Compounds suitable for use as raf kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

 

The text descriptions are given in facsimile form.

The compound of the formula I

or pharmaceutically acceptable salt of the compounds,
where Cy1represents phenyl or 5-6-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Cy represents a 5 to 14-membered saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic ring containing 0 to 4 heteroatoms, independently selected from nitrogen or oxygen, where the specified ring may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl;
L1represents a direct bond or linear or branched alkylenes chain With1-6;
L2represents a direct bond or linear or branched alkylenes chain With1-6while one or two methylene link in the group L2can be independently replaced by-N(R)-, -C(O)-, -C(O)N(R) -, or-N(R)C(O)-;
each group R independently represents hydrogen or an aliphatic group C1-6;
R1represents hydrogen or an aliphatic group C1-6;
each of Rxand Ryindependently selected from the following groups: -R2, -halogen, -CN, -OR2, -SR2, -N(R2)2, -CO2R2, -C(O)N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2, -NH2CH2CH2N(CH3)2or-N(R2)SO2R2: and
each R2independently represents hydrogen or a group selected from the following groups of aliphatic C 1-6, monocyclic or bicyclic aryl rings6-10or 5-10-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring, containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
two groups of R2at the same nitrogen atom together with the indicated nitrogen atom form a 5-8-membered saturated, partially unsaturated or aromatic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

2. The compound according to claim 1, in which each of Rxand Ryindependently selected from the following groups: R2, halogen, -OR2, -N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2or-N(R2)SO2R2.

3. The compound according to claim 2, in which Rxrepresents hydrogen, an aliphatic group, a C1-6or halogen.

4. The compound according to claim 2, in which Ryselected from R2, -OR2or-N(R2)2.

5. The compound according to claim 4, in which Ryrepresents-NH2, -NH3, -NHCH2CH3, -N2CH2CH3, -NH(CH3)2, -NH(C3H5), -NHCH2CH2CH2OH, -N(CH2CH2)2O or-N2CH2CH2N(CH3)2 .

6. The compound according to claim 4, in which Ryrepresents an aliphatic group1-6.

7. The connection according to claim 6, in which Ryrepresents a group selected from C2-6alkenylphenol or2-6alkenylphenol group.

8. The compound according to claim 4, in which Ryis a 5-10-membered saturated monocyclic or bicyclic ring, containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

9. The connection of claim 8, in which Ryrepresents a group chosen from:
(a) a 5-6-membered saturated monocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
(b) a 5-6-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
(c) an 8-10 membered saturated, partially unsaturated or aromatic bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

10. The connection of claim 8, in which Ryrepresents a group selected from phenyl, octahydrate, citicapital, thiacyclohexane, pyrrolidinyl, piperidinyl, piperazinil, tetrahydrothiopyran, tetrahydrothiophene, dithiolane, tetrahydrofuranyl, tetrahydropyranyl, dioxane, dioxane, morpholine oxathiolane, imidazolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazoline, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, piratininga, pyridazinyl, triazinyl, tetrazine, tetrahydropyridine, benzofuranyl, tianeptine, pyrrolidinyl, indolyl, chinoline, izochinolina, benzimidazolyl, imidazopyridine, purinol, indazole, pyrrolopyridine, cinnoline, heatline, phthalazine, naphthyridine or khinoksalinona.

11. The compound according to claim 1, in which R1represents hydrogen, a L1represents a linear or branched alkylenes chain C1-4.

12. Connection by claim 11, in which L1represents a branched alkylenes chain With1-4.

13. The compound according to claim 1, in which Cy1represents a 5-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

14. The connection 13, in which Cy1represents pyrrolidino, pyrazolidine, imidazolidine, triazoline, tetrazolyl, tiffaniejoy, fornillo, thiazolidine, isothiazolinone, thiadiazolidine, oxazolidinyl, isoxazolyl or oxadiazolyl group.

15. The compound according to claim 1, in which L2represents a direct bond and a is linear or branched alkylenes chain With 1-4while one or two methylene link in the group L2substituted with-N(R)- or-C(O)N(R).

16. The connection indicated in paragraph 15, in which L2represents-C(O)N(R).

17. Connection P16, where L2represents-C(O)N(H)-.

18. The compound according to claim 1, in which Cy2represents a group chosen from:
(a) a 5-membered saturated, partially unsaturated or aromatic monocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen or oxygen;
(b) phenyl or 6-membered saturated, partially unsaturated or aromatic monocyclic ring containing 1 to 4 nitrogen atoms; or
(c) a 5-10 membered saturated, partially unsaturated or aromatic bicyclic ring containing 1 to 4 nitrogen atoms;
where the specified cyclic Deputy may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

19. Connection p in which Cy2represents a group chosen from:
(a) a 5-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen or oxygen;
(b) phenyl or 6-membered heteroaryl ring containing 1 to 3 nitrogen atoms; or
(c) 5,6-condensed bicyclic heteroaryl cycle containing the t 1 to 4 nitrogen atoms,
where the specified cyclic Deputy may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

20. The connection according to claim 19, in which Cy2represents a group selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazine, pyrrolidinyl, indolyl, chinoline, izochinolina, benzimidazolyl, imidazopyridine, indazole, purine, cinnoline, hypotonia, phthalazine, natricinae, khinoksalinona, tianeptine or benzofuranyl;
where the specified cyclic Deputy may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

21. The compound according to claim 1, characterized in that the said compound is a compound of formula II

or pharmaceutically acceptable salt of the compounds.

22. Connection item 21, characterized in that the said compound is a compound of formula II-a or II-b

23. Connection p.22, in which Cy1represents a 5-membered heteroaryl ring, with the holding from 1 to 3 heteroatoms, independently selected from nitrogen, oxygen or sulfur.

24. A compound selected from the following compounds:




























































































































































































































































































































































































































or pharmaceutically acceptable salts of such compounds.

25. A method of inhibiting the activity of Raf kinase in a patient or in a biological sample, comprising the introduction of a specified patient connection according to claim 1 or the pharmaceutical compositions of the compounds or the conversion of a specified biological sample into contact with a compound according to claim 1 or a pharmaceutical composition of the compounds.

26. A method of treating or reducing the severity of the violation, mediated Raf, a mammal suffering from or to such breach, and the breach is selected from proliferative disorders, cardiac abnormalities, neurodegenerative disorders, autoimmune disorders, conditions associated with organ transplantation, inflammatory disorders, and immunologically mediated disorders, viral diseases or lesions of the bones, with the specified method includes the step of introducing a specified patient connection according to claim 1 or pharmaceutical composition based on the specified connection.

27. The method according to p in which the breach is selected from melanoma, leukemia, colon cancer, breast cancer, cancer of jeludochno-intestinal tract, ovarian cancer, lung cancer, brain cancer, larynx cancer, cervical cancer, kidney cancer, cancer of the lymphatic system, cancer of the genitourinary tract (including bladder cancer and prostate cancer), gastric cancer, bone cancer, lymphoma, melanoma, glioma, papillary thyroid cancer, neuroblastoma, and pancreatic cancer.

28. The method of obtaining the compounds of formula II-a'

or pharmaceutically acceptable salts of the compounds,
where Cy1is a 5-6-membered aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Cy2represents a 5-10 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring containing 0 to 4 heteroatoms, independently selected from nitrogen or oxygen, where the specified ring may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl;
each of the groups Rxand Ryindependently selected from R2, -halogen, -CN, -OR2, -SR2, -N(R2)2, -CO2R2, -C(O)N(R2)2, -N(R2)C(O)R2, -N(R2)N(R2)2, -N(R2)SO2N(R2)2or-N(R2)SO2R2;
each group R2n is dependent represents hydrogen or the group selected from the following groups: aliphatic group C1-6, monocyclic or bicyclic aryl rings6-10or 5-10-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring, containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two groups R2at the same nitrogen atom together with the indicated nitrogen atom form a 5-8-membered saturated, partially unsaturated or aromatic ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, comprising the stage of the reaction of a combination of compounds of formula II-viii

with a compound of formula II-vii

with the formation of the compounds of formula II-a'.

29. The method according to p, in which the compound of formula II-vii are obtained from the compounds of formula II-vi-b

where a' represents a suitable chiral anion,
including the stage of processing the compounds of formula II-vi-b with a suitable base to form compounds of formula II-vii.

30. The method according to clause 29, in which the compound of formula II-vi-b are obtained from the compounds of formula II-v

includes the following stages:
(a) treating the compounds of formula II-v chiral agent with the formation with the organisations of the formula II-vi-a

and
(b) separating the received diastereomers using appropriate physical methods
obtaining the compounds of formula II-vi-b.

31. The method according to item 30, in which the compound of formula II-v

obtained from the compounds of formula II-iv

including phase transformations Aksenovo fragment of formula II-iv in the amino group of the formula II-v.

32. The method according to p, in which the compound of formula II-iv are obtained from the compounds of formula II-iii

including the stage of processing the compounds of formula II with hydroxylamine to form compounds of formula II-iv.

33. The method according to p, in which the compound of formula II is obtained by implementation of a combination of compounds of formula II-i

with a compound of formula II-ii

34. A compound selected from

and

35. The compound of formula II-iv

in which Cy1is a 5-6-membered saturated, partially unsaturated or aromatic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
Cy2represents a 5-10 membered saturated, partially n is saturated or aromatic monosilicide or bicyclic ring, containing 0 to 4 heteroatoms, independently selected from nitrogen or oxygen, where the specified ring may be mono - or disubstituted with groups independently selected from halogen, -CF3With1-4the alkyl and 1-methylcyclopropyl.

36. The compound according to claim 1 the following formula:

or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE:

which involves recyclisation of a furan ring of 2-amino-N-(furan-2-ymethyl)acetamides at room temperature in a mixture of glacial acetic acid and concentrated hydrochloric acid for 24 hours, after which sodium bicarbonate is added and then boiled for 5 minutes.

EFFECT: novel method of producing 1,2-dihydropyrrolo[1,2-α]pyrazin-3(4H)-ones as a result of simultaneous formation of a pyrrole ring and a pyrazine ring, which in turn can be used as biologically active substances.

1 cl, 3 tbl, 5 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to new salts of a compound 1:

,

which represents hemi- or monosalts with C4 organic dibasic acid, which have improved properties when used. The invention also refers to method of specified salts production.

EFFECT: improved acid stability.

24 cl, 8 dwg, 4 tbl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives of the following structures (I) and (II) wherein X represents NH or O; R represents H or C1-6alkyl; R1 represents a structure specified in wherein R1' means a substitution in n-, o- or m-positions by one or more substitutes from halogen, -OCF3, -CF3 or -OCH3; R2 represents -(CH2)1;2-piperid-4-yl or substituted -(CH2)1,2-piperid-4-yl, substituted by C1-6alkyl or C(O)cyclopropyl; or R2 represents -(CH2)n-cyclohexyl wherein n means 0 or 1, wherein -(CH2)n-cyclohexyl is optionally substituted by one or more substitutes specified in halogen, oxo, cyano, amino, alkylamino, alkyl, alkoxy, hydroxyalkyl, morpholinyl, -NReC(=O)Rf, -S(=O)2NH2, -NReS(=O)2Rf, wherein Rf and Re are identical or different and independently represent hydrogen, alkyl or morpholinylalkyl. The invention also refers to a composition possessing activity inhibiting Pim-1 kinase activity.

EFFECT: there are produced new compounds and composition on their basis which can find application in medicine for treating cancer expressing Pim-1 kinase.

13 cl, 5 dwg, 9 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

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18 cl, 393 ex

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

FIELD: medicine, pharmaceutics.

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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.

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21 cl, 4 tbl, 13 ex

FIELD: medicine, pharmaceutics.

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EFFECT: new compounds are presented.

11 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

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11 cl, 73 ex

FIELD: chemistry.

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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: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: chemistry.

SUBSTANCE: invention provides to a high degree a safe pharmaceutical drug which is effective for diseases caused by MMP-2 and/or MMP-9. The pharmaceutical drug contains, as an active ingredient, at least one member selected from a group which consists of thiazole derivatives of formula (1): where R1 is a phenyl group which can have 1-3 lower alkoxy groups as substitutes in the phenyl ring, and R2 is a pyridyl group which can have 1-3 carboxyl groups as substitutes in the pyridine ring, or salts thereof.

EFFECT: high activity and use when treating diseases such as fibrosis and pulmonary emphysema.

4 cl, 4 ex, 2 tbl

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

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 compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

EFFECT: obtaining compounds, which are alpha-adrenergic agonists.

3 cl, 1 tbl

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