Pyridincarboxamides as 11-beta-hsd1 inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (1):

where Q represents a single bond, -O-, -S - or-N(R15)-, where R15represents hydrogen or C1-3alkyl, or R15and R1together with the nitrogen atom to which they are attached, form a 4-7-membered saturated ring;
R1represents a C1-6alkyl With 3-7cycloalkyl,3-7cycloalkyl1-3alkyl, phenyl, panels1-3alkyl, heteroaryl, heteroaryl1-3alkyl, heterocyclyl or heterocyclyl1-3alkyl [each of which may substituted by 1, 2 or 3 substituents, independently selected from C1-3of alkyl, halogeno, carboxy1-3of alkyl, C1-3S(O)n- (where n is 0, 1, 2 or 3), R5'C(O)-; and R5'and R5"independently selected from hydrogen and C1-3the alkyl], and possible substituents heterocyclyl and heterocyclyl group heterocyclic1-3the alkyl optionally is selected from R21, R21CO-, R21S(O)k(where k is equal to 2) and R21CH2OC(O)-, where R21represents phenyl, possibly substituted by 1 or 2 substituents, independently selected from halogeno; or
when Q is a bond, then R1may also represent hydrogen;
R2selected from the groups C3-7cycloalkyl(CH2)mand C6-12politically(CH2)m- (where cycloalkyl and polycyclohexylene ring may contain 1 or 2 ring atoms independently selected from nitrogen and oxygen, m is 0, 1 or 2, and these rings may substituted by 1, 2 or 3 substituents, independently selected from R6);
R3selected from hydrogen, C1-4of alkyl, C3-5cycloalkyl and C3-5cycloalkenyl;
R2The R 3together with the nitrogen atom to which they are attached, form a saturated monocyclic, bicyclic or bridged ring system which may contain 1 or 2 additional ring heteroatoms of nitrogen, but the resulting ring system may be substituted by 1, 2 or 3 substituents, independently selected from R7;
R4independently selected from halogeno and C1-7of alkyl;
R6and R7independently selected from hydroxyl, halogeno, trifloromethyl, R9, R9O-, (R9')(R9")NC(O)-, R9S(O)a-where is a number from 0 to 2, phenyl and heteroaryl [where the resulting ring system may be substituted by trifluoromethyl];
R9independently represents a C1-3alkyl, possibly substituted by 1, 2 or 3 substituents, independently selected from hydroxyl, halogeno;
R9'and R9"represent hydrogen;
p is 0 or 1;
or X represents-O(CH2)q-, -S(CH2)q- or-N(R12)(CH2)q-where R12represents hydrogen or C1-3alkyl, and q is 0 or 1; and
Y represents:
1) C3-7cycloalkyl ring, fenelonov ring, adamantly group, or -[C(Rx)(Ry)]v- (where Rxand Ryrepresent hydrogen, and v is 2); or
2) -X-Y - together represent a group is ormula:

where ring A is linked to the pyridine group and a group -(Z)t[C(R13)(R14)s- linked to a carboxyl group; and
A is a 4-7-membered mono-, bi - or spiroheterocyclic ring system containing a ring nitrogen atom through which it is attached to the pyridine ring, and optionally one ring heteroatom selected from nitrogen and oxygen;
Z represents-O - or-N(R16)-, where R16represents hydrogen or C1-3alkyl;
t is 0 or 1, provided that when s is 0, then t is 0;
R10represents a C1-3alkyl;
u is 0 or 1;
R13and R14independently selected from hydrogen and C1-3the alkyl, or R13and R14together with the carbon atom to which they are attached, may form a C3-7cycloalkyl ring; and
s is 0, 1 or 2;
or its pharmaceutically acceptable salt or hydrolyzable in vivo esters;
provided that the compound is not:
{(3S)-1-[5-(adamantane-1-ylcarbonyl)pyridine-2-yl]piperidine-3-yl}acetic acid; or
{(3S)-1-[5-(cyclohexylcarbonyl)-6-(piperazine-1-yl)pyridin-2-yl]piperidine-3-yl}acetic acid;
or their pharmaceutically acceptable salt or hydrolyzable in vivo ester.

2. The compound according to claim 1, where:
Q represents the FDS is th O S or a single bond, and R1represents a C1-6alkyl, C3-7cycloalkyl or C3-7cycloalkyl1-3alkyl [each of which may substituted by 1, 2 or 3 substituents, independently selected from C1-3of alkyl, halogeno and C1-3S(O)n- (where n is 0, 1, 2 or 3).

3. The compound according to claim 1, where Q represents-S-, and R1represents a C1-6alkyl, C3-7cycloalkyl or C3-7cycloalkyl1-3alkyl.

4. The compound according to claim 1, where p is equal to 0.

5. The compound according to claim 1, where R2selected from the groups C3-7cycloalkyl(CH2)mand
C6-12politically(CH2)m- (where m is 0, 1 or 2, and ring possibly substituted by 1 or 2 substituents independently selected from R6and R6independently selected from hydroxyl, halogen and trifloromethyl).

6. The compound according to claim 1, where R3represents hydrogen.

7. The compound according to claim 1, where R2and R3together with the nitrogen atom to which they are attached, form a saturated 5 - or 6-membered monocyclic ring system which may contain 1 additional ring nitrogen atom, and possibly substituted by 1 or 2 substituents independently selected from R7where R7selected from hydroxy, halogeno and trifloromethyl.

8. The compound according to claim 1, where X represents-O-, -S - or-N(R12)-, where R12before the hat is hydrogen or C 1-3alkyl, and Y represents a C3-7cycloalkyl ring.

9. The compound according to claim 1, where-X-Y - together represent a group of the formula:

where ring A is linked to the pyridine group and a group -[C(R13)(R14)s- linked to a carboxyl group; and
A is a 4-7-membered mono-, bi - or spiroheterocyclic ring system containing a ring nitrogen atom through which it is attached to the pyridine ring, and optionally one ring heteroatom selected from nitrogen and oxygen;
R10represents a C1-3alkyl;
u is 0 or 1;
R13and R14independently selected from hydrogen and C1-3the alkyl, or R13and R14together with the carbon atom to which they are attached, may form a C3-7cycloalkyl ring; and
s is 0, 1 or 2.

10. The compound according to claim 1, which is:
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]piperidine-3-carboxylic acid
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]piperidine-4-carboxylic acid,
2-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-piperidyl]acetic acid,
2-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl the-pyridine-2-yl]-3-piperidyl]acetic acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]piperazine-1-yl]acetic acid,
(3R,5S)-4-[[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]amino]adamantane-1-carboxylic acid
(3R,5S)-4-[[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]amino]adamantane-1-carboxylic acid
4-[[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-methyl-amino]cyclohexane-1-carboxylic acid
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
3-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxybenzoyl acid,
3-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]sulfonylamino acid,
4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]sulfonylamino acid,
4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxybenzoyl acid,
2-[4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxyphenyl]acetic acid,
3-[4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxyphenyl]propanoic acid,
2-[4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]sulfanilamide]acetic acid,
2-[4-[5-(CEC who hexylbenzoyl)-6-propylsulfonyl-pyridine-2-yl]okefenokee]acetic acid,
2-[4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxyphenyl]propanoic acid,
2-[4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]sulfanilyl]acetic acid,
2-[3-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxyphenyl]acetic acid,
2-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]sulfonylamino acid,
4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]oxocyclohexa-1-carboxylic acid
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]piperidine-2-carboxylic acid,
(2S)-1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-2-carboxylic acid,
2-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-piperidyl]propanoic acid,
4-[[[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]amino]methyl]cyclohexane-1-carboxylic acid
3-[[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]amino]propanoic acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]azepin-4-carboxylic acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-methyl-piperidine-4-carboxylic acid,
(1S,5R)-3-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
4-[[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]amino]cyclohexane-1-karbonova the acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-propan-2-yl-piperidine-4-carboxylic acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-methyl-piperidine-4-carboxylic acid,
2-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]-2-methyl-propanoic acid,
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
3-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]propanoic acid,
2-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]azetidin-3-yl]oxucusu acid,
1-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]CYCLOBUTANE-1-carboxylic acid
1-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]cyclopropane-1-carboxylic acid
2-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]oxy]propanoic acid,
2-[[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]oxy]-2-methyl-propanoic acid,
2-[[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]oxy]acetic acid,
1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-methyl-piperidine-3-carboxylic acid
2-[1-[5-(cyclohex ylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-piperidyl]-2-methyl-propanoic acid,
1-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-piperidyl]CYCLOBUTANE-1-carboxylic acid
1-[1-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]-4-piperidyl]cyclopropane-1-carboxylic acid
4-[5-(cyclohexylcarbonyl)-6-propylsulfonyl-pyridine-2-yl]morpholine-2-carboxylic acid,
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-cyclohexylsulfamic-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-cyclohexylsulfamic-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-cyclopentylmethyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-cyclopentylmethyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-cyclopentylmethyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-cyclopentylmethyl-pyridine-2-yl]-3-piperidyl]acetic acid,
1-[1-[5-(cyclohexylcarbonyl)-6-cyclopentylmethyl-pyridine-2-yl]-3-piperidyl]cyclopropane-1-carboxylic acid
2-[(3S)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[(3R)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[3S)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
(3R)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
2-[(3R)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
(2S)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-2-carboxylic acid,
(1S,5R)-3-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
(3S)-1-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
4-[5-(2-adamantylidene)-6-propylsulfonyl-pyridine-2-yl]morpholine-2-carboxylic acid,
2-[(3S)-1-[5-(2-adamantylidene)-6-cyclopentylmethyl-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[(3R)-1-[5-(2-adamantylidene)-6-cyclopentylmethyl-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[(3S)-1-[5-(2-adamantylidene)-6-cyclohexylsulfamic-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[(3R)-1-[5-(2-adamantylidene)-6-cyclohexylsulfamic-pyridine-2-yl]pyrrolidin-3-yl]oxucusu acid,
2-[(3R)-1-[5-(2-adamantylidene)-6-ethylsulfanyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
(3R)-1-[5-(2-adamantylidene)-6-ethylsulfanyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
(3S)-1-[5-(2-adamantylidene)-6-ethylsulfanyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
(1S,5R)-3-[5-(2-adamantylidene)-6-atlanfa the Il-pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
2-[(3R)-1-[5-(2-adamantylidene)-6-methylsulfanyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
(3R)-1-[5-(2-adamantylidene)-6-methylsulfanyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
(1S,5R)-3-[5-(2-adamantylidene)-6-methylsulfanyl-pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
2-[(3S)-1-[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
4-[[[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]amino]methyl]cyclohexane-1-carboxylic acid
4-[[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]amino]cyclohexane-1-carboxylic acid
4-[[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]amino]cyclohexane-1-carboxylic acid
2-[(3S)-1-[5-[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]piperidine-4-carboxylic acid,
2-[(3R)-1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-4-piperidyl]acetic acid,
(1R,5S)-3-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
1-[5-[[(2R,5S)5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-4-methyl-piperidine-4-carboxylic acid,
1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
2-[(3R)-1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
3-[1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]propanoic acid,
2-[1-[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]-2-methyl-propanoic acid,
2-[(3S)-1-[6-cyclopentylmethyl-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3S)-1-[6-cyclopentylmethyl-5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3R)-1-[6-cyclopentylmethyl-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
(3R)-1-[6-cyclopentylmethyl-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]pyrrolidin-3-carboxylic acid
(2S)-1-[6-cyclopentylmethyl-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]pyrrolidin-2-carboxylic acid,
(1R,5S)-3-[6-cyclopentylmethyl-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
1-[6-cyclopentylmethyl-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]piperidine-4-carboxylic acid,
2-[(3R)-1-[6-cyclohexylsulfamic-5-[((2R,5S)-5-hydroxy-2-adamantanol]pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
(2S)-1-[6-cyclohexylsulfamic-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]pyrrolidin-2-carboxylic acid,
(3R)-1-[6-cyclohexylsulfamic-5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]pyridine-2-yl]pyrrolidin-3-carboxylic acid
2-[(3S)-1-[6-cyclohexylsulfamic-5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-(3-methylbutanoyl)pyridine-2-yl]-3-piperidyl]acetic acid,
(3R)-1-[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-(3-methylbutanoyl)pyridine-2-yl]pyrrolidin-3-carboxylic acid
(1R,5S)-3-[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-(3-methylbutanoyl)pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
2-[(3S)-1-[6-benzylmethyl-5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-penicillanic-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]-6-propoxy-pyridin-2-yl]-3-piperidyl]acetic acid,
2-[1-[5-[((2R,5S)-5-hydroxy-2-substituted)carbarnoyl]-6-propoxy-pyridin-2-yl]-3-piperidyl]-2-methyl-propanoic acid,
(1R,5S,6r)-3-(6-(cyclopentyl)-5-(3-(pyridin-3-yl)pyrrolidin-1-carbonyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
(1S,5R)-3-[6-cyclohexylsulfamic-5-(3-pyridin-3-iparralde-1-carbon is l)pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
2-[(3S)-1-[6-propylsulfonyl-5-(3-pyridin-3-iparralde-1-carbonyl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-propylsulfonyl-5-(3-pyridin-2-iparralde-1-carbonyl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(piperidine-1-carbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-propylsulfonyl-5-(3-pyrazin-2-iparralde-1-carbonyl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(4,4-deformability-1-carbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-propylsulfonyl-5-[3-(trifluoromethyl)piperidine-1-carbonyl]pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-propylsulfonyl-5-[4-(trifluoromethyl)piperidine-1-carbonyl]pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(4-carbamoylbiphenyl-1-carbonyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-cyclopropyl-carbarnoyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-(cyclopropylmethyl)carbarnoyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-ethyl-carbarnoyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-propan-2-yl-carbarnoyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-[(4-hydroxycyclohexyl)carbarnoyl]-6-propylsulfonyl-pyrid the h-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-propylsulfonyl-5-[3-[2-(trifluoromethyl)phenyl]pyrrolidin-1-carbonyl]pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-[((2R,5S)-5-methylsulphonyl-2-substituted)carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-cyclopentylmethyl-5-(3-pyridin-3-iparralde-1-carbonyl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3R)-1-[5-(cyclohexylcarbonyl)-6-penicillanic-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-penicillanic-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(2-pyridin-3-reticular)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(2-pyrazin-2-reticular)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-[2-(4-forfinal)ethoxy]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(3-methylbutoxy)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(3-phenylpropoxy)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(2-pyridin-3-ylethoxy)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-methoxy-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-ol is poxi-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(1-piperidyl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-[2-(4-chlorophenyl)ethylamino]-5-(cyclohexylcarbonyl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-[3-(4-forfinal)pyrrolidin-1-yl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(3,4-dihydro-1H-isoquinoline-2-yl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(3,4-dihydro-1H-isoquinoline-2-yl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(4-phenylpiperazin-1-yl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-[4-(4-perbenzoic)piperazine-1-yl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-(4-acetylpiperidine-1-yl)-5-(cyclohexylcarbonyl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(4-ethylsulphuric-1-yl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-[4-(benzazolyl)piperazine-1-yl]-5-(cyclohexylcarbonyl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(4-formatexception-1-yl)pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-propylamino-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(phenethylamine)pyridine-2-yl]-3-piperidyl]acetic acid is the one
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(methyl-phenethyl-amino)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-(methyl-propyl-amino)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-pyrrolidin-1-yl-pyridin-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-morpholine-4-yl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-methyl-carbarnoyl)-6-propylamino-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-methyl-carbarnoyl)-6-(methyl-propyl-amino)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-methyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(1-adamantylamine)-6-methyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(2-adamantylidene)-6-methyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(2-adamantylidene)-6-butyl-pyridine-2-yl]-3-piperidyl]acetic acid,
3-[5-(2-adamantylidene)-6-butyl-pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
2-[(3S)-1-[6-butyl-5-(cyclohexylcarbonyl)pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexylcarbonyl)-6-cyclopropyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(2-adamantylidene)-6-cyclopropyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-cyclopropyl-5-[[(2R,5S)-5-hydroxy-2-substituted]carbarnoyl]p is ridin-2-yl]-3-piperidyl]acetic acid,
2-[(3R)-1-[5-(cyclohexyl-methyl-carbarnoyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-(cyclohexyl-methyl-carbarnoyl)-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic acid,
[(3S)-1-{5-[((2R,5S)-5-methoxyamino-2-yl)(methyl)carbarnoyl]-6-(propylthio)pyridine-2-yl}piperidine-3-yl]acetic acid,
[(3S)-1-{5-[((2R,5S)-5-hydroxyadamantane-2-yl)(methyl)carbarnoyl]-6-(propylthio)pyridine-2-yl)piperidine-3-yl]acetic acid,
{(3S)-1-[5-(adamantane-1-ylcarbonyl)-6-(propylthio)pyridine-2-yl]piperidine-3-yl}acetic acid,
{(3S)-1-[6-(propylthio)-5-(tetrahydro-2H-Piran-4-ylcarbonyl)pyridine-2-yl]piperidine-3-yl}acetic acid,
[(3S)-1-{5-[methyl(tetrahydro-2H-Piran-4-yl)carbarnoyl]-6-(propylthio)pyridine-2-yl}piperidine-3-yl]acetic acid,
2-[(3S)-1-[6-cyclohexylsulfamic-5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3S)-1-[6-cyclohexylsulfamic-5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[6-cyclopentylmethyl-5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3S)-1-[6-cyclopentylmethyl-5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]pyridine-2-yl]-3-piperidyl]acetic acid,
2-[(3S)-1-[5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]-3-piperidyl]acetic KIS the GTC,
2-[(3S)-1-[5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
2-[(3S)-1-[5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]-6-propoxy-pyridin-2-yl]-3-piperidyl]acetic acid,
(3R)-1-[6-cyclopentylmethyl-5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]pyridine-2-yl]pyrrolidin-3-carboxylic acid
(1R-,5S)-3-[6-cyclopentylmethyl-5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]pyridine-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid,
2-[(3R)-1-[5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-yl]acetic acid,
1-[5-[[(2R,5S)-5-(deformedarse)-2-substituted]carbarnoyl]-6-propylsulfonyl-pyridine-2-yl]pyrrolidin-3-carboxylic acid
(S)-2-(1-(5-(cyclohexylcarbonyl)-3-fluoro-6-(propylthio)pyridine-2-yl)piperidine-3-yl)acetic acid or (R)-2-(1-(5-(cyclohexylcarbonyl)-3-fluoro-6-(propylthio)pyridine-2-yl)piperidine-3-yl)acetic acid,
or its pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable diluent or carrier, for the treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis, glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders or depression.

12. The compound according to claim 1 for use in the method of prevention is whether therapeutic treatment of metabolic syndrome, diabetes type II, obesity, atherosclerosis, glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders or depression in a warm-blooded animal such as man.

13. The compound according to claim 1 for use as a drug for the treatment of metabolic syndrome, type II diabetes, obesity or atherosclerosis.

14. The compound according to claim 1 for use as a drug for the treatment of glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders or depression.

15. The use of compounds according to claim 1 in the manufacture of a medicinal product for use for producing inhibitory effect on 11βHSD1 in a warm-blooded animal such as man.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new thiophene derivatives of formula (I) where A is represented by *-CO-CH2CH2-, *-CO-CH=CH, where the asterisks indicate the link through which the formula (I) thiophene group is bound; R1 is represented by C2-5alkyl; R2 is represented by hydrogen, methyl or ethyl; R3 is represented by hydrogen; R4 is represented by C1-4alkyl; R5 is represented by a hydroxy group, 2,3-di-hydroxypropoxygroup or -OCH2-CH(OH)-CH2-NHCOR52; R52 is represented by hydroxymethyl, and R6 is represented by C1-4alkyl; and to its salt. The invention also refers to the pharmaceutical composition that is agonistic in relation to S1P1/EDG1 receptor on the basis of the mentioned compounds.

EFFECT: new compounds and a composition based on them that may find their application in medicine as immunomodulating agents.

17 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 denotes C1-C6alkyl; W denotes pyrazolyl, triazolyl or imidazolyl; R14 denotes phenyl or a 6-member heteroaromatic ring containing 1-3 nitrogen ring atoms, which is may be substituted with at least one substitute selected from F, Cl, CN and CF3; R3 denotes phenyl, substituted with a trifluoromethyl substitute; R4 denotes hydrogen or C1-C6alkyl; X denotes -C1-C6alkylene-Y-, and Y denotes a single bond, and the alkylene group is a straight or branched C1-C6alkylene, possibly substituted with OH, CO2R66 or C1-C3alkoxy; R5 denotes phenyl or pyridinyl, substituted with -S(O)vR21; or R5 denotes an unsubstituted C3-C6cycloalkyl ring; or R5 can also denote H; R21 denotes hydrogen, C1-C6alkyl or C3-C8cycloalkyl; v equals 1 or 2; and R66 denotes hydrogen or C1-C6alkyl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing said compounds, intermediate compounds and a pharmaceutical composition for treating or reducing the risk of disease or condition, in which inhibiting neutrophil elastase activity based on compounds of formula (I) is useful.

EFFECT: obtaining novel compounds which can be used in medicine to treat or reduce the risk of disease or condition in which inhibiting neutrophil elastase activity is useful.

19 cl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to the use of pyrimidylaminobenzamide derivatives, particularly 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula

, or its pharmaceutically acceptable salt for preparing drugs applicable for treating and preventing systemic mastocytosis. The invention refers to a drug, a method of treating or preventing systemic mastocytosis. The invention also refers to a combination to be used for treating systemic mastocytosis containing the compound of formula (II) and imanitib taken in a therapeutically efficient amount.

EFFECT: compound (II) and combination are applicable in treating systemic mastocytosis which is characterised by resistance to imanitib and preferentially bound with FIPlLl-PDGFRa hybrid gene.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I), treating a disease related to proteinkinase activity inhibition, specifically cancer, particularly leukaemia, a method of treating such disease and a method of producing such compounds. In formula (I) R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl; R2 represents lower alkyl substituted by one or more identical or different radicals R3, cyclohexyl, cycloheptyl, benzcyclopentyl(indane), benzcyclohexyl, penta-, hexa- or heptamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen and oxygen which can be unsaturated or completely saturated, and is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl or oxo; phenyl which is unsubstituted or substituted by one or two substituted specified in a group consisting of lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkoxycarbonyl, lower alkylcarbamoyl, amino mono- or disubstituted lower alkyl, morpholino, lower alkylsulphonyl, halogen and benzoyl; and the value R3 is specified in the patent claim, or R1 and R2 together represent alkylene with four, five or six carbon atoms, optionally mono- or disubstituted by lower alkyl; hexamerous heterocyclic system with one or two heteroatoms specified in a group consisting of nitrogen which can be unsaturated or completely saturated, and is unsubstituted or substituted according to the patent claim, R4 represents hydrogen or lower alkyl.

EFFECT: preparing the composition for treating a disease related to proteinkinase activity inhibition.

5 cl, 99 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

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