Hormonal or non-hormonal steroid compounds, a method of therapeutic treatment

 

(57) Abstract:

The invention relates to a new class of 17-acyl-17-prominentnych steroids of formula I, where R1- (CH3)2N-CH3NH-, NH2-, CH3CO - or CH3S-; R2- CH3or CF3-; R3- H, CH3-, CH3O-CH3COO-; R4- H, CH3-, F - or Cl-, and X, which have antiprogesterone activity. 4 C. and 8 C. p. F.-ly.

The scope of the invention

This invention relates to a new class of 17-acyl-17-propenyloxy steroids, which are believed to bind to the receptor and progestin-only demonstrating strong antiprogestin activity. Such compounds can be used to treat or fibrous tumors, endometriosis and certain tumors, to accelerate the ripening of cervix of the uterus before delivery, hormone replacement therapy and birth control and reproduction.

Discussion of the preconditions of the invention

Progesterone plays a leading role in reproductive health and functioning of reproductive organs. Its action, for example, in the uterus, breast, cervix and the hypothalamic-pituitary system is well defined. He is also the subject vascular-endothelial system and lipid metabolism. The combination of these effects indicates that compounds that have similar effects with the effects of progesterone (agonists), antagonism to these effects (antagonists) or show mixed effects (partial agonists, or a mixture of agonists/antagonists) can be used to treat various illnesses and conditions.

Steroid hormones exert their effects, in part, by joining intracellular receptors. Compounds that bind to corresponding receptors and are antagonists or partial agonists of estrogenic and androgenic hormones have long been known, but until about 1982 were not open connections that are associated with progesterone receptor, and were not known antagonistic effects of progesterone. Since then, many of these compounds were reported in specific and patent literature, and their effects in vitro have been studied in animals and in humans. Although compounds such as estrogens and some enzyme inhibitors that can interfere with the physiological effects of endogenous progesterona in this discussion "antiprogestin" refers to so connect deelstra about that antiprogestin could be effective for a number of medical conditions. These data were summarized in the article in the Institute of Medicine (Donaldson, Molly S.; Dorflinger, L; Brown, Sarah S.; Benet, Leslie Z., Editors, Clinical Applications of Mifepristone (RU 486) and Other Antiprogestines, Committee on Antiprogestines: Assessing the Science, Institute of Medicine, National Academy Press, 1993). Given the Central role of progestins play in reproduction, it is not surprising that antiprogestin can play a partial role in the control of fertility, including contraception (long and for the case of extreme necessity, or postcoital), promotion of menstruation and medical abortion, and, in addition, many other uses, which were supported by limited clinical or preclinical studies. Including for the following purposes:

1. Childbirth and obstetrics - antiprogestin can be used to accelerate the ripening of the cervix to stimulate childbirth, as in time, and when the delivery will be stimulated because of the death of the fetus. They can also be used to stimulate delivery on time or late pregnancy.

2. Treatment of uterine leiomyoma (fibroids) - these non-cancerous tumors can disturb up to 20% of women in the targeted age the reproductive period. Hysterectomy, treatment in case of persistent symptoms is the result of sterility.

3. Treatment of endometriosis - this is a common (5 to 15% of cases, more frequently in infertile women) and often painful condition currently treated with drugs such as danazol, or analogues of gonadotropin-releasing hormone, which causes significant side effects, or remove surgical methods.

4. Hormone replacement therapy when they can be assigned for terminating or reducing the activities of progestins.

5. Malignant tumors, in particular breast cancer - the presence of progestin-only receptors in many malignant breast tumors suggests about the use of antiprogestins for the treatment of metastasis of a tumor or prevention of recurrence, or the initial development of malignant tumors.

6. Other tumors, such as meningioma - this tumor of the meninges, although it is not malignant, leading to the death of patients and the inability of non-surgical treatment.

7. Male contraception - antiprogestin can affect the viability of sperm, gtglucocorticoids action of these compounds.

8. Antiestrogenic effects - at least some antiprogestin prevent the effects of estrogen in some trials, but, obviously, using a mechanism that does not involve classical hormone receptors. This opens up opportunities for their medical use.

9. Antiglucocorticoid effects - the side effects of antiprogestins that can be used in some cases, such as the treatment of Cushing's syndrome, and may play a role, for example, when immune disorders. In other cases, these effects should be minimized.

Effects and use of agonists of the progesterone carefully documented. In addition, it was recently shown that some compounds structurally similar to well-known antiprogestins, have a strong agonistic activity in some biological systems (for example, classical progestin effects on the immature rabbit uterus in primary-estrogenic phase of the cycle; cf. C. E. Cook et al. Life Sciences, 52, 155-162 (1993)). Such compounds are partial agonists, cell receptor systems that are associated with the site other than the site progestin and antiprogestin (Wagner et al., Proc. Natl. Acad. Sci., 93, 8739-8744 (indescomp profile.

As a rule, antiprogestational activity is associated with the presence of 11-aryl substituent on the steroid ring together with4,9-3-ketone, or4-3-ketone group. However, it was shown that the substituents on the D-ring of the steroid can have a significant impact on the biological profile of these compounds (see above). Early antiprogestin were replaced by the 17-hydroxyl group and the various 17-substituents. (See for example, Teutsch, Jean G.; Costerousse, Germain; Philibert, Daniel, and Deraedt, Roger. New steroids. U.S. patent 4386085. 1983; Philibert, Daniel; Teutsch, Jean G.; Costerousse, Gennain, and Deraedt, Roger. 3-keto-19-nor-4,9-steroids. U.S. patent 4477445. 1983; Teutsch, Jean G.; Pantin, Germain; Costerousse, Saint-Maurice; Daniel Philibert; La Varenne Saint Hilaire; Roger Deraedt, inventors. Steroid derivatives. Roussel Uclaf, assignee. U. S. 4447424. 1984; Cook, C. Edgar, Tallent, C. Ray; Reel, Jerry R., and Wani, Mansukh C. 17 -(Substituted-methyl) -17-hydroxy/esterificated hydroxysteroid and pharmaceutical compositions containing them. U.S. patent 4774236 (1988) and 4861763 (1989)). Then it was found that the 17-acetyl, 17-alloctype can also cause antiprogestational effects (Cook, C. Edgar; Lee, Y. W.; Reel, Jerry R.; Wani, Mansukh C., Rector, Douglas. 11-Substituted progesterone analogues. U.S. patent 4954490 (1990) and 5073548 (1991)), and have been studied sufficiently different permutations of these detected deputies. However, in the agonistic or partial agonistic activity (C. E. Cook et al., Life Sciences, 52, 155-162 (1993)). Thus, changes in the D-ring of the steroid lead to a wide variety of effects number of effects on biological activity. In accordance with these shortcomings, there is a need in antiprogesterone connections, which would demonstrate a higher specificity.

Cook et al., U.S. patent 5073548 report a 17-quinil-11 -(substituted phenyl) -19-norpregna-4,9-diene-3,20-deanovich connections, but do not illustrate the 17-acyl-17 (-propyne-1-silt connection.

Cook et al., in concurrently filed U.S. patent 09/035,949, registered on March 16, 1998, report 17-acyl-11-cyclic aminophenylacetamido.

Therefore, the aim of the present invention are new and effective progestin antagonists (antiprogestin) and mixtures or partial agonists progestin methods medical use in mammals, including humans, and methods for their synthesis.

Despite the clinical perspective of antiprogestins, such as those described by November 1, 1998, in the U.S. and other countries, not progestin-only preparations. Only one antiprogesterone the drug is approved and available for clinical use in the world, and this drug, mifepristone, is Central to ebnet in new antiprogestational drugs, which can be used in the conditions described above.

Therefore, the aim of the present invention is a new and effective antagonists progestins (antiprogestin) and the mixture, or partial agonists progestin, and how medical use in mammals, including humans.

The INVENTION

The present invention relates to a group of new 17-acyl-17-propenyloxy steroids, which are characterized by 11 -(4-substituted phenyl) substitution.

In accordance with the first embodiment, the present invention relates to hormonal or non-hormonal steroid compound of structure I,

where R1represents (CH3)2N-CH3NH-, NH2-;

R2represents CH3-, CF3-, HOCH2-;

R3represents N, CH3-, CH3O, CH3COO-;

R4represents N, CH3-, F-, Cl-; and

X represents O, (H,H), NOH, DOWN3,

and its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention relates to hormonal or non-hormonal steroid compounds structure is B>S(O)2-, CH3O-;

R6represents CH3-, CF3-, HOCH2-;

R7represents N, CH3-, CH3O, CH3COO-;

R8represents N, CH3-, F-, CL-; and

X represents O, (H,H), NOH, DOWN3,

and their pharmaceutically acceptable salts.

These and other objects of the present invention were made possible by the discovery that the 17-acyl-17-PROPYNYL-11 -(4-substituted phenyl)steroids demonstrate exceptional agonist or antagonist hormonal activity.

BRIEF DESCRIPTION of SCHEMES

A more complete understanding of the invention and its many attendant advantages will become better understood from the following detailed description, considered together with the attached diagrams, where:

Scheme 1 shows the reaction scheme for the 17-acyl-17-propenilfenola derivative of the present invention.

A DETAILED DESCRIPTION of the PREFERRED EMBODIMENTS

The above compounds of formula I, in particular, include compounds that are substituted on the ring And at the 3-position of two atoms of hydrogen. These compounds are believed to powergem, the present invention relates to hormonal or non-hormonal steroid compound of structure I,

where R1represents (CH3)2N-CH3NH-, NH2-;

R2represents CH3-, CF3-, HOCH2-;

R3represents N, CH3-, CH3O, CH3COO-;

R4represents N, CH3-, F-, Cl-; and

X represents O, (H,H), NOH, DOWN3,

and their pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention relates to hormonal or non-hormonal steroid compound of structure II,

where R5represents CH3CO, CH3S-, CH3S(O)-, CH3S(O)2-, CH3O-;

R6represents CH3-, CF3-, HOCH2-;

R7represents N, CH3-, CH3O, CH3COO-;

R8represents N, CH3-, F-, C1 -, and

X represents O, (H,H), NOH, DOWN3,

and their pharmaceutically acceptable salts.

In the scope of the present invention includes, in particular, carried the represents (CH3)2N-CH3NH-, NH2-.

Especially preferred is the compound of formula (IV)

Compounds of the present invention may also include salt, formed by the amine. Suitable pharmaceutically acceptable salts are well-known experts in this field and include carboxylates, sulfates, phosphates and halides.

In the context of the present invention, the group R4patterns I and R8structure II can be either or stereochemical configuration.

Specific compounds of formula I are

1. 11 -(4-AMINOPHENYL)-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

2. 11 -(4-AMINOPHENYL)-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

3. 11 -(4-AMINOPHENYL)-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

4. 11 -(4-AMINOPHENYL)-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

5. 11 -(4-AMINOPHENYL)-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

6. 11 -(4-AMINOPHENYL)-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

7. 11 -(4-AMINOPHENYL)-21-methoxy-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

8. 11 -(4-AMINOPHENYL)-21-methoxy-3-ox is(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

10. 11 -(4-AMINOPHENYL)-21-methoxy-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11. 11 -(4-AMINOPHENYL)-21-methoxy-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

12. 11 -(4-AMINOPHENYL)-21-methoxy-6-fluoro-17 (-(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

13. 11 -(4-AMINOPHENYL)-21-methoxy-6-fluoro-3-oximino-17 (-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

14. 11 -(4-AMINOPHENYL)-21-methoxy-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

15. 11 -(4-AMINOPHENYL)-21-methoxy-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

16. 11 -(4-AMINOPHENYL)-21-methoxy-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

17. 11 -(4-AMINOPHENYL)-21-methoxy-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

18. 11 -(4-AMINOPHENYL)-21-methoxy-6-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

19. 11 -(4-AMINOPHENYL)-21-methoxy-6-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

20. 11 -(4-AMINOPHENYL)-21-methoxy-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

21. 11 -(4-AMINOPHENYL)-21-methoxy-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

22. 11 -(4-cropin-1-yl)-19-norpregna-4,9-diene-3,20-dione;

24. 11 -(4-AMINOPHENYL)-21-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

25. 11 -(4-AMINOPHENYL)-21-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

26. 11 -(4-AMINOPHENYL)-21-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

27. 11 -(4-AMINOPHENYL)-21-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

28. 11 -(4-AMINOPHENYL)-21-methyl-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

29. 11 -(4-AMINOPHENYL)-21-methyl-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

30. 11 -(4-AMINOPHENYL)-21-methyl-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

31. 11 -(4-AMINOPHENYL)-21-methyl-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

32. 11 -(4-AMINOPHENYL)-21-methyl-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

33. 11 -(4-AMINOPHENYL)-21-methyl-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

34. 11 -(4-AMINOPHENYL)-6,21-dimethyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

35. 11 -(4-AMINOPHENYL)-6,21-dimethyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

36. 11 -(4-AMINOPHENYL)-6,21-dimethyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-di">

38. 11 -(4-AMINOPHENYL)-6,21-dimethyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

39. 11 -(4-AMINOPHENYL)-6,21-dimethyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

40. 11 -(4-AMINOPHENYL)-3-oximino-17 -(1-PROPYNYL)-norpregna-4,9-diene-3,20-dione;

41. 11 -(4-AMINOPHENYL)-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

42. 11 -(4-AMINOPHENYL)-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

43. 11 -(4-AMINOPHENYL)-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

44. 11 -(4-AMINOPHENYL)-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

45. 11 -(4-AMINOPHENYL)-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

46. 11 -(4-AMINOPHENYL)-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

47. 11 -(4-AMINOPHENYL)-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

48. 11 -(4-AMINOPHENYL)-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

49. 11 -(4-AMINOPHENYL)-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

50. 11 -(4-AMINOPHENYL)-6-methyl-17 -(3,33-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

51. 11 -(4-AMINOPHENYL)-6-methyl-17 -(3-norpregna-4,9-diene-3,20-dione;

53. 11 -(4-AMINOPHENYL)-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

54. 11 -(4-AMINOPHENYL)-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

55. 11 -[4-(N,N-dimethylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

56. 11 -[4-(N,N-dimethylamino)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

57. 11 -[4-(N,N-dimethylamino)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

58. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

59. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

60. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

61. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

62. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

63. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

64. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

65. 11 -[4-(N,N-dimethy is amino)phenyl]-21-methoxy-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

67. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

68. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

69. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

70. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

71. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

72. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

73. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-methyl-3-oximino-1 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

74. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-methyl-3-oximino-1 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

75. 11 -[4-(N,N-dimethylamino)phenyl]-21-methoxy-6-methyl-3-oximino-1 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

76. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

77. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

78. the ethylamino)phenyl]-21-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

80. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

81. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

82. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

83. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-17 -(3,33-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

84. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

85. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

86. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

87. 11 -[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

88. 11 -[4-(N,N-dimethylamino)phenyl]-6,21-dimethyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

89. 11 -[4-(N,N-dimethylamino)phenyl]-6,21-dimethyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

90. 11 -[4-(N,N-dimethylamino)phenyl]-6,21-dimethyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

91. 11 -[4-(N,N-dimethylamino)phenyl]-6,21-dim is ximeno-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

93. 11 -[4-(N,N-dimethylamino)phenyl)-6,21-dimethyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

94. 11 -[4-(N,N-dimethylamino)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

95. 11 -[4-(N,N-dimethylamino)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

96. 11 -[4-(N,N-dimethylamino)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

97. 11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

98. 11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

99. 11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

100. 11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

101. 11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

102. 11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

103. 11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

104. 11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

107. 11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

108. 11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

109. 11 -[4-(N-methylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

110. 11 -[4-(N-methylamino)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

111. 11 -[4-(N-methylamino)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

112. 11 -[4-(N-methylamino)phenyl]-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

113. 11 -[4-(N-methylamino)phenyl]-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

114. 11 -[4-(N-methylamino)phenyl]-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

115. 11 -[4-(N-methylamino)phenyl]-21-methoxy-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

116. 11 -[4-(N-methylamino)phenyl]-21-methoxy-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione; hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

118. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

119. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-the 3,20-dione;

121. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4, 9-diene-3,20-dione;

122. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

123. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

124. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

125. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

126. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

127. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

128. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

129. 11 -[4-(N-methylamino)phenyl]-21-methoxy-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene 3,20-dione;

130. 11 -[4-(N-methylamino)phenyl]-21-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

131. 11 -[4-(N-methylamino)phenyl]-21-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

132. 11 -[4-(N-methylamino)phenyl]-21-many-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

134. 11 -[4-(N-methylamino)phenyl]-21-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

135. 11 -[4-(N-methylamino)phenyl]-21-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

136. 11 -[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

137. 11 -[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

138. 11 -[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

139. 11 -[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-3-oximino-17 -(1-PROPYNYL) -19-norpregna-4,9-diene-3,20-dione;

140. 11 -[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

141. 11 -[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

142. 11 -[4-(N-methylamino)phenyl]-6,21-dimethyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

143. 11 -[4-(N-methylamino)phenyl]-6,21-dimethyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

144. 11 -[4-(N-methylamino)phenyl]-6,21-dimethyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

145. 11 -[4-(N-methylamino)phenyl]-6,21-dimethyl-3-oximino-17 -(1-PROPYNYL)-19-H9-norpregna-4,9-diene-3,20-dione;

147. 11 -[4-(N-methylamino)phenyl]-6,21-dimethyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

148. 11 -[4-(N-methylamino)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

149. 11 -[4-(N-methylamino)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

150. 11 -[4-(N-methylamino)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

151. 11 -[4-(N-methylamino)phenyl]-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

152. 11 -[4-(N-methylamino)phenyl]-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

153. 11 -[4-(N-methylamino)phenyl]-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

154. 11 -[4-(N-methylamino)phenyl]-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

155. 11 -[4-(N-methylamino)phenyl]-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

156. 11 -[4-(N-methylamino)phenyl]-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

157. 11 -[4-(N-methylamino)phenyl]-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

158. 11 -[4-(N-methylamino)phenyl]-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

159. 11 -[4-(N-methylamino)phenyl]-6-methyl-1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

161. 11 -[4-(N-methylamino)phenyl]-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

162. 11 -[4-(N-methylamino)phenyl]-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

163. 21-acetoxy-11 -(4-AMINOPHENYL)-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

164. 21-acetoxy-11 -(4-AMINOPHENYL)-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

165. 21-acetoxy-11 -(4-AMINOPHENYL)-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

166. 21-acetoxy-11 -(4-AMINOPHENYL)-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

167. 21-acetoxy-11 -(4-AMINOPHENYL)-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

168. 21-acetoxy-11 -(4-AMINOPHENYL)-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

169. 21-acetoxy-11 -(AMINOPHENYL)-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

170. 21-acetoxy-11 -(4-AMINOPHENYL)-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

171. 21-acetoxy-11 -(4-AMINOPHENYL)-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

172. 21-acetoxy-11 -(4-AMINOPHENYL)-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

173. 21-acetoxy-11 -(4-AMINOPHENYL)-6-fluoro-Christ.-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

175. 21-acetoxy-11 -(4-AMINOPHENYL)-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

176. 21-acetoxy-11 -(4-AMINOPHENYL)-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

177. 21-acetoxy-11 -(4-AMINOPHENYL)-6-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

178. 21-acetoxy-11 -(4-AMINOPHENYL)-6-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

179. 21-acetoxy-11 -(4-AMINOPHENYL)-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

180. 21-acetoxy-11 -(4-AMINOPHENYL)-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

181. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

182. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

183. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

184. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

185. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

186. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-3-oximino-17 -(3-hydroxypropan-1-egna-4,9-diene-3,20-dione;

188. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

189. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

190. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

191. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

192. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

193. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

194. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

195. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

196. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

197. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

198. 21-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-6-methyl-3-oximino-17 -(3-hydroxypropy-diene-3,20-dione;

200. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

201. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

202. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

203. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

204. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

205. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-fluoro-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

206. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-fluoro-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

207. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-fluoro-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

208. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-fluoro-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

209. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-fluoro-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

210. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-fluoro-3-oximino-17 (-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione

211. 21-acetoxy-11 -[4-(N-metalmetal-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

213. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

214. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

215. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

216. 21-acetoxy-11 -[4-(N-methylamino)phenyl]-6-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione.

Specific compounds of formula II are

1. 11 -(4-acetylphenyl)-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

2. 11 -(4-acetylphenyl)-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

3. 11 -(4-acetylphenyl)-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

4. 11 -(4-acetylphenyl)-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

5. 11 -(4-acetylphenyl)-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

6. 11 -(4-acetylphenyl)-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

7. 11 -(4-acetylphenyl)-21-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

8. 11 -(4-acetylphenyl)-21-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

9. 11 -(4-acetylphenanthrene-4,9-diene-3,20-dione;

11. 11 -(4-methoxyphenyl)-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

12. 11 -(4-methoxyphenyl)-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

13. 11 -(4-methoxyphenyl)-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

14. 11 -(4-methoxyphenyl)-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

15. 11 -(4-methoxyphenyl)-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

16. 11 -(4-methoxyphenyl)-21-methoxy-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

17. 11 -(4-methoxyphenyl)-21-methoxy-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

18. 11 -(4-methoxyphenyl)-21-methoxy-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

19. 11 -(4-methoxyphenyl)-21-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

20. 11 -(4-methoxyphenyl)-21-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

21. 11 -(4-methoxyphenyl)-21-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

22. 11 -(4-methoxyphenyl)-21-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

23. 11 -(4-methoxyphenyl)-21-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

24. 11 -(4-what enyl)-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

26. 11 -(4-methoxyphenyl)-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

27. 11 -(4-methoxyphenyl)-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

28. 11 -[4-(methylsulphonyl)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

29. 11 -[4-(methylsulfinyl)phenyl]-17 -(3,3,3-cryptochrome-yl)-19-norpregna-4,9-diene-3,20-dione;

30. 11 -[4-(methylsulfinyl)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

31. 11 -[4-(methylsulfinyl)phenyl]-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

32. 11 -[4-(methylsulfinyl)phenyl]-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

33. 11 -[4-(methylsulfinyl)phenyl]-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

34. 11 -[4-(methylsulfinyl)phenyl]-21-methoxy-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

35. 11 -[4-(methylsulfinyl)phenyl]-21-methoxy-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

36. 11 -[4-(methylsulfinyl)phenyl]-21-methoxy-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

37. 11 -[4-(methylsulfinyl)phenyl]-21-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

38. 11 -[4-(methylsulfinyl)phenyl]-21-methoxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

40. 11 -[4-(methylsulfinyl)phenyl]-21-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

41. 11 -[4-(methylsulfinyl)phenyl]-21-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

42. 11 -[4-(methylsulfinyl)phenyl]-21-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

43. 11 -[4-(methylsulfinyl)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

44. 11 -[4-(methylsulfinyl)phenyl]-3-oximino-17 -(3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

45. 11 -[4-(methylsulfinyl)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

46. 11 -[4-(methylthio)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

47. 11 -[4-(methylthio)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

48. 11 -[4-(methylthio)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

49. 11 -[4-(methylthio)phenyl]-21-methoxy-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

50. 11 -[4-(methylthio)phenyl]-21-methoxy-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

51. 11 -[4-(methylthio)phenyl]-21-methoxy-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

52. 11 -[4-(methylthio)phenyl]-21-methoxy-3-oximino-17 -(1-PROPYNYL)-19-but egna-4,9-diene-3,20-dione;

54. 11 -[4-(methylthio)phenyl]-21-methoxy-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

55. 11 -[4-(methylthio)phenyl]-21-methyl-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

56. 11 -[4-(methylthio)phenyl]-21-methyl-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

57. 11 -[4-(methylthio)phenyl]-21-methyl-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

58. 11 -[4-(methylthio)phenyl]-21-methyl-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

59. 11 -[4-(methylthio)phenyl]-21-methyl-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

60. 11 -[4-(methylthio)phenyl]-21-methyl-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

61. 11 -[4-(methylthio)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

62. 11 -[4-(methylthio)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

63. 11 -[4-(methylthio)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

64. 21-acetoxy-11 -(4-acetylphenyl)-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,2-dione;

65. 21-acetoxy-11 -(4-acetylphenyl)-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

66. 21-acetoxy-11 -(4-acetylphenyl)-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-di-acetoxy-11 -(4-methoxyphenyl)-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

69. 21-acetoxy-11 -(4-methoxyphenyl)-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

70. 21-acetoxy-11 -(4-methoxyphenyl)-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

71. 21-acetoxy-11 -(4-methoxyphenyl)-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

72. 21-acetoxy-11 -(4-methoxyphenyl)-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

73. 21-acetoxy-11 -[4-(methylsulfinyl)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

74. 21-acetoxy-11 -[4-(methylsulfinyl)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

75. 21-acetoxy-11 -[4-(methylsulfinyl)phenyl]-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

76. 21-acetoxy-11 -[4-(methylsulfinyl)phenyl]-3-oximino-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

77. 21-acetoxy-11 -[4-(methylsulfinyl)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

78. 21-acetoxy-11 -[4-(methylsulfinyl)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione;

79. 21-acetoxy-11 -[4-(methylthio)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

80. 21-acetoxy-11 -[4-(methylthio)phenyl]-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

83. 21-acetoxy-11 -[4-(methylthio)phenyl]-3-oximino-17 -(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

84. 21-acetoxy-11 -[4-(methylthio)phenyl]-3-oximino-17 -(3-hydroxypropan-1-yl)-19-norpregna-4,9-diene-3,20-dione.

Compounds according to this invention can be synthesized by conventional methods known to experts in this field, such as those schematically depicted in figure 1, on the basis of estrone, which was converted into its methyl ester (2) with a quantitative yield, by reacting TO a2CO3and Me in the Meon. Methyl ether of estrone then transformed into the corresponding 17-cenocoeliinae (3) interaction ketone tert-GFCF and TosMIC In DME (Oldenziel O. N. and van Leusen, A. M. Tetrahedron Lett., 13, 1357-1360 (1973); Bull. J. R. and A. Tuinman Tetrahedron, 31, 2151-2155 (1975). 17-Carbonitrile was obtained with 76% yield as a mixture of 17 and 17-isomers. Using Memduh by boiling under reflux in THF, 17-carbonitrile converted into the corresponding 17-acetyl compound (4) with a quantitative yield (compare Bull and Tuinman, 1975). Boiling under reflux 4 in toluene with acetic anhydride and p-TsOH gave the enol acetate 5 in the form of a mixture of E and Z isomers in 70% yield.

The enol acetate was converted into 17-acetyl-17-hydroxym dry ether [cf., J. R. Reel and C. E. Cook, U.S. patent 4512986 (1985)].

20-Ketone restored in an appropriate mixture of epimeres 20-alcohol with 90% yield using lithium aluminum hydride (LAH) Vahom tetrahydrofuran (THF). No need to split this mixture and the mixture could be used in the following three stages according to the scheme of the synthesis without purification of intermediate products. The recovery Birch lithium and liquid NH3in THF and tert-VION gave ether Enola 8, which was treated with oxalic acid to obtain 5(10)-EN-3-one (9). Treatment of this compound with tribromide pyridine in dry pyridine was allowed to oxidize it to the desired 4,9-Dien-3-one (10) with 3-stage with getting 55-60% after purification.

Oxidation of the two alcohol groups in the ketone and the aldehyde was achieved by the interaction of 10 Swern conditions to give the desired 17-acetyl-17-formyl compound (11) with 70-75% yield after purification. Aldehyde interacted (cf Reel and Cook, 1985) Seyferth/Gilbert reagent (Brown D. G.; Velthuisen, E. J.; Commenford, J. R.; Brisbois, R. G.; and Hoye, T. R. J. Org. Chem., 61, 2540-2541 (1996)) to obtain the 17-acetyl-17-etinilnoy connection (12) with 78% yield.

Monoculture 12 was achieved with 80% yield by treatment of the diketone in benzene with ethylene glycol and a catalytic amount of p-TsOH with and the resulting alcohol 14 in dry pyridine by trimethylsilylpropyne (TMSCl) gives the TMS ether 15 with 80% yield. Treatment of this compound lithium N-tert-butyl-N-trimethylsilylmethyl and methyliodide led to propenylidene the compound (16) with 80-90% yield.

Getting 5(10)-epoxide 17 easily reached by processing 16 HEXAFLUOROACETONE, H2O2and Na2HPO4in CH2Cl2at 0 C over night. This interaction gave both a and epoxide, but when cleaning-epoxide was isolated from approximately 60% yield and 90% purity. The interaction of the epoxide with aryl Grignard reagent derived from p-N,N-dimethylaminopropylamine and CuCl gives aryl compound 18a with getting 70-75%.

Demetalizarea 3 position, dehydration C5-hydroxyl and remove protection 20-hydroxyguanine reached one by treating compounds 18a water triperoxonane acid in CH2CL2. After purification was obtained the desired 20-gidroksosoedinenii 19a to receive up to 90%. Oxidation of the 20-ketone-1 then carried out by treatment of o-iodoxybenzoic acid (IBX) (cf Frigerio M. and Santagostino, M. Tetrahedron Lett., 35(43), 8019-8022 (1994)), although it was reported that IBX is not valid in the presence of aniline (Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem., 60, 7272-7276 (1995)). The use of a large excess of IBX led to obtaining the desired product of the groups N,N-dimethylaminophenyl fragment to formyl. When using dimethyl sulfoxide (DMSO) as the solvent and only 1.52 equivalent IBX, a-1 was obtained with 43-51% yield, with 20-25% of the regeneration of the original alcohol (19a), which can be recollision to improve the overall output.

The synthesis of other 17-prominentnych compounds can be carried out in a similar way (see examples).

Steroids with progestational, antiprogestational and/or antiglucocorticoid activity are used to control fertility in humans and mammals, such as primates, Pets and farm animals and in the treatment of medical conditions in animals or humans in which these desirable activities. Thus, they can be used in the treatment of conditions such as fibroids, Cushing's syndrome, glaucoma, endometriosis, increased ripening of the cervix to delivery, hormone replacement therapy, premenstrual syndrome and malignant tumors, in addition to their use for control of fertility and reproduction.

Compounds of the present invention can be administered in various ways. Thus, the products in the picture is bleak, including sublingual and intrabuccal tablets, soft gelatin capsules, including solutions used in soft gelatin capsules, aqueous or oily suspensions, emulsions, pills, lozenges, trosha, tablets, syrups or elixirs and the like. The products according to the invention, which is active when the parenteral route of administration may be introduced by injection depo-drug implants, including Silastic and biodegradable implants, intramuscular and intravenous injections.

The composition can be obtained by any method known to specialists in this field for the preparation of pharmaceutical compositions and such compositions may contain one or more agents selected from the group comprising sweeteners, flavors, coloring tools and preservatives. Acceptable are tablets containing the active ingredient in a mixture of non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or loosening agents such as corn starch or originalart magnesium, stearic acid or talc. Tablets may be uncoated or may be coated with known techniques to delay disintegration and adsorption in the gastrointestinal tract that provides prolonged action over a long period. For example, can be used to delay the release of a substance, such as glycerylmonostearate or glycerylmonostearate, by itself or together with wax.

Formulations for oral use may also be presented in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is a mixture of water or oil environments, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspension according to this invention contain the active ingredient mixed with excipients suitable for receiving water suspensions. Such excipients include suspendisse agent, such as sodium carbometalation, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth Kama the purpose of accelerated with a fatty acid (for example, polyoxyethylenated), a condensation product of ethylene oxide with long-chain aliphatic alcohol (e.g., heptadecafluorooctyl), a condensation product of ethylene oxide with partial ether derivatives of fatty acids and hexitol (for example, monooleate polyoxyethylenesorbitan) or a condensation product of ethylene oxide with partial ether derivative of fatty acid and anhydride hexitol (for example, monooleate of polyoxyethylenesorbitan). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweeteners, such as sucrose, aspartame or saccharin. Ophthalmic compositions, as is well known to specialists in this field, should be brought to the osmotic pressure.

Oil suspensions can be obtained by suspendirovanie active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Podcastalley additional amount of antioxidant, such as ascorbic acid.

Dispersible powders and granules of the present invention suitable for obtaining an aqueous suspension by adding water, is obtained from active ingredients mixed with dispersant, suspenders and/or moisturizing agent, and one or more conservative. Suitable dispersing or moisturizing agents and superdeluxe agents represents, for example, such as described above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be submitted.

The pharmaceutical composition of the present invention can also be obtained in the form of oil-in-water emulsions. The oil phase is a vegetable oil, such as olive oil or peanut oil, mineral oil such as liquid paraffin, or a mixture. Suitable emulsifying agents include natural gums, such as gum Arabic and tragacanth gum, natural gums, such as soy lecithin, esters or partial ether derivatives of fatty acids and the anhydrides hexitol, such as monooleate sorbitan and condensed products of these partial esters with ethylene oxide, such as monooleate polyoxyethylene is to be made with sweeteners, such as glycerol, sorbitol or sucrose. Such compositions may also contain analgesic agents, preservatives, fragrances or dyes.

The pharmaceutical compositions of the present invention can also be in the form of sterile compositions for injection such as a sterile injectable aqueous or oily suspension. This suspension can be prepared in accordance with well-known experts in this field method using suitable dispersing or wetting agents described above. Sterile compositions for injection can also be a sterile injectable solution or suspension in a nontoxic parenterally suitable diluent, such as a solution of 1,3-butanediol. Additional suitable carriers or solvents that can be used, you can specify the water and environment of ringer's solution, isotonic sodium chloride. In addition, sterile undiluted oils can be respectively used as a solvent or suspendida environment. For these purposes may be used any soft undiluted oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid, may also be istam in this area, such as aseptic filtration, radiating or heat sterilization (e.g., autoclaving).

Aqueous compositions (e.g., oil-in-water emulsions, syrups, elixirs and compositions for injection can be obtained by bringing to a pH of optimum stability. The optimal pH may be produced by conventional methods known to experts in this field. Suitable buffers to achieve the pH of the compositions can also be used.

Compounds according to this invention can also be introduced in the form of suppositories for rectal administration of the drug. These compositions can be obtained by mixing the drug with a suitable non-irritating by excipients, which represents the normal temperature solid, and when rectal temperature becomes liquid and melts at rectal introduction with the release of the drug. Non-limiting examples of such substances are cocoa butter and polyethylene glycols.

They can also be administered intranasal, intraocular, intravaginal, and intrarectal routes including the introduction of suppositories, powders, aerosol compositions and formulations for injection.

Products related to izobretenii, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

Products with antiglucocorticoid activity, are of particular value in pathological conditions characterized by a sharp increase of endogenous glucocorticoids, such as Cushing's syndrome, hirsutism, particularly when it is associated with adrenogenital syndrome, eye diseases associated with a sharp increase of glucocorticoids, such as glaucoma, stress symptoms associated with a sharp increase in glucocorticoid secretion, and the like.

Products with progestational activity, are of particular value as progestational agents, inhibitors of ovulation, regulate menstruation, contraceptive agents, agents sync fertile period in cattle and the like. When used in contraceptive purposes, they can be appropriately mixed with estrogenic agents such as, for example, esters, ethinyl estradiol, or estradiol.

Products with antiprogestational activity, characterized by antagonistic effects of progesterone. Essentially, they are important for childbirth and delivery, for the treatment of fibroids and the us for control of fertility throughout the reproductive cycle. They are of particular value as a postcoital contraceptive, to bring the condition of the uterus in a condition unfavorable for implantation, and as a monthly contraceptive agent. They can be used to bind to the prostaglandins, oxiracetam, estrogen and the like.

A further important use of the products according to the invention due to their ability to slow the growth hormonesand malignant tumors. Such malignant tumors include tumors of the kidney, breast, endometrial, ovarian and prostate cancer, are characterized by the content progesterone receptors and are likely to have the answer to the products according to this invention. Other applications antiprogestational agents include treatment fibromatoses diseases of the mammary glands. Some malignant tumors, and, in particular, melanoma can be successfully subjected anticarcinogenic therapy.

Compounds of the present invention can be any warm-blooded mammal such as a human, pet and farm animals. Pets include dogs, cats and so on. Agricultural ivorie can be combined with the material of the carrier to obtain a standard dosage forms, will vary depending on the subject to the treatment of the disease, the type of mammal, and the particular route of administration. therapeutically effective amount can be determined using conventional research methods and by analogy with the amounts used to treat the same medical conditions similar steroid compounds. For example, the dosage form of steroid may preferably contain from 0.1 milligrams to 1 gram of the active ingredient. A more preferred dosage form contains from 0.001 to 0.5 grams. For specific treatment of endometriosis or fibroids can enter the amount from 0.01 to 10 mg/kg body weight, preferably from 0.1 to 3 mg/kg, this dose can be used for other therapeutic purposes of this invention. Typically, the compounds can be administered daily from 1 to 4 times per day, preferably from 1 to 2 times a day, but when using, for example, hormone replacement therapy, they can be entered in cicloferon mode. In any case, the frequency and timing of doses will depend on factors such as the specific half-life in the body, from the measured doses of the drug and pathways of introduction. Note, however, that specific urago used connection; age, body weight, General health, sex and diet of the subject being treated; the time and route of administration; rate of excretion; other drugs which had been used previously; and the severity of the particular disease being treated, that is well understood to a person skilled in the field.

Such compounds can be used in the treatment of endometriosis, uterine leiomyoma (fibroids) and some malignant diseases and tumors, hormone replacement therapy, as well as when controlling for the various stages of reproduction and fertility, such as contraception. A more detailed description of the possible use of such compounds are given Donaldson, Molly S.; Dorflinger L.; Brown, Sarah S.; Benet, Leslie Z., Editors, Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins. Committee on Antiprogestins: Assessing the Science, Institute of Medicine, National Academy Press, 1993. They can also be used as intermediates in the synthesis of other steroids.

Methods synthesis

Describing in General the invention, further understanding can be achieved through reference to specific examples which are given here only for purposes of illustration and are not intended to limit in any way. Connections really hard is peremontirovan.

Examples

General methods. If not stated otherwise, the initial reaction products with purity were obtained from commercial sources and were used without additional purification. Ether and tetrahydrofuran (THF) were souperman over sodium benzophenantridin couple in nitrogen atmosphere. All are sensitive to moisture and air reaction and conversion of the reactants was carried out in an atmosphere of dry nitrogen or argon. Thin-layer chromatography (TLC) was performed on plates 60 F254-coated silica gel EM Science. The connection is usually visualized by spraying UV light (254 nm) or by using pair-anisaldehyde. In preparative column chromatography was used silica gel EM Science, 60 (230-400 mesh mesh). The solutions were concentrated using a rotary evaporator with a water pump at room temperature. The melting point was determined on a MeI-Temp II and not corrected. Unless otherwise stated,1H NMR spectra were obtained at 250 MHz spectrometer Bruker AC 250 V Dl3as solvent and tetramethylsilane was as an internal standard (TMS). Chemical shifts are presented in units of memorial plaques relative to TMS. The mass spectrum is usually received via e-bombing at 70 e is intes 11 -[4-(N,N-dimethylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (a-1). 3-Petoksista-1,3,5(10)-triene-17-one (2).

Estrone (1, 100.0 g, 370 mmol) was dissolved in Meon (1.5 l), after which was added TO2CO3(300,0 g, 2,17 mol). Added Me (310 ml, to 4.98 mol) and the mixture was stirred at room temperature for 70 hours, the Reaction mixture was concentrated in vacuo to remove a certain amount of Meon and then poured into ice-cold water to obtain a precipitate. The solid is collected, extragere CH2CL2, The organic layer was dried over SB2SO4, and the solvent was removed in vacuum to obtain compound 2 (105,0 g) as white crystals with a quantitative yield.1H NMR of 0.91 (s, 3, C-18 H), of 3.78 (s, 3, MeO), of 6.65 (s, 1, C-4 H), 6,72 (d, 1, J=8.6 Hz, 2 H), 7,21 (d, 1, J=8.6 Hz, 1 H).

17-Cyan-3-petoksista-1,3,5 (10) - triene (3).

Compound 2 (50.0 g, 176,0 mmol) was dissolved in dimethoxyethane (DME, 1,2 L) in an inert atmosphere. Added tert-VION (170 ml), and then tert-GFCF (197,0 g of 1.76 mol) in DME (50 ml). Was slowly added n-toluensulfonate (TosMIC, of 68.7 g, 352,0 mmol) in DME (600 ml) and tert-VION (50 ml) for 1.5 hours, the Reaction mixture was extinguished after 1.3 h saturated NH4Cl (2 l). After stirring for several hours the reaction mixture was extracted with CH2Cl2organic layers objetion brown oily solid product. Purification column flash chromatography (SiO2; 3:1 EtOAc/hexane increasing to 5:1 EtOAc/hexane) gave compound 3 (39,8 g) in a mixture of 17 / isomers with 76% yield.1H NMR 0,86 (C, 3, C-18 H, major), of 0.96 (s, 3, S-18 N, side), of 3.78 (s, 3, MeO), only 6.64 (s, 1, C-4 H) of 6.71 (d, 1, J = 8,5 Hz, 2 H), 7,21 (d, 1, J = 8,7 Hz, 1 H).

3-Methoxy-19-norpregna-1,3,5(10)-triene-20-he (4).

Connection 3 (73,0 g, 247 mmol) was dissolved in dry THF (800 ml) under inert atmosphere. Added MeMgBr in THF (800 ml, 1.12 mol) and the reaction mixture is boiled under reflux for 3.5 h, then was cooled to room temperature. The reaction mixture was extinguished cold saturated NH4Cl and then was acidified using Hcl, the reaction mixture was extracted with CH2Cl2(2 300 ml). The organic layers were combined and washed with saturated saline, dried over gSO4and concentrated in vacuum to yield compound 4 (77.0 g) as light-yellow solid product with a quantitative yield. The product was a mixture of 17 / isomers, and it was isolated without further purification.1H NMR of 0.65 (s, 3, C-18 H, major), were 0.94 (s, 3, S-18 N, side), of 2.16 (s, 3, C-21 H), of 3.78 (s, 3, MeO), 6,63 (d, 1, J = 2.7 Hz, C-4 H) of 6.71 (DD, 1, J = 8,6, 2,8 Hz, 2 H), 7,21 (d, 1, J = 8,7 Hz, S-1 N).

20-Acetoxy-3-methoxy-19-norpregna-1,3 is alali AU2O (300 ml, 3,17 mol) and p-TsOH (5.0 g,45 mmol). The mixture was boiled under reflux and drove 500 ml of toluene. The reaction mixture was cooled and added AU2(210 ml, 2.22 mol) and p-TsOH (5.0 g, 45 mmol). The reaction mixture is then boiled under reflux during the night. The reaction mixture was cooled to room temperature and extinguished chilled on ice with a mixture of NaOH and NaHCO3up until the reaction mixture did not cease to be acidic. Aqueous and organic layers were separated. The aqueous layer was extracted with CH2Cl2organic layers were combined, washed with saturated saline and was dried over MgSO4the solvent was removed in vacuum to obtain a brown oily solid product. Purification column flash chromatography (SiO2; 4:1 CH2CL/hexane) gave compound 5 (44,5 g) as a mixture of E/Z isomers in 70% yield.1H NMR of 0.87 (s, 3, C-18 H, major), to 0.92 (s, 3, S-18 N, side), 2,11 (C, 3, C-21 N, side), and 2.14 (s, 3, 21 N. main), of 3.77 (s, 3, MeO), 6,63 (s, 1H, C-4 H) of 6.71 (d, 1, J = 8,4 Hz, 2 H), 7,21 (d, 1, J = 8,5 Hz, 1 H).

17-Hydroxymethyl-3-methoxypropane-1,3,5 (10) -triene-20-he (6).

Compound 5 (49,0 g,138,4 mmol) was dissolved in dry ether (1.3 l) in an inert atmosphere and cooled to 0 C. Slowly dobavlenny ZnCl (39,0 g, 286,1 mmol) in dry ether (250 ml). After an additional 20 min of stirring at 0 C, paraformaldehyde (20,0 g, 605 mmol) was heated and was barbotirovany in the reaction mixture, which was muddy, cream color. The reaction mixture was heated to room temperature, extinguished NH4Cl and was extracted with CH2Cl2organic layers were combined, washed with saturated saline and was dried over MgSO4The solvent was removed in vacuum to obtain a yellow solid product. Purification column flash chromatography (pure SN2CL2increasing to 5% acetone) gave 6 (32,4 g) as a white solid product with 68% yield.1H NMR to 7.18 (d, 1, J-8.5 Hz, 1 H) 6,70 (d, 1, J = 8.6 Hz, 2 H), 6,63 (s, 1, C-4 H), 4,24 (DD, 1, J = 4.2, and a 10.2 Hz, CH2HE, of 3.77 (s, 3, MeO), to 3.64 (DD, 1, J = 3,7, 10.4 Hz, CH2IT), and 2.26 (s, 3, C-21 H) of 0.71 (s, 3, C-18 H).

17-Hydroxymethyl-3-methoxy-19-norpregna-1,3,5(10)-trien-20-ol (7).

Compound 6 (12.0 g,35,0 mmol) was dissolved in dry THF (300 ml) under inert atmosphere and cooled to 0 C. LAH (2.7 g, a 71.1 mmol) was added in portions during 10 minutes the Reaction mixture was stirred at 0 C for 1.5 h and then slowly extinguished saturated Rochelle salt solution (60 ml). Organic and aqueous layers were separated. The aqueous layer ekstragirovaniem white solid product in the form of a mixture With 20 epimeres. Purification column flash chromatography (SiO2; CH2Cl2cleared over 10% acetone) gave three fractions [less purified isomer (3.7 g, 31%), a mixture of less and more polar isomer (3,45 g, 26%) and cleaner polar isomer (3,85 g, 32%)] to obtain compound 7 with a total yield of 89%.1H NMR (less polar isomer) of 1.01 (s, 3, C-18 H) of 1.34 (d, 3, J = 6,5 Hz, C-21 H), of 3.78 (s, 3, MeO), 6,62 (DD, 1, J = 2.7 Hz, C-4 H), 6.75 in (d, 1, J = 2,75, 8.6 Hz, 2 H), 7,21 (d, 1, J = 8.53 Hz, 1 H).

17-Hydroxymethyl-3-methoxy-19-norpregna-2,5(10)-Dien-20-ol (8) (less polar isomer).

Liquid NH.3 (250 ml) are condensed at -78 C in inert atmosphere. Compound 7 (less purified polar isomer; 2,75 g 7,98 mmol) in THF (150 ml) and tert-VION (30 ml) was slowly added over 20 minutes and then was added lithium wire (1.0 g, 144, 0mm mmol). The reaction mixture was blue and it was stirred for 2 h at -78 C. the Precipitate slowly extinguished Meon (30 ml) and was heated to room temperature for evaporation of NH3. The reaction mixture was treated with unsaturated NH4Cl and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with NH4Cl and saturated saline and dried over Na2SO4. The solvent was removed in vacuum to obtain compound 8 in l-19-norpregna-5(10)-EN-3-one (9, less polar isomer).

The crude compound 8 (original 7,98 mmol) was dissolved in a mixture of THF and dioxane and then added oxalic acid (1.8 g, 20.0 mmol) in water (50 ml). The mixture was stirred at room temperature overnight and slowly extinguished dilute NaHCO3. The aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with NH4Cl, H2O and saturated saline and dried over Na2SO4. The solvent was removed in vacuum to obtain compound 9 as a white solid product. It was used without further purification.

20-Hydroxy-17-hydroxymethyl-19-norpregna-4,9-Dien-3-one (10) (less polar isomer).

The crude compound 9 (original 7,98 mmol) was dissolved in dry pyridine (75 ml) under inert atmosphere and cooled to C. was Added dibromopyridin (3.11 g, 9,72 mmol), the reaction mixture became orange. The reaction mixture was left to slowly warm to room temperature over night. The reaction mixture was extinguished 5% Na2SO3(100 ml) and the mixture was extracted three times with CH2Cl2. The organic layers were combined and washed with dilute Hcl, dilute CuSO4H2O and saturated salt product. Purification column flash chromatography (SiO2; 1:1 EtOAc/hexane increasing to 3:2 EtOAc/hexane) gave compound 10 (1,38 g) as a white solid product with a total yield of 53% over 3 stages.

17-Hydroxymethyl-3-methoxy-19-norpregna-2,5 (10)-Dien-20-ol (8) (isomeric mixture).

Liquid NH3(1.5 l) are condensed at -78 C in inert atmosphere. Compound 7 (isomeric mixture; 39,0 g of 113.2 mmol) in THF (1.1 l) and tert-VION (400 ml) was slowly added over 50 min, and then was added lithium wire (8,3 g 1,195 mol). The blue reaction mixture was stirred for 3 h at -78 C. the Reaction mixture is slowly extinguished Meon (250 ml) and was heated to room temperature for evaporation of NH3during night. The reaction mixture was treated with aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3 500 ml). The organic layers were combined, washed with N2O and saturated saline, and dried over gSO4the solvent was removed in vacuum to obtain compound 8 as a white solid product with a quantitative yield of crude product. It was used immediately without further purification.

20-Hydroxy-17-hydroxymethyl-19-norpregna-5 (10) -EN-3-one (9) (isomeric mixture).

The crude compound 8 (the source of 113.2 m is (500 ml). The reaction mixture was stirred at room temperature overnight and slowly extinguished diluted Panso3. The aqueous layer was extracted three times with CH2CL2. The organic layers were combined, washed with saturated NaHCO3and saturated saline, and dried over MgSO4. The solvent was removed in vacuum to obtain compound 9 as a white solid product. Purification column flash chromatography (1:1 EtOAc/hexane) gave 9 (35,7 g) as a white solid product with a 95% yield over two steps.

20-Hydroxy-17-hydroxymethyl-19-norpregna-4,9-Dien-3-one (10) (isomeric mixture).

The crude compound 9 (35.5 g,106,7 mmol) was dissolved in dry pyridine (600 ml) under inert atmosphere and cooled to -20 C. was Added tribromide pyridine (41.7 g,117,3 mmol) and the reaction mixture was left to slowly warm to room temperature over night. The reaction mixture was extinguished Na2SO3. The main solvent was removed in vacuum. The remaining suspension was diluted with water and was extracted three times with CH2Cl2. The organic layers were combined and washed with N2Oh, diluted CuSO4H2O and saturated saline solution, dried over Na2SO4and the solvent was removed is about 2:1 EtOAc/hexane) gave compound 10 (22,32 g, 63% yield) as a white solid product.1H NMR (less polar isomer) to 1.14 (s, 3, C-18 H) of 1.33 (d, 3,7 = 6,47 Hz, C-21 H), 3,74 (d, 1, J = 9,2 Hz), of 3.97 (DD, 1, J = 3.3V, 8.0 Hz), 5,67 (s, 1, C-4 H); (more polar isomer) 5 0,93 (C, 3, C-18 H) of 1.35 (d, 3, J = 6.42 per Hz, C-21 H), 3,52 (t, 1, J=3,52 Hz), 5,67 (s, 1, C-4 H).

17-Formyl-19-norpregna-4,9-diene-3,20-dione (11).

Oxalicacid (31.8 ml of 63.6 mmol) in CH2Cl2(10 ml) was cooled in an inert atmosphere to 60 C. was added dropwise dimethyl sulfoxide (DMSO, 6.0 ml, and 84.6 mmol); observed the evolution of gas. The reaction mixture was stirred for 30 minutes, then slowly added compound 10 (7.0 g, of 21.2 mmol; isomeric mixture) in dry CH2Cl2(44 ml). The reaction mixture was stirred for 30 minutes at 60 C. and Then was added et 3 n (19,5 ml, 140,0 mmol) and the mixture was stirred for 20 min at 60 C and then slowly warmed up to room temperature for 1 hour. The reaction mixture was extinguished H2O, was extracted three times with CH2Cl2and washed with H2O and saturated salt solution. The organic layer was dried over MgSO4and the solvent was removed in vacuum to obtain a brown oily solid product. The product was used directly in the next stage.1H NMR 5 9,84 (s, 1, formyl is OK (is 3.08 g, of 25.2 mmol) in dry THF (50 ml) and (CH3O)2POCHN2(of 3.78 g, 25,18 mmol; Seyferth/Gilbert reagent) in dry THF (25 ml) was cooled separately in an inert atmosphere to -78 C. the Reagent Seyferth/Gilbert then slowly treated with a solution of tert-BuOK and was stirred for 10 min at -78 C. was Slowly added compound 11 obtained by the above interaction (source 19.0 mmol) in dry THF (80 ml). The reaction mixture was stirred at -78 C and slowly warmed up to room temperature over night. The reaction mixture was extinguished H2O and was extracted four times CH2Cl2. The organic layers were combined, washed with saturated saline and was dried over MgSO4. The solvent was removed in vacuum to obtain a brown solid product. Purification column flash chromatography (1:1 EtOAc/hexane) gave the desired product 12 as a light yellow solid product (to 4.98 g) with a total output of 10, equal to 73%.1H NMR 5,70 (s, 1, C-4 H) of 2.45 (s, 1, ethinyl N), 2,32 (C, 3, C-21 H) 0,76 (C, 3, C-18 H).

3,3-[1,2-etienville(oxy)]-17-ethinyl-19-norpregna-5 (10),9(11)-Dien-20-he (13).

Compound 12 (5,67 g, 17.6 mmol) was dissolved in benzene (300 ml) and was treated with ethylene glycol (11.8 ml, 211,8 mmol) and p-TsOH (330 mg, of 1.74 mmol). The reaction mixture capacity layer was extracted with EtOAc twice. The organic layers were combined, washed with N2O and saturated saline and was dried over MgSO4. The solvent was removed in vacuum to obtain a yellow solid product. Purification using flash column-chromatography (1:1 EtOAc/hexane) gave the desired product 13 (6.11 g, 95% yield).1H NMR ceiling of 5.60 (user. C, 1, C-11 H), Android 4.04 (s, 4, ketal), 2,43 (s, 1, ethinyl N), 2,31 (C, 3, C-21 H), 0,59 (C, 3, C-18 H).

3,3-[1,2-Atanderson (oxy)]-17-ethinyl-19-norpregna-5(10),9(11)-Dien-20-ol (14).

Compound 13 (6,1 g of 16.6 mmol) was dissolved in dry THF (90 ml) and EtOH (50 ml) under inert atmosphere. Added NaBH4(1.26 g,33,3 mmol) and the reaction mixture was heated for 8 h, the Reaction mixture was extinguished aqueous NH2OH-HCl (pH brought to 7). The reaction mixture was extracted three times with CH2CL2. The organic layers were combined, washed with saturated saline and dried over Na2SO4. The solvent was removed in vacuum to obtain a white solid product. Crude yield was quantitative and the substance was used without further purification in the next stage.lH - NMR 5,59 (user. C, 1, C-11 H) to 3.99 (s, 4, ketal), of 3.94 (m, 1, S-20 N) to 2.29 (s, 1, ethinyl N) of 1.27 (d, 3, J = 6.2 Hz, C-21 H) of 0.82 (s, 3, C-18 H).

3,3-[1,2-Atanderson (oxy)]-17-ethinyl-20-trim plan into a solution of compound 14 (16,64 mmol) in dry pyridine (60 ml) under inert atmosphere. The reaction mixture was slowly heated to room temperature over 2 h and extinguished H2O. the Aqueous layer was extracted three times with EtOAc, washed with H2O and saturated saline and dried over Na2SO4. The solvent was removed in vacuum. The compound was purified column flash chromatography (3:1 hexane/EtOAc) to give compound 15 (6,33 g) with a total yield of 13 equal to 85%.1H NMR 5,58 (user. C, 1, C-11 H), of 3.95 (s, 4, ketal), 3,85 (kV, 1, J = 6,1 Hz, S-20 N), 2,24 (s, 1, ethinyl N) to 1.22 (d, 3, J = 6.2 Hz, C-21 H) to 0.73 (s, 3, C-18 H) of 0.11 (s, 9, (CH3)3Si).

3,3-[1,2-Atanderson(oxy))-17 -(1-PROPYNYL)-20-trimethylsilyloxy-19-norpregna-5(10), 9(11)-the diene (16) (method A).

Compound 15 (280 mg, 0.64 mmol) was dissolved in dry THF (3.5 ml) and was cooled to -78 C in argon atmosphere. Then added 1 ml of freshly prepared diisopropylamide lithium (GAVE, 0.75 mmol). The reaction mixture was stirred at -78 C for 1.5 h and then added Me (0.2 ml, 3.2 mmol). The reaction mixture was slowly warmed to -40 C for 2 h, the Reaction mixture was extinguished saturated NH4Cl and extracted twice CH2CL2. The organic layers were combined, washed with water and saturated saline, and dried over NB2SO4. The solvent was removed in vacuum with PoE product/educt again subjected to the same conditions as described above, in order to maximize yield of the desired product (16) in the mixture.

3,3-[1,2-Atanderson(oxy)]-17 -(1-PROPYNYL)-20-trimethylsilyloxy-19-norpregna-5(10), 9(11)-the diene (16) (method B).

N-Tert-butyldimethylsilyl (6.2 ml, 32.5 mmol) dissolved in dry THF (31 ml) was cooled to -78 C in inert atmosphere. By adding n-BuLi (13,0 ml, 32.5 mmol) for 3 min the solution became light yellow. Anionic solution was stirred for 20 min at -78 C and then heated to 0 C for 40 min prior to use.

Compound 15 (5.7 g, 12,93 mmol) was dissolved in dry THF (40 ml) and was cooled to -78 C in inert atmosphere. Then add 25 ml of freshly prepared anion solution described above (16,25 mmol). The reaction mixture was stirred at -78 C for 1.75 h and then added Me (5.0 ml, 80,34 mmol). The reaction mixture is slowly heated in the course of 2.25 hours, the Reaction mixture was extinguished saturated NH4Cl and the mixture was extracted four times CH2Cl2. The organic layers were combined, washed with water and saturated saline, and dried over Na2SO4the solvent was removed in vacuum to obtain a light-yellow solid product. Purification column flash chromatography (3:1 hexane/EtOAc) developing CH3), to 1.19 (d, 3, J = 6.2 Hz, C-21 H) to 0.72 (s, 3, C-18 H) to 0.12 (s, 9, (CH3)3Si). MS (El, m/z 454 (M+).

3,3-[1,2-Atanderson(oxy)]-5,10-oxido-17 -(1-PROPYNYL)-20-trimethylsilyloxy-19-norpregna-9(11)-ene (17).

Compound 16 (3,68 g, 8.1 mmol) was dissolved in CH2CL2(80 ml) was cooled to 0 C in an inert atmosphere, after which was added solid Na2HPO4(575 mg, of 4.05 mmol). After 5 min was added hexaferrite (0.63 ml, 4.5 mmol) and 50% H2O2(1,10 ml, 16.2 mmol). The reaction mixture was slowly heated to room temperature over night. The reaction mixture was extinguished saturated NaHCO3and the mixture was extracted three times with CH2Cl2. The organic layers were combined, washed with saturated Panso3and saturated saline and dried over Na2SO4. The solvent was removed in vacuum to obtain a mixture and epoxides with a quantitative yield of crude product. The crude product was used in the next stage.1H NMR of 6.02 (user. C, 1, C-11 H), 3,92 (m, 4, ketal), 3,82 (d, 1, J = 6,1 Hz, S-20 N), of 1.80 (s, 3, PROPYNYL CH3), of 1.18 (d, 3, J = 6.2 Hz, C-21 H), 0,70 (C, 3, C-18 H) to 0.10 (s, 9, (CH3)3Si).

11 -[4-(N,N-Dimethylamino)phenyl]-3,3-[1,2-atanderson(oxy)]-5-hydroxy-17 -(1-PROPYNYL) -20-trimethylsilyloxy-19-norpregna-9-ene (18a). the alali 2.0 M solution freshly prepared from 4-bromo-N,N-dimethylaniline (36,0 ml, 72 mmol) of the Grignard reagent. After 10 min through konulu was added compound 17 (3,35 g, 7,12 mmol) in dry THF (35 ml). The reaction mixture was slowly heated to room temperature for 1.5 h and extinguished saturated NH4Cl, the aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with saturated NH4Cl and saturated saline and dried over Na2SO4. The solvent was removed in vacuum to obtain a green solid product. Purification column flash chromatography (3:1 hexane/tO) gave compound 18a (2,52 g) with 60% yield over two steps.1H NMR? 7.04 baby mortality (d, 2, J = 8.5 Hz, ArH), 6,62 (d, 2, J = 8,8 Hz, ArH), to 4.38 (s, 1, C-5), 4,16 (user. C, 1, C-11 H), 3,95 (m, 4, ketal), 3,68 (d, 1, J = 6,1 Hz, S-20 N), 2,89 (s, 6, (CH3)2N) to 1.86 (s, 3, PROPYNYL CH3), to 1.14 (d, 3, J = 6.2 Hz, C-21 H), 0,38 (C, 3, C-18 H) of 0.11 (s, 9, (CH3)3Si).

11 -[4-(N,N-Dimethylamino) phenyl] -17 -(1-PROPYNYL) -19-norpregna-4,9-Dien-20-ol (19a).

Compound 18a (2.85 g, to 4.81 mmol) was dissolved in CH2Cl2(200 ml) and cooled to 0 C. then was added H2O (5 ml) and triperoxonane acid (TN, 6 ml). The reaction mixture was extinguished after 45 min intense Panso3and the mixture was extracted twice, CH2CL2. Organic layers of objednavku obtaining a yellow solid product. Purification column flash chromatography (1:1 EtOAc/hexane) gave compound 19a (1.9 grams) with 86.4% of output. 1H NMR 7,02 (d, 2, J = 8.6 Hz, AGN), only 6.64 (d, 2, J = 8,8 Hz, AGN), of 5.75 (s, 1, C-4 H), 4,29 (user. d, 1, J = 6,6 Hz, C-11 H), 3,70 (d, 1, J = 4,2, 6,1 Hz, S-20 N), 2,90 (s, 6, (CH3)2N) 1,90 (C, 3, PROPYNYL CH3), to 1.19 (d, 3, J = 6.2 Hz, C-21 H) 0,51 (C, 3, C-18 H).

11 -(4-(N/N-Dimethylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (a-1).

Compound 19a (1.9 grams, is 4.15 mmol) was dissolved in DMSO (30 ml) and then added a solid o-iodoxybenzoic acid (IBX, of 1.75 g of 6.25 mmol). The reaction mixture was stirred over night at room temperature. TLC showed a mixture of product and educt. The reaction mixture was extinguished diluted Panso3(pH = 9). The resulting mixture was extracted five times with ether. The organic layers were combined, washed with N2O and saturated saline and dried over Na2SO4the solvent was removed in vacuum to obtain the crude mixture of the product and educt. Purification and separation column flash chromatography (2:1 hexane/EtOAc) gave compound a-1 (800 mg) with 43% yield and was also allocated starting material 19a (500 mg, 26% regenerated). For a-1:1H NMR of 7.00 (d, 2, J = 8.6 Hz, ArH), only 6.64 (d, 2, J = 8,8 Hz, AGN), USD 5.76 (s, 1, C-4 H), 4

This product was combined with the previously selected (total 900 mg) and purified preparative HPLC reverse phase (85% Meon:15% H2O as eluent in column (C-18) to obtain 700 mg a-1, more than 97% purity according to analytical HPLC. MS (El, m/z 455 (M+). Analytically calculated for C13H37NO2: 81,72; N 8,19; N 3,07. Found: 81,55, N 8,24, N 3,06.

Example 2. Synthesis of 11 -(4-acetylphenyl) -17 -(1-PROPYNYL) -19-norpregna-4,9-diene-3,20-dione (A-16).

3,3-[1,2-Atanderson(hydroxy)]-11 -{4-{1,1-[1,2-atanderson(oxy)]ethyl}phenyl)-5-hydroxy-17 -(1-PROPYNYL)-20-trimethylsilyloxy-19-norpregna-9-ene (18b).

CuCl (461 mg, of 4.66 mmol) was stirred in dry THF (7 ml) and cooled to 0 C in an inert atmosphere. Was slowly added a 0.5 M solution freshly prepared from bromoacetonitrile Grignard reagent (46,1 ml, 23,0 mmol). After 10 min through a cannula was added epoxide 17 (1,095 g of 2.33 mmol) in dry THF (18 ml). The reaction mixture was slowly heated to room temperature for 1.5 h and extinguished a saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with water and saturated saline and dried over Na2SO4. The solvent was removed in vacuum. Purification of the crude product behaviour in the next stage.

11 -(4-Acetylphenyl)-20-hydroxy-17 -(1-PROPYNYL)-19-norpregna-4,9-Dien-3-one (19b).

The crude compound 18b (original 2.0 mmol) was dissolved in CH2Cl2(100 ml) and cooled to 0 C. was Added N2O (4 ml) and triperoxonane acid (3.0 ml). The reaction mixture was extinguished after 1 h, a saturated solution Panso3and the mixture was extracted twice, CH2CL2. The organic layers were combined, washed with water and saturated saline, and dried over Na2SO4. The solvent was removed in vacuum to obtain a greenish-yellow solid product. The solid cleaning product column flash chromatography (3:2 EtOAc-hexane) gave compound 19b (690 mg) in 62% yield over three steps.lH NMR 7,87 (d, 2, J = 8,2 Hz, ArH), 7,29 (d, 2, J = 8.0 Hz, AGN), 5,79 (s, 1, C-4 H), and 4.40 (d, 1, J = 5,9 Hz, C-11 H), 3,68 (m, 1, S-20 N), to 2.57 (s, 3, arylacetic CH3), with 1.92 (s, 3, PROPYNYL CH3), of 1.20 (d, 3, J = 6,1 Hz, C-21 H), 0,45 (C, 3, C-18 H).

11 -(4-Acetylphenyl)-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (A-16).

Compound 19b (690 mg and 1.51 mmol) was dissolved in dry DMSO (15 ml) and then added a solid o-iodoxybenzoic acid (IBX) (2,95 g, 10,53 mmol). The reaction mixture was stirred over night at room temperature. The reaction is not finished. The mixture p is placed in brine and was dried over Na2SO4. The solvent was removed in vacuum to obtain an orange solid product. Purification column flash chromatography (3:2 EtOAc-hexane) gave compound a-16 (480 mg) in 70% yield and some re-recycled source materials. The compound was then purified preparative HPLC (80% Meon/20% N2O) to obtain compound A-16 in the form of a white solid product with purity of more than 97%. So pl. 113-118;1H NMR 7,88 (d, 2, J = 8,4 Hz, AGN), 7,28 (d, 2, J = 8,5 Hz, AGN), 5,80 (s, 1, C-4 H), 4,50 (d, 1, J = 7,7 Hz, C-11 H), to 2.57 (s, 3, arylacetic CH3), 2,28 (C, 3, C-21 H), 1,90 (C, 3, PROPYNYL CH3), and 0.25(s, 3, S-N). MS (El, m/z 454 (M+). Analytically calculated WITH31H34O30,25 H2O: 81,10; N EUR 7.57. Found: From 81.15; N 7,60.

Example 3. Synthesis of 11 -[4-(methylthio) phenyl] -17 -(1-PROPYNYL) -19-norpregna-4,9-diene-3,20-dione (a-31). 3,3-[1,2-Atanderson (oxy)] -5-hydroxy-11 -[4-(methylthio)phenyl]-17 -(1-PROPYNYL)-20-trimethylsilyloxy-19-norpregna-9-ene (18C).

CuCl (400 mg, 4.0 mmol) was stirred in dry THF (8 ml) and cooled to 0 C in an inert atmosphere. Was slowly added a freshly prepared 1.0 M solution of the Grignard reagent from bromothioanisole (20,0 ml, 20 mmol). After 10 minutes via cannula was added to the crude compound 17 (original 2,0 molydenum solution of NH4Cl. The aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with saturated NH4Cl and saturated saline and dried over Na2SO4. The solvent was removed in vacuum. Immediate cleanup column flash chromatography (3:1 hexane-EtOAc) gave compound 18C, which was used directly in the next stage. 11 -[4-(Methylthio)phenyl]-20-hydroxy-17 -(1-PROPYNYL)-19-norpregna-4,9-Dien-3-one (19s).

Compound 18C (original 2.0 mmol) was dissolved in CH2Cl2(80 ml) and cooled to 0 C. was Added N2About (3 ml) and triperoxonane acid (2.5 ml). The reaction mixture was extinguished after 1 h, a saturated solution of NaHCO3and the mixture was extracted three times with CH2CL2. The organic layers were combined, washed with water and saturated saline and dried over gSO4. The solvent was removed in vacuum. Cleaning the sediment column flash chromatography (1:2 EtOAc-hexane) gave compound 19 (C) (495 mg) with 46% yield over three steps.1H NMR to 7.15 (d, 2, J = 8.7 Hz, ArH), to 7.09 (d, 2, J = 8,5 Hz, AGN), USD 5.76 (s, 1, C-4 H), 4,32 (d, 1, J = 6,6 Hz, C-11 H), 3,69 (user. t, 1, S-20 N), of 2.45 (s, 3, S3), at 1.91 (s, 3, PROPYNYL CH3), 1,19 (l, 3,7 = x 6.15 Hz, C-21 H), 0,48 (C, 3, C-18 H).

11 -[4-(Methylthio) phenyl] -17 -(1-PROPYNYL) -19-norpregna the solid IBX (1.5 g, are 5.36 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture was extinguished H2Oh and the mixture was extracted four times with ether. The organic layers were combined, washed with water and saturated saline and dried over Na2SO4the solvent was removed in vacuum. Cleaning the sediment column flash chromatography (3:2 hexane-EtOAc) gave compound a-31, the purity of which is on this preparative HPLC over 97%. Further purification preparative HPLC (85% Meon-15% H2O) gave pure a-31 (340 mg) with 69% yield. So pl. 164-167,5;1H NMR 7,16 (d, 2, J = 8.5 Hz, ArH), was 7.08 (d, 2, J = 8,5 Hz, AGN), 5,78 (s, 1, C-4H), 4,35 (d, 1, J = 7,3 Hz, C-11 H), 2, (C, 3, SCH,), 2,28 (C, 3, C-21 H), 1,89 (C, 3, PROPYNYL CH3), and 0.28 (s, 3, C-18 H). MS (EI, m/z 458 (M+). Analytical calculation for C30H34O2S: 78,56; N 7,47; S 6,99. Found 78,48; N 7,50, S 6,91.

Biological activity of compounds according to this invention was investigated using in vitro and in vivo methods.

Binding receptors. The affinity of compounds to the hormonal receptors were determined by conventional methods, such as those that have been described, among others, Wagner et al., Proc. Natl. Acad. Sci., 93, 8739-8744 (1996) for cells COS-1. Cell lines of breast carcinoma human T-47D) COI Collection and kept frozen at -135 With in the week before the week before the survey. The cells were thawed and konturirovany to achieve the desired number of cells (average from 5 to 7 days). They were maintained at 37 C in the medium for growth, until they formed a 90-100% confluent, after which they were allocated from the flasks for cell growth and dispersible in separate wells of a 12-hole tablet for tissue culture in the amount of 4.0 105cells in one ml of medium in the well. After 24 h cells were desirability on the bottom of a 12-hole of the tablet. At this time he began conducting research on receptor binding by adding the test or standard compounds with3H-R5020 (promegestone). After incubation overnight, the medium was removed, cells were washed and solubilizers, and radioactivity was measured using liquid scintillation spectrometer. Nonspecific binding was determined by incubation with excess unlabeled R5020 and subtracted from total binding to calculate specific binding.

Study of the binding of progesterone spent several concentrations of the specified standard (promegestone, R-5020) and internal standard (progesterone). These hormones left for competitive binding with the processed competitor (3H-promegestone,3H-R5020} to evaluate otnee offset 3H-R5020 from the receptor has not achieved the target substance to achieve the goal researched high or low concentrations, as needed. All compounds examined twice, at least two tests.

The percentage of specifically associated3H-R5020 was calculated for each studied concentration, and binding curves were presented by displaying the percentage of specific binding3H-R5020 on the concentration of the competitor. The relative binding activity (RBA) of the studied compounds relative to the specified standard (R5020) and the internal standard was determined by the ratio of the concentrations causing 50% substitution for each of the unknown and standard, and expressed as a percentage. These concentrations obtained by graphical interpolation curves. In the result, it was found that the combination of 11 -[4-(N/N-dimethylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (a-1) has the RBA 313% relative to R-5020. A similar connection 11 -[4-acetylphenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (A-16) has the RBA 439% relative to R-5020.

In vivo study. Antiprogestational activity was determined in vivo by studying the response to a dose of immature rabbits W the ti research are standard methods, well-known specialists in this field. To determine antiprogestational (antagonistically) activity compound is administered orally together with subcutaneous injection of progesterone. Research conducted with orally administered at a total dose of 0.5, 1 and 2 mg in immature female rabbits in the initial-estrogenic phase of the cycle, which simultaneously was subcutaneously injected progesterone. Rabbits, weighing about 1.5 kg, were in the estrogenic phase of the cycle from one to six days and once a day for 5 days was administered 0.8 mg of progesterone, or 160 μg/day, while at the same time introduced the analyzed compound orally once daily in the diluent, which represented a 10% ethanol/sesame oil (volume 0.5 ml). An autopsy was performed the day after the last dose. Endometrial effects on the uterus was determined according to McPhail and strength were evaluated by statistical comparison with a standard mixture of 17-acetoxy-11 -[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione. Introduction 17-propanolol group unexpectedly gave exceptionally strong antiprogestin answer, because the connection 11 -[4-(N,N-dimethylamino)phenyl]-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (the al, Human Reproduction, 9, Supplement 1, 32-39, June 1994) standard connection is about 3 times stronger than the drug mifepristone, which is currently used for the treatment of humans as a drug with antiprogestin activity, making Propylamine connection according to this invention is 15 times stronger than mifepristone.

A similar compound, 11 -(4-acetylphenyl)-17 -(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione (A-16), also has antiprogestin activity, and it was from 0.15 to 0.23 times more efficient than standard connections. A much smaller effect compared to the standard and especially dimethylamino analog, binding affinity to progestin-only receptor suggests that the compound a-16 has agonistic activity, and weak antagonistically activity.

In light of the above research is the obvious possibility of numerous modifications and alterations of the present invention. Therefore, it should be clear that within the formulas presented, the invention can be implemented in ways other than specified here.

a) Mel, K2SO4, MeOH

b) TosMIC, tert-BuOK, t-BuOH, DME

c) MeMgBr, THF, boiling with the inverse CLASS="ptx2">

f) ZnL2(melted), ether, 0°C

g) formaldehyde (gas), ether, 0°C

h) L, THF, 0°C

i) LiNH3 (I), THF, tert-BuOH, -78°C

j) (COOH)2, THF, dioxane, N2About

k) tribromide pyrimidine, pyridine, -78°C

1) ll, DMSO, Et3N, CH,Cl2, -60°C

m) (CH3O)2POCHN2, tert-BuOK, THF, -78°C

n) HOCH2CH20H, n-TsOH, benzene, boiling under reflux

a) NaBH4, THF, tO

R) TMSCl, pyridine, 0°C to room temperature

q) (CH3)3NSi(CH3)3n-BuLi

g) Me

s) Hexaferrite, N2ABOUT2, Na2HPO4, 0°C

t) R'-C6H4MgBr, CuCt, THF, 0°C

and) TFU, CH2CL2N2O, 0°C

v) IBX, DMSO, room temperature

1. Hormonal or non-hormonal steroid compound of the formula I

where R1represents (CH3)2N-CH3NH-, NH2-, CH3CO - or CH3S-;

R2represents CH3or CF3-;

R3represents H, CH3-, CH3O-CH3COO-;

R4represents H, CH3-, F - or Cl-;

where R1represents (CH3)2N-CH3NH - or-NH2-.

3. Hormonal or negormonalna steroid compound under item 1, of the formula IV

4. Steroid under item 1 selected from the group including

11-(4-AMINOPHENYL)-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-21-methyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-21-methyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-21-methyl-6-fluoro-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-21-methyl-6-fluoro-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-6,21-dimethyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-6,21-dimethyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-6-fluoro-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-6-fluoro-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-6-methyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-(4-AMINOPHENYL)-6-methyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,laminitis)phenyl]-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-21-methyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-21-methyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-21-methyl-6-fluoro-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-6,21-dimethyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-6,21-dimethyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-6-fluoro-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-6-fluoro-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-6-methyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N,N-dimethylamino)phenyl]-6-methyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-21-methyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-21-mobinil)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-21-methyl-6-fluoro-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-6,21-dimethyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-6,21-dimethyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-6-fluoro-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-6-fluoro-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl-6-methyl-17-(1-PROPYNYL)-19-norpregna-4,9-diene-3,20-dione;

11-[4-(N-methylamino)phenyl]-6-methyl-17-(3,3,3-cryptochrome-1-yl)-19-norpregna-4,9-diene-3,20-dione.

5. The method of therapeutic activity of progesterone, including the introduction of a therapeutically effective amount of the compounds on p. 1 patients in need of such treatment in a therapeutic purposes.

6. The method according to p. 5, where the specified therapeutic purpose is the treatment of endometriosis or uterine fibroids.

7. The method according to p. 5, where the specified therapeutic goal is the strengthening of ripening of the cervix before delivery or birth of offspring.

8. The method according to p. 5, where the specified therapeutic goal is to control Rozhdestvenka tumors or tumors.

10. The method according to p. 5, where the specified therapeutic goal is hormone replacement therapy.

11. The method according to p. 1, including the additional introduction of one or more pharmacologically active compounds.

12. Hormonal or non-hormonal steroid compound of the formula II

where R5represents CH3CO - or CH3S-;

R6represents CH3or CF3-;

R7represents H;

R8represents H, CH3-, F - or Cl-;

X represents O

or their pharmaceutically acceptable salts.

 

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