Diaminothiazoles possessing property of cyclin-dependent kinase 4 inhibitor

FIELD: organic chemistry, biochemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel diaminothiazoles of the formula (I) , their pharmaceutically acceptable salts and esters, and to a pharmaceutical composition based on thereof. Proposed compounds inhibit activity of cyclin-dependent kinase 4 (Cdk4), shows selectivity with respect to Cdk2 and Cdk1 and can be used in treatment against cancer, in particular, against solid tumors. In the general formula (I) R2 and R3 represent hydrogen atom; R4 is chosen from group comprising lower alkyl, (C3-C6)-cycloalkyl, O-lower alkyl, halogen atom, -NO2, S-lower alkyl, -CF3 and -CN; R5 is chosen from group comprising hydrogen atom, O-lower alkyl, lower alkyl, halogen atom and -OH, or, alternatively, R4 and R in common with two carbon atoms and a bond binding them belonging to benzene cycle (C) to which R4 and R5 are bound can form a cycle consisting of 5-6 atoms comprising one or two heteroatoms chosen from oxygen atom and optionally substituted with (C1-C4)-alkyl; R6 and R are chosen independently from group comprising hydrogen atom, lower alkyl and -COOR12, or, alternatively, group -NR6R7 can mean cycle consisting of 5-6 atoms optionally comprising heteroatom chosen from nitrogen or oxygen atoms; R8 and R9 are chosen independently from group comprising hydrogen atom and lower alkyl; R10 is chosen from group comprising hydrogen atom, lower alkyl, lower alkyl substituted with hydroxyl, and -COOR12; R11 is chosen from group comprising hydrogen atom, lower alkyl and -COOR12 wherein R12 means lower alkyl; m can mean 1 or 2; n can mean 0, 1 or 2 under condition that if m means 2 and R4 means fluorine atom then R5 is not hydrogen atom, and under condition if m means 1 and R4 means lower alkyl then R5 is not hydroxyl.

EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical compositions.

20 cl, 6 sch, 3 tbl, 153 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula

,

in which O-R1is a group selected from the

,and

R2and R3are you hydrogen;

R4selected from the group comprising lower alkyl, C3-C6cycloalkyl, O-lower alkyl, halogen, -NO2, S-lower alkyl, -CF3and-CN;

R5selected from the group comprising hydrogen, O-lower alkyl, lower alkyl, halogen, and-HE,

or, alternatively,

R4and R5together with the two carbon atoms and connecting link belonging to the benzene cycle (S)to which R4and R5attached, may form a cycle consisting of 5-6 atoms containing one or two heteroatoms selected from oxygen and optionally substituted C1-C4by alkyl;

R6and R7independently selected from the group comprising hydrogen, lower alkyl,- COOR12,

or, alternatively,

the group-NR6R7may be a cycle consisting of 5-6 atoms, optionally including a heteroatom selected from nitrogen or oxygen;

R8and R9independently selected from the group comprising hydrogen and lower alkyl;

R10selected from the group comprising hydrogen, lower alkyl, lower alkyl substituted by hydroxyl, and-COOR12;

R11selected from the group comprising hydrogen, lower alkyl, and-COOR ;

R12is lower alkyl;

m takes on the values 1 or 2; and

n takes on the values 0, 1 or 2;

provided that in the case when m is 2; and R4is fluorine, R5is not hydrogen and with the proviso that when m is 2; and R4is lower alkyl, R5is not hydroxyl;

or its pharmaceutically acceptable salt or ester.

2. Compounds according to claim 1, in which R4is a halogen.

3. Compounds according to claim 1 in which R4is fluorine.

4. Compounds according to claim 1, in which R4is lower alkyl.

5. Compounds according to claim 9, in which R4is stands.

6. Compounds according to claim 1, in which R5is halogen or hydrogen.

7. Compounds according to claim 6, in which R5is fluorine.

8. Compounds according to claim 1, in which R4is fluorine, and R5is O-stands.

9. The compound of the formula

in which R2and R3represent hydrogen;

R4selected from the group comprising lower alkyl, C3-C6cycloalkyl, O-lower alkyl, halogen, -NO2, S-lower alkyl, -CF3and-CN;

R5selected from the group comprising hydrogen, O-lower alkyl, lower alkyl, halogen, and-HE, or, alternative is,

R4and R5together with the two carbon atoms and connecting link belonging to the benzene cycle (S)to which R4and R5attached, may form a cycle consisting of 5-6 atoms, optionally comprising one or two heteroatoms selected from oxygen, and optionally substituted (C1-C4)alkyl;

R6and R7independently selected from the group comprising hydrogen, lower alkyl, and-COOR12or, alternatively,

the group-NR6R7may be a cycle consisting of 5-6 atoms, optionally including a heteroatom selected from nitrogen and oxygen;

R8and R9independently selected from the group comprising hydrogen and lower alkyl;

R12is lower alkyl;

m takes on the values 1 or 2;

provided that in the case when m is 2; and R4is fluorine, R5is not hydrogen and with the proviso that when m is 2; and R4is lower alkyl, R5is not hydroxyl,

or its pharmaceutically acceptable salt or ester.

10. The connection according to claim 9, in which m takes the value 1.

11. The compound of formula Ia according to claim 9, selected from the group including

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazole-5-is](4-ethyl-3-forfinal)methanon; connection with triperoxonane acid;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(2-dimethylamino-2-methylpropoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

(R)-[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

(R)-[4-Amino-2-[4-(2-pyrrolidin-1 ipropose)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(2-morpholine-4-ylethoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](4-methoxy-3-nitrophenyl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](4-methoxy-3-nitrophenyl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl]-m-trimeton;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl]-m-trimeton;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-nitrophenyl)methanon;

[4-Amino-2-[4-(2-morpholine-4-ylethoxy)the dryer is laminitis]thiazol-5-yl](2,3-dihydrobenzo[1,4]dioxin-6-yl)methanon;

[4-Amino-2-[4-(2-morpholine-4-yl-ethoxy)phenylamino]-thiazol-5-yl]benzo[1,3]dioxol-5-ylmethanol;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl]benzo[1,3]dioxol-5-ylmethanol;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](2,3-dihydrobenzo[1,4]dioxin-6-yl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl]benzo[1,3]dioxol-5-ylmethanol;

3-[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazole-5-carbonyl]benzonitrile;

[4-Amino-2-[4-(2-dimethylamino-2-methylpropoxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-ethoxyphenyl)methanon;

(R)-[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-bromophenyl)methanon;

(R)-[4-Amino-2-[4-(2-pyrrolidin-1 ipropose)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

(R)-[4-Amino-2-[4-(2-pyrrolidin-1 ipropose)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

(R)-[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

[4-Amino-2-[4-(2-dimethylamino-2-methylpropoxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon;

(R)-[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon;

[4-Amino-2-[4-(2-dimethylamino-2-methylpropoxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-ethyl-4-forfinal)methanon;

(R)-[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](3-ethyl-4-forfinal)methanon;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl]-m-trimeton; compound with acetic acid;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](3-ethyl-4-forfinal)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-dimethylaminoethoxy and)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

(R)-[4-Amino-2-[4-(2-dimethylaminopropoxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-dimethylamino-2-methylpropoxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

(R)-[4-Amino-2-[4-(2-pyrrolidin-1 ipropose)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-fluoro-4-hydroxyphenyl)methanon; compound with acetic acid;

(R)-[4-Amino-2-[4-(2-pyrrolidin-1 ipropose)phenylamino]thiazol-5-yl](3-methoxyphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(2-diethylaminoethoxy)phenylamino]thiazol-5-yl]-(3-fluoro-4-hydroxyphenyl)methanon;

[4-Amino-2-[4-(2-diethylaminoethoxy)phenylamino]thiazol-5-yl](3-fluoro-4-methoxyphenyl) methanon;

[4-Amino-2-[4-(2-diethylaminoethoxy)phenylamino]thiazol-5-yl](3-methylsulfinylphenyl)methanon;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-trifluoromethyl who enyl)methanon;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](3-methoxyphenyl)methanon;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl]benzo[1,3]dioxol-5-ylmethanol;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](2,3-dihydrobenzo[1,4]dioxin-6-yl)methanon;

[4-Amino-2-[4-(2-isopropylaminoethyl)phenylamino]thiazol-5-yl](2,3-dihydrobenzo[1,4]dioxin-6-yl)methanon;

1-(1,3-Benzodioxol-5-yl)-2-brometane;

[4-Amino-2-[4-(2-diethylaminoethoxy)phenylamino]thiazol-5-yl](3-methyl-2,3-dihydrobenzofuran-5-yl)methanon;

[4-Amino-2-[4-(2-pyrrolidin-1 ylethoxy)phenylamino]thiazol-5-yl](3-methyl-2,3-dihydrobenzofuran-5-yl)methanon;

[4-Amino-2-[4-(2-diethylaminoethoxy)phenylamino]thiazol-5-yl](2,3-dihydrobenzofuran-5-yl)methanon;

[4-Amino-2-[4-(2-ethyleneoxy)phenylamino]thiazol-5-yl](2,3-dihydrobenzofuran-5-yl)methanon;

[4-Amino-2-[4-(2-dimethylaminoethoxy)phenylamino]thiazol-5-yl](3-methoxyphenyl)methanon;

[4-Amino-2-[4-(2-diethylaminoethoxy)phenylamino]thiazol-5-yl](3-methoxyphenyl)methanon; and

[4-Amino-2-[4-(2-imidazol-1-ylethoxy)phenylamino]thiazol-5-yl](3-methoxy-phenyl)methanon.

12. The connection according to claim 9, in which m is 2.

13. The connection section 12, selected from the group comprising [4-Amino-2-[4-(3-amino is repossi)phenylamino]thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon; and

[4-Amino-2-[4-(3-Ethylenedioxy)phenylamino]thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon.

14. The compound of the formula

,

in which R2and R3represent hydrogen;

R4selected from the group comprising lower alkyl, C3-C6cycloalkyl, halogen;

R5selected from the group comprising hydrogen, lower alkyl, and-HE,

R10selected from the group comprising hydrogen, lower alkyl, and-COOR12;

R12is lower alkyl,

or its pharmaceutically acceptable salt or ester.

15. The connection 14, selected from the group including

[4-Amino-2-[4-(pyrrolidin-2-ylethoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

(S)-[4-Amino-2-[4-(1-methylpyrrolidine-2-ylethoxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

(S)-[4-Amino-2-[4-(1-methylpyrrolidine-2-ylethoxy)phenylamino]thiazol-5-yl]-m-trimeton;

(S)-[4-Amino-2-[4-(1-methylpyrrolidine-2-ylethoxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

(S)-[4-Amino-2-[4-(1-methylpyrrolidine-2-ylethoxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

(S)-[4-Amino-2-[4-(1-methylpyrrolidine-2-ylethoxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon; and

(S)-[4-Amino-2-[4-(1-methylpyrrolidine-2-ylethoxy)phenylamino]thiazol-5-yl](4-what hydroxy-3-propylphenyl)methanon, the acetate.

16. The compound of the formula

,

in which R2and R3represent hydrogen;

R4selected from the group comprising lower alkyl, C3-C6cycloalkyl, halogen;

R5selected from the group comprising hydrogen, O-lower alkyl, lower alkyl, halogen and HE;

R11selected from the group comprising hydrogen, lower alkyl, and-COOR12;

R12is lower alkyl;

n takes on the values 0, 1 or 2,

or its pharmaceutically acceptable salt or ester.

17. Connection P16 selected from the group including

[4-Amino-2-[4-(1-ethylpyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(piperidine-3-yloxy)phenylamino]thiazol-5-yl](3-forfinal)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl]-m-trimeton;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](3-this is l-4-forfinal)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](3-fluoro-4-hydroxyphenyl)methanon;

[4-Amino-2-[4-(1-ethylpyrrolidin-3-yloxy)phenylamino]thiazol-5-yl]-m-trimeton;

[4-Amino-2-[4-(1-ethylpyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(1-ethylpyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon;

[4-Amino-2-[4-(1-ethylpyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon;

[4-Amino-2-[4-(1-ethylpiperidine-3-yloxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(1-ethylpyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl]-m-trimeton; compound with acetic acid;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-cyclopropylmethyl)methanon; compound with acetic acid;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-fluoro-4-were)methanon; compound with acetic acid;

[4-Amino-2-[4-(pyrrolidin-3-yloxy)phenylamino]thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon;

[4-Amino-2-[4-(piperidine-3-yloxy)phenylamino]thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon;

[4-Amino-2-[4-(piperidine-3-yloxy)phenylamino]thiazol-5-yl](3-ethylphenyl)methanon;

[4-Amino-2-[4-(piperidine-3-yloxy)phenylamino]thiazol-5-yl](4-hydroxy-3-propylphenyl)methanon;

tert-butyl ester 3-[4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]phenoxy]azetidin-1-carboxylic acid; and

[4-Amino-2-[4-(azetidin-3-yloxy)phenylamino]thiazol-5-yl](3-forfinal)methanon.

18. Pharmaceutical composition having the properties of an inhibitor of the cyclin-dependent kinase 4 (Cdk4) and selectivity for Cdk2 and Cdk1, containing as active ingredient an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

19. The pharmaceutical composition according p suitable for parenteral administration.

20. The compound according to any one of claims 1 to 17, having the properties of an inhibitor of the cyclin-dependent kinase (Cdk4) and selectivity for Cdk2 and Cdk1.



 

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1 cl, 1 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

FIELD: organic chemistry, medicine, biology.

SUBSTANCE: invention relates to novel derivatives of thiazole that are strong antagonists, agonists or partial agonists of cannabinoid CB1 receptors. Compounds show the general formula (I): wherein R and R1-R4 have values given in the invention claim. Also, invention relates to using compounds of the formula (I) or their stereoisomers for preparing a pharmaceutical composition. Also, invention relates to intermediate compounds of the formula (V): wherein R2 and R8 have values given in the invention claim.

EFFECT: valuable medicinal and biological properties of compounds.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of phenoxy-N-[4-(1,1-dioxoisothiazolidin-2-yl)-valeramide and describes compounds of the formula (I): wherein E represents phenyl or isoquinoline each of that is monosubstituted with group R1 wherein R1 represents -CN, amidino-group, halogen atom, -NH2, -CH2NH2 or compound of the formula: W represents -OCHAr', -OCHA, -NHCHAr', -NHCHA, -NHCOOCHAr', -NHCONHCHAr' or piperidine-1,2-diyl; Ar' represents unsubstituted phenyl or mono- or disubstituted phenyl, Hal, A or -CF3; A represents alkyl with 1, 2, 3, 4, 5, 6 or 7 C-atoms; X represents -CONH; Y represents Ar-diyl; T represents group -(CH2)3; Ar represents unsubstituted phenyl or mono- or disubstituted phenyl, Hal, A or -CF3; Hal represents fluorine (F), chlorine (Cl), bromine (Br) or iodine (J) atoms. These compounds are the coagulation factor Xa inhibitors. Also, invention relates to a method for synthesis of compounds of the formula (I), a medicinal agent containing these compounds and using compounds of the formula (I) for preparing a drug used in treatment of thrombosis, myocardium infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, restenosis after plastic surgery in vessels, intermittent lameness, migraine, tumors, tumor diseases and/or tumor metastasis and a kit (set). Also, invention relates to intermediate compounds of the formula (I-1): wherein R1 represents -NO2 or -NH2; R represents methyl, chlorine atom or trifluoromethyl and their salts. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 14 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes substituted benzoylpyrazoles of the general formula (I): wherein Q means oxygen atom (O); R1 means alkyl with 1-6 carbon atoms; R2 means hydrogen atom; R3 and R4 mean independently of one another hydrogen atom, halogen atom, alkyl with 1-4 carbon atoms substituted with halogen atom; R5 means hydrogen atom, alkyl with 1-6 carbon atoms; Y means hydrogen atom; Z means alkoxyamino-group with 1-6 carbon atoms, alkylamino-group with 1-6 carbon atoms, substituted alkoxy-group with 1-4 carbon atoms, N-alkylalkoxyamino-group with 1-4 carbon atoms, phenyl substituted with halogen atom, monocyclic heterocyclyl, heterocyclylamino-group, group -N=(heterocyclyl) chosen from the group: furyl, tetrahydrofurylmethylamino-group, isoxazolyl, dihydroisoxazolyl (isoxazolinyl), tetrahydroisoxazolyl (isoxazolidinyl), tetrahydro-(2H)-1,2-oxazine-2-yl, dihydrothiazolyl (thiazolinyl), oxadiazolylamino-, thiadiazolylamino-group, piperidinyl, piperidinylamino-group, 2-oxo-1,3-diazacyclohexyl, morpholinyl, morpholinylamino-group, respectively, and substituted if necessary with alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms involving their all possible tautomeric forms and possible salts. Also, invention describes a herbicide agent based in proposed compounds. Proposed compounds possess herbicide activity.

EFFECT: valuable properties of compounds and agent.

4 cl, 5 tbl, 77 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds of the general formula (I): wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents hydrogen atom, -CO-R3 wherein R3 represents (C2-C6)-alkyl substituted optionally with halogen atom, -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom or (C1-C4)-alkyl; R5 represents (C1-C8)-alkyl, (C2-C8)-alkenyl and others; Y represents compound of the formula: wherein R7 represents hydrogen atom or (C1-C4)-alkyl; R8 represents (C5-C8)-alkyl, (C4-C8)-cycloalkyl and others; X represents oxygen atom or sulfur atom and others. Also, invention relates to pharmaceutically acceptable salts of these compounds. Compounds of the formula (I) possess hypoglycemic and/or hypolipidemic activity and can be used in medicine in treatment of diabetes mellitus, hyperlipidemia, hyperglycemia, diseases caused by resistance to insulin and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 tbl, 131 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, chemical technology, pesticides.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein Q means nitrogen atom (N); Y means nitro-group (-NO2); Z means -NR3; R1 and R2 mean in common alkylene bridge that comprises two or three carbon atoms and, optionally, a heteroatom chosen from the group comprising -NR5 and oxygen atom (O); R3 means unsubstituted (C1-C12)-alkyl; R5 means hydrogen atom (H) or (C1-C12)-alkyl. Method involves the following steps: (a) interaction of compound of the formula (II): wherein X means a leaving group with a halogenated agent to yield compound of the formula (III): wherein W means halogen atom and wherein treatment of compound of the formula (III) involves extraction of compound of the formula (III) with hydrochloric acid taken in the concentration 10-50 wt.-%, and (b) interaction of the synthesized compound of the formula (III) with compound of the formula (IV): wherein R1, R2, Y, Z and Q have above given values. In the process for synthesis of compound of the formula (III) the stage (a) involves purification stage wherein formed crude product is treated with water at acid range of pH values.

EFFECT: improved method of synthesis.

3 cl, 6 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

14 cl, 2825 ex

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