Retinoid compounds (options), composition, method of determination of retinoid antagonists hormones, the treatment method and intermediate products

 

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II. In the above compounds of formulas I, II, III, IV, X is selected from O, S, [C(R1)2]n', R1means hydrogen or alkyl with the number of carbon atoms from 1 to 6; R2means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6, F, Cl, Br, J, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6; R3means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6, or F; m = 0 to 3; o = 0 to 3; Z Is-WithS-, -CO-NH, -COO-, -CSNH-, -CH=CH-, -(CR1=CR1)n'where n' = 0 to 5, or Z is absent, Y represents phenyl or naftalina group or heteroaryl selected from the group consisting of pyridyl, teinila, and other futile 8 C. and 159 C.p. f-crystals, 18 tab., 20 Il.

Table T T T T

Claims

1. The compounds of formulawhere X is S or O; R2means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6, F, Cl, Br, J, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6; R3means hydrogen or lower alkyl with the number of carbon atoms from 1 to 6, or F; m = 0 - 3;
on = 0 - 3;
Z- S-, -CO-NH, -COO-, -CSNH-, -CH= CH-, -(CR1= CR1)n'where R1denotes H or alkyl with the number of carbon atoms from 1 to 6; n' = 0 to 5, or Z is absent;
Y represents phenyl or naftalina group or heteroaryl selected from the group consisting of pyridyl, teinila, furil, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, while the phenyl and heteroaryl groups, if possible, have as substituents one or two R2groups, or when Z means -(CR1= CR1)n'and;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR), CHOR13O, -COR7, CR7(OR12)2, CR70R13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower ALK radical with the number of carbon atoms from 2 to 5;
R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5, R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)- COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms.

2. Connection on p. 1, in which Y represents phenyl, pyridyl, thienyl or furyl.

3. Connection on p. 1, in which Y represents phenyl.

4. Connection on p. 3, in which the substituents in the phenyl ring are in the 1,4-(para) position.

5. Connection on p. 1, in which Y represents naphthyl.

6. Connection on p. 1, in which Y represents pyridyl.

7. Connection on p. 1, in which Y means thienyl or furyl.

8. Connection on p. 1, in which Z means a specified group -(CR1= CR1)n'and Century

9. Connection on p. 1, in which R3means H, F, or CF3.

10. Connection on p. 1, in which R3means H or methyl.

11. Connection on p. 1, in which R2means (R15)ris phenyl.

12. Connection on p. 1, in which R14means (R15)r-heteroaryl.

13. Connection on p. 12, in which R2means (R15)r-heteroaryl, where the heteroaryl group is a five - or six-membered cycle with 1 or 2 heteroatoms.

14. Connection on p. 13, in which the heteroaryl group is selected from 2-pyridyl, 3-pyridyl, 2-tanila and 2-thiazolyl.

15. Connection on p. 1, in which the group R15means N, CF3, F, lower alkyl, lower alkoxy, hydroxy or chlorine.

16. Connection on p. 1, in which Z means WithWith-.

17. Connection on p. 1, in which Z denotes-CO-NH-.

18. Connection on p. 1, in which Z means-CS-NH-.

19. Connection on p. 1, in which Z denotes-COO-.

20. Connection on p. 1, in which Z means -(CR1= CR1)n'where n' = 1.

21. A method of treating a pathological state in a mammal, which is susceptible to treatment with retinoid antagonist or negative is/img>
or

in which X is S, O or X is [C(R1)2]n'where R1denotes H or alkyl with the number of carbon atoms from 1 to 6, and n' = 0 - 2;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
Z means CS-, -CO-NH, -COO-, -CSNH-, -CHCH-, -(CR1= CR1)n'where n' = 0 to 5, or Z is absent;
Y represents phenyl or naftalina group or heteroaryl selected from the group consisting of pyridyl, teinila, furil, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, while the phenyl and heteroaryl groups, if possible, have as substituents one or two R2groups, or when Z means -(CR1= CR1)n'where n' = 3, 4 or 5 then Y represents a direct valence bond between the specified group -(CR1= CR1)n'and;
And oshacademy from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11, Cho, CH(OR), CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower askil, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5, and R14means (R15)15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8), COR8, NR8CON(R8)]2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl groups; with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms;
R16means lower alkyl with the number of carbon atoms from 1 to 6;
R17means H, lower alkyl with the number of carbon atoms from 1 to 6;
as a retinoid antagonist or negative hormone capable of contact with a subtype of the receptor retinova acid selected from the group consisting of RAR, RARand RAR.
22. Method of treatment for p. 21 to reduce toxicity or unwanted side effects from the introduction of the retinoid compound to the mammal.

23. Way leva or vitamin a or precursors of vitamin A.

24. The method according to p. 21 for local use.

25. The method according to p. 21 for systematic implementation.

26. The method according to p. 21, wherein the retinoid antagonist or negative hormone binds to a subtype of receptor retinoid with Kdless than about 1 MK/mol.

27. The method according to p. 21, characterized in that as the antagonist or negative hormone is used as a compound of General formula

in which X is S, O or X is [C(R1)2]n'where R1denotes H or alkyl with the number of carbon atoms from 1 to 6, and n' = 0 - 2;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
o = 0 -3;
Z means CC-, -CO-NH, -COO-, -CSNH-, -CHCH-, -(CR1= CR1)n'where n' = 0 to 5, or Z is absent
Y represents phenyl or naftalina group or heteroaryl selected from the group consisting of pyridyl, teinila, furil, peridocally group, if possible, have as substituents one or two R2groups, or when Z means -(CR1= CR1)n'where n' = 3, 4 or 5 then Y represents a direct valence bond between the specified group -(CR1= CR1)n'and;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl. containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR), CHOR13O, -COR7, CR7(OR12)2, CR70R13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10NGO group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5, and R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, g = 0 to 5, and R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)- COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms.

28. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound where Y represents phenyl, pyridyl, thienyl or furyl.

29. The method according to p. 27, characterized in that kachestvenaia fact, that the antagonist or negative hormone connection is used, where the phenyl ring has substituents in 1,4-position.

31. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound where Y represents naphthyl.

32. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound where Y represents pyridyl.

33. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound where Y means thienyl or furyl.

34. The method according to p. 27, characterized in that as the antagonist or negative hormone connection is used, where Z means -(CR1= CR1)n'and n' = 3, 4 or 5, and Y represents a valence bond between the specified group -(CR1= CR1)n'and Century

35. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound, where R2means H, F, or CF3.

36. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound, where R3means H or methyl.

37. The method according to p. 27, characterized in that as an is 38. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-heteroaryl.

39. The method according to p. 38, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-heteroaryl, where the heteroaryl group means a five - or six-membered cycle with 1 or 2 heteroatoms.

40. The method according to p. 39, characterized in that as the antagonist or negative hormone connection is used, where the heteroaryl group is selected from 2-piricola, 3-pyridyl, 2-tanila and 2-thiazolyl.

41. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound, where R15means N, CF3, F, lower alkyl, lower alkoxy, hydroxy or chlorine.

42. The method according to p. 27, characterized in that as the antagonist or negative hormone connection is used, where Z means WithWith-.

43. The method according to p. 27, characterized in that as the antagonist or negative hormone connection is used, where Z denotes-CO-NH-.

44. The method according to p. 27, characterized in that as an antagonist of Il is about as antagonist or negative hormone is used as a compound where R1means N.

46. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound where Z denotes-COO-.

47. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound Z means -(CR1= CR1)n'and n' = 1.

48. The method according to p. 27, characterized in that as the antagonist or negative hormone use connection, where X is [C(R1)2]nand n = 1 or 0.

49. The method according to p. 27, characterized in that as the antagonist or negative hormone is used as a compound where X is S or O.

50. The method according to p. 21, wherein the antagonist or negative hormone has the formula

in which R1denotes H or alkyl with the number of carbon atoms from 1 to 6;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
And means Rashi from 3 to b carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR), CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkline group with the number of carbon atoms from 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5;
R14means (R1515means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8), COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms.

51. The method according to p. 50, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pyridyl, (R15)r-thiazolyl and(R15)r-thienyl.

52. The method according to p. 51, characterized in that as the antagonist or negative hormone is used as a compound, where R15means independently N, CH3With2H5, F, CF3, Cl, CH3About or HE.

53. The method according to p. 52, characterized in that as the antagonist or negative hormone connection is used, where And ub>9R10.

54. The method according to p. 53, characterized in that as the antagonist or negative hormone is used as a compound, where R1means of CH3, R2means H or F and R3means N.

55. The method according to p. 54, characterized in that as the antagonist or negative hormone is used as a compound where n = 0, and the means COOH, its pharmaceutically acceptable salt or sea2H5.

56. The method according to p. 21, wherein the antagonist or negative hormone has the formula

in which R1denotes H or alkyl with the number of carbon atoms from 1 to 6;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
X1means O or S;
X2means O or NR8;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl, Sorainen ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR), CHOR13O, -COR7, CR7(COR12)2, CR7OR13O, or three-dizisi alkyl silyl, where R7means alkyl, cycloalkyl or alkeneamine group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5;
R14means (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms, you ሺ/sub>, NH(R8)- COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms.

57. The method according to p. 56, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pyridyl, (R15)r-thiazolyl and (R15)r-thienyl.

58. The method according to p. 57, characterized in that as the antagonist or negative hormone is used as a compound, where R15means independently N, CH3With2H5, F, CF3, CL, CH3About or HE.

59. The method according to p. 58, characterized in that as the antagonist or negative hormone connection is used, where a represents (CH2)nwhere n = 0 to 5 and means COOH or its pharmaceutically acceptable salt, COOR8or CONR9
1means of CH3, R2means H or F and R3means N.

61. The method according to p. 60, characterized in that as the antagonist or negative hormone is used as a compound where n = 0, and the means COOH, its pharmaceutically acceptable salt or sea2H5.

62. The method according to p. 21, wherein the antagonist or negative hormone has the formula

in which R2 signifies hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 atoms upgrade and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8CONR9R10, -CH2HE, CH2OR11CH2OCOR7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5;
R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5; R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8) - COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted Alky the carbon and 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms.

63. The method according to p. 62, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pernil, (R15)r-thiazolyl and (R15)r-thienyl.

64. The method according to p. 63, characterized in that as the antagonist or negative hormone is used as a compound, where R15means independently N, CH3With2H5, F, CF3, CL, CH3About or HE.

65. The method according to p. 64, characterized in that as the antagonist or negative hormone connection is used, where means And means (CH2)nwhere n = 0 to 5 and means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10.

66. The method according to p. 65, characterized in that as the antagonist or negative hormone is used as a compound, where R2means H or F and R3means CH3and o = 2.

67. The method according to p. 66, characterized in that as the antagonist or negative hormone 68. The method according to p. 21, wherein the antagonist or negative hormone has the formula

in which X is O or S;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 to 3;
o = 0 to 3;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkyl silyl, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means Alki is about 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5;
R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5, and R15means independently H, F, ClrI, NO2N(R8)2, NH(R8)- COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or the p. 67, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pyridyl, (R15)r-thiazolyl and (R15)r-thienyl
70. The method according to p. 69, characterized in that as the antagonist or negative hormone is used as a compound, where R15means independently N, CH3With2H5, F, CF3, CL, CH3About or HE.

71. The method according to p. 70, characterized in that as the antagonist or negative hormone connection is used, where means And means (CH2)nwhere n = 0 to 5, and means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10.

72. The method according to p. 71, characterized in that as the antagonist or negative hormone is used as a compound where X is s

73. The method according to p. 72, characterized in that as the antagonist or negative hormone is used as a compound, where R2means H or F and R3means N.

74. The method according to p. 73, characterized in that as the antagonist or negative hormone use connection, means COOH, its pharmaceutically acceptable salt or COOC2H5.
in which R1denotes H or alkyl with the number of carbon atoms from 1 to 6;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkyl silyl, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl which includes lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5, and
R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5; R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)- COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilanes, where the alkyl groups independently contain from 1 to 6 carbon atoms.

76. The method according to p. 75, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pyridyl, (R15)r-thiazolyl and (R15)r-thienyl.

77. The method according to p. 76, characterized those who Simo N, CH3With2H5, F, CF3, CL, CH3About or HE.

78. The method according to p. 77, characterized in that as the antagonist or negative hormone connection is used, where In denotes COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10
79. The method according to p. 78, characterized in that as the antagonist or negative hormone is used as a compound, where R1means of CH3, R2means H or F and R3means N or CH3.

80. The method according to p. 79, characterized in that as the antagonist or negative hormone is used as a compound where n = 0, and the means COOH, its pharmaceutically acceptable salt or sea2H5.

81. The method according to p. 21, wherein the antagonist or negative hormone has the formula

in which R1denotes H or alkyl with the number of carbon atoms from 1 to 6;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, verzameling alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the total number of carbon atoms is, aderrasi from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means'neill, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5; R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)-COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alilou group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilanes, where the alkyl groups independently contain from 1 to 6 carbon atoms.

82. The method according to p. 81, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pyridyl, (R15)r-thiazolyl and (R15)r-thienyl.

83. The method according to p. 82, characterized in that as the antagonist or negative hormone is used as a compound, where R15means independently N, CH3With2H5, F, CF3, Cl, CH3About or HE.

84. How will psyche (CH2)qwhere q = 0 to 5, means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10.

85. The method according to p. 84, characterized in that as the antagonist or negative hormone is used as a compound, where R1means of CH3, R2means H or F and R3means N.

86. The method according to p. 85, characterized in that as the antagonist or negative hormone is used as a compound where n = 0, and the means COOH, its pharmaceutically acceptable salt or sea2H5.

87. The method according to p. 21, wherein the antagonist or negative hormone has the formula

in which R1denotes H or alkyl with the number of carbon atoms from 1 to 6;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from I to 6 or F;
m = 0 - 3;
on = 0 - 3;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3T 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5;
R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains from 1 to 3 sub>)2, NH(R8), COR8, NR8CON(R8)2, OH, OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilanes, where the alkyl groups independently contain from 1 to 6 carbon atoms.

88. The method according to p. 87, characterized in that as the antagonist or negative hormone is used as a compound, where R14means (R15)r-phenyl, (R15)r-pyridyl, (R15)r-thiazolyl and (R15)r-thienyl.

89. The method according to p. 88, characterized in that as the antagonist or negative hormone is used as a compound, where R15means independently N, CH3With2H5, F, CF3, Cl, CH3About or HE.

90. The method according to p. 89, characterized in that as the antagonist or negative hormone connection is used, where a represents (CH2)qwhere q = 0 to 5, means COOH or its pharmaceutically acceptable salt, COOR8or CONR1means of CH3, R2means H or F and R3means N or CH3.

92. The method according to p. 91, characterized in that as the antagonist or negative hormone is used as a compound where n = 0, and the means COOH, its pharmaceutically acceptable salt or sea2H5.

93. The compound of the formula

in which X denotes O or S, or X is [C(R1)2]nwhere R1denotes H or alkyl with the number of carbon atoms from 1 to 6, and n' = 0 - 2;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
Y represents phenyl or naftalina group, or heteroaryl selected from the group consisting of pyridyl, teinila, furil, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, while the phenyl and heteroaryl groups, if possible, have as substituents one or two R2group;
And means (Rashi from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5;
R14snpa contains from 1 to 3 heteroatoms, selected from the group consisting of O, S and N, r = 0 to 5, and R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)-COR8, NR8CON(R8)2HE OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilanes, where the alkyl groups independently contain from 1 to 6 carbon atoms;
R16means lower alkyl with the number of carbon atoms from 1 to 6;
R17means H, lower alkyl with the number of carbon atoms from 1 to 6;
94. Connection on p. 93, in which Y represents phenyl, pyridyl, thienyl or furyl.

95. Connection on p. 93, in which Y represents phenyl.

96. Connection on p. 95, in which the phenyl ring is 1,4-(para) substituted.

97. Connection on p. 93, in which Y represents pyridyl.

98. Connection on p. 93, in which Y means thienyl or furyl.

99. Connection on p. 93, in which R14means (R15)r-phenyl,
100. Connection on p. 93, in which R14-heteroaryl, where the heteroaryl group is a five - or six-membered cycle with 1 or 2 heteroatoms.

102. Connection on p. 101, in which the heteroaryl group is selected from 2-pyridyl, 3-pyridyl, 2-tanila and 2-thiazolyl.

103. Connection on p. 93, in which the group R15represents H, CF3, F, lower alkyl, lower alkoxy, hydroxy or chlorine.

104. Connection on p. 93, in which X is [C(R1)2]n'.

105. Connection on p. 93, in which the group R1means of CH3and n = 1.

106. Connection on p. 93, in which the group X is O or S.

107. Connection on p. 93, in which a represents (CH2)qwhere q = 0 to 5, means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10
108. The compound of the formula

in which R1independently denotes H or alkyl with the number of carbon atoms from 1 to 6;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 the rd from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to b carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5 carbon atoms, R8means alkyl group with carbon atoms of 1 to 10, or trimethylsilyloxy, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with 5)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5, and R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)-COR8, NR8CON(R8)2, HE, OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and 1 to 3 triple links, or trialkylsilyl or trialkylsilanes, where the alkyl groups independently contain from 1 to 6 carbon atoms; containing from 1 to 10 carbon atoms and 1 to 3 triple relations, or trialkylsilyl or trialkylsilyl group, where the alkyl groups independently contain from 1 to 6 carbon atoms;
r = 0 - 5;
R16means lower alkyl with the number of carbon atoms from 1 to 6;
R17means H, lower alkyl with the number of carbon atoms from 1 to 6.

109. Connection on p. 105, in which a represents (CH2)qwhere q = 0 to 5, means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10.

110. Connection appoints hydrogen.

112. Connection on p. 111, in which R15means N or CH3and if R15means of CH3he is in position 4 of the phenyl ring.

113. Connection on p. 112, which is 4-[3-oxo-3-(7,8-dihydro-5-(4-were)-8,8-dimethyl-2-naphthalenyl)-1-propenyl] benzoic acid or 4-[3-oxo-3-(7,8-dihydro-5-phenyl-8,8-dimethyl-2-naphthalenyl)-1-propenyl] benzoic acid.

114. The method of determining the retinoid antagonists hormones, contains the following stages: obtaining transformed cells containing the marker gene with transcriptional activity and ability to bind to recombinant retinoid receptor, with the specified protein receptor retinoid has at least a region located C-terminal with respect to the domain DNA binding of intact receptor retinoid; measurement of basal levels of expression of the marker gene in transfected raw cells, these transfetsirovannyh cells obtained in the absence of retinoid; treatment of transfected cells retinoid compound, and tested negative hormonal activity; measuring the level of expression of the marker gene in treated cells; against echinoidea negative hormones, this retinoid compounds cause a lower level of expression of the marker gene in treated cells compared with basal level of expression of the marker gene in untreated cells.

115. The method according to p. 114, characterized in that a retinoid receptor is a receptor for retinoic acid selected from the group consisting of RAR, RARand RAR.
116. The method according to p. 114, characterized in that the receptor retinoid is a retinoid X receptor selected from the group consisting of RXR-, RXR-and RXR-.
117. The method according to p. 114, wherein the recombinant receptor retinoid is selected from the group consisting of RAR and RXR.

118. The method according to p. 114, wherein the recombinant retinoid receptor is a chimeric receptor retinoid, having a domain is a constitutive activator of transcription.

119. The method according to p. 118, wherein the domain is a constitutive activator of transcription contains many amino acids, having the General (result) negative charge.

120. The method according to p. 118, wherein the domain-activator IRS.

121. The method according to p. 120, wherein the domain-activator of viral transcription is a herpes virus VP-16.

122. The method according to p. 118, wherein the domain is a constitutive activator of transcription result has a negative charge, and recombinant retinoid receptor deleterows of the DNA-binding domain.

123. The method according to p. 114, wherein the recombinant retinoid receptor has domain DNA binding, specific to CIS-regulatory element, other than the active element retinoic acid.

124. The method according to p. 123, characterized in that the CIS-regulatory element, other than the reactive element retinoic acid and is a reactive element of estrogen.

125. The method according to p. 114, wherein transtitional cell get in a nutrient medium, almost devoid of retinoids.

126. The method according to p. 122, wherein the nutrient medium contains serum, emaciated activated carbon.

127. The method according to p. 114, wherein the marker gene is a luciferase gene and stage measurements include luminometry.

128. The method according to p. 115, wherein the marker gene is a gene of p-galactosidase and Studio transfusiona cell is transtitional mammal cells.

130. The method according to p. 129, wherein transfusiona cell of a mammal is transtorno transtitional mammal cells.

131. The method according to p. 129, wherein transfusiona cell of a mammal is transtitional cage green monkey.

132. The method according to p. 129, wherein transfusiona cell of a mammal is transtitional human cell.

133. Composition for joint introduction of the mammal with an agonist of the receptor of the steroid superfamily containing a pharmaceutically effective dose of a compound of General formula


in which X is S, O or X is [C(R1)2]n'where R1denotes H or alkyl with the number of carbon atoms from 1 to 6, and n' = 0 - 2;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6, F, CL, Br, I, CF3, fluoro-substituted alkyl with the number of carbon atoms from 1 to 6, HE, SH, alkoxy with the number of carbon atoms from 1 to 6 or alkylthio with the number of carbon atoms from 1 to 6;
R3means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6 or F;
m = 0 - 3;
on = 0 - 3;
b> where n' = 0 to 5, or Z is absent;
Y represents phenyl or naftalina group or heteroaryl selected from the group consisting of pyridyl, teinila, furil, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, while the phenyl and heteroaryl groups, if possible, have as substituents one or two R2groups, or when Z means -(CR1= CR1)n'where n' = 3, 4 or 5 then Y represents a direct valence bond between the specified group -(CR1= CR1)n'and;
And means (CH2)qwhere q = 0 to 5, lower branched alkyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms and 1 or 2 double bonds, quinil containing from 2 to 6 carbon atoms and from 1 to 2 triple ties;
In the mean hydrogen, COOH or its pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2HE, CH2OR11CH2OCOR11CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilane, where R7means alkyl, cycloalkyl or alkenylphenol group containing from 1 to 5, in which the alkyl group has from 1 to 10 carbon atoms, or cycloalkyl group with the number of carbon atoms from 5 to 10, or R8means phenyl or lower alkylphenyl, R9and R10independently mean hydrogen, alkyl group with carbon atoms of 1 to 10 carbon atoms, cycloalkyl group with the number of carbon atoms from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R11means lower alkyl, phenyl or lower alkylphenyl, R12means lower alkyl, and R13means a divalent alkyl radical with the number of carbon atoms from 2 to 5, and R14means (R15)r-phenyl, (R15)r-naphthyl, (R15)r-heteroaryl, where the heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of O, S and N, r = 0 to 5, and R15means independently H, F, Cl, Br, I, NO2N(R8)2, NH(R8)-COR8, NR8CON(R8)2, OH, OCOR8OR8CN and alkyl group with carbon atoms of 1 to 10, fluoro-substituted alkyl group with the number of carbon atoms from 1 to 10 carbon atoms, alkenylphenol group containing from 1 to 10 carbon atoms and from 1 to 3 double bonds, alkylamino group containing from 1 to 10 carbon atoms and from 1 may contain from 1 to 6 carbon atoms, R16means lower alkyl with the number of carbon atoms from 1 to 6;
R17means H, lower alkyl with the number of carbon atoms from 1 to 6,
as retinoid negative hormone to increase pharmacological activity of the indicated agonist receptor superfamily of steroid.

134. The composition according to p. 133, wherein the pharmacological activity of the indicated agonist receptor superfamily of steroid is an antiproliferative activity.

135. The composition according to p. 133, wherein the antiproliferative activity measured in the epithelium retinal pigment.

136. The composition according to p. 133, wherein the agonist receptor superfamily of steroid is selected from the group consisting of a receptor agonist retinoids, agonist of the receptor of vitamin D agonist of the glucocorticoid receptor, agonist-activated proliferation receptor peroxisomes and agonist of the estrogen receptor.

137. The composition according to p. 136, wherein the receptor agonist is an RAR agonist.

138. The composition according to p. 137, wherein the RAR agonist is selected from the group consisting of all-TRANS-retinova acid, 13-CIS-retinova acid, 4-[[(5,6,7,8-tetrahydro-2-naphthalenyl)-2-propenyl] -benzoic acid (TTNPB).

139. The composition according to p. 133, wherein the receptor agonist is an agonist of RXR.

140. The composition according to p. 139, wherein the RXR agonist is selected from the group consisting of all-TRANS-retinova acid, 9-CIS-retinova acid, 4-[3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethynyl] -benzoic acid and 4-[3,5,5,8,8-pentamethyl-2-(5,6,7,8-tetrahydro-2-naphthalenyl)-1-cyclopropyl] -pyridine-5-carboxylic acid.

141. The composition according to p. 133, wherein the receptor agonist is a 1,25-dihydroxy-vitamin D3.

142. The composition according to p. 133, wherein the receptor agonist is a dexamethasone.

143. The composition according to p. 133, wherein the receptor agonist is 3,3', 5-trijodthyronin.

144. The composition according to p. 133, wherein the retinoid negative hormone is a RAR-specific retinoid negative hormone.

145. The composition according to p. 144, characterized in that the RAR-specific retinoid negative hormone has a dissociation constant less than or approximately equal to 30 nm.

146. The composition according to p. 145, wherein the RAR-specific retinoid negative hormone is selected from the group consisting of AGN 193109, AGN 193385, AGN now dose retinoid negative hormone, further comprises an agonist of the steroid superfamily.

148. The compound of the formula

in which X is [C(R1)2]n, R1means alkyl with the number of carbon atoms from 1 to 6, and n = 1;
R2means hydrogen, lower alkyl with the number of carbon atoms from 1 to 6,
R3means hydrogen;
m = 0 or 1;
on = 1;
Z means -(CR1= CR1)n'where n' = 0 or 2 to 5;
Y means naftalina group which may have as substituents one or two R2group, where Z means -(CR1= CR1)n'where n = 2-5, then Y is a valence bond between the specified group -(CR1= CR1)n'- and;
And means (CH2)qwhere q = 0, means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10where R8means alkyl with the number of carbon atoms from 1 to 10;
R14means (R15)r-phenyl, r = 0 to 5; R15means independently an alkyl group with carbon atoms of 1 to 10.

149. Connection on p. 148, in which n' = 3.

150. Connection on p. 148, in which n' = 0.

151. Connection on p. 150, in which a represents (CH2)q, where q = 0.

152. Connection on p. 151, which isn 152, in which Y represents naphthyl.

154. Connection on p. 153, in which naftalina group is a 2,6-substituted.

155. Connection on p. 154, in which a represents (CH2)q, where q = 0.

156. Connection on p. 155, which means COOH or its pharmaceutically acceptable salt, COOR8or CONR9R10.

157. Connection on p. 1, in which X is S.

158. Connection on p. 157, in which Z means WithWith-.

159. Connection on p. 158, in which Y represents phenyl.

160. Connection on p. 159, in which R14means (R15)ris phenyl.

161. Connection on p. 160, in which R15means lower alkyl.

162. Connection on p. 161, in which a represents (CH2)qwhere q = 0.

163. Connection on p. 162, which means COOH, or its pharmaceutically acceptable salt, COOR8.

164. Connection on p. 163, in which m = 0.

165. The compound of the formula

in which R15means lower alkyl with the number of carbon atoms from 1 to 6;
R8* denotes H, lower alkyl with the number of carbon atoms from 1 to 8
or pharmaceutically acceptable salt of the compounds.

166. Connection on p. 165, in which R15means methyl.

167. Connection on p. 166 points and features:
01.09.1995 on PP. 1-20, 148-167; PP. 21-92, 133-147 for compounds that are not negative hormone;
13.10.1995 on PP. 93-113;
11.03.1996 on PP. 21-92, 133-147.

 

Same patents:

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to new heterocyclic condensed to benzoylpyridine General formula I, where R1and R2denote independently from each other H or A; X denotes CR4R5; C=Z or O, Y represents CR6R7Z denotes O or CH2, R4, R5, R6or R7denote independently from each other H, A, HE or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A; And denotes alkyl with 1 to 6 C-atoms; n represents 0 or 1, and their physiologically acceptable salts

The invention relates to non-steroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds

The invention relates to new triazinyl compounds of formulas Ia and Ib:

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or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment
The invention relates to the selection of 2.5-biphenyldicarboxylic acids from oxidation products of 2,5-dimethylbiphenyl

The invention relates to a method for producing monomer, in particular 2,5-biphenyldicarboxylic (filteredfiles) acid, which can be used together with other aromatic acids and dialami for the production of thermotropic liquid crystal polyesters (TGCP) industrial

Retinoids // 2166499
The invention relates to new retinoids formula I, where the relationship C7-C8is a double bond, and one of R1and R2represents C1-C4alkyl and the other represents chlorine, bromine or iodine, or R1and R2together denote C3-C6alkylene; or the relationship of C7-C8is a triple bond, and R1and R2together denote C3-C6alkylen; and their pharmaceutically acceptable salts or esters

The invention relates to organic chemistry, in particular to a method of obtaining 13Z-retinoic acid and can be used in the production of pharmaceuticals

The invention relates to liquid compositions containing gonadotropin, the method of manufacturing the specified composition, the cartridge containing the specified composition, and to a device for injection that contains the specified cartridge

The invention relates to an improved method for producing adducted end of the condensation products, which are Schiff bases, components of which include a protein having useful activity in animals, and aromatic o-hydroxyaldehyde, which connect the above components in an aqueous medium at pH 7.0 or higher to form a reaction mixture under conditions effective to conduct specified the condensation reaction essentially to completion by using the stage of fast compared to drying in ambient conditions removal 97,0 to 99.9% by weight, preferably approximately 98,0 - 99,0% by weight of water, already present or formed during this reaction, condensation, consistent with maintaining the integrity of reagents condensation and adductor final product

-acetoxy-3-phenylpropionate-6-methylpregna-4,6-dien - 20-he, with gestagennami activity, and the drug based on it" target="_blank">

The invention relates to medicine, more specifically to medicines designed to maintain pregnancy, and may find application in obstetrics and gynecology

The invention relates to a peptide GnRH antagonists having the formula: X-D-Nal-(A)D-Phe-D-Pal-Ser-Xaa5-Xaa6-Leu-Xaa8-Pro-Xaa10and their pharmaceutically acceptable salts, where X = acyl group having more than 7 carbon atoms; A = 4Cl or 4F; XAA5represents Арh(Q1or Аmf(Q1), where Q1represents Q or

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where Q is aand where R represents H or lower alkyl; XAA6represents the D-Aph(Q2), D-Amf(Q2), D-Cit or D-Pal, where Q2represents AC or Q1; Xaa8represents Lys(ipr); and XAA10represents the D-Ala-NH2D-Ala-ol, Ala-ol, NHCH2CH3, Gly-NH2or Ala-NH2provided that if XAA5contains Q, XAA6also contains Q; pharmaceutical compositions for inhibiting the secretion of gonadotropins in mammals, comprising as active ingredient an effective amount of a GnRH antagonist; method of inhibiting the secretion of gonadotropins in mammals and connection of X1-D-Nal-(A)D-Phe-D-Pal-Ser (X2)-Xaa52= N or hidroxizina group; XAA5represents Aph(Q1) or Amf(Q1), where Q1= patterns I and II, or carbarnoyl, or methylcarbamoyl; XAA6= D-Aph(Q2), D-Amf(Q2) or D-Pal, where Q2= AC; X4represents susceptible to the action of acid aminosidine group; and X5represents the D-Ala-, Gly-, Аlа-[polymer carrier], N(Et)-[polymer carrier], amide D-Ala, Gly or Аlа; or ethylamide, which is an intermediate compound for obtaining a peptide antagonist GnRH

The invention relates to medicine

The invention relates to zinc-containing crystals of insulin, which has a diameter less than 10 microns, suitable for introduction through the lungs
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