Novel compounds and use thereof in therapy

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzo[4,5]thiophene[2,3-d]pyrimidine derivatives, including groups of known compounds, having formula (I), for preparing a medicinal agent for treating and/or preventing diseases and disorders which require inhibition of the 17β-hydroxysteroid-dehydrogenase (17β-HSD) enzyme, more preferably which require inhbition of type 1 17β-HSD enzyme, type 2 17β-HSD enzyme or type 3 17β-HSD enzyme. In formula X denotes S or SO2, R1 and R2 are separately selected from a group which includes -C1-C12alkyl, where the alkyl can be straight, cyclic, branched or partially unsaturated, and can be optionally substituted with up to three substitutes, independently selected from a group consisting of hydroxyl, C1-C12alkoxy group, thiol, C1-C12alkylthio-, aryloxy group, -CO-aryl, -CO-OR, -O-COR, -O-CO-heteroaryl and a -N(R)2 group; where the said aryl group is phenyl or naphthyl and can be optionally substituted with up to 3 halogen atoms; where the said heteroaryl group is thienyl, furyl or pyridyl; -aryl and arylC1-C12alkyl, where the aryl is selected from a group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl. Other values of substitutes are given in the formula of invention.

EFFECT: high efficiency of using novel compounds in therapy.

32 cl, 3 tbl, 7 dwg, 151 ex

 

The text descriptions are given in facsimile form.

1. The use of the compounds of formula (I)

where X is S or SO2,
R1 and R2 are individually selected from the group including
With1-C12alkyl, where alkyl may be linear, cyclic, branched or partially unsaturated, and may be optionally substituted by up to three substituents, independently selected from the group consisting of hydroxyl, C1-C12alkoxygroup, thiol,1-C12alkylthio, alloctype, -CO-aryl, -CO-OR, -O-COR, -O-CO-heteroaryl and group-N(R)2;
where this aryl group is a phenyl or naphthyl and may be optionally substituted by up to 3 halogen atoms;
where this is heteroaryl group represents thienyl, furyl or pyridyl;
aryl and arils1-C12alkyl, where aryl is chosen from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl,
while the alkyl portion may be optionally substituted by one
or two hydroxyl groups and
however aryl part may be optionally substituted by substituents, up to five selected individually from the group comprising halogen, hydroxyl, (C1-C12)alkoxygroup, a nitrogroup, nitrile, (C1-C12)alkyl, halogenated (C1-C12)alkyl, -SO2N(R)2and (C1-C12)alkylsulfonyl;
or where the aryl may be optionally substituted by two groups associated with the adjacent carbon atoms and are combined into a saturated cyclic system of 5-, 6 - or 7-membered rings, optionally containing up to three heteroatoms, such as nitrogen or oxygen, and the number of nitrogen atoms is 0-3, and the number of oxygen atoms is 0-2 each,
this cyclic system of rings may be optionally replaced by oxopropoxy;
heteroaryl and heteroaryl(C1-C12)alkyl, where heteroaryl selected from the group
including pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, chinoline from chinoline, benzimidazolyl, 1,3-dehydrobenzperidol, benzofuran and benzo[b]thiophene,
this heteroaryl group may be optionally substituted by substituents, up to three selected individually from the group consisting of halogen, (C1-C12)alkyl, halogenated (C1-C8)alkyl, -CO-OR, aryl or alloctype, while aryl group selected from phenyl or naphthyl, and it may be optionally substituted by halogen atoms, up to three;
cyclogeranyl and cyclogeranyl(C1-C8)alkyl, where cyclogeranyl part selected from the group including piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxole, morpholinyl, tetrahydrothiophene, tetrahydropyridine, azetidine, diazolidinyl, oxazolidinyl, thiomorpholine, piperazinil, azepane, diazepan, oxazepines, thiazepines, dihydro-1H-pyrrolyl and 1,3-dehydrobenzperidol,
this cyclogeranyl part can be optionally substituted by substituents, up to two selected individually from the group comprising oxoprop, (C1-C12)alkyl, hydroxyl, (C1-C12)alkoxygroup and aryl(C1-C12)alkyl;
or R2 itself may be independently selected from-CO-R or-CO-O-R;
when R1 and R2 cannot both be unsubstituted alkyl;
the hydrocarbon chain is-C(R3)-C(R4)-C(R5)-C(R6)- sixth ichinohe ring is saturated or contains one or two double bonds between carbon atoms;
R3 and R4 are individually selected from the group including hydrogen, oxoprop, tigroup, halogen or dihalogen, -CO-R, preferably Cho, -CO-OR, nitrile, -CO-N(R)2, -O-CO-R, -OR, -SR, -N(R)2-(C1-C12)alkyl, where the alkyl can be linear, cyclic, branched or partially unsaturated and may optionally contain substituents, up to three selected individually from the group consisting of hydroxyl, (C1-C12)alkoxygroup, thiol, and-N(R)2;
where R represents hydrogen, (C1-C12)alkyl, phenyl(C1-C4)alkyl or phenyl, optionally substituted on the phenyl ring substituents, up to three, selected from the group consisting of halogen, hydroxyl and (C1-C4)alkoxygroup, preferably metoxygroup;
R5 means hydrogen and
R6 means hydrogen or halogen,
for the preparation of drugs for the treatment and/or prevention of diseases or disorders requiring the inhibition of the enzyme, which is 17β-hydroxysteroid-dehydrogenases (17β-HSD).

2. The compound of formula (I)
,
where X represents S, SO or SO2,
R1 and R2 are individually selected from the group including
With1-C12alkyl, where alkyl may be linear, cyclic, branched or partially unsaturated, and may be optional is entrusted substituted by up to three substituents, independently selected from the group consisting of hydroxyl, C1-C12alkoxygroup, thiol,1-C12alkylthio, alloctype, -CO-aryl, -CO-OR, -O-COR, -OCO-heteroaryl and group-N(R)2;
where this aryl group is a phenyl or naphthyl and may be optionally substituted by up to 3 halogen atoms;
where specified heteroaryl group represents thienyl, furyl or pyridyl;
aryl and arils1-C12alkyl, where aryl is chosen from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl,
while the alkyl portion may be optionally substituted by one or two hydroxyl groups, and aryl can be optionally substituted by substituents, up to five selected individually from the group comprising halogen, hydroxyl, (C1-C12)alkoxygroup, a nitrogroup, nitrile, (C1-C12)alkyl, halogenated (C1-C12)alkyl, -SO2N(R)2and (C1-C12)alkylsulfonyl;
or where the aryl may be optionally substituted by two groups associated with the adjacent carbon atoms and are combined into a saturated cyclic system of 5-, 6 - or 7-membered rings, optionally containing up to three heteroatoms, such as nitrogen or oxygen, and the number of nitrogen atoms is 03 and the number of oxygen atoms is 0-2 each,
this cyclic system of rings may be optionally replaced by oxopropoxy;
heteroaryl and heteroaryl(C1-C12)alkyl, where heteroaryl chosen from the group comprising pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, chinoline, ethenolysis, benzimidazolyl, 1,3-dehydrobenzperidol, benzofuran and benzo[b]thiophene,
this heteroaryl group may be optionally substituted by substituents, up to three selected individually from the group consisting of halogen, (C1-C12)alkyl, halogenated (C1-C8)alkyl, -CO-OR, aryl or alloctype,
this aryl group selected from phenyl or naphthyl, and it may be optionally substituted by halogen atoms, up to three;
cyclogeranyl and cyclogeranyl(C1-C8)alkyl, where cyclogeranyl part selected from the group including piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxole, morpholinyl, tetrahydrothiophene, tetrahydropyridine, azetidine, diazolidinyl, oxazolidinyl, thiomorpholine, piperazinil, azepane, diazepan, oxazepines, thiazepines, dihydro-1H-pyrrolyl and 1,3-dehydrobenzperidol, while cyclogeranyl part can be optionally substituted with up to two substituents, selected individually from the group comprising oxoprop, (C1-C12)alkyl, hydroxyl, (C1-C12)alkoxygroup and aryl(C1-C12)alkyl;
or R2 itself may be independently selected from-CO-R or-CO-O-R;
moreover, R1 and R2 cannot both be unsubstituted alkyl and
thus R2 must be other than methyl, if all the substituents R3, R5 and R6 simultaneously denote hydrogen, and R4 means hydrogen or methyl;
R3 and R4 are individually selected from the group including hydrogen, oxoprop, tigroup, halogen or dihalogen, -CO-R, preferably Cho, -CO-OR, nitrile, -CO-N(R)2, -O-CO-R, -OR, -SR, -N(R)2-(C1-C12)alkyl, where the alkyl can be linear, cyclic, branched or partially unsaturated and may optionally contain substituents, up to three selected individually from the group consisting of hydroxyl, (C1-C12)alkoxygroup, thiol, and-N(R)2;
where R is hydrogen, (C1-C12)alkyl, phenyl(C1-C4)alkyl or phenyl,
optionally substituted on the phenyl ring substituents, up to three, selected from the group consisting of halogen, hydroxyl and
(C1-C4)alkoxygroup, preferably metoxygroup,
R5 means hydrogen,
R6 means hydrogen or halogen, and
the hydrocarbon chain is-C(R3)-C(R4)-C(R5)-C(R6)- chesticles the ring is saturated or contains one or two double bonds between carbon atoms;
this six-membered ring including hydrocarbon chain-C(R3)-C(R4)-C(R5)-C(R6)-must be an aromatic ring, if all the substituents R3, R4, R5 and R6 are both hydrogen atoms;
for use in the treatment and/or prevention of steroid-dependent hormone diseases or disorders, preferably dependent steroid hormone diseases or disorders requiring the inhibition of the enzyme, which is 17β-hydroxysteroid-dehydrogenases (17β-HSD), most preferably requiring inhibition of the enzyme 17β-HSD type 1 17β-HSD type 2 or 17β-HSD type 3.

3. The compound of formula (I)
,
where X is S, SO or SO2,
R1 and R2 are individually selected from the group including
With1-C12alkyl, where alkyl may be linear, cyclic, branched or partially unsaturated, and may be optionally substituted by up to three substituents, independently selected from the group consisting of hydroxyl, C1-C12alkoxygroup, thiol,1-C12alkylthio, alloctype, -CO-aryl, -CO-OR, -O-COR, -O-CO-heteroaryl and group-N(R)2;
where this aryl group is a phenyl or naphthyl and may be optionally substituted by up to 3 halogen atoms;
where specified heteroaryl group represents thienyl, futilely pyridyl;
aryl and arils1-C12alkyl, where aryl is chosen from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, while the alkyl portion may be optionally substituted by one or two hydroxyl groups, and aryl can be optionally substituted by substituents, up to five selected individually from the group comprising halogen, hydroxyl, (C1-C12)alkoxygroup, a nitrogroup, nitrile, (C1-C12)alkyl, halogenated (C1-C12)alkyl, -SO2N(R)2and (C1-C12)alkylsulfonyl;
or where the aryl may be optionally substituted by two groups associated with the adjacent carbon atoms and are combined into a saturated cyclic system of 5-, 6 - or 7-membered rings, optionally containing up to three heteroatoms, such as nitrogen or oxygen, and the number of nitrogen atoms is 0-3, and the number of oxygen atoms is 0-2 each,
this cyclic system of rings may be optionally replaced by oxopropoxy;
heteroaryl and heteroaryl(C1-C12)alkyl, where heteroaryl chosen from the group comprising pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, chinoline, ethenolysis, benzimidazolyl,1,3-dehydrobenzperidol, benzofuran and benzo[b]thiophene,
this heteroaryl group may be optionally substituted by substituents, up to three selected individually from the group consisting of halogen, (C1-C12)alkyl, halogenated (C1-C8)alkyl, -CO-OR, aryl or alloctype, while aryl group selected from phenyl or naphthyl, and it may be optionally substituted by halogen atoms, up to three;
cyclogeranyl and cyclogeranyl(C1-C8)alkyl, where cyclogeranyl part selected from the group including piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxole, morpholinyl, tetrahydrothiophene, tetrahydropyridine, azetidine, diazolidinyl, oxazolidinyl, thiomorpholine, piperazinil, azepane, diazepan, oxazepines, thiazepines, dihydro-1H-pyrrolyl and 1,3-dehydrobenzperidol, while cyclogeranyl part can be optionally substituted by substituents, up to two selected individually from the group comprising oxoprop, (C1-C12)alkyl, hydroxyl, (C1-C12)alkoxygroup and aryl(C1-C12)alkyl;
or R2 itself may be independently selected from-CO-R or-CO-O-R;
moreover, R1 and R2 cannot both be unsubstituted alkyl, and R2 must be other than methyl, if all the substituents R3, R5 and R6 simultaneously OSN is given hydrogen, and R4 means hydrogen or methyl;
R3 and R4 are individually selected from the group including hydrogen, oxoprop, tigroup, halogen or dihalogen, -CO-R, preferably Cho, -CO-OR, nitrile, -CO-N(R)2, -O-CO-R, -OR, -SR, -N(R)2-(C1-C12)alkyl, where the alkyl can be linear, cyclic, branched or partially unsaturated and may optionally contain substituents, up to three selected individually from the group consisting of hydroxyl, (C1-C12)alkoxygroup, thiol, and-N(R)2;
where R is hydrogen, (C1-C12)alkyl, phenyl(C1-C4)alkyl or phenyl, optionally substituted on the phenyl ring substituents, up to three, selected from the group consisting of halogen, hydroxyl and (C1-C4)alkoxygroup, preferably metoxygroup,
R5 means hydrogen,
R6 means hydrogen or halogen, and
the hydrocarbon chain is-C(R3)-C(R4)-C(R5)-C(R6)- six-membered ring is saturated or contains one or two double bonds between carbon atoms;
this six-membered ring including hydrocarbon chain-C(R3)-C(R4)-C(R5)-C(R6)-must be an aromatic ring, if all the substituents R3, R4, R5 and R6 are both hydrogen atoms;
provided that the compound does not mean methyl ether (3-benzyl-7-tert-butyl-4-oxo-3,4,5,6,7,8-hexahydrobenzo,5]thieno[2,3-d]pyrimidine-2-yl)-acetic acid or 2,3-dibenzyl-7-tert-butyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-4]pyrimidine-4-one.

4. The compound of formula (I) according to claim 3, where the six-membered ring containing hydrocarbon chain-C(R3)-C(R4)-C(R5)-C(R6)-, is an aromatic ring.

5. The compound of formula (I) according to claim 3, where the six-membered ring containing hydrocarbon chain-C(R3)-C(R4)-C(R5)-C(R6)-, differently from the aromatic ring, and where at least one of the substituents on R3 to R6 is other than hydrogen atom.

6. The compound of formula (I) according to claim 3, where R2 is chosen from the group comprising -(C1-C8)alkyl which may be linear, cyclic, branched or partially unsaturated and which may optionally contain substituents, up to three selected individually from the group consisting of hydroxyl, (C1-C8)alkoxygroup, thiol, (C1-C8)allylthiourea, alloctype, -CO-O-(C1-C8)alkyl and-O-CO-R',
in fact the aryl group is phenyl or naphthyl and may be optionally substituted by halogen atoms, up to three;
aryl and aryl(C1-C8)alkyl, where aryl is chosen from the group comprising phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl,
however aryl part may be optionally substituted by substituents, up to five selected individually from the group comprising halogen, hydroxyl, (C1-C8)alkoxygroup, a nitrogroup, nitrile, halogenated (C1-C 8)alkyl, -SO2-N(R')2heteroaryl and heteroaryl(C1-C8)alkyl, which is chosen from the group comprising pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, chinoline, ethenolysis, benzimidazolyl, 1,3-dehydrobenzperidol, benzofuran and benzo[b]thiophene,
this heteroaryl group may be optionally substituted by substituents, up to three selected individually from the group comprising halogen, (C1-C8)alkyl, halogenated (C1-C8)alkyl, aryl or alloctype,
this aryl group selected from phenyl or naphthyl, and it may be optionally substituted by halogen atoms, up to three;
-CO-R',
and
-CO-O-R',
where R' means hydrogen or (C1-C8)alkyl.

7. The compound of formula (I) according to claim 6, where R2 means
i) a residue of formula (II)
,
where R7 denotes hydrogen, halogen, hydroxyl or (C1-C4)alkoxygroup, preferably a methoxy group,
R8 means hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, hydroxyl, nitrile, halogen or halogenated (C1-C4)alkyl, preferably trifluoromethyl,
R9 means hydrogen, (C1-C4)alkoxygroup, preferably methoxy is the SCP, hydroxyl, nitrile, halogen or-SO2-N(C1-C4alkyl)2,
R10 denotes hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, hydroxyl, nitrile, halogen or halogenated (C1-C4)alkyl, preferably trifluoromethyl,
R11 denotes hydrogen, halogen, hydroxyl or (C1-C4)alkoxygroup, preferably a methoxy group, or
ii) -(C1-C8)alkyl, where the alkyl can be linear, cyclic, branched or partially unsaturated;
-(C1-C4)alkyl, substituted with one or two substituents selected from the group including
-CO-O-R",
-OR",
-O-Ar, where Ar denotes phenyl, optionally substituted with halogen,
-O-CO-R",
phenyl or biphenyl, optionally substituted by phenyl group (C1-C4)alkoxygroup, up to three, preferably by methoxypropane,
-CO-O-R",
-CO-R", preferably SNO,
-naphthyl,
-heteroaryl, which can be selected from the group comprising thienyl, furyl, pyridinyl, sensational and pyrazolyl,
this heteroaryl group may be optionally substituted by one or two substituents selected individually from the group comprising halogen, (C1-C4)alkyl, halogenated (C1-C4)alkyl, preferably trifluoromethyl, phenyl and fenoxaprop,
thus fenil the second group may be optionally substituted by halogen atoms, up to three, where R ' means hydrogen or (C1-C4)alkyl, preferably methyl or ethyl.

8. The compound of formula (I) according to claim 7, where R2 is chosen from the group comprising phenyl, methoxyphenyl, trimethoxyphenyl, trihydroxyphenyl, 3,5-dihydroxy-4-methoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, 2-bromo-5-methoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, cyanophenyl, forfinal, di(trifluoromethyl)phenyl, differenl, dichlorophenyl, 4-N,N-dipropylacetamide, methyl, cyclopropyl, cyclopentylmethyl, 1-ethylphenyl, 2-methylprop-1-enyl, propyl, benzyl, phenethyl biphenylyl, dimethoxybenzyl, naphthyl, thienyl, furyl, pyridinyl, benzothiazyl, bromanil, 1-phenyl-5-trifluoromethyl-4H-pyrazole-4-yl, 2-(4-chlorophenoxy)pyridine-3-yl, hydroxymethyl, acetoacetyl, methoxymethyl, -CH2-CO-O-CH3, -CH2-CO-O-CH2-CH3, -CH2-CH2-CO-O-CH2-CH3, 1-(3-chlorophenoxy)-1-methylethyl, -Cho and-CO-O-CH3.

9. The compound of formula (I) of claim 8, where R2 means methoxyphenyl, trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl or propyl.

10. The compound of formula (I) according to claim 3, where R1 is chosen from the group comprising -(C1-C8)alkyl which may be linear, cyclic, branched or partially unsaturated and which may optionally contain substituents, up to three selected individually from the group, comprising hydroxyl, (C1-C8)alkoxygroup, thiol, -NH2, (C1-C8)allylthiourea, alloctype, -CO-aryl, -CO-O-(C1-C8)alkyl, -O-CO-(C1-C8)alkyl, -O-CO-heteroaryl and-N((C1-C8)alkyl)2while the aforementioned aryl group means phenyl or naphthyl and may be optionally substituted by halogen atoms, up to three, while mentioned heteroaryl group means thienyl, furyl or pyridinyl;
aryl and aryl(C1-C8)alkyl, the aryl portion of which is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, where the alkyl portion may be optionally substituted by one or two hydroxyl groups, and
where the aryl portion can be optionally substituted by substituents, up to five selected individually from the group comprising halogen, hydroxyl, (C1-C8)alkoxygroup, (C1-C8)alkylsulfonyl, -SO2-N(/C1-C8/alkyl)2, (C1-C8)alkyl, halogenated (C1-C8)alkyl, or aryl may be optionally substituted by two groups attached to adjacent carbon atoms and are combined into a saturated cyclic system from a 5 - or 6-membered rings, optionally containing up to three heteroatoms, such as nitrogen or KIS is orod, moreover, the number of nitrogen atoms is 0-3, and the number of oxygen atoms is 0-2 each, with a circular system of rings may be optionally replaced by oxopropoxy;
heteroaryl and heteroaryl(C1-C8)alkyl where the heteroaryl portion is chosen from the group including chinoline, thiazolyl, pyrimidinyl, furyl, pyridinyl, thienyl, pyrrolyl, imidazolyl, isothiazolin, oxazolyl, isoxazolyl, pyrazolyl, pyrazinyl, indolyl, ethenolysis, benzimidazolyl, 1,3-dehydrobenzperidol, benzofuran and benzo[b]thiophene, while heteroaryl group can be optionally substituted by substituents, up to three selected individually from the group consisting of halogen, (C1-C8)alkyl and-CO-O-(C1-C8)alkyl;
cyclogeranyl and cyclogeranyl(C1-C8)alkyl, where cyclogeranyl part selected from the group including piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxole, morpholinyl, tetrahydrothiophene, tetrahydropyridine, azetidine, diazolidinyl, oxazolidinyl, thiomorpholine, piperazinil, azepane, diazepan, oxazepines, thiazepines, dihydro-1H-pyrrolyl and 1,3-dehydrobenzperidol, while cyclogeranyl part can be optionally substituted by substituents, up to two selected individually from the group comprising oxoprop, (C1 -C8)alkyl, hydroxyl, (C1-C8)alkoxygroup and aryl(C1-C8)alkyl.

11. The compound of formula (I) according to claim 10, where R1 is chosen from a group that includes
-(C1-C8)alkyl, where the alkyl can be linear, cyclic or branched;
-(C1-C4)alkyl, substituted with one or two substituents, independently selected from the group comprising-O-R", -O-Ar, -O-CO-HetAr, -CO-Ar, -CO-O-R and-N(R')2;
aryl and aryl(C1-C4)alkyl, where the aryl part is chosen from the group comprising phenyl, indanyl and fluorenyl,
where the alkyl portion may be optionally substituted hydroxyl group, and where the aryl part can be substituted by substituents, up to three selected individually from the group consisting of halogen,- O-R", -SO2-R", -SO2-N(R')2or
such aryl may be optionally substituted by two groups attached to adjacent carbon atoms and are combined into a saturated cyclic system from a 5 - or 6-membered rings, optionally containing up to two oxygen atoms, while the cyclic system of rings may be optionally additionally substituted by oxopropoxy;
heteroaryl and heteroaryl(C1-C4)alkyl where the heteroaryl portion is chosen from the group including chinoline, thiazolyl, pyrimidinyl, furyl, pyridinyl, pyrazinyl and thienyl,
if e is ω heteroaryl group can be optionally substituted by one or two substituents, selected individually from the group comprising halogen, -(C1-C4)alkyl and
-CO-O-R";
cyclogeranyl and cyclogeranyl(C1-C4)alkyl, where cyclogeranyl part selected from the group including piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl and dioxole,
this cyclogeranyl part can be optionally substituted by substituents, up to two selected individually from the group comprising oxoprop, (C1-C4)alkyl, preferably methyl, and -(C1-C4)alkyl-Ar, preferably benzyl or phenethyl;
where Ar denotes phenyl, optionally substituted with halogen or methoxy group,
HetAr means thienyl, furyl, pyridinyl, and
R ' means hydrogen or (C1-C4)alkyl, preferably methyl or ethyl.

12. The compound of formula (I) according to claim 11, where R1 is selected from the group including cyclopropyl, butyl, isobutyl, 3-methylbutyl, cyclohexyl, benzyl, phenethyl, 2-hydroxy-2-phenylethyl, methoxybenzyl, 5-bromo-2-methoxybenzyl, 5-bromo-2-hydroxybenzyl, 3,4-dichlorobenzyl, 3,4-dihydroxybenzyl, 4-methylsulfonylbenzoyl, 4-aminosulphonylphenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxole, phenyl, fluorenyl, indanyl, 3-oxo-2,3-dihydrobenzofuranyl, chinoline, methylthiazolyl, 2 CH3-O-CO-pyrazinyl, furylmethyl, pyridylmethyl, titilate, thienylmethyl, pyridinoline is, bromperidol, benzylpiperidine, morpholinylmethyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, 2,2-dimethyl[1,3]dioxolane-4-ylmethyl, hydroxyethyl, methoxyethyl, 2-oxo-2-phenylethyl, -CH2-CH2-CH2-CO-O-CH3phenoxyethyl, ethyl ester thiophene-2-carboxylic acid and dimethylaminoethyl.

13. The compound of formula (I) indicated in paragraph 12, where R1 is chosen from the group comprising isobutyl, 3-methylbutyl, benzyl, tetrahydrofuranyl, furylmethyl, 5-bromofuran-2-ylmethyl, 5-bromo-2-methoxybenzyl, ethyl ester thiophene-2-carboxylic acid and methoxyethyl.

14. The compound of formula (I) according to claim 3, where R3 is selected from the group consisting of hydrogen, carbonyl group, -O-R', -O-Ar, -O-CO-R', halogen, tigroup, -S-R' and-S-Ar,
where R' means hydrogen or (C1-C8)alkyl,
Ar denotes phenyl, optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl or methoxy group.

15. The compound of formula (I) 14, where R3 is chosen from the group comprising hydrogen, hydroxyl, oxoprop, chlorine, bromine, phenoxy, phenylthio-, (C1-C4)alkoxy-, (C1-C4)allylthiourea and-O-CO-(C1-C4)alkyl.

16. The compound of formula (I) according to item 13, where R3 is chosen from the group comprising hydroxyl, oxoprop, -O-CO-CH3and the group-S-ethyl.

17. The compound of formula (I) according to claim 3 wherein R4 is chosen from the group, including the setup portion of the hydrogen, (C1-C8)alkyl, optionally substituted by hydroxyl;
-CO-R', -CO-O-R', halogen and dihalogen, where R' means hydrogen or (C1-C8)alkyl.

18. The compound of formula (I) 17, where R4 is chosen from the group consisting of hydrogen, -CO-N-CO-O-CH2-CH3, bromine, dibromo, chlorine, dichloro, hydroxymethyl and bromide.

19. The compound of formula (I) p, where R4 is chosen from the group consisting of hydrogen, bromine and-CO-N,

20. The compound of formula (I) according to claim 3, where R6 means hydrogen.

21. The compound of formula (I) according to claim 3
,
where X is S or SO2,
R1 is chosen from a group including:
-(C1-C8)alkyl which may be linear, cyclic or branched(C1-C4)alkyl, substituted with one or two substituents, independently selected from the group comprising-O-R", -O-Ar, -O-CO-HetAr, -CO-Ar, -CO-O-R and-N(R')2, aryl and aryl(C1-C4)alkyl, where the aryl part is chosen from the group consisting of phenyl, indanyl and fluorenyl,
where the alkyl portion can be optionally substituted with one hydroxyl group, and
where the aryl portion can be optionally substituted by substituents, up to three selected individually from the group consisting of halogen, -O-R"; -SO2-R", -SO2-N(R')2or
where the aryl may be optionally substituted by two groups, in the United States to an adjacent carbon atoms and are combined into a saturated cyclic system from a 5 - or 6-membered rings, optionally containing up to two oxygen atoms, while the cyclic system of rings may be optionally additionally substituted by oxopropoxy;
heteroaryl and heteroaryl(C1-C4)alkyl where the heteroaryl portion is chosen from the group including chinoline, thiazolyl, pyrimidinyl, furyl, pyridinyl, pyrazinyl and thienyl,
this heteroaryl group may be optionally substituted by one or two substituents selected individually from the group comprising halogen, hydroxyl, -(C1-C4)alkoxy, (C1-C4)alkyl and
-CO-O-R";
cyclogeranyl and cyclogeranyl(C1-C4)alkyl, where cyclogeranyl part selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl and dioxolane,
this cyclogeranyl part can be optionally substituted by substituents, up to two selected individually from the group comprising oxoprop, (C1-C4)alkyl, preferably methyl, and -(C1-C4)alkyl-Ar, preferably benzyl or phenethyl;
R2 is chosen from a group that includes
i) a residue of formula (II)
,
where R7 denotes hydrogen, halogen, hydroxyl or (C1-C4)alkoxygroup, preferably a methoxy group,
R8 means hydrogen, (C1-C4)alkoxygroup the PU, preferably a methoxy group, hydroxyl, nitrile, halogen or halogenated (C1-C4)alkyl, preferably trifluoromethyl,
R9 means hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, hydroxyl, nitrile, halogen or N,N-di(C1-C4)alkylsulfonate,
R10 denotes hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, hydroxyl, nitrile, halogen or halogenated (C1-C4)alkyl, preferably trifluoromethyl,
R11 denotes hydrogen, halogen, hydroxyl or (C1-C4)alkoxygroup, preferably a methoxy group; and
ii) -(C1-C8)alkyl which may be linear, cyclic, branched or partially unsaturated;
-(C1-C4)alkyl, substituted with one or two substituents selected from the group consisting of-CO-O-R", -OR',- O-Ar, where Ar denotes phenyl, optionally substituted with halogen; -O-CO-R", and phenyl or biphenyl, optionally substituted by phenyl group (p1-C4)alkoxygroup, up to three, preferably by methoxypropane,
-CO-O-R",
-CO-R", preferably SNO,
-naphthyl and
-heteroaryl, which can be selected from the group consisting of tanila, furil, pyridinyl, benzothiazyl and pyrazolyl,
this heteroaryl group may be optionally substituted by one or the two substituents, selected individually from the group comprising halogen, (C1-C4)alkyl, halogenated (C1-C4)alkyl, preferably trifluoromethyl, phenyl and fenoxaprop,
this phenyl group may be substituted by halogen atoms, up to three;
R3 is chosen from the group consisting of hydrogen, carbonyl group, -O-R", -O-Ar, -O-CO-R', halogen, tigroup, groups-S-R and-S-Ar;
R4 is chosen from the group consisting of hydrogen, (C1-C4)alkyl, optionally substituted by hydroxyl; -CO-R, -CO-O-R', halogen and dihalogen;
where Ar denotes phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl group or metoxygroup,
HetAr means thienyl, furyl, pyridinyl and
R ' means hydrogen or (C1-C4)alkyl, preferably methyl or ethyl.

22. The compound of formula (I) according to item 21, where R1 is chosen from a group including:
-(C3-C8)alkyl which may be linear, cyclic or branched(C1-C4)alkyl, substituted with one or two substituents selected independently from the group consisting of (C1-C4)alkoxygroup, hydroxyl, and-O-CO-HetAr, phenyl(C1-C4)alkyl,
where the aryl portion can be optionally substituted by substituents, up to three selected individually from the group status is the present from halogen, (C1-C4)alkoxygroup and hydroxyl,
heteroaryl(C1-C4)alkyl where the heteroaryl portion is chosen from the group consisting of pyrimidinyl, furil, pyridinyl and tanila,
this heteroaryl group may be optionally substituted by one or two substituents selected individually from the group consisting of halogen, (C1-C4)alkoxygroup and hydroxyl, and
cyclogeranyl(C1-C4)alkyl, where cyclogeranyl part is chosen from the group consisting of tetrahydrofuryl, piperidinyl, morpholinyl and pyrrolidinyl,
R2 is chosen from a group that includes
i) a residue of formula (II)
,
where R7 denotes hydrogen, bromine, chlorine or fluorine,
R8 means hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, or a hydroxyl,
R9 means hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, or a hydroxyl,
R10 denotes hydrogen, (C1-C4)alkoxygroup, preferably a methoxy group, or a hydroxyl,
R11 denotes hydrogen, and
ii) -(C3-C6)alkyl which may be linear, cyclic or branched, optionally replaced by groups-O-(C1-C4)alkyl, or
-CO-O-(C1-C4)alkyl;
-heteroaryl, which can be selected from the group consisting of tanila, is urila, pyridinyl, benzothiazyl and pyrazolyl;
R3 is chosen from the group comprising hydrogen, oxoprop, hydroxyl, (C1-C4)alkoxygroup, -O-CO1-C4)alkyl and (C1-C4)allylthiourea;
R4 is chosen from the group comprising hydrogen, halogen, Cho, -CO(C1-C4)alkyl, and R6 means hydrogen or bromine.

23. The compound of formula (I) according to article 22, where
R1 is chosen from the group comprising isobutyl, 3-methylbutyl, benzyl, tetrahydrofuranyl, furylmethyl, 5-bromofuran-2-ylmethyl, 5-bromo-2-methoxybenzyl, ethyl ester thiophene-2-carboxylic acid and methoxyethyl;
R2 is chosen from the group comprising methoxyphenyl, trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl and propyl;
R3 is chosen from the group comprising hydroxyl, oxoprop, -O-CO-CH3and-S-ethyl;
R4 is chosen from the group consisting of hydrogen, bromine and SNO, and R6 means hydrogen or bromine.

24. The compound of formula (I) in item 23, where
R1 means a linear, cyclic or branched(C3-C8)alkyl,
R2 means trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl or 2-chloro-3,4,5-trimethoxyphenyl,
R3 means hydrogen or hydroxyl,
R4 means hydrogen,
R6 means hydrogen or bromine, and
where the six-membered ring containing hydrocarbon chain-C(R3)-C(R4)-C(R5)-
C(R6)-, is an aromatic ring.

25. The compound of formula (a) according to claim 3, where X represents S.

26. The compound of formula (I) according to claim 3, selected from the group including
3-benzyl-8-ethylsulfonyl-2-(n-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde,
3-benzyl-2-(n-methoxyphenyl)-4-oxo-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde,
3-benzyl-8-ethylsulfonyl-2-(n-methoxyphenyl)-4-oxo-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde,
3-benzyl-8-hydroxy-2-thiophene-2-yl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
2-(8-hydroxy-4-oxo-2-thiophene-2-yl-4H-benzo[4,5]thieno[2,3-d]pyrimidine-3-yl)-ethyl ester thiophene-2-carboxylic acid,
3-butyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
3-benzyl-3-(5-bromo-2-methoxybenzyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
3-benzyl-3-(5-bromo-2-methoxybenzyl)-4-oxo-2-propyl-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidine-8-silt ether acetic acid,
3-(5-bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
3-(5-bromofuran-2-ylmethyl)-4-oxo-2-propyl-3,4-dihydrobenzo[4,5]thieno[2,3-d]pyrimidine-8-silt ether acetic acid,
8-hydroxy-3-isobutyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
3-benzyl-2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
7-bromo-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione,
8-hydroxy-3-(2-what ethylbutyl)-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
5-bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione,
2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methylbutyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
7-bromo-8-hydroxy-3-(2-methoxyethyl)-2-thiophene-2-yl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one,
3-butyl-8-hydroxy-2-(2-methoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one and
3-butyl-2-(2,4-differenl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one.

27. The compound of formula (I)as defined in one of p-26, having the properties of an inhibitor of the enzyme 17β-hydroxysteroid-dehydrogenase (17β-HSD) type 1 17β-HSD type 2 and/or 17β-HSD type 3.

28. The use of the compounds of formula (I)as defined in one of p-26, for the treatment or prevention of diseases or disorders requiring the inhibition of 17β-hydroxysteroid-dehydrogenase (17β-HSD) type 1, type 2 and/or type 3.

29. Use p where-dependent steroid hormone disease or disorder chosen from the group comprising breast cancer, prostatic carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, endometriosis, uterine fibroids, leiomyoma uterus, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, is rotatet, acne, seborrhea, hirsutism, androgenic alopecia, premature puberty, adrenal hyperplasia, polycystic ovarian syndrome, and osteoporosis.

30. The use of the compounds of formula (I)as defined in one of p-26, for preparing a medicinal product for treating and/or preventing diseases or disorders requiring the inhibition of 17β-hydroxysteroid-dehydrogenase, most preferably 17β-HSD type 1 17β-HSD type 2 or 17β-HSD type 3.

31. The application of article 30, where the dependent steroid hormone disease or disorder chosen from the group comprising breast cancer, prostatic carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, endometriosis, uterine fibroids, leiomyoma uterus, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, premature puberty, adrenal hyperplasia, polycystic ovarian syndrome, and osteoporosis.

32. Pharmaceutical composition having the properties of an inhibitor of 17β-hydroxysteroid-dehydrogenase type 1, type 2 or type 3, containing as an active means of at least one of the compounds of formula (I)as defined in one of p-26, and at least a pharmaceutically priemel the range of the media.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of formula where values of radicals are given in the formula of invention, and a pharmaceutically acceptable salt thereof. Said compounds have 17β-hydroxysteroid dehydrogenase enzyme (17β-HSD) inhibiting activity. The invention describes use of the formula (I) compound in treating or preventing diseases or disorders which require inhibition of 17β- hydroxysteroid dehydrogenase enzyme, use of the formula (I) compound to prepare a medicinal agent for treating or preventing diseases or disorders which require inhibition of 17β- hydroxysteroid dehydrogenase enzyme, and a pharmaceutical composition based on the formula (I) compound.

EFFECT: derivatives are highly effective.

18 cl, 7 tbl

FIELD: chemistry.

SUBSTANCE: use of compounds of formula (I): where: X denotes >CR1R2 or, when R6 denotes H, X denotes >SO2; Y denotes >CR1R2; Z denotes >C=O, >CH2, single bond; R1 denotes H, R2 denotes H, -COOH, -OH; or R1 and R2 together denote =O, ethylenedioxy or hydroxyimino group; R3 denotes H, lower alkyl group; R4 denotes two H, =O, hydroxyimino group; R5 denotes H, lower alkyl group, halogen; R6 denotes H, lower alkoxy, COOH; R7 and R8 are identical or different from each other and each denotes H, lower alkyl, halogen; and pharmaceutically acceptable salts thereof and esters for preparing a medicinal agent.

EFFECT: agent having neuroprotective action against hypoxia.

2 tbl, 24 ex, 13 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and formula (II), their tautomers and pharmaceutically acceptable salts. In formula (I) and in formula (II), X - S; R1 - H; R2 - NR5R6; R3 - 5-6-member heteroaryl with 1 heteroatom, selected from N and S, or phenyl, optionally substituted with one or two substituents, selected from halogen, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenalkyl and C1-C6-halogenalkoxy; R4 - H, C1-C6 alkyl, C1-C6 alkoxy or XR3, where X and R3 are determined above; R5 - H; R6 - H; L - N or CR7, where R7 - H; M - S. Invention also relates to pharmaceutical composition, containing as active component invention compound, to method of inhibiting activity of caseinkinase lε and to method of obtaining compounds of formula (I) or formula (II).

EFFECT: compounds of claimed invention possess properties of casein kinase lε inhibitors.

13 cl, 5 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention describes a neutral semiconductor organic compound of formula (I) , where R1 and R2 denote a hydrogen atom, n is the number links in formula (I) and is an integer between 2 and 1000, terminal groups of the compound R3 and R4 denote a hydrogen atom or a linear or branched alkyl group with 1-20 carbon atoms. The invention also describes use of the said compound as a semiconductor in electronic functional elements.

EFFECT: higher oxidation resistance, which enables use of the compound in transistors and other electronic functional elements.

5 cl, 3 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: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 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 novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

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

Pyrazolepyrimidines // 2412186

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat tumourous diseases, such as solid tumours, breast, lung, large intestine or prostate gland tumours. In compounds of formula

: R1 is selected from a group comprising: (a) saturated cyclic radical containing 3-8 ring atoms, from which 1-3 atoms are N atoms, which can contain up to four substitutes independently selected from a group comprising: (i) lower alkyl; and (ii) CO2R3, OR7 or S(O)nR8; (b) C6-C10aryl, which can contain up to four substitutes independently selected from a group comprising: (i) S(O)nR8, lower alkyl; OR7 and halogen; (c) C3-C8cycloalkyl, which can be substituted with NR5R6; and (d) lower alkyl, which can be substituted: (i) OR7, NR5R6; R2 is selected from a group comprising: (i) H; (ii) lower alkyl; (iii) C6-C10aryl which can be substituted with a halogen, lower alkyl, lower alkoxy group; R3 is selected from a group comprising: (i) H; (ii) lower alkyl; (iv) C3-C8cycloalkyl; R5 and R6 are independently selected from a group comprising: (i) H; (ii) lower alkyl; (iii) C3-C8cycloalkyl; (v) SO2R3; and (vi) CO2R3; R7 is selected from a group comprising H and lower alkyl; R8 is selected from a group comprising: (iii) NR5R6; (iv) lower alkyl; and n equals 1 or 2.

EFFECT: capacity to inhibit activity of cyclin-dependant kinase.

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) in form of (R) or (S) isomers, separately or in a mixture, as well as their physiologically acceptable salts and hydrates, having vitronectin receptor antagonist properties. In formula (I)

G denotes Het-NH-CO-, Het-NH-CH2-, Het-; Het denotes a mono- or bicyclic system, where each ring is a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-2 nitrogen atoms as heteroatoms, where Het is unsubstituted or substituted with R9 groups; R1 denotes H, (C6-C14)-aryl, (C6-C14)aryl(C1-C4)alkyl; amino, unsubstituted, mono-or disubstituted with alkyl and/or acyl, containing 1-4 C atoms; R2 denotes H, halogen, nitro-group; alkyl containing 1-4 C atoms; amino, unsubstituted, mono- or disubstituted with alkyl and/or acyl containing 1-4 C atoms; a -(CH2)0-2-OR5 group; R3 denotes H, -CO2R5, -SO2R5 or mono- or bicyclic system, where each ring denotes a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-4 heteroatoms selected from N, O or S, unsubstituted or substituted with R9 radicals; R4 denotes OH, (C1-C8)alkoxy-; amino, unsubstituted, mono- or disubstituted with (C1-C4)alkyl; or an aminoacid residue; R5 denotes (C1-C8)alkyl; (C6-C14)aryl; (C6-C14)aryl(C1-C4)alkyl; (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bi- and tricycloalkyl(C1-C4)alkyl. Aryls, alkyls, cycloalkyls are not substituted or substituted with R9 groups; R9 denotes halogen, amino, nitro, hydroxyl, (C1-C4)alkyloxy-, carboxy, (C1-C4)alkyloxycarbonyl-, (C1-C8)alkyl, unsubstituted or substituted with halogen atoms; phenyl. The invention also relates to a methods for synthesis of formula (I) compounds, a medicinal agent and a pharmaceutical composition containing said compounds, as well as use thereof in preparing the medicinal agent.

EFFECT: improved properties of the compound.

21 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to anthracenedione derivatives which are suitable for therapy of oncological diseases, having the formula:

, where W is a fragment of a five-member heterocycle containing one or two heteroatoms selected from N, O or S, optionally substituted with alkyl, halogen; Y is a monocyclic diamine residue containing an exocyclic amine group, or a polycyclic diamine with bridging amine groups, which is a compound in which two amine groups are involved in formation of 4- or 6-member ring systems containing 2-6 carbon atoms and bonded by one, two or three bridging atoms, where Y is optionally substituted with one or more substitutes selected from alkyl, halogenalkyl, halogen, hydroxyl, hydroxyalkyl, carbamoyl and CO2R, where R denotes alkyl; X denotes alkylene, CO or SO2; n and m are independently range from 0 to 2; Z1 is selected from hydroxy, alkoxy -NH2, -NHR1, -NR1R2, where R1 and R2 denote alkyl, aminoalkylamino, halogen; Z2 is selected from hydroxy, alkoxy, fluorine.

EFFECT: obtaining novel anti-tumour compounds.

1 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to anthracenedione derivatives which are suitable for therapy of oncological diseases, having the formula:

, where W is a fragment of a five-member heterocycle containing one or two heteroatoms selected from N, O or S, optionally substituted with alkyl, halogen; Y is a monocyclic diamine residue containing an exocyclic amine group, or a polycyclic diamine with bridging amine groups, which is a compound in which two amine groups are involved in formation of 4- or 6-member ring systems containing 2-6 carbon atoms and bonded by one, two or three bridging atoms, where Y is optionally substituted with one or more substitutes selected from alkyl, halogenalkyl, halogen, hydroxyl, hydroxyalkyl, carbamoyl and CO2R, where R denotes alkyl; X denotes alkylene, CO or SO2; n and m are independently range from 0 to 2; Z1 is selected from hydroxy, alkoxy -NH2, -NHR1, -NR1R2, where R1 and R2 denote alkyl, aminoalkylamino, halogen; Z2 is selected from hydroxy, alkoxy, fluorine.

EFFECT: obtaining novel anti-tumour compounds.

1 cl, 18 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel group of chemical-pharmaceutical bioconjugates, which can be obtained by indirect synthesis by means of molecular spacer between hyaluronic caid and/or its derivatives and medications with anti-tumour activity, belonging to different groups, method of their obtaining. Invention also relates to anti-tumour pharmaceutical compositions and three-dimensional biomaterials based on said conjugate.

EFFECT: novel derivatives, depending on bond type and substitution degree, have different physical-chemical properties, which improve their tolerance and efficiency and ensure possibility of more accurate modulating dosage by using mechanism of active targeting.

31 cl, 4 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be used in treatment of mammary gland cancer (MGC). Method is realised in the following way. After confirmation of malignant character of tumour tissue in patient sampling of 200 ml of blood from peripheral vein into reservoir with hemopreservative is carried out, after that it is centrifuged with separation of plasma, which is combined with cyclophosphane in amount 400 mg/m2, doxorubincin in dose 40 mg/m2 is introduced into erythrocyte mass; both reservoirs are incubated in thermostat for 30 minutes at temperature 37°C. After that, sucking of blood from the place of tumour tissue sampling is carried out with further introduction into it of 200 mg of cyclophosphane diluted in 5 ml of physiological solution. Tissue of mammary gland around tumour is infiltrated with incubated plasma with cyclophosphane, and erythrocyte mass with doxorubicin is introduced intravenously by drop infusion.

EFFECT: application of the invention makes it possible to increase efficiency of MGC treatment due to creation of maximal concentration of chemical preparations in leision focus and prevention of tumour process dissemination.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with application of miliacin as medication which increases antitumour effect of methotrexate.

EFFECT: extension of arsenal of medications, which increase antitumour effect of methotrexate.

3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to photosensitiser, which represents nanostructured water dispersion based on bacteriochlorin p derivative, namely methyl ester of O-ethyloxime N-etoxycycloimide bacteriochlorin p C38H46N6O6. Invention also relates to method of said photosensitiser obtaining, including reaction of methyl ester of bacteriopurpurin in main solvent with etoxyamine chlorhydrate at room temperature for 72-80 hours, which is finished after displacement of spectral maximum of reaction mixture absorption to 802 nm. Invention also relates to method of photodynamic therapy, which includes introduction of said photosensitiser and irradiation of pathologic part with optic irradiation in spectrum range 790-810 nm 0.7-5 hours after introduction.

EFFECT: invention ensures high efficiency and selectivity of action of photodynamic therapy of large-size tumours and pigment tumours, including melanoma.

6 cl, 5 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to pharmaceutical composition for treatment of oncologic diseases in form of phospholipid nanoparticles with size 10-30 nm, which includes phosphatidelcholin, maltose and doxorubicine with the following ratio of components, wt. %: phosphatidelcholin 20-43, maltose 55-78, doxorubicine 2-8. Composition is accumulates in tumour tissue more actively and slows down tumour growth in mice with carcinoma LLC more efficiently in comparison with free doxorubicine.

EFFECT: composition represents freeze-dries powder, stable in long storage, which dissolving in water gives nanophpospholipid particles with included doxorubicine.

3 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new capmtotecin derivatives of a following structure of formula (I) where R1 represents H, C1-C4alkyl, branched C1-C4alkyl or vinyl, as well as to a pharmaceutical composition exhibiting antineoplastic activity and based on the given compounds, and to application thereof for making a drug for treating tumours.

EFFECT: there are produced and described new compounds which exhibit high antineoplastic activities and have good water-solubility; they can be applied for creating new drugs.

7 cl, 3 ex, 3 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular, to ophthalmology, and can be used for treatment and prevention of nuclear type of age cataract. For this purpose antagonist of serotonin receptors is applied in efficient concentration.

EFFECT: invention allows to carry out treatment and prevention of said disease, due to efficient impact on bioamine status and phenotype of lens cells.

1 tbl, 3 ex

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