, propionyl, butylcarbamoyl and the like), nitro, C1-6alkyl (e.g. methyl, ethyl, tert-butyl and the like), WITH6-10aryl (e.g. phenyl, naphthyl and the like) and the like, and the number of substituents is 1 to 3.

As a protective group for hydroxy, for example, use C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, C7-11aralkyl (for example, benzyl and the like), formyl, C1-6alkylsulphonyl (for example, acetyl, propionyl and the like), vinyloxycarbonyl,7-11Uralelectromed (for example, benzyloxycarbonyl and the like), tetrahydropyranyl, tetrahydrofuranyl, forces the t atoms, halogen (for example, fluorine, chlorine, bromine, iodine and the like), C1-6alkyl (e.g. methyl, ethyl, tert-butyl and the like), WITH7-11aralkyl (for example, benzyl and the like), WITH6-10aryl (e.g. phenyl, naphthyl and the like), nitro and the like, and the number of substituents is 1 to 4.

In addition, as a method of removal of the protective group used a method known per se or a corresponding method, for example, removal by treatment with acid, base, ultraviolet rays, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium, palladium acetate and the like or recovery method.

In any case, the compound (I) can be synthesized with additional optional carrying out the known reactions, such as removing protection, acylation, alkylation, hydrogenation, oxidation, reduction, elongation of the carbon chain and the exchange of substituents, separately or in combination of two or more of them. As such reactions using the reaction described in Shinjikkenkagakukoza 14, volume 15, 1977 (Maruzen Press).

As mentioned above, “spirits”, for example, serve as methanol, ethanol, propanol, isopropanol, tert-butanol and the like.

In the initial ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like.

As mentioned above “halogenated hydrocarbons”, for example, serve as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like.

As the above “aliphatic hydrocarbons”, for example, serve as hexane, pentane, cyclohexane and the like.

As the above “aromatic hydrocarbons”, for example, are benzene, toluene, xylene, chlorobenzene and the like.

As the above “aromatic amines”, for example, serve as pyridine, lutidine, quinoline and the like.

As mentioned above amides, for example, are N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide and the like.

As mentioned above “ketones”, for example, serve as acetone, methyl ethyl ketone, and the like.

As mentioned above “sulfoxidov”, for example, serve as dimethyl sulfoxide and the like.

As mentioned above NITRILES, for example, serve as acetonitrile, propionitrile and the like.

As the above organic acids, for example, serve as acetic acid, propionic acid, trithorax is in free form, it can be converted in the usual way in salt, and when it is obtained as a salt, it can in the usual way be converted to a free form or another salt. The resulting compound (I) can be isolated from the reaction solution and purified by the known methods, for example, TRANS-solvation, concentrated, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.

When the compound (I), (Ia), (Ib), (IC) or (Id) is present in the form of spatial isomer, diastereoisomer, conformer or the like, it may be optionally selected above methods of separation and purification. In addition, when compound (I), (Ia), (Ib), (Ic) or (Id) is in the form of a racemate, it can be separated into S - and R-forms of any traditional way optical separation.

When the compound (I), (Ia), (Ib), (Ic) or (Id) exists in the form of a stereoisomer, as isomers separately, and a mixture of each isomer are included in the scope of the present invention.

In addition, compound (I), (Ia), (Ib), (Ic) or (Id) can be gidratirovannym or UN-hydrated.

The compound (I) can be observed isotope (for example,3H,14Alternatively, the prodrug of compound (I) may also be a compound which is converted into compound (I), (Ia), (Ib), (Ic) or (Id) in physiological conditions, as described in “lyakuhin no kaihatsu”, published by Hirokawashoten in 1990, vol.7. Molecular Design, pages 163-198.

The compound (I) of the present invention exhibits high affinity for adenosine receptor, in particular to a3-receptor, and has a low toxicity and minimal side effects, and therefore is useful as a safe drug.

The pharmaceutical composition of the present invention containing compound (I) having a high antagonistic activity against adenosine A3-receptor in a mammal (e.g. mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, clout to be used as a means for prevention or treatment of diseases, associated with adenosine A3receptor, for example, asthma, allergic diseases, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, diseases of the Central nervous system (e.g., intracerebral hemorrhage, infarction of the brain, head trauma, spinal trauma, brain edema, multiple sclerosis, and the like), neurodegenerative diseases (such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), diabetes and the like. Preferably the compound (I) is the agent for the prevention or treatment of diseases of the Central nervous system, asthma, allergic diseases and the like.

The compound (I) of the present invention exhibits a high inhibitory activity against R MAR-kinase and high inhibitory activity against TNF- (inhibition of production of TNF-, inhibition of TNF-) and is also useful as a safe pharmaceutical products based on these activities.

For example, the pharmaceutical composition of the present invention containing compound (I) can be used as a means for PTA (for example, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis), toxemia (e.g., sepsis, septic shock, endotoxin bacterial-toxic shock, gram negative sepsis, toxic shock syndrome), inflammatory intestinal diseases (eg, Crohn's disease, ulcerative colitis), inflammatory pulmonary diseases (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis) or cachexia (e.g., cachexia from infection, carcinogenicty, cachexia from acquired immune deficiency syndrome (AIDS)), arteriosclerosis, diseases of Creutzfeldt-Jakob disease, viral infections (such as viral infections, such as cytomegalovirus, hippotraginae, herpes virus and the like), atopic dermatitis, systemic lupus erythematosus, encephalopathy from AIDS, meningitis, strokes, heart attacks, congestive heart failure, hepatitis, transplantation, hypotension on dialysis, disseminated intravascular coagulation, and the like, in a mammal (e.g. mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human and the like). Preferably the compound (I) use the gain, containing the compound (I) has low toxicity and can be safely administered orally or parenterally (for example, locally, rectally or intravenously, or the like) itself, or by mixing the compound (I) with a pharmaceutically acceptable carrier receiving, for example, pharmaceutical preparations such as tablet (including tablets, tablet with a film coating, and the like), powders, granules, capsules (including soft capsules), solutions, injectable forms, suppositories, drugs, sustained release, and the like known per se manner, usually used in the manufacture of pharmaceuticals. The content of the compound (I) in the preparation of the present invention is about 0.01 to 100% by mass relative to the whole preparation. The dose varies depending on subject of administration, route of administration, disease and the like, and the drug can be introduced as, for example, the antagonist of adenosine A3-receptor in the form of oral contraceptives patient with asthma (weighing about 60 kg) with providing from about 0.1 to about 30 mg of the active ingredient (compound (I))/kg of body weight per day, preferably 1-20 mg/kg of body weight per day, one or more times in su the drug of the present invention, serve various conventional organic or inorganic carriers in the form of a pharmaceutical material, for example, excipient, a lubricant, a coupling agent and the cage in solid preparations, or solvent, a solubilizer, a suspending agent, agent, providing isotonicity, buffer and soothing agent for liquid preparations. In addition, if necessary, can be appropriately and in a suitable amount of additives used, usually such as preservative, antioxidant, colorant, podslushivaet, adsorbing agent, moisturizer, and the like.

As excipient, for example, serve as lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic acid anhydride and the like.

As a lubricating agent, for example, serve as magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like.

As a bonding agent, for example, serve as crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, starch, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.

As a solvent, for example, serve as water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

As a solubilizer, for example, are polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

As a suspending agent, for example, are surface-active substances, such as steartrimonium, sodium lauryl sulfate, lauramidopropyl, lecithin, benzalkonium chloride, chloride benzathine, glycerylmonostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.

As an agent, providing isotonicity, for example, are glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

As a buffer, for example, serve as buffer solutions such as phosphate, acetate, carbonate, citrate solution is OE.

As the preservative, for example, are p-hydroxybenzoate, chlorbutanol, benzyl alcohol, finitely alcohol, dehydroacetic acid, sorbic acid and the like.

As an antioxidant, for example, serve as sulfites, ascorbic acid, -tocopherol, and the like.

Further, the present invention is illustrated in detail in the following reference examples, examples, examples, and examples of tests that are merely examples and do not limit the present invention and may be changed without extending the scope of the present invention.

“Room temperature” in the following reference examples and examples usually indicates a temperature of from about 10C to about 35C. “%” means percentage by weight, provided that the output is presented in mol./mol.%.

Used further abbreviations have the following meanings:

s: singlet

d: doublet

t: triplet

kV: Quartet

DD: double doublet

DDD: doublet of double doublets

dt: double triplet

W: wide

J: constant interaction

Hz: Hertz

CDCl3: deuterated chloroform

1H-NMR: proton spectrum is-4-methylpyridin

Sodium hydride (60% dispersion in paraffin, 5.0 g, 120 mmol) was washed with hexane (5 ml) twice and suspended in tetrahydrofuran (200 ml). To the suspension was added dropwise a solution of benzyl alcohol (14 g, 120 mmol) in tetrahydrofuran (50 ml) at 0C and then the mixture was allowed to warm to room temperature with stirring over 15 minutes To the resulting solution was added a solution of 2-bromo-4-methylpyridine (19,5 ml, 110 mmol) in tetrahydrofuran (50 ml) and the mixture was heated at the boil under reflux for 14 hours To the reaction mixture were added water (200 ml) and the mixture was extracted with ethyl acetate. The extract was dried and put away the solvent. The crude product was distilled under reduced pressure to obtain 13 g specified in the connection header (67 mmol, yield 67%).

Boiling point 116-S (400 PA).

1H-NMR (CDCl3) : 2,30 (3H, s), lower than the 5.37 (2H, s), 6,63 (1H, s), 6,72 (1H, d, J=5,1 Hz), 7.29 trend is 7.50 (5H, m), 8,03 (1H, d, J=5,1 Hz).

Reference example 2: N-(3,5-dimethylbenzoyl)PROPYLENEIMINE

3,5-Dimethylbenzoic acid (25 g, 0,17 mmol) and N,N-dimethylformamide (0.1 ml) was added to thionyl chloride (50 ml) at 0C. The mixture was heated at the boil under reflux for 2 hours, the Excess thionyl chloride drove under reduced pressure and to the residue is lorida. The solution propylenimine (14 ml, 0.18 mol) in tetrahydrofuran (160 ml) was added to 1 N. aqueous sodium hydroxide solution (180 ml). To the solution was added dropwise 3.5 dimethylbenzophenone at 0C. At the end of the addition the mixture was stirred for further 30 minutes the Reaction mixture was extracted with ethyl acetate. The extract was dried and kept off the solvent to obtain 31 g specified in the title compound (0.16 mol, yield 99%).

The oily product

1H-NMR (CDCl3) : of 1.39 (3H, d, J=5.5 Hz), 2,13 (1H, d, J=3,7 Hz), 2,37 (6N, (C), 2,47-2,62 (2H, m), 7,19 (1H, s), to 7.64 (2H, s).

Reference example 3: 1-(3, 5dimethylphenyl)-2-(2-phenylmethoxy-4-pyridyl)alanon

The solution Diisopropylamine (9.6 ml, 69 mmol) in anhydrous tetrahydrofuran (60 ml) was cooled to-50C was added thereto dropwise with stirring, 1.6 M solution of n-utility in hexane (43 ml, 69 mmol). At the end of the addition the mixture was stirred 10 min and then was added a solution of 2-phenylmethoxy-4-methylpyridine (12 g, 62 mmol) in anhydrous tetrahydrofuran (12 ml) at-30C. After additional stirring for 1 h, was added at -30 solution of N-(3,5-dimethylbenzoyl)PROPYLENEIMINE (12 g, 62 mmol) in anhydrous tetrahydrofuran (12 ml). At the end of the addition the mixture was allowed to warm to room tatom. The extract was washed with water and dried, and then drove the solvent. The residue was purified by chromatography on a column of silica gel (hexane-ethyl acetate 5:1) to give 9.1 g specified in the connection header (27 mmol, yield 44%).

The oily product

1H-NMR (CDCl3) : 2,37 (6N, C) 4,20 (2H, s), lower than the 5.37 (2H, s), 6,72 (1H, s), for 6.81 (1H, d, J=5,1 Hz), 7,22 (1H, s), 7,30-7,49 (5H, m), to 7.59 (2H, s) to 8.12 (1H, d, J=5,1 Hz).

Reference example 4: 2-bromo-1-(3, 5dimethylphenyl)-2-(2-phenylmethoxy-4-pyridyl)economicreport

1-(3, 5dimethylphenyl)-2-(2-phenylmethoxy-4-pyridyl)alanon (3.3 g, 10 mmol) was dissolved in acetic acid (10 ml) and to the solution was added bromine (0.51 ml, 10 mmol) and the mixture was stirred at room temperature for 30 minutes, Dropped precipitated crude crystals were collected by filtration and washed with diethyl ether to obtain 4.8 g specified in the connection header (9.8 mmol, yield 98%).

so pl. 88-90

Reference example 5: N-(4-methoxybenzoyl)PROPYLENEIMINE

The solution propylenimine (25 ml, 0.36 mol) in tetrahydrofuran (200 ml) was added to 2 N. aqueous sodium hydroxide solution (180 ml). To the mixture was added dropwise a solution of 4-methoxybenzylamine (51 g, 0.30 mol) in tetrahydrofuran (100 ml) at 0C. At the end of dopaminergically to obtain 49 g specified in the title compound (0.26 mol, yield 86%).

The oily product

1H-NMR (CDCl3) : of 1.39 (3H, d, J=5.6 Hz), 2,11 (1H, d, J=3.0 Hz), of 2.51-2.57 m (2H, m), a 3.87 (3H, s) 6,94 (2H, d, J=8,8 Hz), 8,00 (2H, d, J=8,8 Hz).

Reference example 6: 1-(4-methoxyphenyl)-2-(2-tert-butoxy-carbylamine-4-pyridyl)alanon

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (20 g, 97 mmol) in anhydrous tetrahydrofuran (300 ml) was cooled to-S was added thereto dropwise with stirring, 1.6 M solution of n-utility in hexane (140 ml, 0.22 mol). At the end of the addition the mixture was stirred at room temperature for 30 minutes Then the mixture was cooled to-S. Was added dropwise a solution of N-(4-methoxybenzoyl) PROPYLENEIMINE in anhydrous tetrahydrofuran (50 ml). At the end of the addition the mixture was stirred at room temperature for 2 hours To the reaction mixture were added water (100 ml) and diisopropyl ether (300 ml) and the resulting crude crystals were collected by filtration. The crude crystals are recrystallized from a mixture of tetrahydrofuran-hexane to obtain 23 g specified in the connection header (67 mmol, yield 69%).

so pl. 187-190S

Reference example 7: 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine

To a solution of 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonyl at room temperature for 30 minutes The reaction mixture was concentrated. The residue was dissolved in acetonitrile (40 ml), to the solution was added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 ml, 14 mmol) and the mixture was stirred at 80 ° C for 2 h, the Reaction mixture was cooled to room temperature and concentrated. To the residue was added saturated aqueous sodium hydrogen carbonate solution (200 ml) and the obtained solid substance was collected by filtration and washed with water. Hard citizen added 2 N. hydrochloric acid (35 ml) and the mixture was stirred at 100C for 45 minutes the Reaction mixture was cooled to room temperature and then added to it 8 N. aqueous sodium hydroxide solution (10 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml). The obtained crude crystals were collected by filtration and washed with water. The crude crystals are recrystallized from ethanol to obtain 2.7 g specified in the connection header (9.1 mmol, yield 69%).

so pl. 251-S

Referential example 8: 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl) alanon

To 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone (6,1 g, 18 mmol) was added 2 N. hydrochloric acid (30 ml) and the mixture was stirred at 100C for 2 hours Then the reaction mixture ohnie crystals were filtered off and washed with water. The crude crystals are recrystallized from a mixture of tetrahydrofuran-hexane to obtain 4.0 g specified in the connection header (16 mmol, yield 92%).

so pl. 170-S

Referential example 9: 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)alanon

The benzoyl chloride (4.4 g, 31 mmol) and 4-dimethylaminopyridine (0,57 g, 4.7 mmol) was added to a solution of 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (3.8 g, 16 mmol) in N,N-dimethylacetamide (80 ml) and the mixture was stirred at 70 C for 12 h and Then the reaction mixture was cooled to room temperature and added to water (50 ml). The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. Layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (80 ml) was added methanol (20 ml) and 1 N. aqueous sodium hydroxide solution (50 ml). The mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated and added water (100 ml). The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. Layer was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from a mixture of ethyl acetate-hexane with polr 10: 1-(3, 5dimethylphenyl)-2-(2-tert-butoxy-carbylamine-4-pyridyl)alanon

A solution of 2-tert-butoxycarbonylamino-4-methylpyridine (17 g, 82 mmol) in anhydrous tetrahydrofurane (250 ml) was cooled to-S and was added dropwise with stirring a 1.6 n solution of n-utility in hexane (120 ml to 0.19 mol). At the end of the addition the mixture was stirred at 0C for 30 min and cooled to-S. Was added dropwise a solution of N-(3,5-dimethylbenzoyl)PROPYLENEIMINE (21 g, 0.11 mol) in anhydrous tetrahydrofuran (50 ml). At the end of the addition the mixture was stirred at room temperature for 2 hours To the reaction mixture were added water (100 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from a mixture of tetrahydrofuran-hexane to obtain 13 g specified in the connection header (63 mmol, yield 46%).

so pl. 133-S

Referential example 11: 2-(2-amino-4-pyridyl)-1-(3, 5dimethylphenyl)alanon

To 1-(3, 5dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl) ethanone (12 g, 36 mmol) was added 2 N. hydrochloric acid (50 ml) and the mixture was stirred at 100C for 1 h Then the reaction mixture was cooled to room temperature, was added 8 N. aqueous solution of hydrohloride sodium, was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate to obtain 6.8 g specified in the connection header (28 mmol, yield 77%).

so pl. 123-S

Reference example 12: 2-(2-benzoylamino-4-pyridyl)-1-(3, 5dimethylphenyl)alanon

The benzoyl chloride (7.5 g, 53 mmol) and 4-dimethylaminopyridine (1.0 g, 8.3 mmol) was added to a solution of 2-(2-amino-4-pyridyl)-1-(3, 5dimethylphenyl)ethanone (6.4 g, 27 mmol) in N,N-dimethylacetamide (100 ml) and the mixture was stirred at 70 C for 12 h and Then the reaction mixture was cooled to room temperature and added to water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. Layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (150 ml) - methanol (40 ml) was added 1 N. aqueous sodium hydroxide solution (50 ml). The mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated, added water (100 ml) and neutralized 2 N. hydrochloric acid and saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous cromatografia on a column of silica gel (hexane-ethyl acetate, 2:1) to give 6.4 g specified in the connection header (19 mmol, yield 70%).

The oily product

1H-NMR (CDCl3) : 2,39 (6N, C) to 4.33 (2H, s), 6,98-7,01 (1H, m), 7.23 percent (1H, s), 7,45-7,58 (3H, m), 7,63 (2H, s), 7,89-7,94 (2H, m), 8,21 (1H, d, J=5,2 Hz), at 8.36 (1H, s) 8,71 (1H, ush.)

Reference example 13

In accordance with the reference example 5, using, respectively, 3-methylbenzophenone and 3-methoxybenzoate instead of 4-benzoyl chloride, was synthesized following compounds of reference examples 13-1 and 13-2.

The compound of reference example 13-1:

N-(3-methylbenzoyl)PROPYLENEIMINE

The oily product

1H-NMR (CDCl3) : of 1.39 (3H, d, J=5.5 Hz), and 2.14 (1H, d, J=3.3 Hz), is 2.41 (3H, s), of 2.51-of 2.66 (2H, m), 7,32-7,39 (2H, m), 7,79-7,87 (2H, m).

The compound of reference example 13-2:

N-(3-methoxybenzoyl)PROPYLENEIMINE

The oily product

1H-NMR (CDCl3) : of 1.40 (3H, d, J=5,9 Hz), and 2.14 (1H, d, J=2,9 Hz), 2,52-to 2.65 (2H, m), 3,86 (3H, s), 7,10 (1H, DDD, J=8,4, 2,6, 1.1 Hz), 7,37 (1H, DD, J=8,4, 7,3 Hz), 7,55 (1H, DD, J=2,6, 1.5 Hz), 7,63 (1H, DDD, J=7,3, 1,5, 1,1 Hz).

Reference example 14

In accordance with reference example 6 using N-(3-methylbenzoyl)PROPYLENEIMINE instead of N-(4-methoxybenzoyl) PROPYLENEIMINE, synthesized following compound of reference example 14.

SOER CLASS="ptx2">Reference example 15: 4-(methylthio)thiobenzamide

4-Methylthiofentanyl (12 g) was dissolved in 4 BC solution of hydrogen chloride in ethyl acetate (130 ml). To the resulting solution was added O,O-diethyldithiophosphate (15 ml) and the mixture was stirred at room temperature for 22 hours To the reaction mixture were added water (100 ml) and the mixture was extracted with ethyl acetate. Filtering insoluble materials, the filtrate was washed with a saturated aqueous solution of sodium chloride and dried, and then drove the solvent. The residue was recrystallized from ethyl acetate to obtain 10 g specified in the title compound (yield 67%).

so pl. 176-S

Reference example 16:

In accordance with reference example 15, using, respectively, 4-perbenzoate, 2-chlorobenzonitrile, butyronitrile and valeronitrile instead of 4-methylthioamphetamine, synthesized the following compounds of reference examples 16-1-16-4.

The compound of reference example 16-1: 4-fortiasic

so pl. 156-S

Connection smacznego example 16-2: 2-chlorobenzamide

so pl. 58-59S

The compound of reference example 16-3: thiobutyrate

The oily product

1H-NMR (CDCl3) : 0,99 (3H, t, J=7,6 Hz), 1,72-of 1.93 (2H, m) of 2.64 (2H, t, J=7,6 Hz), 7,02 SS="ptx2">1H-NMR (CDCl3) : of 0.94 (3H, t, J=7,3 Hz), 1,31-1,49 (2H, m), 1,68 of-1.83 (2H, m) to 2.67 (2H, t, J=7, 7 Hz), 6,92 (1H, ush.C) 7,73 (1H, ush.C).

Reference example 17: 4-[2-methyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine

To a solution of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-were)ethanone (6.0 g, 18 mmol) in acetic acid (50 ml) was added bromine (1.0 ml, 18 mmol) and the mixture was stirred at room temperature for 30 minutes the Reaction mixture was concentrated. The residue was dissolved in N,N-dimethylformamide (50 ml), the solution was added thioacetamide (1.4 g, 19 mmol) and the resulting mixture was stirred at room temperature for 20 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (200 ml) and was extracted with ethyl acetate. The extract was dried and put away the solvent. To the obtained solid substance was added 2 N. hydrochloric acid (30 ml) and the mixture was stirred at 100C for 1 h, the Reaction mixture was cooled to room temperature and then was podslushivaet adding 2 N. aqueous sodium hydroxide solution (200 ml) and saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified chromate is CLASS="ptx2">so pl. 152-S

Reference example 18:

In accordance with reference example 17, using, respectively, thiopropionate and 4-(methylthio)thiobenzamide instead of thioacetamide, synthesized the following compounds of reference examples 18-1 and 18-2.

The compound of reference example 18-1: 4-[2-ethyl-4-(3-methyl-phenyl)-1,3-thiazol-5-yl]-2-pyridylamine

so pl. 144-146S

The compound of reference example 18-2: 4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine

so pl. 181-S

Reference example 19:

In accordance with reference example 17, using 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)Etalon instead of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-were)ethanone, synthesized following compound of reference example 19.

The compound of reference example 19: 4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine

so pl. 140-S

Reference example 20:

In accordance with reference example 8, using 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-were)Etalon instead of 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl) ethanone, synthesized following compound of reference example 20.

The compound of reference example 20: 2-(2-amino-4-pernil)economicreport

To a solution of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-were)ethanone (20 g, 61 mmol) in acetic acid (60 ml) was added bromine (3.2 ml, 62 mmol) and the mixture was stirred at 80 ° C for 2 h Then the reaction mixture was cooled to room temperature and the precipitate was filtered to obtain 19 g (yield 81%) specified in the connection header.

so pl. 182-S

Reference example 22:

In accordance with reference example 9 using 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)Etalon instead of 2-(2-amino-4-pyridyl)-1-(3-were)ethanone, synthesized following compound of reference example 22.

The compound of reference example 22: N-[4-[2-(3-were)-2-oxoethyl]-2-pyridyl]benzamide

so pl. 67-S

Reference example 23: 4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine

2-(2-Amino-4-pyridyl)-2-bromo-1-(3-were)economicreport (5.0 g, 13 mmol) was dissolved in N,N-dimethylformamide (40 ml), to the solution was added 4-fortiasic (2.1 g, 13 mmol) and the mixture was stirred at room temperature for 16 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried and put away the solvent. The residue was recrystallized and Ilony example 24:

In accordance with the reference example 23, using, respectively, 2-chlorobenzamide, thiobutyrate and towleroad instead of 4-fertiberia, synthesized the following compounds of reference examples 24-1 - 24-3.

The compound of reference example 24-1: 4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine

so pl. 175-S

The compound of reference example 24-2: 4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine

so pl. 113-115S

The compound of reference example 24-3: 4-[2-butyl-4-(3-were) -1,3-thiazol-5-yl]-2-pyridylamine

The oily product

1H-NMR (CDCl3) : and 0.98 (3H, t, J=7,3 Hz), 1,39-to 1.59 (2H, m), 1,74-of 1.92 (2H, m), of 2.34 (3H, s), totaling 3.04 (2H, t, J=7.4 Hz), 4,14 (2H, ush.C) 6,44 (1H, s), 6,56 (1H, DD, J=5,1, 1.5 Hz), 7,09-7,26 (3H, m), 7,41 (1H, s), of 7.96 (1H, d, J=5.4 Hz).

Reference example 25: 2-fluoro-4-methylpyridin

Specified in the title compound was obtained as described in Journal of Medicinal Chemistry, vol. 33, 1667-1675, 1990.

Boiling point 82-S (10 kPa)

Reference example 26: 2-(2-fluoro-4-pyridyl)-1-(3-were) alanon

The solution Diisopropylamine (44 ml, 0.31 mol) in anhydrous tetrahydrofuran (300 ml) was cooled to-C in an atmosphere of nitrogen was added dropwise a 1.6 M solution of n-utility in hexane (190 ml, 0.31 mol). After adding the furan (30 ml). The reaction mixture was stirred at-10C for 30 minutes the Reaction solution was cooled to-S and was added dropwise a solution of N-(3-methylbenzoyl)PROPYLENEIMINE (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 ml). After adding the resulting mixture was stirred at room temperature for 2 hours To the reaction mixture were added water (100 ml) and was extracted with a mixture of ethyl acetate. The extract was washed with water and dried, and then drove the solvent. The residue was recrystallized from isopropyl ether to obtain 35 g (yield 52%) specified in the connection header.

so pl. 66-S

Reference example 27:

In accordance with the reference example 26 using N-(3-methoxybenzoyl)PROPYLENEIMINE instead of N-(3-methylbenzoyl) PROPYLENEIMINE, synthesized following compound of reference example 27.

The compound of reference example 27: 2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)alanon

The oily product

1H-NMR (CDCl3) : 3,86 (3H, s), or 4.31 (2H, s) 6,86 (1H, s), 7.03 is-7,19 (2H, m), 7,31-to 7.59 (3H, m), 8,18 (1H, d, J=5.6 Hz).

Reference example 28: [5-(2-fluoro-4-pyridyl)-4-(3-were)-1,3-thiazol-2-yl]Amin

To a solution of 2-(2-fluoro-4-pyridyl)-1-(3-were)ethanone (8.5 g, 37 mmol) in acetic acid (50 ml) was added bromine (1.9 ml, 37 Smolnogo residue and thiourea (3.0 g, 40 mmol) in acetonitrile was added triethylamine (5.2 ml, 37 mmol) and the mixture was stirred at 80 ° C for 2 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (50 ml) and precipitated precipitated solid substance was collected by filtration. Then the obtained solid substance was washed with water and dried. The crude crystals are recrystallized from ethanol to obtain 3.7 g (yield 35%) specified in the connection header.

so pl. 214-S

Reference example 29:

In accordance with the reference example 28 using 2-(2-fluoro-4-pyridyl)-1-(3-methoxyphenyl)Etalon instead of 2-(2-fluoro-4-pyridyl)-1-(3-were)ethanone, synthesized following compound of reference example 29.

The compound of reference example 29: [5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]AMI

so pl. 190-S

Reference example 30: 5-(2-fluoro-4-pyridyl)-4-(3-were) -2-(4-methylthiophenyl)-1,3-thiazole

To a solution of 2-(2-fluoro-4-pyridyl)-1-(3-were)ethanone (12 g, 53 mmol) in acetic acid (90 ml) was added bromine (2.7 ml, 52 mmol) and the mixture was stirred at room temperature for 2 hours the Reaction mixture was concentrated. The obtained residue was dissolved in N,N-dimethylformamide (60 ml), was added 4-(methylthio)thiobenzamide (9,6 the initial aqueous solution of sodium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and put away the solvent. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1) to give 4.7 g (yield 23%) specified in the connection header.

so pl. 97-100C

Reference example 31: 5-(2-fluoro-4-pyridyl)-4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazole

To a solution of 5-(2-fluoro-4-pyridyl)-4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazole (2.7 g, 6,9 mmol) in N,N-dimethylformamide (60 ml) was added m-chloroperbenzoic acid (3.3 g, 14 mmol) and the mixture was stirred at room temperature for 1 h To the reaction mixture were added 8 N. aqueous sodium hydroxide solution and the resulting solid was collected by filtration. Specified the solid is recrystallized from ethanol to obtain 2.5 g (yield 85%) specified in the connection header.

so pl. 196-S

Example 1: [4-(3, 5dimethylphenyl)-5-(2-phenylmethoxy-4-pyridyl)-1,3-thiazol-2-yl]Amin

The triethylamine (1.4 ml, 10 mmol) was added dropwise to a solution of 2-bromo-1-(3, 5dimethylphenyl)-2-(2-phenylmethoxy-4-pyrid-yl)economicsamerica (4.8 g 9.8 mmol) and thiourea (0,77 g, 11 mmol) in acetonitrile (40 ml) and the mixture was stirred at room temperature for 3 hours was Removed under reduced pressure solvent the Organic layer was washed with water, dried and put away the solvent. The crude crystals are recrystallized from ethyl acetate to obtain 2.0 g (5.2 mmol, yield 53%) specified in the connection header.

so pl. 141-S

Example 2: N-[4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

The benzoyl chloride (0,59 g, 4.2 mmol) and 4-dimethylaminopyridine (0.05 g, 0.4 mmol) was added to a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0,42 g, 1.4 mmol) in N,N-dimethylacetamide (10 ml) and the mixture was stirred at 70 C for 19 h Then the reaction mixture was cooled to room temperature and was added saturated aqueous sodium hydrogen carbonate solution (50 ml). The obtained crude crystals were collected by filtration and washed with water. The crude crystals are recrystallized from ethanol to obtain 0.26 g (0.51 mmol, yield 37%) specified in the connection header.

so pl. 230-S

Example 3: N-[4-(4-methoxyphenyl)-5-[2-[(3-pyridylcarbonyl-amino)]-4-pyridyl]-1,3-thiazol-2-yl]nicotinamide Nicotinoyldihydrocodeine (0,72 g, 4.1 mmol) and 4-dimethylaminopyridine (0.05 g, 0.4 mmol) was added to a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0,41 g, 1.4 mmol) in N,N-dimethylacetamide (10 ml) and the mixture was stirred at 70C in acetocarmine sodium (50 ml). The obtained crude crystals were collected by filtration and washed with water. The crude crystals are recrystallized from ethanol to obtain 0,23 g (0.44 mmol, yield 33%) specified in the connection header.

so pl. 229-232C

Example 4: N-[4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

To a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (to 0.72 g, 2.1 mmol) in acetic acid (20 ml) at 0C was added bromine (of 0.11 ml, 2.1 mmol) and the mixture was stirred at room temperature for 1 h the Reaction mixture was concentrated. The residue was dissolved in acetonitrile (20 ml), to the solution was added thiourea (0.17 g, 2.2 mmol) and triethylamine (0.35 ml, 2.5 mmol) and the mixture was stirred at 80 ° C for 5 hours Then the reaction mixture was cooled to room temperature, was added a saturated aqueous solution of sodium bicarbonate (200 ml) and the resulting solid was filtered and washed with water. The obtained crude crystals were collected by filtration and washed with water. The crude crystals are recrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield 21%) specified in the connection header.

so pl. 221-S

Example 5: N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

so pl. 120-S

Example 6: N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine

Aluminosilicate (0.16 g, 4.1 mmol) was added to a suspension of aluminium chloride (0.55 g, 4.1 mmol) in anhydrous tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 15 minutes To the mixture was added a solution of N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] benzamide (0.40 g, 1.0 mmol) in anhydrous tetrahydrofuran (10 ml) and the resulting mixture was heated at the boil under reflux for 2 hours Then the reaction maswali saturated aqueous sodium chloride, was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from a mixture of ethyl acetate-hexane to obtain 0.20 g (0.51 mmol, 51% yield) specified in the connection header.

so pl. 99-1 0 2

Example 7: N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzenedithiol

To a suspension of N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.45 g, 1.1 mmol) in methanol (30 ml) was added 10% solution of hydrogen chloride in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes Drove the solvent and the residue was recrystallized from methanol to obtain 0.36 g (0.83 mmol, yield 73%) specified in the connection header.

so pl. 202-S

Example 8: N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylaminocarbonyl

To a suspension of N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine (0,80 g, 2.1 mmol) in methanol (50 ml) was added 10% solution of hydrogen chloride in methanol (10 ml) and the mixture was stirred at room temperature for 5 hours Drove the solvent and the residue was recrystallized from methanol-ethyl acetate to obtain 0.73 g (1.6 mmol, yield 76%) specified in the connection header.

so pl. 161-S

Example 3

Example 4

Example 5

Example 6

Example 9: N-[5-(2-benzoylamino-4-pyridyl)-4-(3, 5dimethylphenyl)-1,3-thiazol-2-yl]ndimethylacetamide

Acetylchloride (of 0.26 ml, 3.7 mmol) and 4-dimethylaminopyridine (0.09 g, from 0.76 mmol) was added to a solution of N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.96 g, 2.4 mmol) in N,N-dimethylacetamide (20 ml) and the mixture was stirred at 70 C for 16 h Then the reaction mixture was cooled to room temperature, was added a saturated aqueous solution of sodium bicarbonate (50 ml). The crude crystals were filtered off and washed with water. The crude crystals are recrystallized from ethyl acetate to obtain 0.32 g (yield 30%) specified in the connection header.

so pl. 238-S

Example 10:

In accordance with example 9, using N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzylamine instead of N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide was synthesized following compound of example 10.

The compound of example 10: N-[5-(2-benzylamino-4-pyridyl)-4-(3, 5dimethylphenyl)-1,3-thiazol-2-yl]ndimethylacetamide

so pl. 217-S

Example 11:

In accordance with example 4, using N-the EPA 11: N-[4-[4-(4-methoxyphenyl)-2-methylamino-1,3-thiazol-5-yl]-2-pyridyl]benzamide

so pl. 237-S

Example 12:

In accordance with example 4, using N-[4-[2-(3-were)-2-oxoethyl]-2-pyridyl]benzamide instead of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone, synthesized following compound of example 12.

The compound of example 12: N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

so pl. 216-S

Example 13: N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide

To a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (1.2 g, 3.4 mmol) in acetic acid (10 ml) was added bromine (of 0.18 ml, 3.5 mmol) and the mixture was stirred at room temperature for 30 minutes the Reaction mixture was concentrated. The obtained residue was dissolved in N,N-dimethylformamide (20 ml), to the solution was added thioacetamide (0,30 g, 19 mmol) and the mixture was stirred at room temperature for 20 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (20 ml), the mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate =1:1) to obtain 0.68 g (yield 50%) specified in the connection header.

so pl. 134-S

Example 14: N-[4-[2-(4�ritilin (0,31 ml, 2.2 mmol) was added to a solution of 4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine (0,81 g, 2.2 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 13 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (20 ml), the mixture was extracted with ethyl acetate and the extract was washed with water. The obtained extract was dried and concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate =2:1) to obtain the 0,86 g (yield 80%) specified in the connection header.

so pl. 187-190S

Example 15:

In accordance with example 14, using, respectively, 4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridylamine, 4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine, 4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, 4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine, 4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine and 4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine instead of 4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridylamine, synthesized the following compounds of examples 15-1 - 15-6.

Connection example 15-1: N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

so pl. 118-1 107-S

Connection example 15-3: N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

so pl. 109-S

Connection example 15-4: N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

so pl. 92-93S

Connection example 15-5: N-[4-[2-(2-chlorophenyl)-4-(3-were) -1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

so pl. 141-S

Connection example 15-6: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

so pl. 205-S

Example 16:

In accordance with examples 14 and 15, using, respectively, benzoyl chloride, 3-phenylpropionate, 3-(4-methoxyphenyl)propionitrile, 3-(4-forfinal)propionate, 4-phenylbutyrate, 5-phenylalaninamide, 2-thiophenecarboxylate and 2-aftercare instead of phenylacetylide, synthesized the following compounds of examples 16-1 - 16-18.

The compound of example 16-1: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

so pl. 113-S

The compound of example 16-2: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 126-127S

The compound of example 16-3: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide

so pl. 137-S

The compound of example 16 is giving example 16-5: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide

so pl. 92-93S

Connection example sheet 16-6: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-5-phenylvaleric

so pl. 86-S

Connection example 16-7: N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Amorphous powder

1H-NMR (Dl3) : a 1.08 (3H, t, J=7,1 Hz), 1,80-1,99 (2H, m), of 2.34 (3H, s), totaling 3.04 (2H, t, J=7,7 Hz), to 6.88 (1H, DD, J=5,2, 1.7 Hz), 7,15-7,63 (7H, m), of 7.90-of 7.95 (2H, m), 8,11 (1H, d, J=5,2 Hz), 8,51 (1H, s), 8,61 (1H, ush.C)

Connection example 16-8: N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 103-S

Connection example 16-9: N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

Amorphous powder

1H-NMR (CDCl3) : 0,99 (3H, t, J=7.2 Hz), 1,40-1,60 (2H, m), 1,76-of 1.93 (2H, m), of 2.34 (3H, s), 3,06 (2H, t, J=7,7 Hz), to 6.88 (1H, DD, J=5.0 and 1.7 Hz), 7,10-7,26 (3H, m), 7,41 (1H, s), 7,46-to 7.61 (3H, m), 7,94 (2H, DD, J=8,1, 1.5 Hz), 8,10 (1H, d, J=5.0 Hz), charged 8.52 (1H, s) 8,71 (1H, ush.C).

Connection example 16-10: N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 77-S

Connection example 16-11: N-[4-[2-(4-forfinal)-4-(3-were) -1,3-thiazol-5-yl]-2-pyridyl]benzamide

so pl. 126-S

Connection example 16-12: N-[4-[2-(4-forfinal)-4-(3-were) -1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 169-S

Connection example 16-14: N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 156-S

Connection example 16-15: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

so pl. 180-S

Connection example 16-16: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 174-S

Connection example 16-17: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophencarboxylic

so pl. 145-S

Connection example 16-18: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naptime

so pl. 184-S

Example 17: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-methylphenylacetic

Sodium hydride (60% dispersion in paraffin, 58 mg, 1.5 mmol) was added to a solution of N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide (0.50 g, 1.2 mmol) in dimethyl sulfoxide (5 ml) and the mixture was stirred at room temperature for 1 h To the reaction solution was added methyliodide (and 0.09 ml, 1.5 mmol) and the mixture was stirred at room temperature for 1 h To the reaction mixture were added 10% aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract of p. is she on a column of silica gel (hexane:ethyl acetate, 7:14:1) and washed with hexane to obtain 0.18 g (yield 35%) specified in the connection header.

so pl. 75-S

Example 18:

In accordance with example 17, using N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide instead of N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, synthesized following compound of example 18.

The compound of example 18: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-methyl-3-phenylpropionamide

The oily product

1H-NMR (CDCl3) : of 1.46 (3H, t, J=7.5 Hz), 2,32 (3H, s), of 2.51 (2H, t, J=7.9 Hz), with 2.93 (2H, t, J=7.9 Hz), 3,10 (2H, q, J=7.5 Hz), up 3.22 (3H, s), 6,98 (1H, s), 7.03 is-7,29 (N, m), 7,37 (1H, s) of 8.37 (1H, d, J=3.6 Hz).

Example 19:

In accordance with example 6, using, respectively, N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl] benzamide, N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropanamide, N-[4-[4-(3-were)2 propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl] phenylacetamide, N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropanamide, N-[4-[2-butyl-4-(3-were)-1,3-thiazole who yl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropanamide, N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropanamide, N-[4-[4-(3-were)-2-(4-methylthiophenyl) -1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide and N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naptime instead of N-[4-[2-amino-4-(3, 5dimethylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] benzamide was synthesized following compounds of examples 19-1 - 19-20.

The compound of example 19-1: N-benzyl-N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]amine

so pl. 132-S

The compound of example 19-2: N-benzyl-N-[4-[2-ethyl-4-(3-methyl - phenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

so pl. 106-S

Connection example 19-3: N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

so pl. 97-98S

Connection prinnie example 19-5: N-benzyl-N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine

The oily product

1H-NMR (CDCl3) : of 1.06 (3H, t, J=7.4 Hz), 1,77 is 1.96 (2H, m), of 2.33 (3H, s) of 3.00 (2H, t, J=7,7 Hz), to 4.38 (2H, d, J=5.4 Hz), a 4.83 (1H, ush.t), 6,32 (1H, s), 6,53 (1H, DD, J=5,4, and 1.6 Hz), 7,10-7,40 (N, m), 8,01 (1H, d, J=5.4 Hz).

Connection example 19-6: N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

The oily product

1H-NMR (CDCl3) : a 1.08 (3H, t, J=7.5 Hz), 1,78-of 1.93 (2H, m), 2,32 (3H, s), of 2.81 (2H, t, J=7.0 Hz), a 3.01 (2H, t, J=7,7 Hz), 3,42 (2H, dt, J=6,2, 7,0 Hz) to 4.52 (1H, ush.t) 6,30 (1H, s), 6,51 (1H, DD, J=5,2, 1.5 Hz), 7,11-7,34 (8H, m), the 7.43 (1H, s), of 8.00 (1H, d, J=5,2 Hz).

Connection example 19-7: N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

The oily product

1H-NMR (CDCl3) : a 1.08 (3H, t, J=7.4 Hz), 1,78-of 1.93 (4H, m), 2,32 (3H, s) to 2.66 (2H, t, J=7.2 Hz), a 3.01 (2H, t, J=7,7 Hz), and 3.16 (2H, dt, J=6,2, 7,2 Hz) to 4.52 (1H, ush.C) of 6.26 (1H, s), of 6.49 (1H, DD, J=5,2, 1.5 Hz), 7,07-to 7.32 (8H, m), 7,42 (1H, s), 7,98 (1H, d, J=5,2 Hz).

Connection example 19-8: N-benzyl-N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine

The oily product

1H-NMR (CDCl3) : to 0.97 (3H, t, J=7,3 Hz), 1,38-to 1.59 (2H, m), 1,73-1,90 (2H, m), of 2.33 (3H, s), to 3.02 (2H, t, J=7,7 Hz), 4,37 (2H, d, J=5.7 Hz), a 4.83 (1H, t, J=7,3 Hz), of 6.31 (LH, s) of 6.52 (1H, d, J=5.5 Hz), 7,09-7,43 (N, m), of 8.00 (1H, d, J=5,5 Hz).

Connection example 19-9: N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-Piri m), 1,74-of 1.92 (2H, m), 2,32 (3H, s), of 2.81 (2H, t, J=7.0 Hz), totaling 3.04 (2H, t, J=7,7 Hz) to 3.41 (2H, dt, J=6,1, 7,0 Hz), 4,55 (1H, t, J=6,1 Hz), 6,30 (1H, s), 6,51 (1H, d, J=5,1 Hz), 7,06-7,19 (3H, m), 7,20-7,38 (5H, m), the 7.43 (1H, m), to 7.99 (1H, d, J=5,1 Hz).

The compound of example 19 within 10: N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

The oily product

1H-NMR (CDCl3) : and 0.98 (3H, t, J=7,1 Hz), 1,39-of 1.57 (2H, m), a 1.75-to 1.98 (4H, m), 2,32 (3H, s) to 2.67 (2H, t, J=7.8 Hz), totaling 3.04 (2H, t, J=7,7 Hz), and 3.16 (2H, dt, J=5,9, 6,2 Hz) to 4.52 (1H, t, J=5,9 Hz), of 6.26 (1H, s), of 6.49 (1H, d, J=5,1 Hz), 7,06-7,38 (8H, m), 7,42 (1H, s), of 7.97 (1H, d, J=5,1 Hz).

Connection example 19-11: N-benzyl-N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine

so pl. 143-146S

Connection example 19-12: N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

so pl. 97-98S

Connection example 19-13: N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

so pl. 110-S

Connection example 19-14: N-benzyl-N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine

so pl. 84-S

Connection example 19-15: N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

so pl. 113-S

Connection example 19-16: N-[4-[2-(2-chlorophenyl)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)-yl]-2-pyridyl]amine

so pl. 134-S

Connection example 19-18: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine

so pl. 137-S

Connection example 19-19: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

so pl. 106-S

Connection example 19-20: N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-naphthylmethyl)Amin

so pl. 144-S

Example 20: N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide

To a solution of N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (0.50 g, 1.0 mmol) in N,N-dimethylformamide (5 ml) was added m-chloroperbenzoic acid (0.55 g, 2.2 mmol) and the mixture was stirred at room temperature for 1 h To the reaction mixture were added 8 N. aqueous sodium hydroxide solution and the resulting solid was collected by filtration. The solid is recrystallized from ethanol with the receipt of 0.29 g (yield 54%) specified in the connection header.

so pl. 212-S

Example 21:

In accordance with example 20, using, respectively, N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-�[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naptime, N-benzyl-N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine and N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-naphthylmethyl)amine instead of N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide was synthesized following compounds of examples 21-1 - 21-7.

Connection example 21-1: N-[4-[4-(3-were)-2-(4-methyl-sulfanilyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide

so pl. 244-S

Connection example 21-2: N-[4-[4-(3-were)-2-(4-methyl-sulfanilyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide

so pl. 236-S

Connection example 21-3: N-[4-[4-(3-were)-2-(4-methyl-sulfanilyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophencarboxylic

so pl. 199-S

Connection example 21-4: N-[4-[4-(3-were)-2-(4-methyl-sulfanilyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-naptime

so pl. 231-S

Connection example 21-5: N-benzyl-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine

so pl. 148-150C

Connection example 21-6: N-[4-[4-(3-were)-2-(4-methyl-sulfanilyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)-Amin

so pl. 167-168S

Connection example 21-7: N-[4-[4-(">Example 22: N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamine

A mixture of [5-(2-fluoro-4-pyridyl)-4-(3-were)-1,3-thiazol-2-yl]amine (0.29 grams, 1.0 mmol) and benzylamine (1.2 ml, 11 mmol) was stirred at 150 for 3 hours Then the mixture was cooled to room temperature, was added a saturated aqueous solution of sodium bicarbonate (20 ml), the mixture was extracted with ethyl acetate and the extract was washed with water. The obtained extract was dried and concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate =1:1) to give 0.16 g (yield 41%) specified in the connection header.

so pl. 178-S

Example 23:

In accordance with example 22 using 4-methoxybenzylamine, 3-methoxybenzylamine, 2-methoxybenzylamine, 4-chlorobenzylamino, 3-chlorobenzylamino, (R)-1-phenylethylamine, (S)-1-phenylethylamine and N-benzyl-N-methylamine instead of benzylamine, synthesized the following compounds of examples 23-1 - 23-8.

The compound of example 23-1: N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(4-methoxybenzyl)Amin

so pl. 183-S

Connection example 23-2: N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-methoxybenzyl)Amin

so pl. 152-S

The compound of example 23-3: N-[4-[2-amino-4-(3-MetLife is about-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(4-chlorbenzyl)Amin

so pl. 182-S

Connection example 23-5: N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-Chlorobenzyl)Amin

so pl. 180-S

Connection example 23-6: (R)-N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(1-phenylethyl)amine

so pl. 94-98S

Connection example 23-7: (S)-N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(1-phenylethyl)amine

so pl. 93-S

Connection example 23-8: N-[4-[2-amino-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzyl-N-methylamine

so square 138-140 C

Example 24:

In accordance with example 22, using [5-(2-fluoro-4-pyridyl)-4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amine instead of [5-(2-fluoro-4-pyridyl)-4-(3-were)-1,3-thiazol-2-yl]amine was synthesized following compound of example 24.

The compound of example 24: N-[4-[2-amino-4-(3-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-benzylamine

so pl. 217-S

Example 25:

In accordance with example 22, using [5-(2-fluoro-4-pyridyl)-4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazole instead of [5-(2-fluoro-4-pyridyl)-4-(3-were)-1,3-thiazol-2-yl]amine, or 2-phenylethylamine, 4-fluoro-benzylamine, N-benzyl-N-methylamine, N-methyl-2-phenylethylamine and 2-thienylmethyl instead of benzylamine, synthesized the following compounds of examples 25-1 to 25-yl) Amin

so pl. 174-S

Connection example 25-2: N-(4-terbisil)-N-[4-[4-(3-were) -2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] amine

so pl. 155-S

Connection example 25-3: N-benzyl-N-methyl-N-[4-[4-(3-were) -2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] amine

so pl. 165-S

Connection example 25-4: N-methyl-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl) amine

so pl. 116-117S

Connection example 25-5: N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl) -1,3-thiazol-5-yl]-2-pyridyl]-N-(2-thienylmethyl)Amin

so pl. 107-S

Example 26: 4-(3-were)-2-(4-methylsulfinylphenyl)-5-(2-phenylthio-4-pyridyl)-1,3-thiazole

A mixture of 5-(2-fluoro-4-pyridyl)-4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazole (0.40 g, were 0.94 mmol) and thiophenol (1.0 ml, 9.7 mmol) was stirred at 150 for 10 hours Then the reaction mixture was cooled to room temperature, was added a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate and washed with water. The obtained extract was dried and concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate =1:1) and recrystallized from ethanol to obtain 0.34 g (yield 70%) specified whenerver)-1,3-thiazole

After sodium hydride (60% dispersion in paraffin, of 0.13 g, 3.2 mmol) was washed twice in hexane, his suspended in N,N-dimethylformamide (15 ml). To the resulting suspension were added phenylmethanol (0.35 ml, 3.0 mmol) and the mixture was stirred 10 minutes To the mixture was added a solution of 5-(2-fluoro-4-pyridyl)-4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazole (0,49 g, 1.2 mmol) in N,N-dimethylformamide (5 ml) and the mixture was stirred 1 h To the reaction mixture were added 8 N. aqueous sodium hydroxide solution, the resulting mixture was extracted with ethyl acetate and the extract was washed with water. The obtained extract was dried and concentrated. The residue was purified by chromatography on a column of silica gel (hexane:ethyl acetate =2:1) obtaining of 0.48 g (yield 79%) specified in the connection header.

so pl. 182-S

Example 28: 4-(3-were)-2-(4-methylsulfinylphenyl)-5-(2-phenylsulfonyl-4-pyridyl)-1,3-thiazole

To a solution of 4-(3-were)-2-(4-methylsulfinylphenyl)-5-(2-phenylthio-4-pyridyl)-1,3-thiazole (0,48 g of 0.93 mmol) in N,N-dimethylformamide (10 ml) was added m-clorprenaline acid (0.51 g, 2.4 mmol) and the mixture was stirred at room temperature for 1 h To the reaction mixture were added 8 N. aqueous sodium hydroxide solution and the resulting solid matter was settled in the connection header.

so pl. 126-S

The compounds obtained in the examples described above 9-28 presented in tables 1-6.

Example 1 obtaining

(1) Compound of example 1 50 mg

(2) Lactose 34 mg

(3) Corn starch to 10.6 mg

(4) Corn starch (paste) 5 mg

(5) magnesium Stearate 0.4 mg

(6) Calcium carboxymethyl cellulose 20 mg

Total 120 mg

In accordance with the usual method of the above components (1) to(6) were mixed and extruded at a press reception of tablets.

Example 2 obtaining

(1) Connection example 16-1 10.0 mg

(2) Lactose 60,0 mg

(3) Corn starch 35.0 mm mg

(4) Gelatin 3.0 mg

(5) magnesium Stearate 2.0 mg

10.0 mg of the Compound of example 16-1 and the mixture is 60.0 mg of lactose and of 35.0 mg of corn starch was granulated, passing through a sieve with holes of 1 mm diameter, with the use of 0.03 ml of 10% aqueous solution of gelatin (3.0 mg of gelatin), then were dried at 40 ° C and again passed through a sieve. Resulting granules were mixed with 2.0 mg of magnesium stearate and extruded. The resulting core tablets were coated with sugar or suspension of sucrose, titanium dioxide, talc and Arabian gum in CLASS="ptx2">Example 3 obtaining

(1) Connection example 16-1 10.0 mg

(2) Lactose 50.0 mg

(3) Corn starch 50.0 mg

(4) Soluble starch 7.0 mg

(5) magnesium Stearate 3.0 mg

After granulation 10.0 mg of the compound of example 16-1 and 3.0 mg of magnesium stearate from 0.07 ml of an aqueous solution of soluble starch (7.0 mg of soluble starch granules were dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was extruded to obtain pellets.

Example 4 obtaining

(1) Compound of example 18 5.0 mg

(2) sodium Chloride 20.0 mg

(3) Distilled water to total

volume 2 ml

5.0 mg of the Compound of example 18 and 20.0 mg of sodium chloride was dissolved in distilled water and added water to obtain a total volume of 2.0 ml of the Solution was filtered and poured into 2 ml ampoules under sterile conditions. After sterilization, the ampoule was sealed with receipt of a solution for injection.

Example 1 test

Genetic procedures were performed in accordance with the method described in Molecular Cloning, published by Cold Spring Harbor Laboratory, 1989, or by the method described in the attached instructions for use reagent.

1) Cloning of adenosine A3receptor human

Konyrov is carried out using cyclic device (cycler 480) for heat treatment of DNA (Perkin Elmer), using 1 ng of cDNA brain (Toyobo, QUICK-Clone cDNA) as a matrix with the addition of 50 pmol of the primary set of 5’-CGCCTCTAGACAAGATGCCCAACAACAGCACTGC-3’ (SEQ ID NO:1) and 5’-CGGGGTCGACACTACTCAGAATTCTTCTCAATGC-3’ (SEQ ID NO:2) obtained with reference to the primary sequence of a gene adenosine A3-receptor shown in Salvatore et al. (Proc. Natl. Acad. Sci. U. S. A., 90:10365-10369, 1993), and a set of Takara LA PCR Ver.2 (Takara Shuzo) (reaction conditions: 35 cycles of 1 min at C, 1 min at C, 2 min at 75S). The obtained PCR product was subjected to agarose gel electrophoresis and identified 1,0, etc., called DNA fragment, and then cloned gene adenosine A3-receptor, using a set of Original TA Cloning (Funakoshi).

Then, the obtained plasmid was digested with restriction enzymes XbaI (Takara Shuzo), was treated with T4 DNA polymerase (Takara Shuzo) with the formation of fragments with blunt end and then were digested with restriction enzyme SalI (Takara Shuzo) to obtain fragments of the gene adenosine A3-receptor.

2) acquisition of plasmids for the expression of adenosine A3receptor human

The promoter SR produced from RTW described in JP-A 5-076385, were digested with BglII (Takara Shuzo), was blunted and ligated with EcoRI (Takara Shuzo) - split pCI vector (Promega) using a set of DNA Ligation (Takara Shuzo) with polue blunt end. On the other hand, after splitting pGFP-Cl (Toyobo) using Bsu36l (Daiichi Pure Chemicals) was treated with T4 DNA polymerase (Takara Shuzo) to form a blunt end with getting 1,63 etc. N. of a DNA fragment and both fragments ligated using a set of DNA Ligation (Takara Shuzo), and the competent cells of Escherichia coli JM109 was transformed to obtain plasmid pMSRneo.

Next, after splitting pMSRneo using EcoRI (Takara Shuzo) was performed processing of T4 DNA polymerase (Takara Shuzo) to form a blunt end and after further cleavage by the restriction enzyme SalI (Takara Shuzo) received 5,4, etc., called DNA fragment. The obtained DNA fragment and the fragments of the gene adenosine A3-receptor obtained in the above item 1), were mixed, ligated, using a set of DNA Ligation (Takara Shuzo), and the competent cells Escherlchia coli JM109 was transformed to obtain plasmid pA3SR

3) the Introduction of plasmids for the expression of adenosine A3receptor human cells Cho (dhfr-) and expression

Cells Cho (dhfr-), obtained by cultivation on the environment Ham F12 (Nihonseiyaku) containing 10% fetal calf serum (Lifetec Oriental) in 750 ml flask with tissue culture (Vecton Dickinson) was taken away millimetre with a mixture of 0.5 g/l trypsin-0.2 g/l EDTA (Lifetec Oriental) and then the cells were washed using PBS (Lifetec Oriental), and CEI in cells using a pulse generator (BioRad), under the following conditions. In a cuvette with grooves 0.4 cm was introduced 8106cells and 10 μg of plasmid pA3SR for the expression of adenosine A3receptor human and performed electroporation with a volume of 0.8 ml at a voltage of 0.25 kV and a capacitance of 960 μf. The cells are then transferred to the environment Ham F12 containing 10% fetal calf serum, and cultured for 24 h, was again taken away millimetre and centrifuged, and then suspended in the medium Ham F12 containing 10% fetal calf serum, which has already been added Geneticin (Lifetec Oriental), 500 μg/ml, and the suspension was diluted to 104cells/ml to inoculate cells in 96-well plate (Becton Dickinson) to obtain the strain that is resistant to Geneticin.

Then the resulting strain, resistant to Geneticin, were cultured on 24-hole tablet (Becton Dickinson), and then from the resistant strains were selected cell expressing the adenosine A3the receptor. That is, the reaction was performed in buffer I for analyses (HBSS(Wako Pure Chemicals) containing 0,1% BSA, 0.25 mm PMSF, 1 μg/ml of pepstatin and 20 μg/ml leupeptin) for 1 h, washed analytical buffer I measured the radioactivity using a counter to select the cell which specifically binds the ligand is 3receptor

After kulturarbeit strain AND3AG/SNO obtained as described in paragraph (3), in the environment Ham F12 containing 10% fetal calf serum for 2 days, the cells were taken away millimetre with PBS containing 0.02% of EDTA, were isolated by centrifugation, suspended in buffer II for analysis (50 mm Tris-hydrochloric acid (pH 7.5), 1 mm EDTA, 10 mm magnesium chloride, 0.25 mm PMSF, 1 μg/ml of pepstatin and 20 μg/ml leupeptin) and literally three processing patronym homogenizer (model RT-3000, KINEMATICA AG) at 20000 rpm for 20 sec. After the destruction of the cells was centrifuged at 20000 rpm for 10 min to obtain the supernatant containing the membrane fraction. The obtained supernatant was centrifuged at supercentrifuge (model L8-70M, 70Ti rotor, Beckman) at 30,000 rpm for 1 h with obtaining precipitation containing membrane fraction.

Next sediments suspended in buffer II for analyses containing 2 units/ml adenozindezaminazy (Boehringer Mannheim), was treated at 30 ° C for 30 min and then centrifuged as described above, to obtain the precipitation containing membrane fraction.

5) Test the binding of adenosine A3receptor

On 96-well-microplate buffer II, mersham) as ligand and different concentrations of the tested compounds, so that the ligand concentration was 10 nm, after which the reaction was performed at room temperature for 1 h Then the membrane fraction was transferred to unifilter GF/C (Packard) filtering the reaction solution using a collector cell Cell Harvester (Packard) and three times washed with chilled 50 mm Tris-buffer (pH 7.5). After drying the filter they added Microscint 0 (Packard), was measured radioactivity using a TopCount (Packard) was calculated using PRISM 2.01 (Graphpad Software) concentration (IC50) of the test compound required to reduce by 50% the magnitude of the binding of [3H]-NECA with the membrane fraction.

The resulting value IC50the compound of example 1 was equal to 11.6 nm. You can see that the compound (I) has excellent affinity for adenosine a3the receptor.

Example 2 test

Genetic procedures described below were carried out in accordance with the method described in the literature (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or by the method described in attached to the reagent instructions for use.

(1) Cloning of the gene MAR-kinase R man and preparation of recombinant Baculovirus

Cloning of the gene R MAR-kinase were performed by PCR with the use of’ [SEQ ID NO:4], obtained with reference to the primary sequence of a gene R MAR-kinase, shown by Han et al. (Science 265 (5173), 808-811 (1994)), and using kidney cDNA (Toyobo, QUICK-Clone cDNA) as a matrix.

The PCR reaction was performed by Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo). As the bottom of the mixed solution used a mixture of 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mm dNTP solution, each 2.5 μl of 12.5 μm primary solution and 10 μl of sterile distilled water. As the top of the mixed solution used a mixture of 1 μl of cardiac cDNA (1 ng/ml) as a template, 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mm dNTP solution, and 0.5 μl of TaKaRa LA Tag DNA polymerase (Takara Shuzo) and 24.5 μl of sterile distilled water. To the resulting lower mixed solution was added one AmpliWax PCR Gem 100 (Takara Shuzo) and the solution was treated for 5 min at 70 C and for 5 min on ice, then added the upper mixed solution to obtain a reaction solution for PCR. The tube with the reaction solution was installed on thermal cyclic device (Perkin Elmer) and treated with S for 2 minutes Then after a 35-fold repetition of the cycle of 15 s at S and 2 min at 68 PP. spent processing when 72S within 8 minutes, the Obtained PCR product was subjected electro put it in the vector pT7Blue-T (Takara Shuzo) to obtain plasmid RNR.

Fragment (4,8, etc., ad) XhoI-kpni restriction sites of the plasmid pFASTBAC1 (CIBCOBRL) and 1,1, etc. N. a fragment XhoI-Kpn obtained above plasmids RNR ligated to obtain plasmid pFBHP38.

To get the culture YOU NR recombinant Baculovirus used plasmid pFBHP38 YOU-THAT-YOU Baculovirus Expression System (GIBCOBRL).

(2) Cloning of the gene MCCS man and preparation of recombinant Baculovirus

Cloning of the gene MCCS man was produced by PCR using the primary set MKK-U: 5’-ACAAGAATTCATAACATATGGCTCATCATCATCATCATCATTCCAAGCCACCCGCACCCAA-3’ [SEQ ID: NO:5] and MKK-L: 5’-TCCCGTCTAGACTATGAGTCTTCTCCCAGGAT-3’ [SEQ ID NO:6], obtained with reference to the primary sequence of a gene MCCS shown in Derijard, B. et al. (Science 267 (5198), 682-685 (1995)), and using kidney cDNA (Toyobo, QUICK-Clone cDNA).

The PCR reaction was performed by Hot Start method using AmpliWax PCR Gem 100 (Takara Shuzo). As the bottom of the mixed solution used a mixture of 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mm dNTP solution, each 2.5 μl of 12.5 μm primary solution and 10 μl of sterile distilled water. As the top of the mixed solution used a mixture of 1 μl of kidney cDNA (1 ng/ml), 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mm dNTP solution, and 0.5 μl of TaKaRa LA Tag DNA polymerase (Takara Shuzo) and 24.5 μl of sterile distilled water. To the resulting lower CE 5 min on ice, then added the upper mixed solution to obtain a reaction solution for PCR. The tube with the reaction solution was installed on thermal cyclic device (Per-kin Elmer) and treated with S for 2 minutes Then after a 35-fold repetition of the cycle of 15 s at S and 2 min at 68 PP. spent processing when 72S within 8 minutes, the Obtained PCR product was subjected to electrophoresis on agarose gel (1%), was isolated from the gel 1,0, etc., called DNA fragment containing the gene MCC, and then put it in the vector pT7Blue-T (Takara Shuzo) to obtain plasmid RMCC.

To mutate MCC in the composite active form (from Ser to Glu at position 189, from Thr to Glu at position 193) used a primary set of SER-U: 5’-GGCTACTTGGTGGACGAGGTGGCCAAGGAGATGGATGCCGGCTGC-3’ [SEQ ID NO: 7] and SER-L: 5’-GCAGCCGGCATCCATCTCCTTGGCCACCTCGTCCACCAAGTAGCC-3’ [SEQ ID NO:8] to make mutations using a set QuickChange Site-Directed Mutagenesis (Stratagene) to obtain ramcc.

Fragment (4,8, etc., ad) EcoRI-Xbal plasmid pFASTBAC1 (CIBCOBRL) and 1.0 T. p. N. fragment EcoRI-XbaI above plasmids ramcc ligated to obtain plasmid F3.

To get the culture YOU samcc recombinant baculovirus used plasmid F3 YOU-THAT-YOU Baculovirus Expression System (GIBCOBRL).

(3) generation of active forms R MAR-kinase

(4) Measurement of inhibitory activity against R MAR-kinase

Was added 2.5 μl of the test compounds, dissolved in DMSO, to 37.5 μl of reaction solution (25 mm HEPES (pH 7.5), 10 mm magnesium acetate) containing 260 ng active forms R MAR-kinase and 1 μg myelin basic protein, and kept the mixture at 30 ° C for 5 minutes the Reaction was initiated by adding 10 μl of a solution of ATP (ATP) (2.5 μm ATP, of 0.1 µci [g32P]ATP). After the reaction at 30 ° C for 60 min, the reaction was stopped by adding 50 μl of 20% solution of TCA (TCA). After the reaction solution was kept at 0C for 20 min, insoluble in acid pruski at 45C for 60 min, added 40 mm Microscint 0 (Packard Japan) and measured the radioactivity using a TopCount (Packard Japan). Was calculated using PRISM 2.01 (Graphpad Software) concentration (the value of the IC50) of the test compound necessary for inhibiting the uptake of 32P insoluble in the acid fraction of 50%. The results are shown in table 7.

From table 7 one can see that the compound (I) has an inhibitory activity against R MAR-kinase.

Experimental example 3

Measurement of inhibitory activity against the production of TNF-

After cells TNR-1, which were grown on medium PRMI 1640 (Life Technologies, Inc.), containing 1% Deaktivierung fetal calf serum (produced by Life Technologies, Inc., USA) and 10 mm HEPES (pH 7.5), were sown in 96-well tablet to 1106cells/well, were added 1 μl of the test compounds dissolved in DMSO. After incubation at C for 1 h in the incubator with CO2added LPS (Wako Pure Chemicals) to a final concentration of 5 µg/ml After growing at C for 4 h in the incubator with CO2, was obtained by centrifugation of the supernatant. Using ELISA (R&D System, Quantikine Kit) measured the concentration of TNF in the supernatant. Was calculated using PRISM 2.01 (Graphpad Software) is provided in table 8.

From table 8 one can see that the compound (I) has a high inhibitory activity against the production of TNF-.

Industrial applicability

The compound (I) or its salt has a high antagonism to the adenosine A3the receptor and can be used(a) as agent for the prevention or treatment of diseases associated with adenosine A3-a receptor. In addition, compound (I) or its salt exhibits a high inhibitory activity against R MAR kinase and high inhibitory activity against TNF-, and can also be used(a) as a means for prevention or treatment of diseases associated with R MAR-kinase, and diseases associated with TNF-.

1. Optionally N-oxidized compound represented by the formula

in which R1represents (1) hydrogen atom, (2) C1-6alkyl group, (3) phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or (4) an amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

R2PI (2) 5 - or 6-membered aromatic heterocyclic group, containing one sulfur atom or one nitrogen atom;

R3represents a phenyl group optionally substituted by 1 or 2 C1-6alkyl groups or C1-6alkoxy;

X represents a sulfur atom;

Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group;

Z represents a bond, C1-6alkylenes group, optionally substituted by oxo or C1-6alkyl group;

or its salt.

2. Connection on p. 1, where Z represents C1-6alkylenes group, optionally substituted by oxo or C1-6alkyl group.

3. Connection on p. 1, which is a compound represented by the formula

in which n is 0 or 1, and other symbols such as defined in paragraph 1,

or its salt.

4. Connection under item 1 or 3, where R1represents (i) hydrogen atom, (ii) a phenyl group optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, (iii) amino group, optionally substituted C1-6alkyl group; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy; Y represents a new group.

5. Connection on p. 1, where R1represents amino, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

6. Connection on p. 1, where R1represents (i) C1-6alkyl group, (ii) a phenyl group optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or (iii) an amino group, an optionally substituted acyl group,- (C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl.

7. Connection on p. 1, where R1represents the amino group, the optionally substituted acyl group,- (C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl.

8. Connection on p. 1, where R2is6-14aryl group, optionally substituted with halogen or C1-6alkoxy.

9. Connection on p. 1, where R2represents 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom.

10. Connection on p. 1, where R2is6-14aryl group or a 5 - or 6-membered aromatic heterocyclic group is inuu group, optionally substituted by 1 or 2 C1-6alkyl groups.

12. Connection on p. 1, where R3represents a phenyl group, optionally substituted C1-6alkoxy.

13. Connection on p. 1, where Y is O or NR4where R4such, as defined in paragraph 1.

14. Connection on p. 1, where Y represents O, S, SO2or NR4’where R4’represents C1-6alkyl group.

15. Connection on p. 1, where Y represents O, NH or S.

16. Connection on p. 1, where Z represents C1-6alkylenes group, optionally substituted by oxo.

17. Connection on p. 1, where Z represents a bond or C1-6alkylenes group, optionally substituted by oxo.

18. Connection on p. 1, where R1represents (i) C1-6alkyl group, (ii) phenyl group, optionally substituted C1-6alkylthio, C1-6alkylsulfonyl or halogen atom, or (iii) an amino group, an optionally substituted acyl group,- (C=O)-R5’where R5’represents C1-6alkyl group, phenyl or pyridyl;

Y represents O, S, SO2or NR4’where R4’represents C1-6alkyl group.

19. Connection on p. 1, where R1predstavil; Y represents O, NH or S; Z represents a bond or C1-6alkylenes group, optionally substituted by oxo.

20. Connection on p. 1, selected from the group including

N-[5-(2-benzoylamino-4-pyridyl)-4-(3, 5dimethylphenyl)-1,3-thiazol-2-yl]acetamide", she

N-[5-(2-benzylamino-4-pyridyl)-4-(3, 5dimethylphenyl)-1,3-thiazol-2-yl]acetamide", she

N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide,

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide,

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide,

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-felfeli)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,

N-[4-[2-(4-forfinal)-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]phenylpropionamide,

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,

N-benzyl-N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine,

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

N-benzyl-N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine,

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine,

N-[4-[4-(3-were)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

N-benzyl-N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine,

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine,

N-[4-[2-butyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

N-benzyl-N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine,

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine,

N-[4-[4-(3-were)-2-(4-methylthiophenyl)-1,3-tridel]benzamid,

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide,

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide,

N-benzyl-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine,

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)Amin

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine,

N-(4-terbisil)-N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine or its salt.

21. Connection on p. 1, selected from the group including

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide,

N-benzyl-N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine,

N-[4-[4-(3-were)-2-(4-methylsulfinylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine or its salt.

22. Connection on p. 1, representing

N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]benzamide or its salt.

23. Connection on p. 1, representing

N-benzyl-N-[4-[2-ethyl-4-(3-were)-1,3-thiazol-5-yl]-2-pyridyl]amine or its salt.

24. Connection on p. 1, representing

N-[4-[4-(3-were)-2-(4-meuleuse optionally N-oxidized compound of the formula

in which R1represents (1) hydrogen atom, (2) C1-6alkyl group, (3) phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or (4) an amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

R2represents (1)6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or (2) a 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom;

R3represents a phenyl group optionally substituted by 1 or 2 C1-6alkyl groups or C1-6alkoxy;

X represents a sulfur atom,

Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group;

Z represents a bond, C1-6alkylenes group, optionally substituted by oxo or C1-6alkyl group, or its salt or prodrug, is used to obtain means for the prevention or treatment of asthma, allergic diseases, inflammation, Addison's disease, autoi the brain, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, atherosclerosis, diseases of Creutzfeldt-Jakob disease, viral infections, atopic dermatitis, systemic lupus erythematosus, encephalopathy from AIDS, meningitis, strokes, heart attacks, congestive heart failure, hepatitis, transplantation, hypotension on dialysis or disseminated intravascular coagulation.

26. The prodrug compounds on p. 1, representing a compound that is converted into compound (I) under physiological conditions and is a compound in which the amino group of compound (I) allyawan, alkylated or phosphorylated, such as the compound in which the amino group of compound (I) is eicosanoides, albilineans, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinylcarbonyl, pivaloyloxymethyl, tert-butylated; a compound in which hydro is, where the hydroxy-group of the compound (I) is acetylated, palmitoylation, propanolamine, pualeilani, succinylamino, polarisierung, albilineans, dimethylaminomethylphenol; the connection in which carboxypropyl compounds (I) etherification or liderovna, such as the connection in which carboxypropyl the compound (I) is utilitarians, phenylacetylcarbinol, karboksimetilirovannoj, dimethylaminoethylacrylate, pivaloyloxymethyl, ethoxycarbonylmethylene, feliciamirando, (5-methyl-2-oxo-1,3-dioxolan-4-yl) methylethylamine, cyclohexyloxycarbonyloxy, methylaminophenol.

27. A method of obtaining a connection on p. 1, including the interaction of the compounds represented by the formula

each character, as defined in paragraph 1, or its salt with a compound represented by the formula:

R2-ZL, (XVIII)

in which L represents a leaving group, and other symbols, such as defined in paragraph 1, or its salt to obtain the compound represented by the formula

each character, takistan in respect of adenosine A3-receptor inhibitory activity against R MAR-kinase, inhibiting action in respect of the production of TNF-containing compound under item 1, and a pharmaceutically acceptable carrier.

29. The composition according to p. 28, which is an agent for the prevention or treatment of diseases associated with adenosine A3-receptor.

30. The composition according to p. 28, which is an agent for the prophylaxis or treatment of asthma or allergic diseases.

31. The composition according to p. 28, which is an agent for the prevention or treatment of brain edema, vascular diseases of the brain or head injuries.

32. The composition according to p. 28, which is an agent for the prevention or treatment of cytokine-mediated diseases.

33. The composition according to p. 28, which is an agent for the prophylaxis or treatment of inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerotic from AIDS, meningitis, angina, heart attack, congestive heart failure, hepatitis, transplantation, hypotension on dialysis or disseminated intravascular coagulation.

34. The pharmaceutical composition according to p. 28, which contains a connection on p. 21.

35. How antagonization adenosine A3receptor, comprising introducing an effective amount of optionally N-oxidized compound represented by the formula

in which R1represents (1) hydrogen atom, (2) C1-6alkyl group, (3) phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or (4) an amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

R2represents (1)6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or (2) a 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom;

R3represents a phenyl group optionally substituted by 1 or 2 C1-6alkyl groups or C1-61-6alkyl group;

Z represents a bond, C1-6alkylenes group, optionally substituted by oxo or C1-6alkyl group;

or its salts or prodrugs mammals.

36. Method of inhibiting R MAR-kinase, comprising introducing an effective amount of optionally N-oxidized compound represented by the formula

in which R1represents (1) hydrogen atom, (2) C1-6alkyl group, (3) phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or (4) an amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

R2represents (1)6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or (2) a 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom;

R3represents a phenyl group optionally substituted by 1 or 2 C1-6alkyl groups or C1-6alkoxy;

X represents a sulfur atom;

Y represents O, S, SO2or NRUB>1-6alkylenes group, optionally substituted by oxo or C1-6alkyl group,

or its salts or prodrugs mammals.

37. Method of inhibiting production of TNF-including the introduction of effective amounts of optional N-oxidized compound represented by the formula

in which R1represents (1) hydrogen atom, (2) C1-6alkyl group, (3) phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or (4) an amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

R2represents (1)6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or (2) a 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom;

R3represents a phenyl group optionally substituted by 1 or 2 C1-6alkyl groups or C1-6alkoxy;

X represents a sulfur atom;

Y represents O, S, SO2or NR4where R4represents a hydrogen atom or C1-6alkyl group,

or its salts or prodrugs mammals.

38. A method of preventing or treating asthma, allergic diseases, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, cerebral hemorrhage, heart attack, brain, head trauma, spinal trauma, brain edema, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetes, arthritis, toxemia, ulcerative colitis, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, atherosclerosis, diseases of Creutzfeldt-Jakob disease, viral infections, atopic dermatitis, systemic lupus erythematosus, encephalopathy from AIDS, meningitis, angina, heart attack, congestive heart failure, hepatitis, transplantation, hypotension on dialysis or disseminated intravascular coagulation, including the introduction of effective amounts of optional N-oxidized compound represented by the formula

in which R1represents (1) hydrogen atom, (2) C1-6alkyl group, (3) phenyl group, optionally substituted by a halogen atom, With the strong group or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl;

R2represents (1)6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or (2) a 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom;

R3represents a phenyl group optionally substituted by 1 or 2 C1-6alkyl groups or C1-6alkoxy;

X represents a sulfur atom;

Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group;

Z represents a bond, C1-6alkylenes group, optionally substituted by oxo or C1-6alkyl group,

or its salts or prodrugs mammals.

Priority items:

23.04.1999 - PP.1-3, 5, 8, 10, 11, 13-16, 26-31 and 35;

06.08.1999 - PP.25, 32, 33, 36-38.

 

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