Substituted heteroarylpiperidine derivatives as melanocortin-4 receptor modulators

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

and its enantiomers, diastereoisomers, tautomers, solvate and a pharmaceutically acceptable salt,
where R1represents a
-N(R10)-(C(R6)2)m-T
-(C(R6)2)l-T or
-O-(C(R6)2)m-T;
R6independently selected from
N
Och3,
With1-6-alkyl, possibly substituted by 1-3 substituents which are halogen, and
With3-6-cycloalkyl, possibly substituted by 1-3 substituents which are halogen,
T represents NR7R8,
,
,
or;
R7and R8independently from each other selected from
N
With1-6-alkyl;
R9independently chosen is C
HE
With1-6-alkyl,
O-C1-6-alkyl or
NR12R13;
R10represents a
N or
C1-6-alkyl;
R12and R13independently of one another selected from C1-6-alkyl, possibly substituted IT WITH2-6-alkylen-O-C1-6-alkyl, and
W represents CH, O or NR10;
Represents a CR2or N;
G represents CR2or N;
D represents CR2or N;
E is a CR2or N;
provided that one or more of the variables B, G, D, and E must be N;
R2independently selected from
N
F,
Cl,
CH3,
Och3and
CF3;
R3represents a
N
Cl,
F or
CH3;
R4represents a
Cl,
F or
CH3;
R5represents a
,,
morpholine, possibly substituted by 1-3 identical or different substituents R14,
4-7-membered saturated or partially unsaturated heterocycle, containing one ring nitrogen atom and possibly additional heteroatom selected from O, N and S, where the heterocycle may substituted by 1-4 identical or different substituents R11or NR12R13;
R11independently selected from
halogen,
HE
With1-6-alkyl, possibly substituted by 1 to 3 substituents which, which represent halogen,
With2-6-quinil,
-C0-6-alkyl-C3-6-cycloalkyl,
-OC(O)1-6-alkyl,
-NH2,
-NH(C1-6-alkyl) and
-N(C1-6-alkyl)2;
Rather it represents a 3-7-membered saturated ring;
R12and R13independently of one another selected from C1-6-alkyl, possibly substituted IT WITH2-6-alkylen-O-C1-6-alkyl;
R14represents a
C1-6-alkyl;
l is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
o is 0, 1 or 2;
p is 0, 1, 2, 3 or 4;
r is 0, 1, 2, 3 or 4;
s is 1 or 2, and
t is 0 or 1.

2. The compound according to claim 1,
in which
R1represents a
-N(R10)-(C(R6)2)m-T
-(C(R6)2)l-T or
-O-(C(R6)2)m-T;
R6independently selected from
H,
Och3,
With1-6-alkyl, possibly substituted by 1-3 substituents which are halogen, and
With3-6-cycloalkyl, possibly substituted by 1-3 substituents which are halogen;
T represents NR7R8, morpholine,

R7and R8independently of one another selected from
N
C1-6-alkyl;
R9independently selected from
HE
With1-6-alkyl, O-C1-6-alkyl;
R10is the fight
N or
C1-C6-alkyl,
Represents a CR2or N;
G represents CR2or N;
D represents CR2or N;
E is a CR2or N;
provided that one or more of the variables B, G, D, and E represents N;
R2independently selected from
N
F,
Cl,
CH3,
Och3or
CF3;
R3represents a
N
Cl,
F or
CH3;
R4represents Cl or F;
R5represents a
,
morpholine, possibly substituted by 1-3 identical or different substituents R14or
NR12R13;
R11independently selected from
halogen,
HE
With1-6-alkyl, possibly substituted by 1-3 substituents which are halogen,
With2-6-quinil,
-OC(O)1-6-alkyl,
-C0-6-alkyl-C3-6-cycloalkyl,
-NH2,
-NH(C1-6-alkyl) and
-N(C1-6-alkyl)2;
Rather it represents a 3-7-membered saturated ring;
R12and R13independently of one another selected from
With1-6-alkyl, possibly substituted IT,
With2-6-alkylen-O-C1-6-alkyl;
R14represents a
With1-6-alkyl;
l is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
o is 0, 1 or 2;
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 , 2, 3, or 4, and
s is 1 or 2.

3. The compound according to claim 1 or 2 of the formula (I')

in which B, G, D, E, R1, R3, R4and R5defined according to claim 1 or 2.

4. The compound according to claim 1 or 2, in which
R2selected from H, F, Cl and CH3.

5. The compound according to claim 1 or 2, in which
l is 2 or 3, or
m is 2 or 3.

6. The compound according to claim 1 or 2 for the treatment or prevention of disorders, diseases or conditions responsible for inaktivirovanie or activating receptor melanocortin-4 in mammals.

7. The connection according to claim 6 for the treatment or prevention of cancer cachexia, muscular dystrophy, anorexia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), anxiety and/or depression.

8. The connection according to claim 6 for the treatment or prevention of obesity, diabetes, sexual dysfunction in men and women and/or erectile dysfunction.

9. The use of compounds according to any one of claims 1 to 5 to obtain drugs for treatment or prevention of disorders, diseases or conditions responsible for inaktivirovanie or activating receptor melanocortin-4 in mammals.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier for the treatment or prevention of disorders, diseases or conditions responsible what's for inaktivirovanie or activating receptor melanocortin-4 in mammals.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 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: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 or pharmaceutically acceptable derivatives thereof, where values of radicals X, W, R4, Ar1, Ar2, R3, R4, R20 are as described in paragraph 1 of the claim. The invention also describes a composition for treating or preventing pain, UI, ulcers, inflammatory bowel disease or irritable bowel syndrome.

EFFECT: compound which can be used in medicine is obtained and described.

46 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2-piperidino-5-(thienyl-2)-6H-1,3,4-thiadiazines, hydrobromides (of general formula I) and 2-piperidino-5-(thienyl-3)-6H-1,3,4-thiadiazines, hydrobromides (of general formula II) which possess antiaggregant action. wherein R=H; Cl; Br R1=H; Cl.

EFFECT: given compounds may be used for preparing cardiologic drugs and enable better treatment of various cardiovascular diseases, including myocardial infarction and thrombotic apoplexy.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel purified compound PM 181104 of formula I

(with molecular weight 1514 and molecular formula C69H66N18O13S5), pharmaceutically acceptable salts thereof, methods for synthesis via fermentation of a microorganism of the type Kocuria (ZMA B-1 / MTCC 5269), as well as pharmaceutical compositions.

EFFECT: high efficiency of using the composition to produce a medicinal agent for treating bacterial infections.

20 cl, 4 dwg, 4 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or tautomer thereof

or enantiomer or physiologically acceptable salt, where R1 is o-bromo, R2 is n-fluoro, R3 is C1-C4 alkyl, R6 is thiazolyl-2-yl, X is methylene and Z is morpholinyl. The invention also relates to methods of producing (versions) compounds of formula (I) and (Ia). The compound of formula (I) or (Ia) is used to prepare a pharmaceutical composition for treating or preventing HBV infections and HBV-induced diseases such as hepatitis B.

EFFECT: bromophenyl substituted thiazolyl dihydropyrimidines for HBV infection control.

20 cl, 7 tbl, 14 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 refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 or pharmaceutically acceptable derivatives thereof, where values of radicals X, W, R4, Ar1, Ar2, R3, R4, R20 are as described in paragraph 1 of the claim. The invention also describes a composition for treating or preventing pain, UI, ulcers, inflammatory bowel disease or irritable bowel syndrome.

EFFECT: compound which can be used in medicine is obtained and described.

46 cl, 10 ex, 1 tbl

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