Cytokine inhibitors

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

where Ar1means aromatic carbocycle substituted with one R1and where Ar1is independently substituted with two R2;
R1means J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J is-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-;
Q means CRp;
Y represents-N(Rx)-;
where Ra, Rp, Rxand Rydenote each independently hydrogen or (C1-C5)alkyl;
X is-O-;
W stands for N or CH;
m means each independently 0, 1 or 2;
J is chosen from (C1-C10)alkyl, optionally substituted Rb;
R2choose from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or fully halogenated;
R3, R4and R5each independently selected from hydrogen and (C1-C6)alkyl;
R6optional attached in position ortho or meta to the nitrogen atom of the indicated ring and is selected from-O-, -O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or non-branched (C1-C )alkyl; and
where each R6optional optional covalently attached to groups chosen from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where heteroaryl is a pyrimidine, and heterocyclyl(C0-C4)alkyl, where heterocyclyl selected from the research, pyrrolidine, piperazinil, optionally substituted (C1-C6)alkyl;
R7and R8each independently mean hydrogen or a branched or non-branched (C1-C5)alkyl; and
Rbselected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino;
or its pharmaceutically acceptable salt or acid.

2. The compound according to claim 1, where
Y represents-NH-, -N(CH2CH3)- or-N(CH3)-;
X is-O-;
Q means SN;
J is chosen from (C1-C10)alkyl, optionally substituted Rb;
R3, R4and R5each means hydrogen;
Rbselected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino.

3. The compound according to claim 2, where
Ar1selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl, each Ar1substituted with one R1and independently substituted by two groups of R2.

4. Obedinenie according to claim 3, where
Y represents-N(CH3)-.

5. The compound according to claim 1, where
Ar1means the formula (A)

where R1means J-N(Ra)-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J is-S(O)2- N(Ra)-, J-N(Ra)-S(O)2-; and
J means (C1-C5)alkyl, optionally substituted Rb.

6. The compound according to claim 5, where
Ar1means the formula (A)

and R2choose from
,,and;
where R1means J-S(O)2- N(Ra)- or J-N(Ra)-S(O)2-, then J means (C1-C3)alkyl; and
when R1means J-N(Ra)-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, then J means (C1-C3)alkyl, optionally substituted Rb.

7. The connection according to claim 6, where
Rbselected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C3)dialkylamino.

8. The connection according to claim 6, where
Ar1means

9. The compound according to claim 1, chosen from:
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(pyrimidine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-methylaminomethyl the DIN-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-methylaminopropyl-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(4-methylpiperazin-1-yl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(2-morpholine-4-ylethylamine)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-dimethylaminopyridine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(6-methyl-2-methylaminopropane-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(2-pyrrolidin-1 ylethylamine)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(2-pyrrolidin-1 ylethoxy)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(2-morpholine-4-ylethoxy)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
[5-tert-butyl-3-(2-dimethylaminoethanol)-2-methoxyphenyl]amide 1-methyl-7-(2-methyl shall carbamoylation-4-yloxy)-1H-indole-2-carboxylic acid
[5-tert-butyl-3-(2-dimethylaminoethanol)-2-methoxyphenyl]amide 1-methyl-7-(2-methylaminopropyl-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-carbarnoyl-2-methoxyphenyl)amide 1-methyl-7-(2-methylaminopropyl-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methoxy-3-methylcarbamoylmethyl)amide 1-methyl-7-(2-methylaminopropyl-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(morpholine-4-ylamino)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)-amide 1-methyl-7-(2-morpholine-4-iletilerimde-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-morpholine-4-iletileri-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl-amide 1-methyl-7-[2-(4-methylpiperazin-1-ylmethyl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-dimethylaminomethylene-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-methylcarbamoylmethyl-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-benzyloxypyridine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-t is et-butyl-3-dimethylaminomethyl-2-methoxyphenyl)amide 1-methyl-7-(2-methylaminopropyl-4-yloxy)-1H-indole-2-carboxylic acid
(3-amino-5-tert-butyl-2-methoxyphenyl)amide 1-methyl-7-(2-methylamino-pyrimidine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methoxy-3-methylsulfinylphenyl)amide 1-methyl-7-(2-methylaminopropyl-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-2-methoxy-3-methylaminomethyl)amide 1-methyl-7-[2-(4-methylpiperazin-1-yl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-piperazine-1-Yeremey-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-methoxypyridine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-[2-(4-tert-butylpiperazine-1-yl)pyrimidine-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(2-morpholine-4-retil)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-{2-[2-(4-methylpiperazin-1-yl)ethyl]pyrimidine-4-yloxy}-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(2-pyrrolidin-1-retil)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methane is sulfonylamino-2-methoxyphenyl)-amide 7-[2-(2-dimethylaminoethyl)pyrimidine-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 1-methyl-7-[2-(2-morpholine-4-retil)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 1-methyl-7-[2-(4-methylpiperazin-1-yl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-{2-[2-(4-tert-butylpiperazine-1-yl)ethyl]pyrimidine-4-yloxy}-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-[2-(4-tert-butylpiperazine-1-ylmethyl)pyrimidine-4-yloxy]-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-pyrrolidin-1-iletilerimde-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2,6-dimethylpyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-ethyl-pyridine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-amino-pyrimidine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-pyrrolidin-1-iletileri-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(4-methylpiperazin-1-ylmethyl)pyridine-4-yl) - Rev. XI]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-{[(2-dimethylaminoethyl)methylamino]methyl}-2-methoxy-phenyl)amide 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-carbarnoyl-2-methoxyphenyl)amide 1-methyl-7-[2-(4-methyl-piperazine-1-yl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-(2-piperazine-1-espiridion-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(4-methylpiperazin-1-carbonyl)pyridine-4-yloxy]-1H-indole-2-carboxylic acid and
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-[2-(piperazine-1-carbonyl)pyridine-4-yloxy]-1H-indole-2-carboxylic acid
or its pharmaceutically acceptable salt or acid.

10. The compound according to claim 1, chosen from:
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(pyrimidine-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 1-methyl-7-{2-[(pyridine-2-ylmethyl)amino]pyrimidine-4-yloxy}-1H-indole-2-carboxylic acid
(4-chloro-2-methoxy-5-trifluoromethyl-phenyl)amide 1-methyl-7-[2-(4-methylpiperazin-1-yl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 1-methyl-7-[2-(2-morpholine-4-ylethoxy)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(5-tert-butyl-3-carbarnoyl-2-methoxyphenyl)AMI is 7-(2-aminopyrimidine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
[5-tert-butyl-3-(2-dimethylaminoethanol)-2-methoxyphenyl]amide 7-(2-aminopyrimidine-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(4-chloro-2-methoxy-5-triptoreline)amide 1-methyl-7-(2-morpholine-4-iletilerimde-4-yloxy)-1H-indole-2-carboxylic acid
(5-tert-butyl-3-methanesulfonamido-2-methoxyphenyl)amide 7-(2-carbamoylbiphenyl-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 1-methyl-7-(2-morpholine-4-iletilerimde-4-yloxy)-1H-indole-2-carboxylic acid
(3-dimethylaminomethyl-2-methoxy-5-triptoreline)amide 1-methyl-7-[2-(2-morpholine-4-retil)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 7-(2-dimethylaminomethylene-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 7-(2-dimethylaminomethylene-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 1-methyl-7-[2-(4-methylpiperazin-1-ylmethyl)pyrimidine-4-yloxy]-1H-indole-2-carboxylic acid
(3 methanesulfonamido-2-methoxy-5-triptoreline)amide 7-(2-dimethylaminomethylene-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid
(3-dimethylaminomethyl-2-methoxy-5-triptoreline)amide 1-methyl-7-[2-(4-methylpiperazin-1-yl)pyrimidine-4-yloxy]-ningal-2-carboxylic acid and
or its pharmaceutically acceptable salt or acid.

11. Pharmaceutical composition having the properties of inhibitors of cytokines containing a pharmaceutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or auxiliary substances.

12. The use of compounds according to claim 1 for obtaining a pharmaceutical composition having properties of inhibitors of cytokines.

13. The method of obtaining the compounds of formula (I):

where Ar1X, Y, Q, W, R3, R4, R5, R6and Ryhave the meanings given in claim 1,
including condensation Ar1containing the amino group, with a carboxylic acid of formula (III), where R denotes a protective group;
the removal of the protective group P to obtain the intermediate compounds of formula (V);
condensation of the intermediate compound (V) with haloesters a heterocycle (VI) (Z means a halogen containing R6in the presence of an acceptable cause for obtaining the compounds of formula (I):



 

Same patents:

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: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 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: invention relates to new 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives of general formula

and ,

where: X1-X4 denote C; Z denotes H; R1 denotes alkyl, H, -(CH2)3-N-(C2H5)2; R2 and R3 denote alkyl, or together with the nitrogen atom to which they are bonded form a C4-7-monocyclic ring containing 1 or 2 heteroatoms, selected from O and N, possibly substituted with an alkyl; R4 denotes H; Y denotes S, -N-(C2H5); where in formula I compounds R5 and R6 together with the nitrogen atom to which they are bonded form a C9-10 a condensed bicyclic ring containing an N heteroatom, possibly substituted with R, where R denotes -N-(R2)-R3; in formula II compounds R5 denotes phenyl, optionally substituted with OCH3.

EFFECT: obtaining new compounds which can be used as protein kinase inhibiting agents.

2 cl, 6 tbl, 6 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: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

Chemical method // 2386636

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where D is pyrrolidine, X is a radical selected from a group containing C=O, SO2, (C=O)-NH, CH2, O-(C=O), (C=O)-O, (C=S)-NH, Y is a radical selected from a group containing - (CH2)n-E-(CH2)m-L-(CH2)k, where E is O, k, m and n are separately and independently equal to 0, 1, 2 and 3, Z is an alkyl, where the alkyl is CH2 or CH2CH2, A is a radical selected from a group containing benzyl, substituted benzyl, phenyl, substituted phenyl, alkyl and substituted alkyl, cycloalkyl, heterocyclyl, aryl, alkyloxyalkyl, substituted alkyloxyalkyl, alkyloxyaryl, B is a radical of formula (II) , where R1 is selected from a group containing H, alkyl and substituted alkyl, cycloalkyl, R2 is selected from a group containing H, benzyl, substituted benzyl, phenyl, substituted phenyl, alkyl and substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, substituted cycloalkylalkyl, G is an amino group which is substituted by a heteroaryl or substituted heteroaryl, and where Q and L each independently denotes a radical selected from a group containing (C=O)-NH, NH, CH2, NH-(C=O)-NH, NH-(C=O), NH-SO2, NRc, (C=O)-NRc, and where Ra, Rb, Rc and Rd each independently denotes a radical selected from a group containing H, alkyl, cycloalkyl, heterocyclyl, aryl, substituted aryl, as well as to use of these compounds as integrin inhibitor and for making a medicinal and a diagnostic agent, to a pharmaceutical composition based on these compounds and to methods of treating integrin-associated condition.

EFFECT: novel compounds which are integrin inhibitors and can be used to treat diseases where angiogenesis inhibition is necessary are obtained and described.

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: 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 new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with formula (I):

where R1 is (C2-4)alkyl and is substituted with two or more fluorine groups; and R2 is methyl or ethyl; or to pharmaceutically acceptable salts thereof. The invention also relates to a method of obtaining formula (I) compounds, to a pharmaceutical composition, to use of the compounds, as well as to a method of inhibiting collagenase-3 activity.

EFFECT: obtaining new biologically active compounds having inhibitory effect on collagenase-3.

13 cl, 12 ex, 1 tbl

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: invention relates to a compound of formula I

where A, B and D each denotes N or CR5, where one of A, B and D denotes N, R1 denotes OR6, R2 denotes halogen, C1-C4alkyl, halogen(C1-C4)alkyl or OR7, R3 denotes a heteroarylalkyl group in which the heteroaryl fragment contains 5-6 atoms in the ring, at least one of which is an N atom, and the alkyl fragment with a branched or straight chain contains 1-5 carbon atoms, R4 denotes C3-C10cyclalkyl, C6-C14aryl, unsubstituted or substituted with one or more substitutes selected from a group comprising halogen, alkoxy, terazol-5-yl, 2-(heterocyclyl)tetrazol-5-yl or a carboxy group; heteroaryl containing 5-6 atoms in the ring; heterocyclic group saturated or partially saturated, containing 5-6 atoms in the ring, at least one of which is an N atom, unsubstituted or substituted with one or more substitutes selected from a group comprising alkoxy, alkoxyalkoxy, oxo, alkoxycarbonyl, alkylsulfanyl, alkylsufonyl or phenylsulfonyl; R5 denotes H; R6 denotes H or C1-C4alkyl with a branched or straight chain, unsubstituted or substituted with one or more halogens, R7 denotes H or C1-C12alkyl with a branched or straight chain, unsubstituted or substituted with one or more substitutes selected from a group which includes halogen; C3-C10cyclalkyl; saturated heterocyclic group containing 5-6 atoms in the ring, at least one of which is an O atom, or a heterocylcylalkyl group in which the heterocyclic fragment is saturated, partially saturated or unsaturated and contains 5-10 atoms in the ring, at least one of which is an O atom; or to a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition for inhibiting PDE4 enzyme activity and to use of the said compound to prepare a medicinal agent.

EFFECT: novel compounds which can be used in medicine are obtained and described.

65 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-amino-5-cyanopyrimidine derivatives of formula (1) or their pharmaceutically acceptable salts which have agonistic effect on the adenosine A2a receptor. In formula (1): R1 is a hydrogen atom, lower alkylcarbonyl, lower alkenylcarbonyl, phenylcarbonyl or lower alkoxycarbonyl; R2 is a lower alkylene; R3 is any of (1) hydrogen atom, (2) lower alkyl or any of the following groups (3)-(9): group (3) group (4) group (5) group (6). group (7) group (8) group (9) in which: R4 is lower alkylene, R5 is a hydrogen atom or lower alkyl, Z1 , Z2 and Z3 are selected from groups (a1)-(a38), (b1)-(b8) and (c1)-(c22) respectively, which are defined below: Z1: (a1) lower alkyl, (a2) phenyl-lower alkyl, (a3) aminophenyl-lower alkyl, (a4) phenyl-lower alkenyl, (a5) heteroaryl-lower alkyl, (a6) heteroaryl-lower alkenyl, (a7) heteroarylphenyl-lower alkyl, (a8) hydroxy-lower alkyl, (a10) amino-lower alkyl, (a11) aminocarbonyl-lower alkyl, (a12) lower alkylcarbonyl, (a13) lower alkoxy-lower alkylcarbonyl, (a14) amino-lower alkylcarbonyl, (a15) phenylcarbonyl, (a16) phenyl-lower alkylcarbonyl, (a17) phenyl-lower alkenylcarbonyl, (a18) phenoxy-lower alkylcarbonyl, (a19) heteroarylcarbonyl, (a20) heteroaryl-lower alkylcarbonyl, (a21) heteroaryl-lower alkenylcarbonyl, (a22) heteroaryloxy-lower alkylcarbonyl, (a23) heteroarylsulphanyl-lower alkylcarbonyl, (a24) heteroarylphenylcarbonyl, (a25) phenylsulphanyl-lower alkylcarbonyl, (a26) phenylcarbonyl-lower alkylcarbonyl, (a28) lower alkoxycarbonyl, (a29) lower alkylsulphonyl, (a30) phenylsulphonyl, (a31) heteroarylsulphonyl, (a32) hydrogen atom, (a33) lower alkyl containing a saturated heterocycle, (a34) carbonyl-lower alkyl containing a saturated heterocycle, (a35) phenyl-lower alkyl containing a saturated heterocycle, (a36) carbonyl containing a saturated heterocycle, (a37) lower alkylcarbonyl containing a saturated heterocycle, or (a38) phenylcarbonyl containing a saturated heterocycle.

EFFECT: obtained compounds have intraocular pressure reducing properties and can be used in treating ocular hypertension and glaucoma.

9 cl, 112 dwg, 32 tbl, 416 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A, B represent C; D is selected from N; X is selected from -CRaRb-, -O-; Y is selected from O; Z1 and Z2 are independently selected from hydrogen, substituted or unsubstituted alkyl having 1-8 atoms, R1-R4 are independently selected from hydrogen or halogen; R5-R16 independently represent hydrogen; where Ra and Rb independently represent hydrogen; n equals 1-3; m equals 0 or 1, k equals 2; or to pharmaceutically acceptable salts or solvates of the said compounds. The invention also relates to a pharmaceutical composition based on the said compounds which inhibits butyrylcholin esterase (BuChE).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on the said compounds, which can be used for treating or preventing cognitive disorders and/or neurodegenerative disorders.

10 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

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