Compounds used in pharmaceutics

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

 

The text descriptions are given in facsimile form.

1. The combination is intended to inhibit the growth of tumor cells containing an additional tool and compound of formula (IV) in the effective number of

or its pharmaceutically acceptable salts or tautomers or N-oxides, or a solvate;
where R1represents a carbocyclic or heterocyclic group; or (C1-8saturated hydrocarbon group, not necessarily for sennou one or more substituents, selected from fluorine, hydroxy-group, With1-4alkoxygroup and carbocyclic or heterocyclic groups; where 1 or 2 carbon atoms, C1-8the saturated hydrocarbon group may be optionally substituted by an atom or group selected from O, S, NH, SO, SO2;
where the carbocyclic and heterocyclic groups selected from:
(i) substituted or unsubstituted phenyl;
(ii) a heteroaryl group selected from furanyl, indolyl, 2,3-dihydrobenzo[1,4]dioxine, pyrazolyl, pyrazolo[1,5-a] pyridinyl, oxazolyl, isoxazolyl, pyridyl, chinoline, pyrrolyl, imidazolyl and tanila;
(iii) substituted or unsubstituted monocyclic cycloalkyl groups selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
and
(iv) a 5-, 6 - or 7-membered monocyclic heterocyclic group selected from the research, piperidine, pyrrolidine, pyrrolidone, Piran, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazolo, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine;
where the carbocyclic and heterocyclic groups can be optionally substituted 1 or 2, or 3, or 4 alternate groups of R10selected from halogen, ceanography, nitro and monocyclic carbocyclic the fir and heterocyclic groups, containing from 3 to 7 members in the ring; the group Ra-Rbwhere Rarepresents a simple bond, O, CO, X1With(X2), With(X2X1X1With(X2X1, S, SO, SO2, NRc, SO2NRcor NRcSO2; and Rbselected from hydrogen, monocyclic carbocyclic and heterocyclic groups containing from 3 to 7 members in the ring, and C1-8saturated hydrocarbon group, optionally substituted by one or more substituents selected from a hydroxy-group, carbonyl group, halogen, ceanography, nitro, carboxy, amino, mono - or di-C1-4aminosilane saturated hydrocarbon groups, monocyclic carbocyclic and heterocyclic groups containing from 3 to 7 members in the ring, and where one or more carbon atoms C1-8the saturated hydrocarbon group may be optionally substituted
O, S, SO, SO2, NRcX1With(X2), With(X2X1or X1With(X2X1;
Rcselected from hydrogen and C1-4saturated hydrocarbon group;
X1represents O, S or NRcand X2represents =O, =S or-NRc;
provided that, when replacing the group R10contains or includes carbocyclic or heterocyclic group specified CT is acyclically or heterocyclic group can be unsubstituted or substituted one or more substituting groups R 10where such additional surrogate group, R10do not include monocyclic carbocyclic or heterocyclic group and selected from the other groups listed above in the definition of R10;
R2represents hydrogen or methyl;
an optional second bond may be present between carbon atoms numbered 1 and 2;
one of U and T is selected from CH2, CHR13, CR11R13, NR14N(O)R15, O and S(O)t; and the other of U and T is selected from NR14, O, CH2, CHR11C(R11)2and C=O; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2;
R11selected from hydrogen, halogen, C1-3the alkyl and C1-3alkoxygroup;
R13selected from hydrogen, other14, NOH, NOR14and Ra-Rb;
R14selected from hydrogen and Rd-Rb;
Rdselected from simple communication, CO, C(X2X1, SO2and SO2NRcand
R15selected from C1-4the saturated hydrocarbon groups, optionally substituted by a hydroxy-group, With1-2alkoxygroup, halogen or a monocyclic 5 - or 6-membered carbocyclic or heterocyclic group, provided that U and T cannot both be mean About;
where additional means selected from:
(i) a monoclonal antibody which is a monoclonal antibody to antigens CL is accurate surface or anti-CD antibody;
(ii) an alkylating agent selected from compounds of mustard gas, connection nitrosoanatabine and busulfan;
(iii) anticancer agent that is selected from the HDAC inhibitor, inhibitor SOH-2, an inhibitor of DNA methylation and inhibitor proteasome;
(iv) another CDK inhibitor, and
(v) a hormone, hormone agonist, hormone antagonist or garminmobilepc agent selected from antiandrogen, antiestrogen or GnRH analogue.

2. The combination according to claim 1, where R2represents hydrogen.

3. The combination according to claim 1, where R1represents an unsubstituted or substituted carbocyclic or heterocyclic group.

4. The combination according to claim 3, where the carbocyclic and heterocyclic groups are monocyclic.

5. The combination according to claim 3, where the optional substituents R10for carbocyclic and heterocyclic groups selected from halogen, ceanography, nitro group and Ra-Rbwhere Rarepresents a simple bond, O, CO, X1With(X2), With(X2X1X1With(X2X1, S, SO or SO2and Rbselected from hydrogen and C1-8saturated hydrocarbon group, optionally substituted by one or more substituents selected from a hydroxy-group, carbonyl group, halogen, ceanography, nitro, carboxy and monocyclic carbocyclic and Goethe is acyclically groups, containing from 3 to 6 members in the ring, and where one or more carbon atoms saturated With1-8the hydrocarbon group may be optionally replaced by O, S, SO, SO2, NRcX1With(X2), With(X2X1or X1With(X2X1; and X1represents O, S or NRcand X2represents =O, =S or-NRc.

6. The combination according to claim 5, where the above optional substituents R10selected from a halogen group and Ra-Rbwhere Rarepresents a simple bond or O and Rbselected from hydrogen and saturated C1-4hydrocarbon group, optionally substituted by one or more substituents selected from a hydroxy-group, halogen and 5 - and 6-membered saturated carbocyclic and heterocyclic groups.

7. The combination according to claim 5, where R1is a phenyl ring containing 1, 2 or 3 substituent defined in claim 1 or claim 5, or claim 6, located in the 2-, 3-, 4-, 5 - or 6-position of the ring.

8. The combination according to claim 7, where the phenyl group is:
(i) monosubstituted in the 2-position, or disubstituted in the 2 - and 3-position or disubstituted in the 2 - and 6-positions with substituents selected from fluorine, chlorine and Ra-Rbwhere Rarepresents O, and Rbrepresents a C1-4alkyl; or
(ii) monosubstituted in the 2-nd position the AI Deputy selected from fluorine; chlorine; C1-4alkoxy, optionally substituted by one or more fluorine atoms; or a disubstituted in the 2 - and 5-positions with substituents selected from fluorine, chlorine and metoxygroup.

9. The combination according to claim 1, where R1chosen from:
(a) phenyl, optionally substituted by one or more substituents selected from fluorine; chlorine; hydroxy-group; C1-3oxetanemethanol saturated hydrocarbon group and1-3saturated hydrocarbon group; where C1-3saturated hydrocarbon group optionally substituted by one or more substituents selected from a hydroxy-group, fluorine, C1-2alkoxygroup, amino, mono and di-C1-4alkylamino, saturated carbocyclic group containing from 3 to 7 members in the ring, or a saturated heterocyclic group containing 5 or 6 members in the ring, and containing up to 2 heteroatoms selected from O, S and N;
(b) R1represents an unsubstituted phenyl group or 2-monosubstituted, 3-monosubstituted, 2,3-disubstituted, 2,5-disubstituted or 2,6-disubstituted phenyl group, or 2,3-dihydrobenzo[1,4]dioxin, where the substituents are selected from halogen; hydroxy-group; C1-3alkoxygroup and C1-3alkyl groups, where C1-3the alkyl group may be optionally substituted by a hydroxy-group, fluorine,1- alkoxygroup, amino group, mono - or di-C1-4alkylaminocarbonyl or saturated carbocyclic group containing from 3 to 6 members, non-member ring, and/or saturated heterocyclic groups containing 5 or 6 members, non-member ring containing 1 or 2 heteroatoms selected from N and O;
or
(c) R1selected from unsubstituted phenyl, 2-ftoheia, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2-(2-(pyrrolidin-1-yl)ethoxy)phenyl, 3-ftoheia, 3-methoxyphenyl, 2,6-dipthera, 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2,6-dichlorophenyl and 2-chloro-6-ftoheia; and optional extras selected from 5-fluoro-2-methoxyphenyl; or
(d) R1selected from 2,6-dipthera, 2-fluoro-6-methoxyphenyl, 2,6-dichlorophenyl and 2-chloro-6-ftoheia.

10. The combination according to claim 1, where one of U and T is selected from CH2, CHR13, CR11R13, NR14N(O)R15, O and S(O)t; and the other of U and T is selected from CH2, CHR11C(R11)2and C=O; r is 0, 1 or 2; t is 0, 1 or 2;
R11selected from hydrogen and C1-3of alkyl;
R13selected from hydrogen and Ra-Rb;
R14selected from hydrogen and Rd-Rb;
Rdselected from a simple connection, WITH, (X2X1, SO2and SO2NRc;
R15select the h of C 1-4the saturated hydrocarbon groups, optionally substituted by a hydroxy-group, With1-2alkoxygroup, halogen or a monocyclic 5 - or 6-membered carbocyclic or heterocyclic group; and
values of R1, R2, Ra, Rband Rcare as defined in claim 1.

11. The combination of claim 10, comprising additional means and the connection of the formula (Va)

or its pharmaceutically acceptable salts or tautomers or N-oxides, or a solvate;
where additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent;
where R14aselected from hydrogen, C1-4the alkyl optionally substituted by fluorine, cyclopropylmethyl, phenyl-C1-2of alkyl, C1-4alkoxycarbonyl, phenyl-C1-2alkoxycarbonyl, C1-2-alkoxy-C1-2the alkyl and C1-4alkylsulfonyl, where phenyl fragments, if present, optionally substituted from one to three substituents selected from fluorine, chlorine, C1-4alkoxygroup optionally substituted by fluorine, or C1-2-alkoxygroup and C1-4the alkyl, optionally substituted by fluorine or1-2-alkoxygroup;
w stands for 0, 1, 2 or 3;
R 2represents hydrogen or methyl;
values of R11and r are as defined in claim 1; and
R19selected from fluorine; chlorine; C1-4alkoxygroup, optionally substituted by fluorine or1-2-alkoxygroup; and (C1-4the alkyl, optionally substituted by fluorine or1-2-alkoxygroup.

12. The combination according to claim 11, where the phenyl ring is disubstituted in the 2 - and 6-positions with substituents selected from fluorine, chlorine and metoxygroup.

13. The combination according to claim 1, where R11represents hydrogen.

14. The combination according to claim 1, where R14arepresents hydrogen or methyl.

15. The combination of 14, including the additional agent and the compound of formula (VIa)

or its pharmaceutically acceptable salts or tautomers or N-oxides, or a solvate;
where additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent;
where R20selected from hydrogen and methyl;
R21selected from fluorine and chlorine and
R22selected from fluorine, chlorine and metoxygroup; or
one of R21and R22represents hydrogen and the other is selected from chlorine, metoxygroup, ethoxypropan, dipterocarp, triptime is syrupy and benzyloxy.

16. The combination indicated in paragraph 15, including the additional agent and the compound of formula (VIb)

or its pharmaceutically acceptable salts or tautomers or N-oxides, or a solvate;
where additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent;
where R20selected from hydrogen and methyl;
R21aselected from fluorine and chlorine and
R22aselected from fluorine, chlorine and metoxygroup.

17. The combination of article 16 where the compound of formula (VIb) chosen from:
piperidine-4-ylamide 4-(2,6-differentiating)-1H-pyrazole-3-carboxylic acid;
(1 methylpiperidin-4-yl)amide of 4-(2,6-differentiating)-1 H-pyrazole-3-carboxylic acid;
piperidine-4-ylamide 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid and
piperidine-4-ylamide 4-(2-fluoro-6-methoxybenzylamine)-1H-pyrazole-3-carboxylic acid.

18. The combination of 17, where the compound of formula (VIb) is a piperidine-4-alamid 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid.

19. The combination according to claim 1, where the compound of formula (IV) is in the form of pharmaceutically acceptable salts.

20. The combination of p where piperidine-4-alamid 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid is in the Orme pharmaceutically acceptable salt.

21. The combination according to claim 20, where the salt is an additive salt with acid.

22. The combination according to item 21, where the piperidine-4-alamid 4-(2,6-dichloro-benzoylamine)-1H-pyrazole-3-carboxylic acid is in the form of a salt selected from the additive salts with the acid formed with chloroethanol acid, methanesulfonic acid and acetic acid.

23. The combination according to article 22, where salt piperidine-4-ylamide 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid is a salt formed with chloroethanol acid.

24. The combination according to article 22, where salt piperidine-4-ylamide 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid is a salt formed with methanesulfonic acid.

25. The combination at point 24 where the specified salt methanesulfonic acid and piperidine-4-ylamide 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid is in crystalline form.

26. The combination according to article 22, where salt piperidine-4-ylamide 4-(2,6-dichloraniline)-1H-pyrazole-3-carboxylic acid is a salt formed with acetic acid.

27. Combination according to any of claims 1 to 26, where an additional tool is an antiandrogen or antiestrogen.

28. The combination according to item 27, where antiandrogen is an aromatase inhibitor.

29. The combination of p, where the aromatase inhibitor is selected from letrozole, ANAS is rosola, eksemestana and aminoglutethimide.

30. The combination according to item 27, where an additional tool is an antiandrogen selected from tamoxifen, fulvestrant, raloxifene, toremifene, droloxifene, letrazole, anastrazole, eksemestana, bikalutamida, leuprolide, megestrol acetate, aminoglutethimide and bexarotene.

31. The combination according to item 27, where an additional means is an analogue of GnRH.

32. The combination of p, where the GnRH analogue is selected from goserelin or leuprolide.

33. Combination according to any of claims 1 to 26, where an additional tool is a monoclonal antibody to the antigens on the cell surface or anti-CD antibody.

34. The combination of p, where a monoclonal antibody to the antigens on the cell surface selected from CD20, CD22, CD33 and CD52.

35. The combination of p, where a monoclonal antibody to the antigens on the cell surface is selected from rituximab, tositumomab and gemtuzumab.

36. The combination of p, where a monoclonal antibody to the antigens on the cell surface consists of a fully humanized and chimeric antibodies.

37. Combination according to any one of claims 1 to 26, where an additional tool is an alkylating agent.

38. The combination according to clause 37, where the alkylating agent is selected from a compound of mustard gas, connection nitrosoanatabine and busulfan.

39. The combination according to § 38, where the alkylating agent is predstavljaet a compound of mustard.

40. The combination according to clause 37, where the alkylating agent is a melphalan.

41. Combination according to any of claims 1 to 26, where an additional tool is an alkylating agent selected from ifosfamide and hlorambuzila.

42. Combination according to any of claims 1 to 26, where an additional tool is an alkylating agent selected from carmustine and lomustina.

43. Combination according to any of claims 1 to 26, where an additional tool is an alkylating agent, which is a busulfan.

44. Combination according to any of claims 1 to 26, where an additional tool is a HDAC inhibitor selected from the TSA, SAHA, JNJ-16241199, lunar abyss-824, MGCD-0103 and PXD-101.

45. Combination according to any of claims 1 to 26, where an additional tool is an inhibitor SOH-2, selected from celecoxib.

46. Combination according to any of claims 1 to 26, where an additional tool is an inhibitor of DNA methylation, which is temozolomide.

47. Combination according to any of claims 1 to 26, where an additional tool is an inhibitor proteasome.

48. The combination of p, where the inhibitor proteasome is bortezomib.

49. Combination according to any of claims 1 to 26, where an additional tool represents another connection, exhibiting activity against CDK, which is one or more compound of the formula (IV), (Va) and (VIa) Il is (VIb) and the corresponding subgroups.

50. Combination according to any of claims 1 to 26, where an additional tool represents an additional connection, exhibiting activity against CDK selected from seliciclib, alvocidib, 7-hydroxystaurosporine, JNJ-7706621, BMS-387032, Pha533533, PD332991, ZK-304709 and AZD-5438.

51. The combination according to item 50, where another connection, exhibiting activity against CDK selected from JNJ-7706621, BMS-387032, Pha533533, PD332991, ZK-304709 and AZD-5438.

52. The combination according to § 51, where another CDK inhibitor is a JNJ-7706621.

53. The combination according to claim 1, where the additional agent and the compound of formula (IV) are physically associated.

54. The combination according to item 53, where the additional agent and the compound of formula (IV): (a) presented in the form of a mixture; (b) are chemical/ physico-chemically bound; and (C) are chemical/physico-chemically Packed together or (d) are mixed together but packaged or co-presented.

55. The combination according to claim 1, where the additional agent and the compound of formula (IV) are not physically associated.

56. The combination according to § 55, where the combination comprises: (a) at least one of the two or more components combination together with instructions for extemporally Association of at least one component with the physical education Association of two or more components; or (b) at least one of the TLD is or more components together with instructions for combination therapy using two or more components; or (b) at least one of the two or more components together with instructions for administration to a patient, where other components have already been introduced or injected to the patient; or (d) at least one of the two or more components in the amount or in the form of specially adapted for use in combination with another (other) of two or more components.

57. Combination according to any of claims 1 to 52 in the form of pharmaceutical packaging, set or individual packaging.

58. Combination according to any one of claims 1 to 57, intended for use to facilitate or reduce the manifestations of the disease or condition comprising abnormal cell growth or consequential abnormal cell growth in a mammal.

59. Way to ease the condition or reduce the symptoms of a disease or condition comprising abnormal cell growth or consequential abnormal cell growth in a mammal, comprising the administration to a mammal a combination according to any one of claims 1 to 57 in the amount effective for inhibiting abnormal cell growth.

60. The method of treatment of a disease or condition comprising abnormal cell growth or consequential abnormal cell growth in a mammal, comprising the administration to a mammal a combination according to any one of claims 1 to 44 in the amount effective for inhibiting and analnogo cell growth.

61. Combination according to any one of claims 1 to 57, intended for use in the inhibition of tumor growth in a mammal.

62. Method of inhibiting growth of a tumor in a mammal, comprising the administration to a mammal a combination according to any one of claims 1 to 57 in the amount effective for inhibiting tumor growth.

63. Method of inhibiting the growth of tumor cells comprising contacting the tumor cells with a combination according to any one of claims 1 to 57, entered the mammal in an amount effective for inhibiting the growth of tumor cells.

64. The pharmaceutical composition intended to inhibit the growth of tumor cells, comprising the combination according to any one of claims 1 to 57, and a pharmaceutically acceptable carrier.

65. Combination according to any one of claims 1 to 57 for use in medicine.

66. A method for the diagnosis and treatment of cancer in a patient is a mammal, comprising (i) screening a patient to determine whether the cancer, which affects or can be affected by the patient, such that responsive to treatment using a compound having activity against cyclin-dependent kinases, and additional funds; and (ii) in the case where it is shown that the disease or condition of the patient susceptible to a given treatment, carry out the introduction to the patient a combination according to any one of claims 1 to 57, and the stage is niteline means selected from monoclonal antibodies, alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent.

67. The use of a combination according to any one of claims 1 to 57 for the preparation of medicines intended for the treatment or prevention of cancer in a patient, which as a result of screening detected that the patient is exposed to or is at risk for malignant neoplasms which are susceptible to treatment with the combination, as defined in any one of claims 1 to 57.

68. A method of treating cancer in a patient, comprising the administration to a patient a combination according to any one of claims 1 to 57 in number and in accordance with the scheme of introduction, which are therapeutically effective for the treatment of this cancer.

69. The way to prevent, cure or mitigate the symptoms of cancer in a patient in need thereof, comprising the administration to a patient a combination according to any one of claims 1 to 57 in prophylactically or therapeutically effective amount.

70. The use of a combination according to any one of claims 1 to 57 for the preparation of medicinal products intended for receiving anticancer action in warm-blooded animal such as man.

71. Combination according to any one of claims 1 to 57 in the form of pharmaceutical packaging, set or individual packaging.

72. Farmatsevticeski the packaging, set or individual packing, designed for anticancer therapy, including an additional tool in dosage form and the compound of formula (IV), (Va), (VIa) or (VIb) according to any one of claims 1 to 57, also in a unit dosage form, and additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent.

73. A method of treating cancer in a warm-blooded animal, such as man, including the introduction of a specified animal additional funds in the effective number of sequentially or simultaneously with the compound of the formula (IV), (Va), (VIa) or (VIb) in an effective amount, as defined in any one of claims 1 to 57, with an additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent.

74. The method of combination cancer therapy in a mammal, comprising the introduction of additional funds in therapeutically effective amounts, and the compounds of formula (IV), (Va), (VIa) or (VIb) in therapeutically effective amount, as defined in any one of claims 1 to 57, with an additional means selected from monoclonal antibodies, alquiler the existing agent, anticancer means, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent.

75. The way to accelerate the response or the reaction in a patient suffering from a cancer where the patient receives treatment with the use of additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent, comprising the administration to a patient in combination with additional means of compounds of formula (IV), (Va), (VIa) or (VIb)as defined in any one of claims 1 to 26.

76. The use of additional means selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent, for preparing a medicinal product intended for use for the treatment or prophylaxis of a patient undergoing treatment with the compound of formula (IV), (Va), (VIa) or (VIb)as defined in any one of claims 1 to 26.

77. The use of the compounds of formula (IV), (Va), (VIa) or (VIb)as defined in any one of claims 1 to 26, for preparing a medicinal product intended for use for the treatment or prophylaxis of a patient undergoing treatment for more what redston, selected from a monoclonal antibody, an alkylating agent, an anticancer tool, another CDK inhibitor and a hormone, hormone agonist, hormone antagonist or garminmobilepc agent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, where R1 denotes H; R6, R7, R8, R9, R10 independently denote H, F, Cl, Br, CF3, OCH3, OCF3, OCHF2, SCH3, SCF3, phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or NR3R4, where the alkyl and phenyl can be substituted with R2 once or many times, and where any two residues from R6, R7, R8, R9, R10 in neighbouring positions of the phenyl ring can form a -CH=CH-CH-CH- residue together; m equal 0, 1, 2 or 3; X denotes -(CH2)2-; R2 denotes F, Cl, Br, CN, OCH3, OCF3, CH3, CF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl, where the alkyl can be substituted once or many times with OH, F, Cl, Br or CN; R3, R4 independently denote H or (C1-C6)-alkyl; or physiologically acceptable salts thereof, provided that the compound 3-(2-o- tolylamino-benzoxazol-6-yl)-propionic acid is excluded. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent which activates GPR40 receptors and use of said compounds to prepare a medicinal agent for lowering blood sugar level, for treating diabetes and for increasing insulin secretion.

EFFECT: compounds of formula I which activate GPR40 receptors are obtained.

6 cl, 2 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), where A1, A2, A3, A4, A5 ad A6 are independently selected from a group comprising CR3 and N; provided that the biggest one of A1, A2, A , A4, A5 and A6 denotes N; B1, B2 and B3 are independently selected from a group comprising CR2 and N; each R3 independently denotes H or C1-C6 alkyl; and R1, R2, R4, R5, W and n are as given in the description, or salts thereof which are suitable for use in agriculture. The invention also relates to compositions containing compounds of formula (1), and insect-pest control methods which involve contact between the pest or habitat thereof with a biologically effective amount of the compound or composition according to the present invention, as well as to methods of protecting seeds and animals from insects-pests.

EFFECT: high effectiveness of the obtained compounds in insect-pest control.

29 cl, 12 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula I: or salt thereof, where: y equals 0; R1 and R2 are taken together to form a 3-tetrahydrofuran ring; R9 is hydrogen; R10 is 5-oxazolyl; R11 is a methoxy-, ethoxy- or isopropoxy group; each V1 is independently selected from halogen, NO2, CN, OR12, OC(O)R13, OC(O)R12, OC(O)OR13, OC(O)OR12, OC(O)N(R13)2, OP(O)(OR13)2, SR13, SR12, S(O)R13, S(O)R12, SO2R13, SO2R12, SO2N(R13)2, SO2NR12R13, SO3R13, C(O)R12, C(O)OR12, C(O)R13, C(O)OR13, NC(O)C(O)R13, NC(O)C(O)R12, NC(O)C(O)OR13, NC(O)C(O)N(R13)2, C(O)N(R13)2, C(O)N(OR13)R13, C(O)N(OR13)R12, C(NOR13)R13, C(NOR13)R12, N(R13)2, NR13C(O)R12, NR13C(O)R13, NR13C(O)OR13, NR13C(O)OR12, NR13C(O)N(R13)2, NR13C(O)NR12R13, NR13SO2R13, NR13SO2R12, NR13SO2N(R13)2, NR13SO2NR12R13, N(OR13)R13, N(OR13)R12, P(O)(OR13)N(R13)2 and P(O)(OR13)2; where each R12 is a monocyclic or bicyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 4 heteroatoms selected from N, O or S, and where CH2 lying next to said N, O or S can be substituted with C(O); and each R12 optionally contains up to 3 substitutes selected from R11; where each R13 is independently selected from H, (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl; and where each R13 optionally contains a substitute which is R14; where R14 is a monocyclic or bicyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 4 heteroatoms selected from N, O or S, and where CH2 lying next to said N, O or S can be substituted with C(O); and each R14 optionally contains up to 2 substitutes independently selected from H, (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl, 1,2-methylenedioxy-, 1,2-ethylenedioxy group or (CH2)n-Z; where Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C4)alkyl, SO(C1-C4)alkyl, SO2(C1-C4)alkyl, NH2, NH(C1-C4)-alkyl, M((C1-C4)alkyl)2, COOH, C(O)O(C1-C4)alkyl or O(C1-C4)-alkyl; and where any carbon atom in any R13 is optionally substituted with O, S, SO, SO2, NH or N(C1-C4)alkyl; where said method includes a step for reacting a compound of formula II with a compound of formula III in a polar or nonpolar aprotic, virtually anhydrous solvent or mixture thereof, and optionally in an acceptable base selected from an organic base, inorganic base or a combination of an organic base and an inorganic base; and while heating the reaction mixture to temperature ranging from approximately 30°C to approximately 180°C for approximately 1 to 48 hours in a virtually inert atmosphere: where: LG is -OR16; where R16 is -(C1-C6)-straight or branched alkyl; -(C2-C6)-straight or branched alkenyl or alkynyl; or a monocyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 3 heteroatoms selected from N, O or S, and each R16 optionally contains up to 5 substitutes independently selected from (C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or (CH2)n-Z; n equals 0, 1, 2, 3 or 4; V1, y, Z, R1, R2, R9, R10 and R11 are as indicated above; and provided that R16 is not a halogen-substituted (C2-C3)-straight alkyl.

EFFECT: improved method.

19 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a combination for tumour cell growth inhibition containing a cytotoxic compound selected from camptothecin compounds; metabolic antagonists; periwinkle alkaloids; taxanes; platinum compounds; topoisomerase 2 inhibitors; and a combination of two or more said types, or a signal transfer inhibitor selected from antibodies a target of which is EGFR receptor; tyrosine kinase EGFR inhibitors; from antibodies a target of which is a VEGF/VEGF receptor system; PDGFR inhibitors; Raf inhibitors and PKB transfer inhibitors in an effective amount and a compound of formula (IV).

, where R1, R2, R11, T, U and g have the values specified in formula.

EFFECT: what is offered is a pharmaceutical composition, a method for tumour cell growth inhibition, a method of treating a malignant growth in a patient and application of the combination for preparing a drug; the new effective combinations for tumour cell growth inhibition are presented.

77 cl, 20 dwg, 7 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

,

where R1 is selected from formulae

, and ,

n equals 0; R6 and R7 are independently selected from hydrogen, C1-C6alkyl, cyanoC1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; or R6 and R7 together with a carbon atom to which they are bonded form a 6-member heterocycloalkyl with one nitrogen atom; wherein any alkyl in R6 and R7 can optionally contain a methylene group substituted with an O atom; wherein any aryl in R6 and R7 or formed by a combination of R6 and R7 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, -XC(O)OR10; where X denotes a bond; R10 is independently selected from C1-C6alkyl; R8 is selected from C5-C9heteroarylC0-C4alkyl containing 2-3 heteroatoms independently selected from N, O and S; wherein any heteroaryl in R8 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, C3-C6cycloalkyl; R2 denotes hydrogen; R3 and R4 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; wherein any alkyl in R3 and R4 can optionally contain a methylene group substituted with a S(O)2 group; R5 is selected from C5-C6heterocycloalkyl with 1-2 heteroatoms selected from N and O, and NR12R13; where R12 and R13 are independently selected from C1-C6alkyl; as well as pharmaceutically acceptable salts and isomers thereof. The invention also relates to use of compounds of formula (I) in preparing a medicinal agent, and to a pharmaceutical composition having cathepsin S inhibiting properties, which contains a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable filler.

EFFECT: obtaining compounds which can be used as cathepsin S inhibitors.

10 cl, 12 dwg, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a combination for tumour cell growth inhibition containing a cytotoxic compound selected from camptothecin compounds; metabolic antagonists; periwinkle alkaloids; taxanes; platinum compounds; topoisomerase 2 inhibitors; and a combination of two or more said types, or a signal transfer inhibitor selected from antibodies a target of which is EGFR receptor; tyrosine kinase EGFR inhibitors; from antibodies a target of which is a VEGF/VEGF receptor system; PDGFR inhibitors; Raf inhibitors and PKB transfer inhibitors in an effective amount and a compound of formula (IV).

, where R1, R2, R11, T, U and g have the values specified in formula.

EFFECT: what is offered is a pharmaceutical composition, a method for tumour cell growth inhibition, a method of treating a malignant growth in a patient and application of the combination for preparing a drug; the new effective combinations for tumour cell growth inhibition are presented.

77 cl, 20 dwg, 7 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: medicine.

SUBSTANCE: present invention presents new compounds which are modulators of cannabinoid receptors, particularly modulators of cannabinoid receptors 1 (CB1) or cannabinoid receptors 2 (CB2), and an application thereof for treating diseases, conditions and/or disorders regulated by a cannabinoid receptor (such as painful sensations, neurodegenerative disorders, ingestion disorders, weight loss or weight control and obesity), as well as based pharmaceutical compositions. New compounds are characterised by graphic formulas

in which radicals and groups have the values specified in the patent claim.

EFFECT: higher efficiency of applying the composition.

55 cl, 13 tbl, 3 dwg, 802 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

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