Condensed heterocylic kinase modulators

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula:

where L1and L2independently mean a relationship,
R1denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl means an aromatic hydrocarbon Deputy representing one ring or two condensed rings, and heteroaryl contains cyclizes the th system from 1 to 4 heteroatoms, selected from N, S and O, and the substituents selected from the following groups: halogen, -R', -OR', -C(O)R', -C(O)NR'r R", where R' and R" independently are selected from the group including hydrogen, unsubstituted alkyl and alkyl substituted by halogen atoms,
R2denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl and heteroaryl defined above and the substituents selected from the following groups: -R', -OR', -NR'r R", halogen, -C(O)R', -COOH, -C(O)NR'r R", -SO2R', the number of substituents is from zero up to the number equal to the number of free valences in the aromatic system, where R', R" independently are selected from the group containing:
hydrogen,
the unsubstituted heteroalkyl where heteroalkyl contains in the chain 1 or 2 heteroatoms in the chain, independently selected from N and O;
With3-C7cycloalkyl;
substituted or unsubstituted alkyl, where the substituents selected from =NH or a 3-7-membered geterotsiklicheskie, which, in turn, can be substituted by alkyl or heteroalkyl where heteroseksualci contains in the ring 1 to 4 atoms selected from N and O;
substituted or unsubstituted 3-7-membered heteroseksualci, where the substituents are selected from alkyl, heteroalkyl and heteroaryl, where the alkyl and heteroalkyl can be, in turn, is substituted by an oxo group, a 3-7-membered heterocyclization, heteroalkyl or heteroaryl,
provided that R1does not mean Sames the config or unsubstituted pyrrolyl and L 1does not mean unsubstituted 2-5-membered heteroalkyl, if R1and R2both means unsubstituted phenyl, and L1not means-S(O)2-if R2means unsubstituted piperazinil, and that R1does not mean substituted or unsubstituted isoxazolyl, if R2means unsubstituted pyridinyl.

2. The compound according to claim 1, where R1means substituted or unsubstituted 5 - or 6-membered heteroaryl or substituted or unsubstituted aryl.

3. The compound according to claim 1, where R1means substituted or unsubstituted 6-membered heteroaryl or substituted or unsubstituted aryl.

4. The compound according to claim 1, where R1means (3) an unsubstituted heteroaryl, (4) unsubstituted aryl, (7) substituted aryl or (8) substituted heteroaryl where groups (7) and (8) contain as substituents-OH, -CF3the halogen.

5. The compound according to claim 4, where R1means substituted or unsubstituted 6-membered heteroaryl or substituted or unsubstituted aryl.

6. The compound according to claim 5, where R1mean group (7) or (8), and group (7) or (8) contain as substituents-OH, -CF3, halogen or unsubstituted C1-C10alkyl.

7. The compound according to claim 5, where R1mean group (7) or (8), and group (7) and (8) contain as a substituent group,- och3, -F3, -CH3, -CF3, -Och2CH3 or halogen.

8. The compound according to claim 1 or 7, where R2means: (3) the unsubstituted heteroaryl, (4) unsubstituted aryl, (7) substituted aryl or (8) substituted heteroaryl, and groups (7) and (8) contain as substituents-OH, -CF3, -COOH, halogen.

9. The connection of claim 8, where R2means (7) or (8).

10. The connection according to claim 9, where (7) or (8) contain as a substituent group,- C(O)R', -OR', -NR'r R", or-S(O)2R'.

11. The connection of claim 8, where R2mean group (7) or (8), and group (7) and (8) contain as substituents of the group-OH, -CF3, -COOH, amino, halogen, unsubstituted 2 to 10-membered heteroalkyl, unsubstituted With3-C7cycloalkyl, unsubstituted 3-7-membered heteroseksualci or-C(O)R'.

12. Connection to item 11, where R2mean group (7) or (8), where the group (7) and (8) contain as substituents, unsubstituted 2 to 10-membered heteroalkyl or-C(O)R'.

13. The compound according to claim 1, where R1or R2independently denote a substituted or unsubstituted condensed aryl or substituted or unsubstituted heteroaryl.

14. The connection of claim 8, where R1and R2independently denote a substituted or unsubstituted pyrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted, imidazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted oxaz is poured, substituted or unsubstituted pyridyl, substituted or unsubstituted Persil, substituted or unsubstituted, pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazole, substituted or unsubstituted triazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted triazinyl, substituted or unsubstituted thiadiazolyl or substituted or unsubstituted tetrazolyl.

15. The compound of the formula

where L1means linking and L2means bond or-NH-,
R1denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl means an aromatic hydrocarbon Deputy representing one ring or two condensed rings, and heteroaryl contains cyclical from 1 to 4 heteroatoms selected from N, S and O, and the substituents selected from the following groups: halogen, -R', -OR', -C(O)R', -C(O)NR'r R", where R' and R" independently are selected from the group including hydrogen, unsubstituted alkyl and alkyl, substituted by halogen atoms,
R2denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl and heteroaryl defined above and the substituents selected from the following groups: -R', -OR', -NR'r R", halogen, -C(O)R', -COOH, -C(O)NR'r R", -SO2R', the number zamestitelglavy from zero to the number, equal to the number of free valences in the aromatic system, where R', R" independently are selected from the group containing:
hydrogen,
the unsubstituted heteroalkyl where heteroalkyl contains in the chain 1 or 2 heteroatoms in the chain, independently selected from N and O;
With3-C7cycloalkyl;
substituted or unsubstituted alkyl, where the substituents selected from =NH or a 3-7-membered geterotsiklicheskie, which, in turn, can be substituted by alkyl or heteroalkyl where heteroseksualci contains in the ring 1 to 4 atoms selected from N and O;
substituted or unsubstituted 3-7-membered heteroseksualci, where the substituents are selected from alkyl, heteroalkyl and heteroaryl, where the alkyl and heteroalkyl can be, in turn, is substituted by an oxo group, a 3-7-membered heterocyclization, heteroalkyl or heteroaryl.

16. Method of modulating activity of a protein kinase comprising contacting the said protein kinase with a compound according to claim 1 or 15.

17. The use of compounds according to claim 1 or 15 in the manufacture of the medicinal product with the activity of inhibitors of protein kinases, for the treatment of diseases, including cancer, allergies, asthma, inflammation, obstructive airway disease, autoimmune diseases, metabolic disorders, infections, diseases of the Central nervous system, brain tumor, obesity, hematological diseases, the money is erative neuralgic diseases cardiovascular diseases and diseases associated with angiogenesis, revascularization and development of blood vessels.

18. The method of modulation of the activity of a protein kinase comprising contacting the said protein kinase with the compound of the formula

where L1and L2mean relationship,
R1denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl means an aromatic hydrocarbon Deputy representing one ring or two condensed rings, and heteroaryl contains cyclical from 1 to 4 heteroatoms selected from N, S and O, and the substituents selected from the following groups: halogen, -R', -OR', -C(O)R', -C(O)NR'r R", where R' and R" independently are selected from the group including hydrogen, unsubstituted alkyl and alkyl, substituted by halogen atoms,
R2denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl and heteroaryl defined above and the substituents selected from the following groups: -R', -OR', -NR'r R", halogen, -C(O)R', -COOH, -C(O)NR'r R", -SO2R', the number of substituents is from zero up to the number equal to the number of free valences in the aromatic system, where R', R" independently are selected from the group containing:
hydrogen,
the unsubstituted heteroalkyl where heteroalkyl contains in the chain 1 or 2 heteroatoms in the chain, independent is isimo selected from N and O;
With3-C7cycloalkyl;
substituted or unsubstituted alkyl, where the substituents selected from =NH or a 3-7-membered geterotsiklicheskie, which, in turn, can be substituted by alkyl or heteroalkyl where heteroseksualci contains in the ring 1 to 4 atoms selected from N and O;
substituted or unsubstituted 3-7-membered heteroseksualci, where the substituents are selected from alkyl, heteroalkyl and heteroaryl, where the alkyl and heteroalkyl can be, in turn, is substituted by an oxo group, a 3-7-membered heterocyclization, heteroalkyl or heteroaryl.

19. The method according to p, where the specified protein kinase is tyrosinekinase of Abelson, receptor tyrosinekinase Ron, receptor tyrosinekinase Met, Fms-like tyrosinekinase-3, Aurora kinase, p21-activated kinase-4 or 3-postinst-dependent kinase-1.

20. The method according to p, where the specified protein kinase is a kinase SIV-b1 comprising mutations selected from the group comprising M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, EC, E255V, D276G, F311L, T315I, T315N, TA, F317V, F317L, MT, MT, E355G, F359A, F359V, V379I, F382L, L387M, NR, H396R, S417Y, EC and F486S.

21. The method according to claim 20, where the specified protein kinase is a mutant T315I.

22. The use of compounds according to claim 1 or 15 in the manufacture of the medicinal product with the activity of inhibitors of protein kinases, for the treatment of diseases, including cancer, allergies, asthma, vospolenie is, obstructive airway disease, autoimmune diseases, metabolic disorders, infections, diseases of the Central nervous system, brain tumor, obesity, hematological diseases, degenerative neurological diseases, cardiovascular diseases and diseases associated with angiogenesis, revascularization and development of blood vessels.

23. The method according to item 22, where the specified cancer selected from leukemia or myeloproliferative disorders.

24. Pharmaceutical composition for inhibiting protein kinases, including pharmaceutically acceptable excipient and the connection according to claim 1 or 15, or a compound of the formula

where L1and L2mean relationship,
R1denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl means an aromatic hydrocarbon Deputy representing one ring or two condensed rings, and heteroaryl contains cyclical from 1 to 4 heteroatoms selected from N, S and O, and the substituents selected from the following groups: halogen, -R', -OR', -C(O)R', -C(O)NR'r R", where R' and R" independently are selected from the group including hydrogen, unsubstituted alkyl and alkyl, substituted by halogen atoms,
R2denotes a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl, where aryl and heteroaryl definition is trading higher as the substituents selected from the following groups: -R', -OR', -NR'r R", halogen, -C(O)R', -COOH, -C(O)NR'r R", -SO2R', the number of substituents is from zero up to the number equal to the number of free valences in the aromatic system, where R', R" independently are selected from the group containing:
hydrogen,
the unsubstituted heteroalkyl where heteroalkyl contains in the chain 1 or 2 heteroatoms in the chain, independently selected from N and O;
With3-C7cycloalkyl;
substituted or unsubstituted alkyl, where the substituents selected from =NH or a 3-7-membered geterotsiklicheskie, which, in turn, can be substituted by alkyl or heteroalkyl where heteroseksualci contains in the ring 1 to 4 atoms selected from N and O;
substituted or unsubstituted 3-7-membered heteroseksualci, where the substituents are selected from alkyl, heteroalkyl and heteroaryl, where the alkyl and heteroalkyl can be, in turn, is substituted by an oxo group, a 3-7-membered heterocyclization, heteroalkyl or heteroaryl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to use of dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidzo[1,2-a]benzimidazole as a compound which inhibits erythrocyte aggregation and reduces blood viscosity, and also reduces insulin resistance and restores tolerance of the body to glucose. The invention also relates to a pharmaceutical composition based on the said dihydrochloride.

EFFECT: new potential of the of the said compound has been studied.

3 cl, 4 dwg, 9 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a novel method of producing pyrrolo[2,3-d]pyrimidine derivatives of general formula V, which have protein kinase inhibiting properties, including a method of producing novel intermediate compounds. The method of producing compounds of formula V , where X1 is an activating group selected from chlorine, bromine, iodine, R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl, involves linking an activated pyrrolopyrimidine compound of formula IIa , where L1 is a leaving group and X is an activating group selected from chlorine, bromine, iodide; with an amine of formula IIIa or its salt, where R1 is (C1-C6)alkyl; a is an integer from 0 to 4; R2 is hydrogen or (C1-C6)alkyl and P is a nitrogen protecting group labile to hydrogenolysis, such as benzyl; in the presence of a base to obtain a compound of formula IVa and subsequent removal from the obtained compound of formula IVa of the activating group X1 and the nitrogen protecting group P through hydrogenolysis in the presence of hydrogen or a hydrogen source and a catalyst in any order.

EFFECT: method increases output of the desired product.

26 cl, 8 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modulating expression of a target gene induced by β-catenin using an agent which increases linkage of p300 with β-catenin and reduces linkage of CBP with β-catenin, involving bringing a composition containing β-catenin, CBP and p300, where β-catenin is more likely linked to CBP than p300, into contact with an agent in an amount which is effective for changing the probability of linking β-catenin to CBP compared to p300, where the said agent is a compound with a structure selected from formula (I), or its stereoisomers: where A represents -(C=O)-, B represents -(CHR4)-, D represents -(C=O)-, E represents -(ZR6)-, G represents -(XR7)n-> W represents (C=O)NH-, X represents nitrogen or CH, Z represents CH, n = 0 or 1. Values of substitutes R1 and R2 are indicated in the formula of invention. The invention also relates to a composition for modulating expression of a target gene induced by β-catenin.

EFFECT: novel compounds have useful biological properties.

9 cl, 7 tbl, 30 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts which have PDE9A inhibition properties. In formula (I) R1 represents alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms which, if necessary, can have up to three substitutes independently selected from: alkyl with 1-6 carbon atoms, hydroxy, halogen and trifluoromethyl, where the alkyl with 1-6 carbon atoms, if necessary, can be substituted with 1-3 substitutes independently selected from halogen and trifluoromethyl, R2 represents phenyl or aromatic mono- or bicyclic heteroaryl with 5-10 atoms in the ring and up to 5 heteroatoms selected from: sulphur, oxygen and/or nitrogen, where phenyl is substituted with 1-3 substitutes, and the heteroaryl, if necessary, can be substituted with 1-3 substitutes in each case independently selected from: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, hydroxyl and halogen.

EFFECT: compounds can be used for preparing medicinal agents for enhancing perception, ability to concentrate, learning capability and memory enhancement.

9 cl, 1 dwg, 2 tbl, 78 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine-condensed derivatives of formula , where n is selected from 0, 1, 2, 3 and 4, Z1 is selected from N, C(O) and CR3, where R3 represents hydrogen, Z2 is selected from N and CR4, where R4 is selected from hydrogen and halogen, where the bond between Z1 and Z2 is selected from a single bond and a double bond, R1 is selected from C1-C4alkyl and C1-C4alkoxy, R2 is selected from NR5C(O)R6, C(O)NR5R6 and NR5R6, where R5 represents hydrogen, and R6 is selected from hydrogen, C1-C4alkyl and phenyl, where phenyl as R6 is optionally substituted with 1-2 radicals independently selected from a group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heterocycloalkyl(C0-C4)alkyl, where any heteroaryl or heterocycloalkyl substitute R6 can be optionally substituted with a substitute independently selected from C1-C4alkyl and heterocycloalkyl, where the said heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6-member ring containing 1 or 2 N atoms as a heteroatom, and to their pharmaceutically acceptable salts, hydrates, solvates and isomers. The invention also relates to a pharmaceutical composition base on a formula I compound and to use of formula I compound for preparing a medicinal agent which can be used for treating diseases or disorders associated with anomalous or disrupted kinase activity, primarily diseases or disorders related to anomalous activation of kinase Ab1, Bcr-Ab1, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

EFFECT: novel compounds have useful biological properties.

7 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.

EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.

14 cl, 14 tbl, 171 ex

FIELD: chemistry.

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

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

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention provides novel pyrrolo[2,3-c]pyridine derivatives of formula (I), where radicals R1, R2, R3, R4 and R5 are as indicated in paragraph 1 of the formula of invention, or their pharmaceutically acceptable salts, as well as methods of producing the said compounds and a pharmaceutical composition having proton pump inhibiting effect.

EFFECT: novel compounds which exhibit excellent proton pump inhibiting effect and can have reversible proton pump inhibiting effect are obtained and described.

6 cl, 927 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the trihydrate of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula (I) .

EFFECT: novel compound is obtained, which is thermodynamically stable and has antibacterial activity.

1 cl, 3 tbl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of perindopril of formula I: . Also proposed are methods for synthesis of amorphous and crystalline perindopril using starting substance in form of stereospecific amino acid, N-[(S)-carbethoxy-1-butyl]-(S)-alanine, which is protected by a trimethylsilyl group and converted to reactive acid chloride using thionyl chloride or its complex with 1-H-benzotriazole (1:1), which reacts with (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid, having a protected carboxy group. The invention also relates to a pharmaceutical composition based on the said crystalline form of perindopril.

EFFECT: novel form of perindopril is obtained, which can be used in medicine for treating cardiovascular diseases.

8 cl, 4 dwg, 7 ex

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