Benzothiazole cyclobutyl amine derivatives as ligands of histamine h3-receptors, pharmaceutical composition based thereon, method for selective modulation of effects of histamine h3-receptors and method of treating condition or disorder modulated by histamine h3-receptors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

 

The text descriptions are given in facsimile form.

1. The compounds of formula

their stereoisomers or their TRANS - and CIS - isomers, or its racemate, or pharmaceutically acceptable salts, where
m means 0;
one of R1and R2selected from the group comprising hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl or a group of the formula-L2-R6the other of R1and R2selected from the group comprising hydrogen, halogen;
each of R3aand R3bindependently from each other selected from the group comprising hydrogen;
each of R4and R5independently from each other selected from the group comprising C1-10alkyl and C1-10hydroxyalkyl; or R4and R5taken together with the nitrogen atom to which each is attached, form a non-aromatic cycle of the form (a) or (b)


where Q1represents O or S;
Q2represents-N(R20)-;
R20selected from the group comprising hydrogen and C1-10alkoxycarbonyl;
each of P1 and P2 independently from each other represent 1, 2 or 3;
each of q1, q2, q3, q4 and q5 independently of one another denotes 0, 1 or 2; and
each carbon atom in the cycle substituted with hydrogen or 0, 1 or 2 substituents, independently of one another are selected in each case from the group comprising hydrogen, a hydroxy-group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10foralkyl;
R6represents phenyl, heterocycle or heterocyclic1-4alkyl, heterocycle represents a 4 - to 6-membered aromatic or nonaromatic ring containing 1 or 2 heteroatoms independently selected from N, O and S, possibly condensed is passed with the benzene ring, however phenyl or heterocycle can be unsubstituted or possibly substituted by one or more substituents independently selected from the group comprising From1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-;
L is a bond or C1-4alkylen;
L2is a relationship With1-4alkylene, -C(=O)-, -SO2N(R14a)-, - N(R14a)SO2-, -C(O)N(R14a)-, -N(R14a)C(O) -, or-N(R15)-;
R10selected from the group comprising hydrogen;
R14aselected from the group comprising hydrogen;
R15selected from the group comprising hydrogen; and
RAand RBindependently from each other selected from the group comprising hydrogen, C1-10alkyl, C1-4acyl, C1-4halogenated, C1-10alkoxycarbonyl,3-8cycloalkyl and C3-8cycloalkylcarbonyl.

2. Compounds according to claim 1, in which R1represents-L2-R6where L2means a bond, and R6such as defined according to claim 1.

3. Compounds according to claim 2, in which R6represents a heterocycle.

4. Compounds according to claim 3 in which R6selected from the group comprising furyl, imidazolyl, isoxazolyl, isothiazolin, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, pyridazinyl, pyridinyl, pyrimidinyl, indolyl, benzothiazyl, benzofuranyl, indasa the sludge, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiazolyl, benzisoxazole, chinoline, ethenolysis, hintline, honokalani, phthalazine, azetidine, morpholine, piperazinil, piperidinyl, pyrrolidinyl, pyrrolyl, dihydrothiazolo, dihydropyridines, thiomorpholine, dioxane, dithienyl, tetrahydrofuryl, dihydropyran, tetrahydropyranyl and [1,3]DIOXOLANYL.

5. Compounds according to claim 4, in which R6selected from the group comprising pyrazolyl, pyrimidinyl, pyrimidinyl, pyridinyl, pyridazinyl and binodini, and each cycle is optionally substituted by 1 or 2 substituents selected from metoxygroup and bromide.

6. Compounds according to claim 1, in which R4and R5together with the nitrogen atom to which each is attached, form azepane, azetidine, atacanli, morpholinyl, piperazinil, piperidinyl, pyrrolidinyl or hexahydrofuro[3,4-b]pyrrolyl, with each group is substituted by 0, 1 or 2 substituents selected from alkyl, hydroxyalkyl and fluorine.

7. Compounds according to claim 1, in which m is 0, L is a bond and R6represents a heterocycle.

8. Compounds according to claim 1, covered by the General structural formula (II)

where R1, R2, R3a, R3b, R4and R5such as defined according to claim 1.

9. Compounds according to claim 1, covered by the General strukturformel (III)

where R1, R2, R3a, R3b, R4and R5such as defined according to claim 1.

10. Compounds according to claim 1, in which one of R1and R2is a L2R6, L2is a bond and R6represents a structure of the formula

where each of R16and R17independently from each other selected from the group comprising hydrogen; v is 1, 2 or 3.

11. Compounds according to claim 1, selected from the group consisting of:
TRANS-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-6-(2,4-dimethoxypyrimidine-5-yl)-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-6-(2-methoxypyridine-5-yl)-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-6-pyridin-4-yl-1,3-benzothiazole;
TRANS-6-(6-methoxypyridine-3-yl)-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-6-pyridin-3-yl-1,3-benzothiazole;
TRANS-3-(2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline;
TRANS-6-(6-herperidin-3-yl)-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-4-(2-{3-[(2R)-2-methylpyrrolidine-1-yl]cycle is butyl}-1,3-benzothiazol-6-yl)benzonitrile;
TRANS-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-6-(2,4-dimethoxypyrimidine-5-yl)-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-6-(2-methoxypyridine-5-yl)-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-6-(6-methoxypyridine-3-yl)-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-3-(2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline;
CIS-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
CIS-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-6-(2,4-dimethoxypyrimidine-5-yl)-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
CIS-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-2-(2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-she;
TRANS-6-methyl-2-(2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-she;
TRANS-5-methyl-1-(2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridine-2(1H)-she;
TRANS-3-methyl-1-(2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridine-2(1H)-she;
the Rance-2-(2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-it;
TRANS-6-methyl-2-(2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-she;
TRANS-5-methyl-1-(2-{3-[(28)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridine-2(1H)-she;
TRANS-3-methyl-1-(2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridine-2(1H)-she;
CIS-6-pyrimidine-5-yl-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
CIS-6-(2-methoxypyridine-5-yl)-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
CIS-2-(3-piperidine-1-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-6-(2-methoxypyridine-5-yl)-2-(3-piperidine-1-enciclopedie)-1,3-benzothiazole;
CIS-2-(3-azepin-1-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-2-(3-morpholine-4-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-{(2S)-1-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutylmethyl-2-yl}methanol;
CIS-((2S)-1-{3-[6-(2-methoxypyridine-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol;
CIS-2-{3-[(3aR,6aR)-hexahydrofuro[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-2-{3-[(3aR,6aR)-hexahydrofuro[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-(2-methoxypyridine-5-yl)-1,3-benzothiazole;
CIS-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
CIS-N-isopropyl-N-methyl-N-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl] amine;
CIS-{1-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]-piperidine-4-yl}methanol;br/> TRANS-{1-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]-piperidine-4-yl}methanol;
TRANS-2-(3-piperidine-1-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-6-(2,6-dimethylpyridin-3-yl)-2-(3-piperidine-1-enciclopedie)-1,3-benzothiazole;
TRANS-6-(6-methoxypyridine-3-yl)-2-(3-piperidine-1-enciclopedie)-1,3-benzothiazole;
TRANS-6-(2-methoxypyridine-5-yl)-2-(3-piperidine-1-enciclopedie)-1,3-benzothiazole;
TRANS-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-she;
CIS-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-she;
TRANS-6-methyl-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-she;
TRANS-3-methyl-1-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridine-2(1H)-she;
TRANS-6-(1-methyl-1H-pyrazole-4-yl)-2-(3-piperidine-1-enciclopedie)-1,3-benzothiazole;
TRANS-N-isopropyl-N-methyl-N-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;
TRANS-N-isopropyl-N-{3-[6-(2-methoxypyridine-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;
TRANS-N-isopropyl-N-{3-[6-(6-methoxypyridine-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;
TRANS-N-isopropyl-N-{3-[6-(2-methoxypyridine-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;
TRANS-N-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-isopropyl-N-methylamine;
TRANS-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-she;
TRANS--(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-6-methylpyridazin-3(2H)-it;
TRANS-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-3-methylpyridin-2(1H)-she;
TRANS-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-5-methylpyridin-2(1H)-she;
TRANS-2-(3-azetidin-1-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-6-pyrimidine-5-yl-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
TRANS-6-(2,6-dimethylpyridin-3-yl)-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
TRANS-6-(2-methoxypyridine-5-yl)-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
TRANS-6-(2,4-dimethoxypyrimidine-5-yl)-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
TRANS-6-(6-methoxypyridine-3-yl)-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
TRANS-2-[2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-she;
TRANS-6-methyl-2-[2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-she;
TRANS-5-methyl-1-[2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridine-2(1H)-she;
TRANS-3-methyl-1-[2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridine-2(1H)-she;
TRANS-2-(3-azepin-1-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-2-(3-morpholine-4-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-2-{3-[(2S)-2-(permitil)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-{(2S)-1-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]-pyrrolidin-2-yl}methanol;
TRANS-((2S)-1-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-b is societal-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol;
TRANS-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-2-(3-hexahydrofuro[3,4-b]pyrrol-5(1H)-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-2-[3-(4-foreperiod-1-yl)cyclobutyl]-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-2-[3-(4-foreperiod-1-yl)cyclobutyl]-6-(2-methoxypyridine-5-yl)-1,3-benzothiazole;
TRANS-6-(2,6-dimethylpyridin-3-yl)-2-[3-(4-foreperiod-1-yl)cyclobutyl]-1,3-benzothiazole;
TRANS-(3R)-1-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidine-3-ol;
TRANS-N-ethyl-N-propyl-N-[3-(6-pyrimidine-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;
TRANS-diethyl-[3-(6-pyrimidine-5-yl-benzothiazol-2-yl)-cyclobutyl]-amine;
TRANS-diethyl-{3-[6-(2-methoxy-pyrimidine-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine;
TRANS-{3-[6-(2-methoxy-pyrimidine-5-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine;
TRANS-{3-[6-(2,6-dimethyl-pyridine-3-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine;
TRANS-methyl-{3-[6-(1-methyl-1H-pyrazole-4-yl)-benzothiazol-2-yl]-cyclobutyl}-propyl-amine;
TRANS-2-(ethyl-{3-[6-(2-methoxy-pyrimidine-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol;
TRANS-2-({3-[6-(2,6-dimethyl-pyridine-3-yl)-benzothiazol-2-yl]-cyclobutyl}-ethyl-amino)-ethanol;
6-pyrimidine-5-yl-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole;
TRANS-5-(2,6-dimethyl-pyridine-3-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;
TRANS-5-(2,4-dime the hydroxy-pyrimidine-5-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;
TRANS-6-(1-methyl-1H-pyrazole-4-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;
TRANS-2-[3-(4-fluoro-piperidine-1-yl)-cyclobutyl]-6-(1-methyl-1H-pyrazole-4-yl)-benzothiazole;
TRANS-2-(3-azetidin-1-enciclopedie)-6-(2-methoxypyridine-5-yl)-1,3-benzothiazole;
TRANS-2-(3-azetidin-1-enciclopedie)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole;
TRANS-2-(3-azetidin-1-enciclopedie)-6-(1-methyl-1H-pyrazole-4-yl)-1,3-benzothiazole;
TRANS-2-(3-azepin-1-enciclopedie)-6-(2-methoxypyridine-5-yl)-1,3-benzothiazole;
TRANS-2-(3-azepin-1-enciclopedie)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole;
TRANS-2-(3-azepin-1-enciclopedie)-6-(1-methyl-1H-pyrazole-4-yl)-1,3-benzothiazole;
CIS-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-ndimethylacetamide;
CIS-2-chloro-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-ndimethylacetamide;
CIS-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-propionamide;
CIS-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-isobutyramide;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclopropanecarbonyl acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclobutanecarbonyl acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclopentanecarbonyl acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclohexanecarbonyl acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-AMI is furan-2-carboxylic acid;
CIS-4-cyano-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-benzamide;
CIS-4-cyano-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-benzosulfimide;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide thiophene-2-sulfonic acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide thiophene-2-carboxylic acid;
complex isobutyl ether of CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-carbamino acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide morpholine-4-carboxylic acid;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide pyrazin-2-carboxylic acid;
CIS-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-2-thiophene-3-yl-ndimethylacetamide;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-3-thiophene-2-yl-propionamide;
CIS-3-furan-2-yl-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-propionamide;
CIS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide pyrimidine-5-carboxylic acid;
TRANS-4-cyano-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-benzamide;
TRANS-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-propionamide;
TRANS-N-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-isobutyramide;
complex isobutyl ether TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-carbamino acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazole-6-the l]-amide cyclopropanecarbonyl acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclobutanecarbonyl acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclopentanecarbonyl acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide cyclohexanecarbonyl acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide, furan-2-carboxylic acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide morpholine-4-carboxylic acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide pyrimidine-5-carboxylic acid;
TRANS-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amide pyrazin-2-carboxylic acid;
racemic [2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrimidine-5-yl-amine;
racemic [2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrimidine-2-yl-amine;
racemic (5-bromo-pyrimidine-2-yl)-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amine;
racemic (5-methyl-pyridine-2-yl)-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazol-6-yl]-amine;
racemic 6-[2-(3-piperidine-1-yl-cyclobutyl)-benzothiazole-6-ylamino]-nicotinanilide;
2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-azetidin-2-it;
2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-pyrrolidin-2-it;
2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-Pieper is DIN-2-it;
2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-homopyrimidine-2-it;
2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;
N-isopropyl-2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;
N-cyclopropyl-2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;
N-phenyl-2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;
N-thiazol-2-yl-2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;
N-(2-ethylphenyl)-2-((1S,3r)-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl)-benzo[d]thiazole-6-carboxamide;
N-dimethyl-2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;
(pyrrolidin-1-yl)-2-{TRANS-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-methanone;
2-[TRANS-3-(piperidine-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methyl-pyrrolidin-2-it;
2-[TRANS-3-(piperidine-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-oxazolidin-2-it;
2-[TRANS-3-(piperidine-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methylimidazolidine-2-it;
TRANS-6-bromo-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-6-bromo-2-{3-[(2S)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
CIS-6-bromo-2-{3-[(2R)-2-methylpyrrolidine-1-yl]cyclobutyl}-1,3-benzothiazole;
CIS-6-bromo-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
CIS-6-bromo-2-(3-piperid the n-1-enciclopedie)-1,3-benzothiazole;
CIS-2-(3-azepin-1-enciclopedie)-6-bromo-1,3-benzothiazole;
CIS-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;
CIS-tert-butyl(3aR,6aR)-5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-hexahydrofuro[3,4-b]pyrrol-1(2H)-carboxylate;
CIS-6-bromo-2-{S-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole;
CIS-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine;
CIS-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidine-4-yl}methanol;
TRANS-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidine-4-yl}methanol;
TRANS-6-bromo-2-(3-piperidine-1-enciclopedie)-1,3-benzothiazole;
TRANS-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine;
TRANS-2-(3-azetidin-1-enciclopedie)-6-bromo-1,3-benzothiazole;
TRANS-6-bromo-2-(3-pyrrolidin-1-enciclopedie)-1,3-benzothiazole;
TRANS-2-(3-azepin-1-enciclopedie)-6-bromo-1,3-benzothiazole;
TRANS-6-bromo-2-(3-morpholine-4-enciclopedie)-1,3-benzothiazole;
TRANS-6-bromo-2-{3-[(2S)-2-(permitil)pyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;
TRANS-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;
TRANS-6-bromo-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;
TRANS-tert-butyl 5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydrofuro[3,4-b]pyrrol-1(2H)-carboxylate;
TRANS-6-bromo-2-[3-(4-foreperiod-1-yl)cyclobutyl]-1,3-benzothiazole;
TRANS-[3-(6-bromo-benzothiazol-2-the l-cyclobutyl]-diethyl-amine;
TRANS-[3-(6-bromo-benzothiazol-2-yl)-cyclobutyl]-methyl-propyl-amine;
TRANS-2-{[3-(6-bromo-benzothiazol-2-yl)-cyclobutyl]-ethyl-amino}-ethanol;
6-bromo-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole and
TRANS-5-chloro-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole.

12. Compounds according to claim 1, selected from the group consisting of:
TRANS-2-(3-piperidine-1-enciclopedie)-6-pyrimidine-5-yl-1,3-benzothiazole;
TRANS-diethyl-{3-[6-(2-methoxy-pyrimidine-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine;
TRANS-2-(ethyl-{3-[6-(2-methoxy-pyrimidine-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol;
TRANS-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-she; and
CIS-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-it.

13. Pharmaceutical composition for the selective modulation of the histamine H3receptors, comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

14. Process for the selective modulation of the effects of histamine H3receptors, including the introduction of an effective amount of a compound according to claim 1.

15. The use of compounds according to claim 1 in the manufacture of medicaments for the treatment of conditions or disorders modulated histamine H3-receptors.

16. The application indicated in paragraph 15, in which the condition or disorder selected from the group comprising the stry myocardial infarction, Alzheimer's disease, asthma, violation type, attention deficit with hyperactivity disorder, bipolar disorder, cognitive dysfunction, cognitive deficits in psychiatric disorders, deficits of memory, deficits of learning ability, dementia, cutaneous carcinoma, drug dependency, diabetes, diabetes type II, depression, epilepsy, gastrointestinal disorders, inflammation, syndrome of resistance to insulin, cuddling, medullary carcinoma of the thyroid, melanoma, Meniere's disease, metabolic syndrome, mild cognitive disturbance, migraine, mood changes and attention, motion sickness, narcolepsy, neurogenic inflammation, obesity, obsessive-compulsive disorder, pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, cognitive deficits in schizophrenia, seizures, septic shock, syndrome X, Tourette syndrome, dizziness and sleep disturbance.

17. The compound TRANS-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one or its pharmaceutically acceptable salt.

18. The compound CIS-2-[2-(3-piperidine-1-enciclopedie)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) a pharmaceutically acceptable salt thereof wherein each dash line (represented as ---) represents a double bond; X represents N or CH; R1a and R1b independently represent hydrogen or C1-6-jalkyl; L represents -O-; R2 represents hydrogen; R3 represents hydrogen or C1-6-alkyl; R4 represents quinolinyl substituted by one, two or three substitutes specified in C1-6-alkyl, C1-6-alkyloxy, thiazolyl or pyrazolyl, wherein said thiazolyl or pyrazolyl are substituted on any carbon atom by C1-6-alkyl; n is equal to 3, 4, 5 or 6; p is equal to 1 or 2. The invention refers to a pharmaceutical composition possessing the properties of KS3/4a-protease HCV inhibitors, containing a carrier, and an virally effective amount of the compound of formula (I) as an active ingredient. The method for preparing the compound of formula (I), wherein the above method involves forming an amide bond of an intermediate product (2a) and sulphonylamide (2b), as presented by the diagram, wherein G represents a group Also, the invention refers to alternative methods for preparing the compound of formula (I).

EFFECT: there are presented macrocyclic compounds possessing inhibitory activity on hepatitis C virus (HCV) replication.

13 cl, 1 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention provides new imidazo[1,2-b]pyridazine compounds covered by general structural formula (I) wherein the radicals and symbols have the values presented in the patent claim, and pharmaceutically acceptable salts thereof. The compounds of structural formula (I) are effective both for treating or preventing the diseases related to GABA receptor inhibition, anxiety, epilepsy, sleep disorders, including insomnia, and for inducing a sedative-hypnotic, anaesthetic effect, sleep and muscle relaxation.

EFFECT: there are presented methods for preparing the above compounds, and also intermediate compounds for preparing them.

21 cl, 4 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to octahydro-pyrrolo[3,4-b]pyrrol N-oxides or pharmaceutically acceptable salts thereof of general formula (I) wherein Z1 represents N or CH. Octahydro-pyrrolo[3,4-b]pyrrol N-oxides of formula (I) are prodrugs of histamine-3 antagonists, and effective in treating conditions and disorders that can be prevented or relieved by H3-histamine receptor ligands. The present paper discloses N-oxide derivatives of octahydro-pyrrolo[3,4-b]pyrrol, the use of these compounds, compositions thereof and methods of treating a mammal having a condition or disorder wherein the H3-histamine receptor modulation has a therapeutic effect.

EFFECT: new compounds are presented.

11 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are new triazolopyrimidine derivatives of general formula (I): wherein R1 means hydrogen or alkyl; R2 means hydrogen; R3 means optionally substituted C3-8cycloalkyl, optionally substituted bridged monocyclic C6-cycloalkyl, optionally substituted phenyl, optionally substituted 6-member heterocyclyl containing one or two heteroatoms specified in O and N, etc., a pharmaceutical composition containing them, and using the compounds and composition for inhibiting the enzyme type 1 diacylglycerol-O-acyltransferase (DGAT) for treating type 2 diabetes mellitus, obesity, high plasma triglycerides, metabolic syndrome, etc.

EFFECT: there are presented new triazolopyrimidine derivatives.

11 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to tetrahydroimidazo[1,5-a]pyrazine derivatives of formula I or to their pharmaceutically acceptable salts (I), wherein: Ar represents phenyl, wherein phenyl is additionally substituted by 1-3 substitutes independently specified in halogen; R1 represents trifluoromethyl; R2 is specified in a group consisting of hydrohyl, alkyl having 1 to 4 carbon atoms, alkoxyl having having 1 to 4 carbon atoms, cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely, and -NR4R5, wherein each alkoxyl is optionally substituted by one group specified in a group consisting of phenyl and -OC(O)OR8; R3 is specified in a group consisting of a hydrogen atom and alkyl having 1 to 4 carbon atoms; each of R4 and R5 is independently specified is a group consisting of a hydrogen atom, alkyl having 1 to 4 carbon atoms, cycloalkyl representing a 3-8-member monocyclic ring group consisting of carbon completely, phenyl and pyridinyl, wherein each alkyl or phenyl is optionally substituted by one or more group specified in a group consisting of halogen, a cyano group, -SO2R7, -NR4R5 and -C(=O)OCH3; or R4 and R5 together with an atom, whereto attached form a 5-6-member heterocycle wherein the 5-6-member heterocycle optionally contains one or more N, O or S atom, and each 5-6-member heterocycle is optionally substituted by one or more groups consisting of halogen, hydroxyl, an amino group, alkyl having 1 to 4 carbon atoms, hydroxyalkyl 1 to 4 carbon atoms, -SO2R7, -C(O)NR4R5, -C(O)R7, =O; R7 represents alkyl 1 to 4 carbon atoms; and R8 is specified in a group consisting of alkyl 1 to 4 carbon atoms, and cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely. The invention also refers to methods for preparing them, a pharmaceutical composition having dipeptidyl peptidase IV inhibitory activity and containing said derivatives.

EFFECT: there are produced new compounds and composition on their basis which can find application in medicine for treating type 2 diabetes mellitus or hyperglycemia.

17 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel azoindolizines or pharmaceutically acceptable salts thereof having Mek-kinase inhibitory activity in formula : ZA means CRA; RA means H or halogen; each of R1, R2 and R3 means H; W means: , each R4 and R5 means H; X1 represents -OR7; each R7 means C2-C12-hydroxyalkyl, 2,3-dihydroxypropyl, C2-C3-alkenoxyC1-C6-alkoxy, (2,2-dimethyl-[1,3]dioxalan-4-yl)-methyl or piperidinyl; X4 means: R6 means halogen or -SR16; R6 means halogen; p is equal to 1; R16 means C1-C12-alkyl.

EFFECT: invention relates to a pharmaceutical compositions containing these compounds, to a method of inhibiting the abnormal cell growth and the use of the compounds for preparing a drug preparation for inhibiting the abnormal cell growth.

9 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new tetracyclic compounds of general formula (I), wherein is a single or double bond; no bonds or a single bond; or V means N; T and X as shown in structure fragments above; U and W independently mean C or N with one of them shall be N; R3, R4, R5 and R6 - H; Rv is absent; Ru and Rw are independently absent or mean (C1-12)alkyl; Y =N-OR1 or NP'1, wherein R1 - H, (C1-12)alkyl optionally substituted by phenyl, phenyloxy, carboxy, (C1-12)alkoxy, (C1-12)alkoxycarbonyl, or (C2-12)alkenyl; R'1 is phenyl, or pharmaceutically acceptable salts thereof, or diastereomers thereof, or regioisomers thereof, or: mixtures thereof, a pharmaceutical composition containing them, and specific compounds for cysteine protease inhibition.

EFFECT: compounds may be used in medicine in treating cancer, neurodegenerative diseases, inflammatory disorders, cardiovascular diseases, etc.

8 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new pyrimidine substituted macrocyclic compounds of genral formula (I) , wherein A= -C(=O)OR1 or -C(=O)-NH-SO2-R2; R1 = H or C1-6alkyl; R2 = phenyl, thienyl, C3-7cycloalkyl optionally substituted by C1-6alkyl; X = N or CH; E = NR5; R5 = H or C1-6alkyl; n = 4 or 5; R7=H, C1-6alkyl, C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy; R8 =C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy, morpholino or -NRaRb, wherein Ra and Rb independently mean H or C1-6alkyl; R9 = Rq = H; or their pharmaceutically acceptable addition salts, or stereoisomers, and pharmaceutical compositions containing them.

EFFECT: compounds are inhibitors of HCV NS3 serine protease and can find application in treating chronic hepatic disorders, particularly chronic hepatitis.

10 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

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