Kinase modulators based on pyrrolopyridine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

 

The text descriptions are given in facsimile form.

1. The compound of the formula:

where L1and L2independently denote a bond, -S-, -NH - or unsubstituted C1-C5alkylen;
And1mean 6-membered substituted aryl or an unsubstituted heteroaryl;
And2means aryl or heteroaryl;
R1means halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl;
X1means-C(R2)=, -C(R2)(R3)-, -N(R4)- or-O-;
R2and R3independently mean hydrogen, -OR5or alkyl;
R4means hydrogen or alkyl;
Z denotes O or NH;
w denotes an integer from 0 to 2;
R5independently means hydrogen or alkyl;
R6and R7independently mean hydrogen, -S(O)2R11, alkyl or heteroalkyl;
R11means hydrogen or alkyl;
R8independently means hydrogen, -NR14R15, -OR16heteroalkyl or cycloalkyl;
R14, R15and R16independently mean hydrogen, alkyl, cycloalkyl, heteroalkyl or heteroseksualci;
R9independently means hydrogen or alkyl; and
and R6and R7, R14and R15independently and optionally together with the nitrogen atom to which they are attached, the image of the Ute substituted or unsubstituted heteroseksualci.

2. The compound according to claim 1, having the formula

where R19means methyl, ethyl, -CH2CN, CF3CH2OtBu, HE, Cl, F, SMe, -PINES3, CONH2, OMe, OCF3, OEt, O-isopropyl O-propyl, and where x is an integer from 1 to 5, or where two groups R19connected with the formation of substituted or unsubstituted ring selected from indazole, indole, dihydrobenzofuran, methylenedioxybenzene or 2,2-debtor-1,3-benzodioxole;
And2means
or;
R1selected from
(a) Cl, F, IT, CN, NO2, OMe, SMe, SO2NH2, SO2Me, NHSO2Me,
,
-CH2NMeCH2CH2N(Me)2,
,,,,,,;
or
(b) -C(O)NR14R15where NR14R15selected from NH2, NMe2NEt2, NHMe, NHEt, NHCH2CH2NMe2, NHCH(Me)2, NHCH2CH(Me)2,,,,,,,,, ,,
,,and; or
(C) -C(O)NR14R15where R14and R15together with the nitrogen atom to which they are attached, form a piperazinil selected from
,,,,,,,,,,,,,and; or
(d) -C(NH)NR14R15where R14and R15selected from NMe2NEt2N(Me)iPr, NHiPr, NHCH2C(H)Me2,,,,,,,
,,,,,,,,and;
R20selected from HE, OMe, OS is 2(C6H4OMe), F, Cl, Me, isopropyl, NH2N(Et)2, NHCH2CH2N(Me)2, NMeCH2CH2N(Me)2,
,,
-CH2CH2CH2CO2H, -CH2NMeCH2CH2N(Me)2,
,,,, OCH2CH2N(Me)2, OCH2CH2OMe, OCH2CO2H, OCH2CH2CH2CO2H, OCH2CONH2,
,,,and; where y is an integer from 0 to 4.

3. The compound according to claim 2, where R19means halogen.

4. The compound according to claim 2, where R19independently denotes methyl, ethyl, -CH2CN, CF3or CH2OtBu.

5. The compound according to claim 2, where R19independent means HE, SMe, -PINES3, CONH2, OMe, OCF3, OEt, O-isopropyl O-propyl.

6. The compound according to claim 2, where R19selected from methyl, ethyl, -CH2CN, CF3CH2OtBu, HE, Cl, F, SMe, -PINES3, CONH2, OMe, OCF3, OEt, O-isopropyl O-propyl.

7. The compound according to claim 2, where R19attached in position 1, together with a group of R19attached in position 2, form a substituted or unsubstituted shall nasal, indole, dihydrobenzofuran, methylenedioxybenzyl or 2,2-debtor-1,3-benzodioxol.

8. The compound according to claim 2, where R19attached in position 2, together with the group R19attached in position 3, form a substituted or unsubstituted indazole, indole, dihydrobenzofuran, methylenedioxybenzyl or 2,2-debtor-1,3-benzodioxol.

9. The compound according to claim 2, where x is 1, and R19attached in position 1 or 2.

10. The compound according to claim 2, where x is 1, and R19attached in position 1.

11. The compound according to claim 2, where x is an integer from 2 to 5, and at least one group R19attached in position 1.

12. The compound according to claim 2, where x is an integer from 2 to 5 and at least one group R19attached in position 2.

13. The compound according to claim 2, where a2has the formula
.

14. The compound according to claim 2, where a2has the formula
.

15. The connection of item 13 or 14, where R20selected from F, Cl, Me, iPr, -CH2CH2CH2CO2H, -CH2NMeCH2CH2N(Me)2,
,,and.

16. The connection of item 13 or 14, where R20selected from HE, OMe, co2(C6H4OMe), OCH2CH2N(Me)2, OCH2CH2OMe, OC 2CO2H, OCH2CH2CH2CO2H, OCH2CONH2,
,,,and.

17. The connection of item 13 or 14, where R20selected from NH2N(Et)2, NHCH2CH2N(Me)2, NMeCH2CH2N(Me)2,
and.

18. The connection of item 13 or 14, where y is 1, and R20attached at position 3'.

19. The connection indicated in paragraph 13, where y is equal to 2, and R20attached at position 3' in position 4'.

20. The connection 14, where y is 1, and R20attached at position 3'.

21. The connection of item 13 or 14, where y is equal to 0.

22. The connection of item 13 or 14, where R1selected from Cl, F, IT, CN, NO2, OMe, SMe, SO2NH2, SO2Me, NHSO2Me and.

23. The connection of item 13 or 14, where R1selected from-CH2NMeCH2CH2N(Me)2,
,,,,,and.

24. The connection of item 13 or 14, where R1means-C(O)NR14R15.

25. The connection point 24, where NR14R15selected from NH2, NMe2 NEt2, NHMe, NHEt, NHCH2CH2NMe2, NHCH2CH2NMe2, NHCH(Me)2, NHCH2CH(Me)2,
,,,,,,,,,,,and.

26. The connection point 24, where y is equal to 0.

27. The connection point 24, where R14and R15together with the nitrogen atom to which they are attached, form a piperazinil selected from
,,,,,,,,,,,,,and.

28. The connection of item 13 or 14, where R1means-C(NH)NR14R15; a R14and R15selected from NMe2NEt2N(Me)iPr, NHiPr, NHCH2C(H)Me2,
, ,,,,,,,,,,,,,and.

29. The compound according to claim 2, where a2selected from
,and.

30. The connection indicated in paragraph 13, where x is 1 and y is 0.

31. Connection item 30, where the group R19attached in position 1.

32. Connection item 30, where the group R19attached in position 2.

33. The connection indicated in paragraph 13, where x is 2, y is 0, and R19attached in position 1 and 4.

34. The connection indicated in paragraph 13, where x is 2, y is 0, and R19attached in position 1 and 5.

35. The connection indicated in paragraph 13, where x is 1, y is 1, R19attached in position 1, and R20attached at position 3'.

36. The connection indicated in paragraph 13, where x is 1, y is 2, R19attached in position 1, and R20attached at position 3' and 4'.

37. The connection indicated in paragraph 13, where x is 2, y is 0, and one group R19attached in position 2.

38. The connection 14, where is equal to 1, and R20attached at position 3'.

39. The method of modulation of the activity of a protein kinase comprising contacting the specified protein kinase with a compound according to claim 1.

40. The method according to § 39, where the protein kinase is tyrosinekinase of Abelson, receptor tyrosinekinase Ron, receptor tyrosinekinase Met, tyrosinekinase-3 types of Fms, Aurora kinase, p21-activated kinase-4 and 3-postinst-dependent kinase-1.

41. The method according to § 39, where in the compound according to claim 1, R1means-C(O)NR14R15or-C(NH)NR14R15.

42. The method according to paragraph 41, where R1means-C(O)NR14R15.

43. The method according to p, where the protein kinase means Bcr-Ab1 kinase having a mutation 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.

44. The method according to item 43, where the protein kinase is a T315I mutation.

45. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment of cancer.

46. The application of § 45, where the cancer is a leukemia or myeloproliferative disorder.

47. Pharmaceutical composition having a modeling activity against protein kinases, including pharmaceutically acceptable excipient and the connection according to claim 1.



 

Same patents:

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11 cl, 288 ex

FIELD: chemistry.

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90 cl, 162 ex, 2 tbl

FIELD: chemistry.

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16 cl, 4 tbl, 29 ex

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.

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24 cl, 20 tbl, 24 ex

FIELD: chemistry.

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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

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11 cl, 1 tbl, 182 ex

FIELD: chemistry.

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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.

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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: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and concerns a complex containing mequitazine, cyclodextrin and a reaction agent where the molar ration within the system mequitazine/cyclodextrin/the reaction agent and mequitazine/the reaction agent is 1/1 - 1/10 and water-dissolution rate of mequitazine being a part of the complex measured for an aqueous solution with mequitazine concentration 2 g/l at 35°C after 15 minutes of stirring, makes more than 50% at pH 9, to a method for preparing said complex and a based pharmaceutical composition.

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20 cl, 1 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining a mixture of trifluoroacetyl-glatiramer acetate, where the obtained mixture of polypeptides contains not more than 0.1% brominated tyrosine and less than 1000 parts/million metal ion impurities.

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20 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

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13 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: there are offered versions of human IL-13 antibodies, including based on CDR antibody BAK278D6. There is described a based composition, and also isolated nucleic acid, a host cell for preparing antibodies and versions of the method for preparing antibodies. There is disclosed application of antibodies for preparing a drug and a composition for treating various diseases mediated by IL-13 activity. Application of the invention provides antibodies neutralising IL-13.

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52 cl, 32 dwg, 7 tbl, 29 ex

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

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 immunology and biotechnology. Described are versions of the humanised antibody CD45RO/RB which carry a light and a heavy strand. Versions of the following are disclosed: isolated polynucleotide, coding antibody, expression vector containing a polynucleotide and host cells containing the expression vector. Described also is use of the antibody to treat and/or prevent various diseases, including as a component of a pharmaceutical composition.

EFFECT: invention provides antibodies identified as CD45RO and CD45RB, which can find use in medicine.

9 cl, 14 dwg, 2 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: described are novel thiophene derivatives of formula (1) and pharmaceutically acceptable salts thereof, where A is -CH2CH2-, -NH-CH2-, -CH2-O or -CH2NH-, R1 is hydrogen or alkyl, when X is C-R4, R1 additionally represents halogen, and when A is -CH2-CH2- or -CH2NH, R1 additionally represents alkoxy, R2 is hydrogen, alkoxy, fluoralkoxy, hydroxyalkoxy, hydroxyalkyl, di-(hydroxy)alkoxy, pyridinyl-3-methoxy, pyridinyl-4-methoxy, R3 is hydrogen, alkyl, trifluoromethyl, and when X is C-R4, R3 additionally represents halogen, and when A is -CH2-CH2-, R3 additionally represents alkoxy, X is N or C-R4, R4 is hydrogen, alkyl, alkoxy or halogen, R5 is methyl or ethyl. Also described are isomers of the said compounds, an initial compound for synthesis of formula (1) compound, which has agonistic effect on S1P1/EDG1 receptors, as well as a pharmaceutical composition based on formula (1) compound and use of formula (1) compound.

EFFECT: obtaining a pharmaceutical composition for preventing or treating diseases or disorders associated with activated immune system.

19 cl, 2 tbl, 167 ex

Immunostimulants // 2385732

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, specifically to an agent of immunostimulating activity. The immunostimulant which represents a liquid nettle extract is prepared by repercolation under certain conditions.

EFFECT: immunostimulant exhibits effective immunostimulating properties that is expressed in intensified immune response, cell immune response and nonspecific resistance of an organism.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: there are selected strains Lactobacillus capable to raise IL-10 level and simultaneously to reduce TGF-beta-2 level in human breast milk to be applied with the products containing cells of selected strains to improve human milk for breast feeding. Selected strains and said products containing cells of selected strains are applied to increase of levels of anti-inflammatory cytokine IL-10 in human breast milk and reduce risk of allergy development in a breast-fed infant, to improve anti-inflammatory activity of human breast milk and to reduce simultaneously causal factors.

EFFECT: invention provides decreased TGF-beta-2 level in milk that leads to reduced risk of mastitis development in a nursing mother.

22 cl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in treating the patients with Non Hodgkin Lymphoma. That is ensured by administration of a combination containing an effective amount of CCI-779 and rituximab in the form of a dosage form with one or more neutral components added. The combination is introduced simultaneously, separately or consistently with the other agents.

EFFECT: method allows improving clinical effectiveness for the given pathology, including in the patients resistant to rituximab due to synergetic interactions of these preparations.

5 cl

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