2,4-di(phenylamino)pyrimidines, applied in treatment of neoplastic diseases, inflammatory disorders and immune system disorders

FIELD: medicine.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) or their pharmaceutically acceptable salts which possess inhibiting activity with respect to focal adhesion kinase (FAK), proteintyrosinekinase ZAP-70, receptor of insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity of anaplastic lymphoma (ALK) and fusion protein NPM-ALK. In formula (I) , R0, R1 and R2 independently represent hydrogen, C1-C8 alkyl, 5- or 6-member heterocycle, containing 1,2 or 3 heteroatoms, selected from N, O and S, C1-C8alkoxy group, C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, halogen, carbamoyl, sulphamoyl, etc.; R3 represents C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, carbamoyl or sulphamoyl; R4 represents hydrogen or C1-C8alkyl; R5 represents chlorine or bromine; R6 represents hydrogen; R7, R8, R9 and R10 independently represent C1-C8alkyl, C5-C10aryl, possibly substituted by 5- or 6-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N, O and S, where substituents are selected from C1-C8alkyl, hydroxy, hydroxy-C1-C8alkyl, C1-C8alkoxy C1-C8alkyl, cyano, oxo, C1-C8alkylamino, diC1-C8alkylamino, carbamoyl, C1-C8alkylcaronyl, 5-10-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N and O, which is probably substituted by C1-C8alkyl; C1-C8alkoxy group, halogen- C1-C8alkoxy group, etc; A represents C. Invention also relates to pharmaceutical composition and to application of compounds of formula (I) for preparation of medication.

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

in which each R0, R1and R2independently represent hydrogen, C1-C8alkyl, 5 - or 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, which is unsubstituted or substituted With1-C8the alkyl, C1-C8alkoxygroup,1-C8alkylsulfonyl,1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxypropyl, carbarnoyl, which is unsubstituted or substituted With1-C8the alkyl, sulfamoyl, which is unsubstituted or substituted With1-C8the alkyl or Halogens1-C8by alkyl;
R3stands With1-C8alkylsulfonyl,1-C8alkylsulfonyl, C5-C10arylsulfonyl, carbarnoyl, which is unsubstituted or substituted With1-C8the alkyl or sulfamoyl, which is unsubstituted or substituted With1-C8the alkyl or Halogens1-C8by alkyl;
R4denotes hydrogen or C1-C8alkyl;
R5denotes chlorine or bromine;
R6denotes hydrogen; and
each R7, R8, R9and R10independently denote With1-C8alkyl, C5-C10aryl, which is unsubstituted or substituted With1-C8the alkyl or C1-C8Ala is XI, unsubstituted or substituted 5 - or 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, where the substituents are selected from C1-C8of alkyl, hydroxy, hydroxy-C1-With8of alkyl, C1-C8alkoxyl1-C8of alkyl, cyano, oxo, C1-C8alkylamino, dis1-C8alkylamino, carbamoyl, which is unsubstituted or substituted With1-C8the alkyl, C1-C8alkylcarboxylic1-C8of alkyl, C1-C8alkylcarboxylic,1-C8alkylcarboxylic, 5-10-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N and O, which is unsubstituted or substituted With1-C8by alkyl; C1-C8alkoxygroup, 2-methoxyethoxy, Halogens1-C8alkoxygroup,5-C10arils1-C8alkoxy, which is nezamescennych or substituted C1-C8the alkyl or C1-C8alkylcarboxylic, 5 - or 6-membered nitrogen-containing heterocyclics, which is unsubstituted or substituted C1-C8the alkyl or acetyl, amino, methylamino, dimethylamino, propylamino, hydroxyethylamino, di(hydroxyethyl)amino, diethylaminoethylamine, halogen, carboxy, C1-C8alkoxycarbonyl, carbarnoyl, which is unsubstituted or is emenim-cyclohexyl, or nitro-group; R7, R8and R9independently from each other can also denote hydrogen;
or R7and R8, R8and R9and/or R9and R10together with the carbon atoms to which they are attached, form a 5 - or 6-membered carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S, which is unsubstituted or substituted With1-C8Alcala,1-C8alkoxygroup, Halogens1-C8by alkyl, hydroxy, amino, halogen;
And indicates With;
and its pharmaceutically acceptable salt.

2. The compound of formula I according to claim 1, where
each R0or R2independently represent hydrogen, piperazine, N-methylpiperazine;
R1denotes hydrogen, piperazine, N-methylpiperazine, morpholine;
R3indicates sulfamoyl, methylsulfonyl or propylsulfonyl;
R4denotes hydrogen;
R5denotes chlorine or bromine;
R6denotes hydrogen; and
each R7and R9independently represent hydrogen, C1-C8alkyl, C5-C10aryl, which is unsubstituted or substituted With1-C8the alkyl or Halogens1-C8the alkyl, unsubstituted or substituted 5 - or 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, where the substituents in baraut from C 1-C8of alkyl, hydroxy, hydroxys1-C8of alkyl, C1-C8alkoxy-C1-C8of alkyl, cyano, oxo, C1-C8alkylamino, dis1-C8alkylamino, carbamoyl, which is unsubstituted or substituted With1-C8the alkyl, C1-C8alkylcarboxylic1-C8of alkyl, C1-C8alkylcarboxylic,1-C8alkylcarboxylic, 5-10-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N and O, which is unsubstituted or substituted With1-C8the alkyl, C1-C8alkoxygroup, amino, methylamino, dimethylamino, propylamino, hydroxyethylamino, di(hydroxyethyl)amino, diethylaminoethylamine, halogen or carbarnoyl, which is unsubstituted or substituted by cyclohexyl;
R8denotes hydrogen, C1-C8alkyl, C5-C10aryl, unsubstituted or substituted 5 - or 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, where the substituents are selected from C1-C8of alkyl, hydroxy, hydroxys1-C8of alkyl, C1-C8alkoxy-C1-C8of alkyl, cyano, oxo, C1-C8alkylamino, dis1-C8alkylamino, carbamoyl, which is unsubstituted or substituted With1-C8the alkyl, C1-C8killermovies 1-C8of alkyl, C1-C8alkylcarboxylic,1-C8alkylcarboxylic, 5-10-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N and O, which is unsubstituted or substituted With1-C8by alkyl; C1-C8alkoxygroup, Halogens1-C8alkoxygroup, 5 - or 6-membered nitrogen-containing heterocyclics, which is unsubstituted or substituted With1-C8the alkyl, amino, methylamino, dimethylamino, propylamino, hydroxyethylamino, di(hydroxyethyl)amino, diethylaminoethylamine, halogen or nitro-group; and
R10stands With1-C8alkyl, C1-C8alkoxygroup, amino, methylamino, dimethylamino, propylamino, hydroxyethylamino, di(hydroxyethyl)amino, diethylaminoethylamine or halogen; or
each pair of adjacent substituents R7and R8or R8and R9or R9and R10denotes-NH-CH=CH-, -CH=CH-NH-, -NH-N=CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-O - or-O-CF2-O-;
And indicates With;
or its pharmaceutically acceptable salt.

3. The compound of formula I according to claim 1, where
each R0or R2independently represent hydrogen, piperazine, N-methylpiperazine;
R1denotes hydrogen, piperazine, N-methylpiperazine, morpholine;
R 3indicates sulfamoyl, methylsulfonyl or propylsulfonyl;
R4denotes hydrogen;
R5denotes chlorine or bromine;
R6denotes hydrogen;
each R7and R9independently represent hydrogen, methyl, isopropyl, phenyl, o-, m - or p-methoxyphenyl, piperidine, piperazine, N-methylpiperazine, morpholine, methoxy, ethoxy, isopropoxy, dimethylamino, fluorine or cyclohexylcarbonyl;
R8denotes hydrogen, methyl, piperidine, piperazine, N-methylpiperazine, morpholine, methoxy, ethoxy, triptoreline, 1-methyl-4-piperidinyloxy, methylamino, fluorine, chlorine or nitro-group; and
R10denotes methyl, butyl, methoxy, ethoxy, methylamino, dimethylamino or fluorine; or
a pair of adjacent substituents R7and R8or R8and R9denote-O-CH2-O - or a pair of adjacent substituents R9and R10denotes-NH-CH=CH-, -CH=N-NH-, -CH2-CH2-CH2-,
-CH2-CH2-CH2-CH2- or-O-CF2-O-;
And indicates With;
or its pharmaceutically acceptable salt.

4. The compound of formula I according to claim 1, where
each R0, R1or R2represent hydrogen;
R3indicates sulfamoyl, methylsulfonyl or propylsulfonyl;
R4denotes hydrogen;
R5denotes chlorine or bromine;
R6denotes hydrogen;
each R7and R8not avisio denote hydrogen, methyl, isopropyl, phenyl, o-, m - or p-methoxyphenyl, piperidine, piperazine, N-methylpiperazine, morpholine, methoxy, ethoxy, isopropoxy, dimethylamino, fluorine or cyclohexylcarbonyl;
R8denotes hydrogen, methyl, piperidine, piperazine, N-methylpiperazine, morpholine, methoxy, ethoxy, triptoreline, 1-methyl-4-piperidinyloxy, methylamino, fluorine, chlorine or nitro-group; and
R10denotes methyl, butyl, methoxy, ethoxy, methylamino, dimethylamino or fluorine; or
a pair of adjacent substituents R7and R8or R8and R9denotes-O-CH2-O-, or a pair of adjacent substituents R9and R10denotes-NH-CH-CH-, -CH=N-NH-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2- or-O-CF2-O-;
And indicates With;
or its pharmaceutically acceptable salt.

5. The compound of formula I according to claim 1, where each R0, R1or R2denote hydrogen, R3indicates methylsulfonyl, R4denotes hydrogen, R5denotes bromine, R6denotes hydrogen, each R7and R8denote a methoxy group, R9denotes hydrogen and R10denotes methyl, and a represents C, or its pharmaceutically acceptable salt.

6. The compound of formula I according to claim 1, where each R0, R1or R2denote hydrogen, R3indicates methylsulfonyl, R4the seat is tons of hydrogen, R5denotes bromine, R6denotes hydrogen, each R7and R8denotes hydrogen and a pair of adjacent substituents R9and R10denotes-CH2-CH2-CH2-and means, or its pharmaceutically acceptable salt.

7. The compound of formula I according to claim 1, selected from the group of compounds of the following names or formulas:
2-[5-bromo-2-(2,4-dimethoxyaniline)pyrimidine-4-ylamino]-N-methylbenzenesulfonamide;
the compound of the formula

where Rx is one of the values listed in the following table:

ConnectionRx
3-1

ConnectionRx
3-2
3-3
3-4
3-5
3-6
3-7
3-8
3-9

ConnectionRx
3-10
3-11
3-12
3-13
3-14
3-15
3-16
3-17

ConnectionRx
3-18
3-19
3-20
3-23
3-25
3-26
3-27

ConnectionRx
3-28
3-29
3-30
3-31
3-32
3-33
3-34
3-36

ConnectionRx
3-37
3-38
3-39
3-40
3-41
3-43

ConnectionRx
3-44
3-46
3-47
3-48
3-52
3-53

ConnectionRx
3-54
3-55
3-56
3-57
358 for
3-59
3-61
3-62

ConnectionRx
3-63
3-64
3-65
3-66
3-67
3-68
3-69
3-74

ConnectionRx
3-75
3-76
3-77
3-78
3-79
3-80
3-81

ConnectionRx
3-82
3-83
3-84

2-[5-bromo-2-(2,3-[diversitronics]phenylamino)pyrimidine-4-ylamino]-benzosulfimide;
2-[5-chloro-2-(2-methoxy-4-morpholine-4-ilfenomeno)pyrimidine-4-ylamino]-N-methylbenzamide;
the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
7-1

/tr>
ConnectionRx
7-2
7-3
7-5
7-6
7-7
7-8

ConnectionRx
7-11
7-12
7-13
7-14
7-17

ConnectionRx
7-18
7-19
7-22
7-23
7-24
7-25

ConnectionRx
7-26
7-27
7-28
7-29
7-30

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
8-1
8-2
8-3
8-4

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
9-1

ConnectionRx
9-2
9-3
9-4
9-5

ConnectionRx
9-6
9-7

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
10-1

ConnectionRx
10-2
10-3

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
11-1

ConnectionRx
11-2
11-3
11-4

the compound of the formula

where Ry is one of the values listed in the following table:
14-2
ConnectionRy
14-1

ConnectionRy
14-3
14-5

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
15-1
15-2

ConnectionRx
15-3

the compound of the formula

where Ry is one of the values listed in the following table:
ConnectionRy
16-1
16-2
16-3

the compound of the formula

where Rx stands for:
ConnectionRx
18-1

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
19-1

ConnectionRx
19-2
19-4
19-5
19-6img src="https://img.russianpatents.com/1060/10608556-s.jpg" height="24" width="21" />
19-7
19-8

ConnectionRx
19-9
19-11
19-12
19-13
19-14
19-15

ConnectionRx
19-18
19-19
19-20
19-21
19-25

ConnectionRx
19-27
19-28

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
20-1

ConnectionRx
20-2
20-3
20-4
20-5
20-6
20-7
20-8

ConnectionRx
20-11
20-12
20-13
20-14
20-15
20-16

ConnectionRx
20-17
20-18
20-19
20-20
20-23
20-24
20-27
20-28

ConnectionRx
20-29
20-30
20-31
20-32
20-33
20-34
20-35

the compound of the formula

where Rx is one of the values listed in the following table:
Connection21-1
21-2
21-3

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
22-1
22-2

ConnectionRx
22-3

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
23-1
23-2
23-3
23-4

ConnectionRx
23-6
23-7

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
26-1
26-2

ConnectionRx
26-3
26-4
26-5
26-6
26-7

ConnectionRx
26-8
26-9
26-10
26-11

ConnectionRx
26-12
26-13
26-14
26-15
26-17
26-21

ConnectionRx26-2226-2326-2426-2526-26
ConnectionRx
26-27
26-28
26-29
26-30
26-32
26-33
26-34

ConnectionRx
26-35
26-36
26-37
26-38
26-39

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
27-1
27-2
27-3
27-4
Up 27-5
27-6
ConnectionRx
27-8
27-9

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
28-1

ConnectionRx
28-2
28-3
28-4
28-5
28-6
28-7

ConnectionRx
28-8
28-9
28-10
28-11

ConnectionRx
28-12
28-13
28-14
28-15
28-16

ConnectionRx
28-17
28-18
28-19
28-20
28-21

ConnectionRx
28-22
28-23
28-24
28-25

ConnectionRx
28-27
28-28
28-29
28-30
28-31

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
29-1
29-2
29-3

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
31-1

ConnectionRx
31-2

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
32-1
32-2

the compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
34-1
34-3
34-4
34-6

the compound of the formula

the compound of the formula

or a compound of the formula

where Rx is one of the values listed in the following table:
ConnectionRx
35-1
35-2

2-[5-bromo-2-(2-methoxy-4-morpholine-4-ilfenomeno)pyrimidine-4-ylamino]-N,N-dimethylbenzenesulfonamide;
2-[5-bromo-2-(2-methoxy-4-morpholine-4-ilfenomeno)pyrimidine-4-ylamino]-5-fluoro-N-methylbenzenesulfonamide;
or its pharmaceutically acceptable salt.

8. The compound of the formula

where Ry is the formula

or its pharmaceutically acceptable salt.

9. Pharmaceutical composition having inhibitory activity against the focal adhesion kinase (FAK), proteincontaining ZAP-70, receptor insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity anaplastic lymphoma (ALK) and fused protein NPM-ALK, comprising as active ingredient a compound according to any one of claims 1 to 8 together with one or more pharmaceutically acceptable diluents or carriers.

10. The use of compounds according to any one of claims 1 to 8 for preparing a medicinal product intended for the treatment or prevention of neoplastic diseases and disorders of the immune system.

11. The use of compounds according to any one of claims 1 to 8, or its pharmaceutically acceptable salts for preparing a medicinal product intended for the treatment or prevention of a disease that responds to inhibition of CIN the threat of focal adhesion and/or IGF-1 receptors.

12. The application of claim 11, wherein undergoing treatment of a disease selected from among proliferative diseases.

13. The application indicated in paragraph 12, in which at treatment of a proliferative disease selected from the group including tumors of the breast, kidney, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor, and osteosarcoma and melanoma.

14. The use according to any one of PP-13 where the compound is 2-[5-bromo-2-(2-methoxy-5-morpholine-4-ilfenomeno)pyrimidine-4-ylamino]-N-methylbenzenesulfonamide or its pharmaceutically acceptable salt.

15. The use according to any one of PP-13 where the compound is selected from the group comprising 2-[5-chloro-2-(2-methoxy-4-morpholine-4-ilfenomeno)pyrimidine-4-ylamino]-N-methylbenzamide, N2-(4-[1,4']bipyridinyl-1'-yl-2-methoxyphenyl)-5-chloro-N4-[2-(propane-1-sulfonyl)phenyl]pyrimidine-2,4-diamine and 2-{5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino]pyrimidine-4-ylamino}-N-isopropylbenzenesulfonyl or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide and/or one of its physiologically acceptable salts, characterised by that a compound of formula (I),

, in which L is CI, Br, I, SO2F, SO2CF3, SO2C2F5, is reacted with 3-(4-piperazin-1-ylbutyl)indole-5-carbonitrile through transition metal catalysed combination through complex compounds of Pd and/or that the formed 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide is converted to one of its acid addition salt through treatment with an acid, and to a second method which is characterised by that a formula (II) compound, as a base or salt HX (where X=Cl, Br), is reacted with 3-(4-oxobutyl)-1H-indole-5-carbonitrile through reductive amination, and or that 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide is converted to one of its acid addition salt through treatment with an acid.

EFFECT: obtaining a compound which is a 5-HT1A receptor agonist.

4 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chroman derivatives of formula I: , or to their pharmaceutically acceptable salts where m has a value of 0; p has a value of 2; q has a value of 2; Ar represents phenyl optionally substituted with halogen atom; R2 represents ; X represents -NR9-; n has a value of 2 or 3; each R3, R4, R5 and R6 independently represents hydrogen or C1-12alkyl; each R7 and R8 independently represents either hydrogen, or C1-12-alkyl, or R7 and R8 together with nitrogen whereto attached, can form 4-6-members ring, or one of R7 and R8 and one of R5 and R6 together with atoms whereto attached can form 4-6-members ring; and R9 represents hydrogen or C1-12-alkyl, or when R7 represents hydrogen or methyl, R9 together with R8 and atoms whereto attached can form 6-members ring.

EFFECT: preparation of chroman new derivatives and the pharmaceutical composition containing compounds of formula (I).

22 cl, 1 tbl, 5 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel triazole-substituted aminobenzophenone compounds of formula (Ia) or (Ib), (values of radicals are given in the formula of invention) and a pharmaceutical composition containing the said compounds.

EFFECT: obtaining novel compounds which can be used in treating inflammatory, ophthalmological diseases or cancerous growths.

20 cl, 67 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula I: , their pharmaceutically acceptable salts where R1-R7, Y and n are specified in the patent claim. The compounds exhibit inhibitory action in the relation to aurora A tyrosine kinase. There is also described a drug of the compound of formula (I). The drug can be used for control or prevention of diseases, such as cancer.

EFFECT: preparation of new phthalazinone derivatives which can be used for control or prevention of diseases, such as cancer.

17 cl, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula , where X, R1, R2, R3, R4 and R5 assume values given in the description and paragraphs of the formula of invention, and their pharmaceutically acceptable salts.

EFFECT: compounds have antagonistic activity on histamine receptor 3 (H3).

25 cl, 3 tbl, 215 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

Up!