MXPA00011769A - 17&bgr;-AMINO AND HYDROXYLAMINO-11&bgr;-ARYLSTEROIDS AND THEIR DERIVATIVES HAVING AGONIST OR ANTAGONIST HORMONAL PROPERTIES - Google Patents

Abstract

The invention is directed to a novel class of steroids which exhibit potent antiprogestational activity.

Description

17 3-AMINO AND HYDROXYLAMINO-3-ARILESTEROIDS AND THEIR DERIVATIVES THAT HAVE HORMONE PROPERTIES AGONISTS OR ANTAGONISTS BACKGROUND OF THE INVENTION Field of the Invention: This invention relates to a novel class of 17β-amino and hydroxylamino steroids that are believed to bind to the progestin receptor and exhibit potent antiprogestational activity, steroid intermediates that are useful for preparing them and methods for the preparation of steroid intermediaries. These compounds are useful for the treatment of fibroids, endometriosis, and certain tumors, in causing cervical maturity before delivery, in hormone replacement therapy and in control of fertility and reproduction. Discussion of the background: Progesterone plays an important role in reproductive health and functioning. Its effects on, for example, the uterus, the breasts, the cervix and the hypothalamic-pituitary unit are well established. It also has extrareproductive activities that are less well studied, such as effects on the brain, the immune system, the vascular endothelial system and on lipid metabolism. Given this broad array of effects, it is apparent that compounds that mimic some of the effects of progesterone (agonists), antagonize these effects (antagonist), or exhibit mixed effects (partial agonists or mixed agonists / antagonists) may be useful in treating a variety of disease states and conditions. Steroid hormones exert their effects, in part, by binding to intracellular receptors. Compounds that bind appropriate receptors and are antagonists or partial agonists of estrogenic and androgenic hormones have long been known, but it was not until about 1982 that the discovery of compounds that bind to the progesterone receptor and antagonize the effects of progesterone Advertise Since then, several of these compounds have been reported in the scientific and patent literature and their effects in vi tro, animals and humans have been studied. Although compounds such as estrogens and certain enzyme inhibitors can avoid the physiological effects of endogenous progesterone, in this discussion "antiprogestin" is confined to those compounds that bind to the progestin receptor. Information indicating that antiprogestins would be effective in various medical conditions is now available. This information has been summarized in a report from the Institute of Medicine (Donaldson, Molly S., Dorflinger, L .; tea 3 Brown, Sarah S .; Benet, Leslie Z., Editors, Clinical Applications of Mifepristone (RU 486) and Other Antipro- tensins, Committee on Antiprogestins: Assessing the Science, Institute of Medicine, National Academy Press, 1993). In view of the pivotal role played by progesterone in reproduction, it is not surprising that antiprogestins could play a part in the control of fertility, including contraception (long-term and emergency or post-coitus), induction of menses. and medical termination of pregnancy, but there are 0 other potential uses that have been supported by small clinical or preclinical studies. Among these are the following: 1. Part labor and delivery - antiprogestins can be used for cervical maturity before induction of labor as it is term or when it is in labor to be induced due to fetal death . It can also be used to help induce labor in term or post-term pregnancies. 2. Treatment of uterine leiomyomas (fibroids) - 0 these non-malignant tumors can affect up to 20 percent of women after 30 years of age and are one of the most common reasons for surgery in women during their reproductive years. Hysterectomy, the common treatment for persistent symptoms, certainly results in sterility. 3. Treatment of endometriosis - this common condition (from 5 to 20 percent incidence, much higher in infertile women) and often painful is now treated with drugs such as danazol or hormone analogs that releases gonadotrophin that have significant side effects, or can be treated with surgery. 4. Hormone replacement therapy, where it can be given to interrupt or reduce the activity of progestins. 5. Cancers, particularly breast cancers - the presence of progestin receptors in many breast cancers has suggested the use of antiprogestin to treat metastatic cancer or in prevention or recurrence or initial development of cancer. 6. Other tumors such as meningiomas - these tumors of the brain membrane, although not malignant, result in the death of the patient and require nonsurgical treatments. 7. Male contraception - antiprogestins may interfere with sperm viability, although this is an antiprogestational effect or is not controversial, as it may be related to the antiglucocorticoid activity of such compounds. 8. Anti-estrogenic effects - at least some antiprogestins oppose the action of estrogen in certain tests, but apparently through a mechanism that does not involve classical hormone receptors. This opens a variety of possibilities for medical use. 9. Antiglucocorticoid effects - this is a common side effect of antiprogestins, which may be useful in some cases, such as the treatment of Cushing's syndrome, and could play a role in immune disorders, for example. In other cases it is desirable to minimize these effects. The effects and uses of progesterone agonists have been well documented. Furthermore, it has recently been shown that certain compounds structurally related to the known antiprogestins have strong agonist activity in certain biological systems (eg, the effects of classical progestin in the immature rabbit uterus primed with estrogen, see EC, Cook et al. Sciences, 52, 155-162 (1993)). These compounds are partial agonists in receptor systems derived from human cells, where they bind at a site different from both the site of the progestin and that of the antiprogestin (Wagner et al., Proc. Nati. Acad. Sci., 93, 8739 -8744 (1996)). In this way the general class of antiprogestins can have subclasses, which can vary in their clinical profiles. Generally the antiprogestational activity has been associated with the presence of a 1,1 / 5-aryl substituent in the steroid nuclei, together with a? 4 -3- ketone or? -3-ketone. However, it has been shown that substituents on the D-ring of the steroid can have a marked influence on the biological profile of these compounds (see above). The above antiprogestins were substituted with a 17-hydroxyl group and several 17of substituents. (See, for example, Teutsch, Jean G., Costerousse, Germain, Philibert, Daniel, and Deraedt, Roger, Novel steroids, United States Patent No. 4,386,085, 1983, Philibert, Daniel, Teutsch, Jean G., Costerousse. , Germain, and Deraedt, Roger, 3-Keto-19-nor-γ-4, 9-steroids, U.S. Patent No. 4,477,445, 1983, Teutsch, Jean G., Pantin, Germain, Costerousse, Saint- Maurice, Daniel Philibert, La Varenne Saint Hilaire, Roger Deraedt, inventors, Steroid derivatives, Roussel Uclaf, transferee, United States Patent Number 4,447,424, 1984, Cook, C. Edgar, Tallent, C. Ray, Reel, Jerry, ., and Wani, Mansukh C. 17o.- (Substituted-methyl) -170-hydroxy / esterified hydroxy steroids and pharmaceutical compositions containing them Patents of the United States of North America Nos. 4,774,236 (1988) and 4,861,763 (1989)). It was then discovered that a l7ß-acetyl, l7c_-acyloxy group could also generate antiprogestational effects (Cook, C. Edgar; Lee, Y.-W .; Reel, Jerry R .; Wani, Mansukh C, Rector, Douglas. 11/3-Substituted Progesterone Analogs. Patents of the United States of North America Nos. 4,954,490 (1990) and 5,073,548 (1991)), and several permutations of these findings have also been made. However, the introduction of an I6? - ethyl group of a hydrogen substituent at position 17c. in the 17/3-acyl series the compounds lead to agonist or partial agonist activity (EC, Cook et al, Life Sciences, 52, 155-162 (1993)). Thus, changes in the D-ring of the steroid result in a wide variety of effects on biological activity. In accordance with the foregoing, there remains a need for antiprogestin compounds that exhibit greater specificity. It can be seen that the 17/3 position of the present antiprogestins has been characterized by substitution with a carbon atom or a hydrogen atom. No reports have been made on the effect of nitrogen substituents such as amines, amino amides, and hydroxylamines at the 17/3 position of 11/3-aryl steroids on their hormonal or antihormonal activity. Until the present invention there were no methods for its synthesis. Very few 17/3-amino and hydroxylamino steroids and none with 11/3 substitution have been reported in the general chemical literature or in patents. Undoubtedly, one of the few reports of this type of substitution 17 (3 (P. Kaspar and H. Witzel, J. Steroid, Biochem., 23: 259 (1985)) shows that this type of substitution in the estrogen field leads to compounds that have one or more orders of magnitude less potent (measured by receptor link or live standard tests for their estrogenicity) than the corresponding 17/3-hydroxy compounds. A novel feature of the present invention is the finding that the 17/3-nitrogen substituents in the 11/3-arylsteroids result in compounds with good binding to the progestin receptor and with surprisingly potent antiprogestational activity, or with potent antiprogestational activity accompanied by some progestational activity. Another novel feature of the present invention is the finding that the 17/3-nitrogen substituents in the 11/3-arylsteroids result in compounds having unusual antiestrogenic activity. In addition, this invention provides a group of cyclic 17, 17-eepiro tetrahydropyrrolesteroids. Although few tetrahydropyrrolesteroids 17,17-spiro cyclic are known (see Keana, John F. W .; Tamura, Toshinari; McMillen, Debra A., and Jost, Patricia C. Synthesis and characterization of a novel nitroxide spin label. Application to the molecular organization of human high-density lipoprotein. J. Am. Chem. Soc. 1981; 103 (16): 4904-4912), these have been used to develop spin tags and not for their biological properties. None of these compounds with 11/3-aryl substituents has been reported. Again, a novel feature of the present invention is the finding that these compounds surprisingly bind well with the progestin receptor and exhibit antiprogestational activity. It is therefore the purpose of the present invention to provide novel and potent progestin antagonists (antiprogestins) and mixed or partial progestin agonists, to provide methods for their medical use in mammals, including humans, and to provide methods for their synthesis. Despite the clinical promise of antiprogestins, until May 1, 1998, there were no antiprogestin drugs marketed in the United States or in many other countries. Only one antiprogestin drug is approved and available for clinical use anywhere in the world and that drug, mifepristone, is mainly used for medical termination of pregnancy. Several factors are the cause of this situation, but there is certainly a need for new antiprogestational drugs that can be used for the conditions described above. It is therefore the purpose of the present invention to provide novel and potent progestin antagonists (antiprogestin) and mixed or partial progestin agonists, and provide methods for their medical use in mammals, including humans. SUMMARY OF THE INVENTION This invention provides a group of 17/3-amino and hydroxyaminoesteroids, which are characterized by 11/3 substitution, particularly ll / 3-aryl substitution. According to one embodiment of the present invention is a hormonal or antihormonal steroid compound of structure I, wherein R1 is (R2R3N (0) r) -, wherein r is 0 or 1 and R2 and R3 each is independently H, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, or alkynyl with 2 to 6 carbon atoms, any of which may optionally be substituted; where q is 0 or 1, Y is - (CH2) m- where m is an integer from 0 to 5, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer from 0 to 2, and Z is a heteroatom (optionally substituted) and wherein the CH2 groups may be optionally substituted; or R is N-imidazolyl, -N-pyrrolyl-, H, halo-, HO-, CFS020-, alkyl with 1 to 6 carbon atoms -0-, alkyl with 1 to 6 carbon atoms -S-, alkyl having from 1 to 6 carbon atoms -S (0) -, alkyl having from 1 to 6 carbon atoms - S (02) -, alkyl having from 1 to 6 carbon atoms -CO-, alkyl having from 1 to 6 carbon atoms -CH (OH) -, NC-, HCC-, C6H5CC-, 2'-furyl, 3 '-furyl, 2'-thiophenyl, 3'-thiophenyl, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl, 2'-thiazolyl, 2'-N-methylimidazolyl, 5'-pyrimidinyl, C6H5-, H2C = CH-, alkyl of 1 to 6 carbon atoms, MeC (= CH2) -; R12 is H or halo; or R 1 and R1? combine to form a ring wherein W is CH2, CH, NH, N, 0, or S, and R4 is H or alkyl with 1 to 6 carbon atoms; X is 0 or ÑOR5, where R5 is H or alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, aryl with 6 to 12 carbon atoms, or heteroaryl, which can be optionally replaced; or X is (H, H), (H, OH), (H, or Si (alkyl with 1 to 6 carbon atoms) 3), or (H, OCOR 5), wherein R 5 is alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl , heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted; or where Y is - (CH2) m- where m is an integer from 0 to 3, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer from 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two alkyl groups with from 1 to 6 carbon atoms; R6 is H, alkyl having 1 to 6 carbon atoms or halogen; R7 is H, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkenyl atoms, any of which can be optionally substituted, CN, COOR10 or CONHR10, wherein R ° is H, alkyl having from 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may optionally be substituted: s is 0 or 1; R8 and R9 each independently is H, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms or alkynyl with 2 to 6 carbon atoms, R ° CO, OR, any of which it can optionally be substituted, wherein R10 is H, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms , aryl, with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, and wherein R 11 is H, alkyl having from 1 to 6 carbon atoms; carbon, Si (alkyl having 1 to 6 carbon atoms), 2-tetrahydropyranyl or R 10 CO wherein R is defined as above wherein when s is 0, R 8 may also be 0"and R 9 is = CH 2 or = C (H , Cμ6), = C (H, aryl) or = C (C1.6) 2 and the nitrogen attached to position 17 is positively charged, - and pharmaceutically acceptable salts thereof. According to another embodiment of the present invention is a hormonal or antihormonal steroid compound of structure II, wherein R1 is (R2R3N (0) r) -, wherein r is 0 or 1 and R2 and R3 each is independently H, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, or alkynyl with 2 to 6 carbon atoms, any of which may optionally be substituted; where q is 0 or 1, Y is _ (CH2) m- where m is an integer from 0 to 5, or Y is - (CH2) nZ- (CH2) "- where n is an integer from 0 to 2, p is an integer from 0 to 2, and Z is a heteroatom (optionally substituted) and wherein the CH2 groups may be optionally substituted; or R1 is N-imidazolyl, -N-pyrrolyl-, H, halo-, HO-, CF3S020-, alkyl with 1 to 6 carbon atoms -0-, alkyl with 1 to 6 carbon atoms -S-, alkyl having from 1 to 6 carbon atoms -S (0) -, alkyl having from 1 to 6 carbon atoms -S (02) -, alkyl having from 1 to 6 carbon atoms -CO-, alkyl having from 1 to 6 carbon atoms -CH (OH) -, NC-, HCC-, C6H5CC-, 2'-furyl, 3 '-furyl, 2'-thiophenyl, 3'-thiophenyl, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl, 2'-thiazolyl, 2'-N-methylimidazolyl, 5'-pyrimidinyl, C6H5-, H2C = CH-, alkyl of 1 to 6 carbon atoms, MeC (= CH2) -, - R12 is H or halo; or R and R1A combine to form a ring wherein W is CH2, CH, NH, N, 0, or S, and R4 is H or alkyl with 1 to 6 carbon atoms; X is 0 or ÑOR5, wherein R5 is H or alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms. carbon, aryl with 6 to 12 carbon atoms, or heteroaryl, any of which may be optionally substituted; or X is (H, H), (H, OH), (H, or Si (alkyl with 1 to 6 carbon atoms) 3), or (H, OCOR 5), wherein R 5 is alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl , heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted; or where Y is (CH2) m- where m is an integer from 0 to 3, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer of 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two alkyl groups with 1 to 6 carbon atoms; R6 is H, alkyl having 1 to 6 carbon atoms or halogen; s is 0 or 1; R9 is H, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms or alkynyl having from 2 to 6 carbon atoms, R10CO, OR11, any of which can be optionally substituted, wherein R10 is H, alkyl with 1 to 18 a, carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl, with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may optionally be substituted, and wherein R is H, alkyl having from 1 to 6 carbon atoms, Si (alkyl with 1 to 6 carbon atoms), 2'-tetrahydropyranyl or R 10 CO wherein R 10 is defined as above R 13 and R 14 each independently is H, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms , alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 atom carbon, aryl having 6 to 12 carbon atoms, aralkyl, aralkenyl or aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted; or R13 R14 is O; and R15 and R16 each are H or combine to form a group = CH2, optionally substituted, and pharmaceutically acceptable salts thereof. BRIEF DESCRIPTION OF THE DRAWINGS A more complete appreciation of the invention and many expected advantages thereof will be readily obtained as best understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein: 1 represents a reaction scheme for preparing amine and hydroxylamine compounds according to the present invention; Figure 2 depicts a reaction scheme for preparing cyclic amine compounds according to the present invention; and Figure 3 depicts a reaction scheme for preparing cyclic hydroxylamine compounds according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The above-identified compounds of formulas I and II specifically include compounds that are substituted on ring A at the 3-position with two hydrogen atoms. These compounds are believed to undergo oxidation in vivo to the corresponding carbonyl compound. Within the scope of the present invention, the term "heteroatom" means oxygen, nitrogen, sulfur, silicon or boron. Halogen means fluorine, chlorine, bromine or iodine and halo means fluoro, chlorine, bromine or iodine. Aralkyl, aralkenyl, or aralkynyl means an alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms or alkynyl group with 2 to 4 carbon atoms carrying an aryl substituent. "Lower alkyl" means an alkyl group with 1 to 6 carbon atoms. Heteroaryl means a unit of 5 to 12 non-hydrogen atoms that consists of one or more cyclic structures that can be fused or bonded together, which contain from 1 to 5 heteroatoms and which are generally accepted by those skilled in the art for having aromatic electronic character. Heteroaralkyl, heteroaralkenyl, or heteroaralkynyl means alkyl with 1 to 4 carbon atoms, alkenyl with 2 to 4 carbon atoms or alkynyl group with 2 to 4 carbon atoms carrying a heteroaryl substituent. "Optionally substituted" means unsubstituted or substituted with one or more heteroatoms and / or halogens and / or alkyl groups with from 1 to 4 carbon atoms and / or alkenyl and / or alkynyl groups with from 2 to 4 carbon atoms and / or cycloalkyl groups with 3 to 7 carbon atoms and / or aryl groups of 6 to 12 carbon atoms and / or heteroaryl groups, and in which the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl group can be further substituted with one or more heteroatoms and / or halogens. The substitution can occur directly on the CH2 groups of cyclic amine heterocycles. When its valence allows it, heteroatoms can be substituted with either a carbon chain or by joining single or double bonds. For example, -CH2CH2C (= 0) H, -CH2 (C = 0) CH3, -CH2CH2OCH3, -CH2CH2CH2OH, CH3CH2CH20-, CH2CH2C (= 0) NH2, CH3CH2C (= 0) NH-, -CH2CH2COOCH3, CH3CH2COO-, and CF3CC- all fall within this definition. In all cases in which valence and steric considerations permit, the alkyl, alkenyl, alkynyl and cycloalkyl groups may contain double or triple bonds and / or branched chains. The group R6 in C6 as it appears in structures I and II can be either in position. or ß. In a preferred embodiment, the group R6 is located in the OI position. In another embodiment, the Cji / 3-aryl group can be replaced with a pyridine group substituted with R 1 and R 12 groups as previously described. In a preferred embodiment, the steroid having the structure I is substituted as follows: wherein R ^ Ph is 4-aminophenyl, 4- (N-methylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 4- ( N-piperidino) phenyl, 4- (N-pyrrolidino) phenyl, 4- (N-morpholino) phenyl, l-methylindol-5-yl or l-methyl-2,3-dihydroindol-5-yl or R'-Ph is the N-oxide of 4- (N, N-dimethyl) phenyl, 4- (N-piperidino) phenyl, 4- (N-pyrrolidino) phenyl, 4- (N-morpholine) phenyl; X is 0, NOH, or N0CH3; R6 is H, CH3, F or Cl; R7 is H, methyl, ethynyl, 1-propynyl, 3-propynyl, 3-hydroxypropyl, 3-hydroxy-1-propenyl (E- or Z-), 3,3,3-trifluoropropin-1-yl, 3-hydroxypropin-1-yl, (CH 2) 2COOCH 3, (CH 2) 2 COOC 2 H 5, ( CH2) 2COCH3, CC-C6H5, CH2C6H5, CN, or C00CH3; R8 is H, CH3 or CH2C6H5; and R9 is H, OH, 0CH3, CHO, CH3C0, C6H5CO or C6H5CH2CO. In a preferred embodiment, the compound of structure II is substituted where, R'-Ph is 4-aminophenyl, 4- (N-methylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 4- (N-piperidino) ) phenyl, 4- (N-pyrrolidino) phenyl, 4- (N-morpholino) phenyl, l-methylindol-5-yl or l-methyl-2,3-dihydroindol-5-yl); X is 0, NOH, or N0CH3; R6 is H, CH3, F or Cl; R9 is H, OH, CHO, CH3CO, C6H5CO or C6H5CH2CO; R13 and R14 are 0, (H, H), (H, CH3) or (CH3 CH3); and R15 and R16 (H; H) or combine to form (= GH2). In a preferred embodiment of the amino group at C 17, the compound of structure II is such that the aminonitrogen is located on the β-side of the compound, syn with the group C ^ j aryl. The compound of structure I can also carry Q Q a functional group nitrona, where s is 0, R is O and R is an alkene. In this case, the nitrogen in the 17 l position carries a positive charge. Specific non-limiting examples include the compounds: 110- (4- (N, N-dimethylamino) phenyl) -17 / 3- (N-hydroxylamino) -yl- (l-propynyl) -estra-4, 9-dien-3 -one; 11 / 3- (4- (N-piperidino) phenyl) -17 / 3- (N-hydroxylamino) -17c.- (1-propynyl) -estra-4,9-dien-3-one; 11 / 3- (4- (N, N-dimethylamino) phenyl) -17 / 3- (N-hydroxy-N-methylamino) - li - (1-propynyl) estra-4,9-dien-3-one; 11 / 3- (4- (N-piperidino) phenyl) -170- (N-hydroxy-N-methylamino) -17a- (1-propynyl) estra-4,9-dien-3-one; 170-amino-11 / 3- (4- (N, N-dimethylamino) phenyl) -17a- (1-propynyl) estra-4,9-dien-3-one; 170-amino-11 / 3- (4- (N-piperidino) phenyl) -yl- (1-propynyl) estra-4,9-dien-3-one; 17 / 3- (N-acetamido) -110- (4- (N, N-dimethylamino) phenyl) -lia- (1-propynyl) estra-4,9-dien-3-one; 170- (N-acetamido) -110- (4- (N-piperidino) phenyl) -17c.- (1-propynyl) estra-4, 9-dien-3-one, -110- (4- (N, N-dimethylamino) phenyl) -170- (N-formamido) -11 ct- (1-propynyl) estra-4,9-dien-3-one, and its N-oxide; 170- (N-formamido) -110- (4- (N-piperidino) phenyl) - lia- (1-propynyl) estra-4,9-dien-3-one and its N-oxide; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-hydroxylamino) -17c.- (3-hydroxypropyl) estra-4,9-dien-3-one; 110- (4- (N-piperidino) phenyl) -170- (N-hydroxylamino) -17c.- (3-hydroxypropyl) estra-4, 9-dien-3-one, -101- (4- (N, N-dimethylamino) phenyl) -170- (N-hydroxylamino) -lia- (3-hydroxypropyl) estra-4,9-dien-3-one; 110- (4- (N-piperidino) phenyl) -170- (N-hydroxy-N-methylamino) -lia- (3-hydroxypropyl) estra-4,9-dien-3-one; 170-amino-110- (4- (N, N-dimethylamino) phenyl) -lia- (3-hydroxypropyl) -estra-4,9-dien-3-one; 170-amino-17c_- (3-hydroxypropyl) 110- (4- (N-piperidino) phenyl) estra-4,9-dien-3-one; 170- (N-acetamido) -110- (4- (N, N-dimethylamino) phenyl) -lia- (3-hydroxypropyl) estra-4,9-dien-3-one; 170- (N-acetamido) -170-- (3-hydroxypropyl) -110- (4- (N-piperidino) phenyl) estra-4, 9-dien-3-one; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-formamido) -lia- (3-hydroxypropyl) estra-4,9-dien-3-one; 170- (N-formamido) -lia- (3-hydroxypropyl) -110- (4- (N-piperidino) phenyl) estra-4, 9-dien-3-one, -101- (4- (N, N -dimethylamino) phenyl) -170- (N-formamido) -17of- (3-formyloxy-1-propyl) estra-4,9-dien-3-one; 170- (N-formamido) -lia- (3-hydroxypropyl) -11a- (3-formyloxy-1-propyl) -110- (4- (N-piperidino) phenyl) estra-4, 9-dien-3- ona; 110- (4- (N, N-dimethylamino) phenyl) -1'-hydroxy-5'-methyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N-piperidino) phenyl) -l'-hydroxy-5'-methyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -1'-hydroxy-5'-methyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one, -101- ( 4- (N-piperidino) phenyl) -1 '-hydroxy-5' -methyl-spiro [estra-4, 9-di in -170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -5'-methyl-spiro [estra-4,9-dien-170,2'-pyrrolidine] -3-one; 110- (4- (N-piperidino) phenyl) -5'-methyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -spiro [estra-4, 9-dien-l70, 2 'pyrrolidine] -3-one, -101- (4- (N-piperidino) phenyl) - spiro [estra-4 ?, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N-piperidino) phenyl) -5' -oxo-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -l'-formyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one and 110- (4- (N-piperidino ) phenyl) -1'-formyl-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3-one. The compounds of the present invention which carry an amino group also comprise a salt formed with the amine. Suitable pharmaceutically acceptable salts are known to those skilled in the art and comprise carboxylates, sulfates, phosphates and halides. The amino and hydroxylamino compounds of the present invention can be prepared from an intermediate hydroxy nitro compound of structure (III). wherein R1 is (R2R3N (0) r) -, wherein r is 0 or 1 and R2 and R3 each is independently H, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, or alkynyl with 2 to 6 carbon atoms, any of which may optionally be substituted; where q is 0 or 1, Y is - (CH2) m- where m is an integer from 0 to 5, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer from 0 to 2, and Z is a heteroatom (optionally substituted) and wherein the CH2 groups may be optionally substituted; or R1 is N-imidazolyl, -N-pyrrolyl-, H, halo-, HO-, CF3S020-, alkyl having from 1 to 6 carbon atoms -0-,? alkyl having from 1 to 6 carbon atoms -S-, alkyl having from 1 to 6 carbon atoms -S (O) -, alkyl having from 1 to 6 carbon atoms -S (02) -, alkyl having from 1 to 6 carbon atoms -CO-, alkyl having from 1 to 6 carbon atoms -CH (OH) -, NC-, HCC-, C6H5CC-, 2'-furyl, 3 '-furyl, 2'-thiophenyl, 3' -thiophenyl, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl, 2'-thiazolyl, 2'-N-methylimidazolyl, 5'-pyrimidinyl, C6H5-, H2C = CH-, alkyl of 1 to 6 carbon atoms. carbon, MeC (= CH2) R12 is H or halo; or R I and R1? combine to form a ring R4 I ^ wherein W is CH2, CH, NH, N, 0, or S, and R4 is H or alkyl with 1 to 6 carbon atoms; ^ HiO- X is Y NCH2O- where Y is - (CH2) m- where m is an integer from 0 to 3, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer from 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two alkyl groups with from 1 to 6 carbon atoms; R6 is H, alkyl having 1 to 6 carbon atoms or halogen; R7 is H, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl atoms, any of which can be optionally substituted, CN, COOR 10 or CONHR 10, wherein R is H, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, by reduction of the nitro group, followed by hydrolysis of the ketal and removal of the hydroxyl group. This method can be performed by conventional methods known to those skilled in the art. For example, the nitro group can be reduced to an amine or hydroxylamine by treatment with zinc and ammonium chloride. The product of amine or hydroxylamine can favor adjusting the proportion of zinc against the nitro compound, with lower molar proportions of zinc (2-18) favoring the formation of hydroxylamine and higher proportions (20-80) favoring the formation of amine. The compounds of structure III can be made by a method described in the United States of America Patent Application entitled "17 0-Nitro-110-aryl Steroids and Their Derivatives having Agonist or Antagonist Hormonal Properties" (17 0-Nitro- ll0-aryl steroids and their derivatives that have hormonal properties agonists or antagonists) by CE. Cook J.A. Kepler, R.S. Shetty, G.S Bartley and D. Lee, filed in conjunction with this application, (case number 2025-0133-77), relevant portions of which are incorporated herein by reference. Steroids having progestational, antiprogestational and / or antiglucocorticoid activity have use in the control of fertility in humans and in non-human mammals such as primates, domestic animals and farm animals, and in the treatment of medical conditions in animals or humans in humans. which these activities are beneficial. In this way they can be useful in the treatment of conditions such as fibroids, Cushing's syndrome, glaucoma, endometriosis, cervical maturity before delivery, hormone replacement therapy, premenstrual syndrome and cancer in addition to their use in the control of fertility and reproduction. The compounds of the present invention can be administered by a variety of methods. Thus, the products of the invention which are active by the oral route can be administered in solutions, suspensions, emulsions, tablets, including sublingual and intra-oral tablets, soft gelatin capsules, including solutions used in soft gelatine capsules, aqueous suspensions or in oil, emulsions, pills, pills, troches, tablets, syrups or elixirs and the like. Products of the invention active in parenteral administration can be administered by depot injection, implants include Silastic® implants and biodegradable implants, intramuscular and intravenous injections. The compositions can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and those compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. Tablets containing the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and by providing a sustained action over a longer period. For example, a time delay material such as glyceramic monostearate and glyceryl distearate alone or with a wax may be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient it is mixed with water or with an oily medium, such as peanut oil, liquid paraffin or olive oil. The aqueous suspensions of the invention contain the active materials in admixture with suitable excipients for the manufacture of charged suspensions. These excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a product of the condensation of ethylene oxide with long-chain aliphatic alcohol (for example, heptadecaethylene oxicetanol), a product of the condensation of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example, polyoxyethylene mono-oleate sorbitol), or a product of the condensation of ethylene oxide with a partial ester derived from fatty acid and from an anhydride of hexitol (eg, polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame or saccharin. Ophthalmic formulations, as is known in the art, will be adjusted for osmotic suppression. Suspensions in oil can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a good tasting oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules of the invention suitable for the preparation of an aqueous suspension by the addition of water can be formulated from the active ingredients in admixture with a dispersing, suspending and / or humidifying agent, and one or more preservatives. Dispersing or wetting agents suitable for suspension are exemplified by those described above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical composition of the invention can also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally occurring gums, such as acacia gum and tragacanth gum, naturally occurring phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as mono- sorbitan oleate, and products of the condensation of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. These formulations may also contain an emollient, a preservative, a flavoring or a coloring agent. The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents that were mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be used are water and Ringer's solution, an isotonic solution of sodium chloride. In addition, sterile fixed oils can be conveniently employed as a solvent or suspending medium. For this purpose any soft fixed oil can be employed including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables. The sterilization can be carried out by conventional methods known to those of ordinary skill in the art such as aseptic filtration, irradiation or terminal sterilization (e.g., autoclave). Aqueous formulations (ie, oil-in-water emulsions, syrups, elixirs and injectable preparations) can be formulated to achieve the pH of optimum stability. The determination of the optimum pH can be carried out by conventional methods known to those of ordinary skill in the art. Suitable regulators can also be used to maintain the pH of the formulation. The compounds of this invention can also be administered in suppository form for rectal administration of the drug. These compositions can be prepared by mixing the drug with a convenient non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature, and will therefore melt in the rectum to release the drug. Non-limiting examples of these materials are cocoa butter and polyethylene glycols. They can also be administered intranasally, intraocularly, intravaginally and intarrectally including suppositories, insufflation, powders and aerosol formulations. The products of the invention which are preferably administered by topical route can be administered as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, dyes, powders and aerosols. The products having anti-glucocorticoid activity are of particular value in pathological conditions characterized by excess endogenous glucocorticoid such as Cushing's syndrome, hirsutism and in particular when associated with the adrenogenital syndrome, ocular conditions associated with glucocorticoid excess such as glaucoma. , symptoms of stress associated with excess glucocorticoid secretion and the like. Products that have progestational activity are of particular value as progestational agents, ovulation inhibitors, menstruation regulators, contraceptive agents, agents for synchronization of fertile periods in cattle, endometriosis, and the like. When used for contraceptive purposes, they can be conveniently mixed with estrogenic agents, such as for example esters of ethinyl estradiol or estradiol. The products that have antiprogestational activity are characterized by antagonizing the effects of progesterone. As such, they are of value in controlling hormonal irregularities in the menstrual cycle and for synchronizing fertile periods in cattle. The compounds of the invention can be used for fertility control throughout the reproductive cycle. They are of particular value as post-coital contraceptives, for turning the uterus hostile to the implant, and as, "once a month" contraceptive agents. They can be used together with prostaglandins, oxytocics, estrogens and the like. Another important utility of the products of the invention is in their ability to decrease the growth of hormone-dependent cancers. These cancers include cancers of the kidney, breast, endometrium, ovaries, and prostate cancer which are characterized by having progesterone receptors and can be expected to respond to the products of this invention. Other utilities of antiprogestational agents include the treatment of fibrocystic breast disease. Certain cancers and in particular melanomas may respond favorably to corticoid / anticorticoid therapy. The compounds according to this invention can be administered to any warm-blooded mammal such as humans, domestic animals, and farm animals. Domestic animals include dogs, cats, and so on. Farm animals include cows, horses, pigs, sheep, goats, and so on. The amount of active ingredient that can be combined with a carrier material to produce a single dose form will vary depending on the disease being treated, the species of mammal, and the particular mode of administration. A therapeutically effective amount can be determined by routine experimentation and by analogy of the amounts used to treat the same disease states with analogous steroid compounds. For example, a unit dose of the steroid may preferably contain between 0.1 milligram and 1 gram of active ingredient. A preferred unit dose is between 0.001 and 0.5 grams. For the specific treatment of endometriosis or fibroids an amount of 0.01 to 10 milligrams / kilogram of body weight, preferably 0.1 to 3 milligrams / kilogram may be administered. Similar doses can be used for the other therapeutic purposes of these compounds. Ordinarily the compounds can be administered therapeutically 1 to 4 times per day, preferably 1 to 2 times per day, but for uses such as for example in hormone replacement therapy they can be administered in a cyclophasic regimen. In any case, the frequency and timing of the dose will depend on factors such as the average life of the specific compound in the body, the formulation of the dose and the route of administration. It will be understood, however, that the specific dose level for any patient's variety of factors including or specific employee; age, body weight, general health, sex and diet of the individual being treated, time and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the particular disease that the therapy is suffering, as understood by the person skilled in the art. These compounds are useful in the treatment of endometriosis, uterine leiomyomas (fibroids) and certain cancers and tumors, in hormone replacement therapy as well as in the control of several steps in reproduction and fertility, such as contraception. A more detailed description of the potential uses of these compounds is given in Donaldson, Molly S.; Dorflinger, L .; Brown, Sarah S .; Benet, Leslie Z., Editors, Clinical Applications of Mifepristone (RU 486) and Other Antiprocrestins, Committee on Antiprogestins: Assessing the Science, Institute of Medicine, National Academy Press, 1993. They are also useful as intermediates for the synthesis of other steroids. Having generally described the invention, a further understanding may be obtained by reference to certain general examples that are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified. Synthetic Procedures The compounds of this invention can be made according to procedures such as those set forth in Figures 1 to 3 starting with 110-aryl-3, 3- [1,2-ethanedi-ylbis (oxy)] -5c-hydroxy -170-nitroestr-9-enos (for example, the compound Al of Figure 1 or analogous compounds) or with 3 '.4' -dihydro-110-aryl-3, 3- [1,2-ethanedi-ilbis ( oxy)] -1 '-oxo-spiro [estr-9-en-170, 2' (2?) -pyrrole] -5c-oles (for example, Cl compounds of Figure 3 or analogous compounds). Compounds of the Al or Cl type can be prepared according to the procedure given in the United States of America Patent Application entitled "17 0-Nitro-110-aryl Steroids and Their Derivatives having Agonist or Antagonist Hormonal Properties" by CE . Cook J.A. Kepler, R.S. Shetty, G.S Bartley and D. Lee, presented together with this application, (case number 2025-0133-77). Thus, for example, the treatment of Al with excess zinc dust (preferably about 9 atom equivalents) and ammonium chloride in ethanol / water solution around room temperature gives a good production of the compound 170-N-hydroxylamino A-2, which after treatment with aqueous acid (preferably trifluoroacetic acid in water and CH2C12) undergoes ketal hydrolysis and dehydration in 4,9-dien-3-one A-3. If the intermediate hydroxylamine A-2 is treated with formalin and NaBH 3 CN, the nitrogen is methylated to form the intermediate 170-N-methyl-N-hydroxy A-5, which can be hydrolyzed and dehydrated in the same manner as A- 2 to produce the dienone A-7. If the Al compound is treated with excess zinc dust (preferably about 60 atom equivalents) and ammonium chloride in ethanol / water / tetrahydrofuran (THF) solution at elevated temperatures (preferably around 70 ° C), the reduction of the nitro group leads to the 170-amines A-4. These compounds can be hydrolyzed and dehydrated as described above to produce the dienones A-6. The amino group of A-6 can be further derivatized, for example, by conversion to amides by methods well known to those skilled in the art. For example, the treatment of A-6 with formic acid and N.N-dicyclohexylcarbodiimide (DCC) leads to the formamido compounds, while treatment with acetic anhydride in pyridine results in the formation of acetamido compounds. If R7 of the compound A-1 ends in a carboxyl or carboxylic ester function and the chain length allows it, then the reduction of the nitro group can lead to cyclization to the amide. Thus, if R7 is CH2CH2COOEt (compound B-1) and excess zinc is used for the reduction at elevated temperature, the cyclic amide B-2 is formed. Acid hydrolysis and dehydration lead to the dienone B-3. If R of the compound Al contains a carbonyl group (ketone or aldehyde) in a suitable position in the chain, then reduction under more benign conditions leads to the spironithrones such as the compound Cl, the preparation of which is described in Patent Application. of the United States of America entitled "17 0-Nitro-110-aryl Steroids and Their Derivatives having Agonist or Antagonist Hormonal Properties" by CE. Cook J.A. Kepler, R.S. Shetty, G.S Bartley and D. Lee, presented together with this application, (case number 2025-0133-77). The reduction of the nitrone with, for example, sodium hydroborate results in the C-2 N-hydroxyspiropyrrolidines, which can also be hydrolyzed and dehydrated to the dienones as described above. Compounds such as B-2 and C-2 are versatile intermediates, which can be converted to a variety of novel compounds by methods known to those skilled in the art, including N- or O-alkylation and / or reduction by hydride reagents to produce, for example, cyclic amines, which can be further modified, for example, by N-alkylation or N-acylation. In this way, several analogous spiro-pyrrolidines of B-2, B-3, C-2 and C-3 can be obtained.

Having generally described this invention, a further understanding may be obtained by reference to certain specific examples that are provided in the present for purposes of illustration only and are not intended to be limiting unless otherwise specified. General Procedures Unless otherwise stated, reactive grade chemicals were obtained from commercial sources and used without additional coding. The ether and tetrahydrofuran (THF) were freshly distilled from the sodium cetyl benzophenone pair under nitrogen. All unit and air sensitive reactions and reagent transfers were carried out under dry nitrogen or argon. Thin layer chromatography (TLC) was performed on 60 F-254 plates of pre-coated EM Science silica gel. The compounds were usually visualized by ultraviolet light (254 nm) or p-anisaldehyde spray. Preparative column chromatography employed silica gel EM Science, 60A (230-400 mesh). The solutions were concentrated by means of points of a rotary evaporator under the pressure of a water aspirator at room temperature. The melting points were taken in Mel-Temp II and were not corrected. Unless otherwise noted, the nuclear magnetic resonance spectrum * H were obtained at 250 MHz on a Bruker AC 250 spectrometer in CDC13 as a solvent with tetramethylsilane (TMS) as the internal standard. The chemical changes were reported in units per ppm under TMS. Mass spectra were usually obtained by electron impact at 70 eV in a Hewlett Packard 5989A instrument. Elemental analyzes were performed using Atlantic Microlab Inc., Atlanta, GA. Example 1. Synthesis of 110- [4- (N, N-Dimethylamino) phenyl] -170- (N-hydroxylamino) -17a- (1-propynyl) estra-4, 9-dien-3-one [A-3 (R1 = 4-Me2N-, R7 = CH3CC-, R6 = R12 = H)] 110- [4- (N, N-Dimethylamino) phenyl] -3,3- [1,2-ethanedi-ylbis (oxy)] -5o.-hydroxy-170- (N-hydroxylamino) -17a- (l- propinyl) estra-9-ene [A-2 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H)]. In a homogeneous solution of 6.34 grams (12.2 mmol) of nitropropino Al (R = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) and 1.37 grams (25.6 mmol) of? H4C1 in 160 milliliters of THF, 80 milliliters of EtOH, and 80 milliliters of water at room temperature was added 7.17 grams (110 mmol) of zinc powder (-325 mesh). After stirring for 1.5 hours, the mixture was filtered through a pad of Celite with the aid of EtOAc. The filtrate was washed three times with brine, dried over? A2S04, filtered, and the solvent was removed under reduced pressure to yield a white amorphous solid (6.42 grams). Chromatography on silica gel (70 percent EtOAc in hexanes) yielded hydroxylamine A-2 (R = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) (3.60 grams, 60 percent yield). * H RM? (250 MHz, CDC13) d 7.05 (2H, d, J = 8.6 Hz), 6.64 (2H, d, J = 8.8 Hz), 5.02 (1H, br s), 4.43 (1H, s), 4.21 (1H, d, J = 6.2 Hz), 4.02-3.92 (4H, m), 2.90 (6H, s), 1.91 (1H, s), 0.48 (3H, s). 110- [4- (N, N-Dimethylamino) phenyl] -170- (N-hydroxylamino) -17c.- (1-propynyl) estra-4, 9-dien-3-one [A-3 (R1 = 4 -Me2? -, R7 = CH3CC-, R6 = R12 = H)]. A mixture of 3.60 grams (7.11 mmol) of hydroxyketal A-2 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) in 316 milliliters CH2C12 and 6.3 milliliters were vigorously stirred when cooled in a bath of water with ice for 1.5 hours. To the rapidly stirred dispersion was added dropwise 8.80 milliliters (114 mmol) of trifluoroacetic acid. After stirring vigorously for 3 hours, saturated aqueous solution in excess was added slowly to HCO3 and the mixture was allowed to stir at room temperature for 20 minutes. The aqueous layer was separated and extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over α2S ?4, filtered, and the solvent was removed under reduced pressure to yield a yellow solid (3.11 grams). The material was chromatographed on silica gel (70 percent EtOAc in hexanes). The combination of the resulting fractions of > 97 percent purity (as determined by high performance liquid chromatography analysis) presented the hydroxylamine dienone A-3 (R = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) (2.37 grams, 75 percent yield) [pf 100-117 ° C (amorphous)]. The sample could be dried under vacuum at 92 ° C for 14 hours to provide a product without solvent without loss of purity. . * H NMR (250 MHz, CDC13) d 7.01 (2H, d, J = 8.5 Hz), 6.65 (2H, d, J = 8.9 Hz), 5.75 (1H, s), 5.16 (1H, br s), 4.65 (1H, s), 4.31 (1H, br s), 291 (6H, s), 1.94 (3H, s), 0.55 (3H, 2). Anal. Caled, for C29H36N202.0.5 H20: C, 76. 79; H, 8.22; N, 6.18. Found: C, 76.82; H, 8.29; N, 6.12. MS m / z (reí inten) 444 (M +, 12), 428 (12), 411 (23), 134 (51), 121 (100). Example 2. Synthesis of 110- [4- (N, N-Din-ethylamino) phenyl] -170- (N-hydroxy-N-methylamino) -17a- (1-propynyl) estra-4,9-dien-3-one [A-7 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H)]. 110- [4- (N, N-Dimethylamino) phenyl] -3,3- [1,2-ethanedi-ylbis (oxy)] -5a-hydroxy-170- (N-hydroxy-N-methylamino) -17a- (l-propynyl) estr-9-ene [A-5 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H)]. To a solution of 232 milligrams (0.458 mmol) of hydroxylamine A-2 (R = 4-Me2? -, R7 = CHCC-, R6 = R12 = H) in 4.6 milliliters of CH3C? at room temperature 0.19 milliliters (2.3 mmol) of formalin was added, then 49 milligrams (0.733 mmol) of? aBH3C ?. After 45 minutes, the mixture of the basic reaction containing the white precipitate [pH 8-9 (determined by pH paper pre-moistened with water)] was brought to pH 7 by the addition of three small portions (ca. ) of glacial acetic acid, using homogeneity. After 1.5 hours, the solution was measured to have pH 8, then another small amount (about 0.25 drop) of acetic acid was added, then 40 minutes later, were added to saturated NaHCO3 and aqueous EtOAc. The aqueous layer was separated and extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure. The resulting white foam was purified by chromatography on silica gel (60 percent EtOAc in hexanes) produced N-methylhydroxylamine A-5 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) (74 milligrams, 31 percent yield). H RM? (250 MHz, CDC13) d 7.04 (2H, d, J = 8.7 Hz), 6.63 (2H, d, J = 8.7 Hz), 4.42 (1H, s), 4.16 (1H, br S), 4.02-3.92 (4H, m), 2.89 (6H, s), 2.54 ( 3H, s), 1.96 (3H, s), 0.51 (3H, s). 110- [4- (N / N-Dimethylamino) phenyl] -170- (N-hydroxy-N-methylamino) -17a- (1-propynyl) estra-4,9-dien-3-one [A-7 ( R1 = 4-Me2? -, R7 = CH3CC-, R = R = H)]. To a vigorously stirred mixture of 122 milligrams (234 mmol) of α-methylhydroxylamine ketal A-5 (R = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) in 10.2 milliliters of CH2C12 and 0.5 milliliters of CDC1 and 0.21 milliliters of water at 0 ° C was added dropwise to 0.29 milliliters (3.76 mmol) of trifluoroacetic acid. After stirring vigorously for 5.5 hours at 0 ° C, saturated aqueous NaHCO 3 was added and the mixture was stirred for 30 minutes, then diluted with EtOAc. The aqueous layer was separated and extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure, giving a yellow foam (118 milligrams). The product was purified by flash chromatography on silica gel (80 percent EtOAc in hexanes), then by flash chromatography on silica gel (1.1: 30: 68.9, MeOH-THF-hexanes), then by medium pressure gel chromatography. of silica (hexanes, then 30 percent THF in hexanes), and then by reverse phase preparative high-performance liquid chromatography (20 percent H20 in MeOH) to produce methylhydroxylamine dienone A-7 (R1 = 4-Me2N-, R7 = CH3CC-, R6 = R12 = H) (29.0 milligrams, 27 percent yield) on > 97 percent purity, as determined by high performance liquid chromatography analysis. lE NMR (250 MHz, CDC13) d 7.00 (2H, d, J = 8.5 Hz), 6.65 (2H, d, J = 8.8 Hz), 5.75 (1H, s), 4.28 (1H, d, J = 6.4 Hz ), 2.91 (6H, s), 2.57 (3H, s), 1.98 (3H, s), 1.98 (3H, s), 0.58 (3H, s). Anal. Caled. For C30H38N2O2.0.75 H20: C, 76.32; H, 8.43; N, 5.93. found: C, 76.62; H, 8.17; N, 5.87. MS m / z (reí inten) 458 (M +, 13), 441 (32), 411 (21), 320 (24), 278 (23), 225 (23), 121 (100).

Example 3. Synthesis of 17-Amino-110 - [4 - (N, N-Dimethylamino) phenyl] -17a- (1-propynyl) estra-4, 9-dien-3-one [A-6 (R1 = 4 -Me2? -, R7 = CH3CC-, R6 = R12 = H)]. 170-Amino-110- [4- (N, N-Dimethylamino) phenyl] -3,3- [1,2-ethanedi-ylbis (oxy)] -5a-hydroxy-17a- (1-propynyl) estr-9 -eno [A-4 (R '= 4-Me2? -, R7 = CH3CC-, R6 = R12 = H)]. To a homogeneous solution of 5.00 grams (9.60 mmol) of nitropropino Al (R! = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) and 10.3 grams (192 mmol) of? H4C1 in 100 milliliters of THF, 50 milliliters of EtOH, and 50 milliliters of water at 70 ° C were added 37.7 grams (576 mmol) of zinc powder (-325 mesh). After stirring efficiently for 7.5 hours, the mixture was allowed to cool to room temperature and suction filtered through a pad of Celite with the aid of EtOAc. The filtrate was washed three times with brine, dried over? A2S04, filtered, and the solvent was removed under reduced pressure, to produce a yellow foam (4.95 grams) on silica gel chromatography (20 percent MeOH in EtOAc) provided. aminopropin A-4 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) (3.48 grams, 74 percent yield). lE RM? (250 MHz, CDC13) d 7.06 (2H, d, J - 8.5 Hz), 6.64 (2H, d, J - 8.8 Hz), 4.42 (1H, br s), 4.25 (1H, d, J = 6.9 Hz) , 4.03-3.90 (4H, m), 2.91 (6H, s), 1.84 (3H, s), 0.40 (3H, s). 170- Amino- 110- [4- (N, N- di-methyl-amino) phenyl] -17 a- (1-propynyl) estra-4, 9-dien-3 -one [A-6 (R1 = 4 -Me2? -, R7 = CH3CC-, R6- = R12 = H)]. To a mixture of 265 milligrams (0.540 mmol) of α-aminopropin ketal A-4 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) in 24 milliliters of CH2C12 and 0.48 milliliters of water was stirred vigorously in a bath of ice water for 1.5 hours. To the rapidly stirred dispersion was added 0.67 milliliters (8.69 mmol) of trifluoroacetic acid. After vigorous stirring for 4.5 hours, excess saturated aqueous? AHC03 solution was added slowly, then the mixture was stirred for 30 minutes at room temperature. The aqueous layer was separated and extracted three times with brine, dried over? 2S04, filtered, and the solvent was removed under reduced pressure to give a yellow oil (258 milligrams). The material prepared in this way was very pure by MR analysis? H, and in analogous experiments it could be used in subsequent transformations without further purification. A mixture of > 97 percent purity (as determined by HPLC analysis) was prepared by chromatography on silica gel (12 percent MeOH in EtOAc), then by chromatography on silica gel (10 percent MeOH in EtOAc), then by chromatography on silica gel derived from Et3? (50 percent EtOAc in hexanes), and then chromatographed by preparative reverse phase HPLC [30 percent H20 in MeOH containing Et3N (50 mm)] to produce dienone A-6 (R = 4- Me2N-, R7 = CH3CC-, R6 = R12 = H) (44.6 milligrams, 19 percent yield). LH NMR (250 MHz, CDC13) d 7.03 (2H, d, J = 8.7 Hz), 6.66 (2H, d, J = 8.9 Hz), 5.76 (1H, s), 4.36 (1H, d, J = 7.3 Hz ), 2.92 (6H, s), 1.84 (3H, s), 0.48 (1H, s). Anal. Caled. For C29H36N20: .C, 81.27; H, 8.47; N, 6.54. Found: C, 81.21; H, 8.50; N, 6.49. MS m / z (reí inten) 428 (M +, 61), 411 (97), 278 (33), 134 (100). Example 4. Synthesis of 170- (N-acetamido) -110- (N, N-Dimethylamino) phenyl] -17a- (1-propynyl) estra-4, 9-dien-3-one [A-8 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H)]. To a solution of 72 milligrams (0.168 mmol) of aminodienone A-6 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H) in 1.6 milliliters of pyridine at 0 ° C was added 18.0 milliliters (185 mmol) of Ac20. After 2.5 hours, one drop of Ac20 was added, and after 30 minutes, the solution was partially concentrated under a slow stream of nitrogen. The resulting brown yellow oil was combined with 19 milligrams of the product obtained above, then chromatographed on silica gel (90 percent EtOAc in hexanes) to give dienone acetamide A-8 (R1 = 4-Me2? -, R7 = CH3CC- , R6 = R12 = H) (64.8 milligrams) as a solid. Three subsequent reverse phase MPLC purifications (80:20, MeOH-H20, 75:25, MeOH-H20, and 77.5: 22.5, MeOH-H20) produced dienone A-8 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = Rl2 = H) (37.7 milligrams, 38 percent yield [adjusted]) in >97 percent purity was determined by HPLC analysis. H NMR (250 MHz, CDC13) d 7.03 (2H, d, J = 8.6 Hz), 6.70 (2H, d, J = 8.8 Hz), 5.67 (1H, s), 5.55 (1H, br s), 4.36 ( 1H, d, J = 6.2 Hz), 2.92 (6H, s), 1.93 (3H, s), 1.87 (3H, s), 0.49 (3H, S). Anal. Caled. For C31H38N202.0.5 H20: C, 77.63; H, 8.20; N, 5.84. Found: C, 77.30; H, 8.20; N, 5.77. MS m / z (re? Inten) 470 (M +, 100), 411 (9), 280 (44), 121 (41). Example 5. 110 - [4 - (N, N- Dimet ylamino) pheni 1] - 17 - (N-formamido) -17a- (l-propynyl) estra-4, 9 -dien-3-one [A- 8 (R1 = 4-Me2? -, R7 = CH3CC-, R6 = R12 = H)]. To a solution of 2.11 grams (10.2 mmol) of dicyclohexylcarbodiimide in 11 milliliters of CHC13 at room temperature was added 20.4 milliliters (20.4 mmol) of 1.00 M formic acid in CHC13, causing a white precipitate. After 45 minutes, the mixture was added in a solution of 2.19 grams (5.11 mmol) of aminopropin A-6 (R = 4- Me2? -, R7 = CH3CC-, R6 = R12 = H) and 2.47 milliliters (30.7 mmol ) of pyridine in 22 milliliters of CHC13. After 20 minutes, 66 milliliters of ether was added and the resulting mixture was filtered through a pad of Celite, rinsed six times with 10 milliliters of ether. The filtrate was concentrated under reduced pressure, then diluted with 22 milliliters of EtOAc and stirred for 10 minutes. The resulting mixture was filtered through a pad of Celite, rinsed eight times with 3 milliliters of EtOAc. The filtrate was concentrated under reduced pressure. The residue was iteratively diluted three times with 11 milliliters of toluene and concentrated under reduced pressure by rotary evaporation. After more solvent was removed in vacuo, the pale green residue was freed from pyridine by H NMR analysis and chromatographed on silica gel (75 percent EtOAc in hexanes) to produce formamide A-8 (R = 4-Me2N- , R7 = CH3CC-, R10 = R6 = R12 = H) (1.56 grams, 67 percent yield) [pf 128-142 ° C (amorphous)]. The product was determined to be > 97 percent pure by HPLC analysis, and could be heated under vacuum at 90 ° C for 16 hours to provide product without solvent, with preservation of > 97 percent purity by HPLC analysis. This compound exists as a mixture of equilibrating forms (observable by H NMR) H NMR (250 MHz, CDC13) integration adjusted to provide higher and lower) d 8.52 (1H, d, J = 11.7 Hz), 6.98 (2H, d , J = 8.6 Hz), 6.64 (2H, d, J = 8.8 Hz), 6.21 (1H, d, J = 11.8 Hz), 5.77 (1H, s), 4.37 (1H, d, J = 6.7 Hz), 2.91 (6H, s), 1.90 (3H, s), 0.47 (3H, s); minor form: 8.08 (1H, s), 7.04 (shoulder), 5.68 (1H, s), 1.88 (3H, s), 0.50 (shoulder). Anal. Caled., For C30H36N2O2.1.25 H20: C, 75.20; H, 8.10; N, 5.85. Found: C, 75.17; H, 7.56; N, 5.80. MS m / z (reí inten) 456 (M +, 94), 280 (44), 134 (51), 121 (100).

Example 6. Synthesis of 170-Amino-17a- (3-hydroxypropyl) -110- [4- (N-piperidino) phenyl] estra-4, 9-dien-3-one [A-6 (R1 = 4- ( ? -piperidino) -, R7 = - (CH2) 3 OH, R6 = R12 = H)]. 3,3- [1,2-Ethanedi-ylbis (oxy)] -5c-10c-oxidoestr-9 (11) -en-17-one. To a solution of 32.0 grams (102 mmol) of 3,3- [1,2-ethanedi-ylbis (oxy)] estra-5 (10), 9 (11) -dien-17-one in 192 milliliters of CH2C12 a 0 ° C was added 7.04 milliliters (50.9 mmol) of hexafluoroacetone trihydrate (Lancaster Synthesis, Inc.) followed by 2.46 grams (17.3 mmol) of α2HP04, and then 8.64 milliliters (153 mmol) of 50 percent H202 was added by drip for the agitated mixture efficiently (mechanical upper agitation). Efficient stirring was continued for 18 hours, during this time the temperature was allowed to rise gradually to room temperature, then 192 milliliters of saturated aqueous? A2S203 was added. After stirring for 20 minutes, the mixture was combined with another batch (32.0 grams) which had been prepared identically to this point in parallel. The aqueous layer (bottom) was separated and extracted three times with 80 milliliters of EtOAc. The combined organic solutions were diluted with 240 milliliters of EtOAc and washed twice with 80 milliliters of saturated aqueous? AHC03 solution, twice with 80 milliliters of brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. . The yellow solid (76.1 grams) was triturated with 320 milliliters of diethyl ether with magnetic stirring for 12 hours in a closed flask. The resulting white sludge was combined with three other batches (3 x 32.0 grams) that had been prepared identically (and proportionally) up to this point, in parallel, then filtered by suction through a sintered glass funnel of coarse porosity, rinsing three times with 40 milliliters of diethyl ether, then allowed to dry for 1.5 hours. The resulting white filter cake was scraped into a fine powder and dried under vacuum to produce the desired high purity epoxide (89.5 grams, 53 percent yield). lE NMR (250 MHz, CDC13) d 6.06 (1H, br s), 3.98-3.88 (4H, m), 2.52-2.44 (2H, m), 1.32-1.12 (1H, m), 0.88 (3H, S) . 1- (4-Bromophenyl) piperidine. To a solution of 320 grams (1.86 mmol, 1.00 equivalents) of 4-bromoaniline in 1.20 liters of toluene at room temperature in a 5 liter round-bottomed flask equipped with an overhead mechanical stirrer was added 648 milliliters (3.72 mmol, 2.00 equivalents) of di-isopropylethylamine then 253 milliliters (1.86 mmol, 1.00 equivalent) of 1,5-dibromopentane followed by rinsing with 200 milliliters of toluene. With a stirring handle, the efficiently stirred solution was heated to 100 ° C to 115 ° C, as determined by a thermometer immersed in the reaction solution. After 10 hours, high conversion to the desired product was observed by TLC analysis. The coffee mixture containing bulky precipitate was allowed to cool to room temperature. The mixture was triturated with a spatula to a transferable mud with the help of 390 milliliters of toluene. The di-isopropylethylamine hydrochloride solids were removed by suction filtration through a porous glass funnel with coarse porosity followed by rinsing the solids with toluene (3 x 320 milliliters). (Other toluene rinses from the resulting brown solids produced only a negligible amount of material). Rotary evaporation under reduced pressure of the brown filtrate followed by removal of additional solvent under vacuum for 12 hours at room temperature gave a medium brown solid (398 grams, 89 percent crude yield) that was ground into small pieces. 20.0 grams of this rough material was removed for experimental optimization, resulting in the following purification protocol. To the rest of the crude product (378 grams) were added, in five portions 300 milliliters, 1.50 liters of diethyl ether with efficient magnetic stirring. After 30 minutes at room temperature, the agitation was interrupted and the stirring bar was removed. A dark insoluble fine solid was allowed to settle, and the brown solution was carefully decanted, rinsing the brown solids with diethyl ether (3 x 100 milliliters). To the ethereal solutions combined at room temperature were added 38.5 milliliters (406 mmol) of acetic anhydride. After stirring for 3 hours at room temperature, 300 milliliters of 10 percent aqueous hydrochloric acid (i.e., 3.7 percent was added at room temperature and the mixture was stirred efficiently for 5 minutes, during this time a small amount of a The yellow precipitate was formed.The ether layer was separated and extracted with 10 percent hydrochloric acid (5 x 300 milliliters) The combined aqueous solutions were decanted to remove a small amount of yellow solid and then extracted again a Then, with 150 milliliters of diethyl ether, the aqueous solution was basified to pH 10 with efficient stirring at room temperature by the slow addition of 235 milliliters of concentrated ammonium hydroxide for 20 minutes.The mixture containing the resulting yellow / white precipitate they added 600 milliliters of diethyl ether with rapid stirring, thereby completely dissolving the solids after about 10 minutes. The aqueous layer was separated and extracted with diethyl ether (2 x 150 milliliters). The combined ether solutions were washed with brine (2 x 150 milliliters), dried over Na 2 SO 4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. Further removal of the solvent in vacuo for 12 hours produced a highly pure product of an opaque white solid [338 grams, 80 percent yield (adjusted for removal of 20.0 grams)]. lE NMR (250 MHz, CDC13) d 7.29 (2H, d J = 9.1 Hz), 6.76 (2H, d, J = 9.1 Hz), 3.11-3.07 (4H, m), 1.73-1.66 (4H, m), 1.59-1.51 (2H, m). 3,3- [1,2-Ethanedi-ylbis (oxy)] -5a-hydroxy-110- [4- (N-piperidino) phenyl] estr-9-en-17-one. A 3-liter round bottom flask equipped with an overhead mechanical stirrer and charged with 9.67 grams (398 mmol) of magnesium was dried to the flame under a stream of dry nitrogen. After cooling to room temperature, 333 milliliters of THF were added followed by some iodine crystals, thereby imparting a brown coloration. To the stirred mixture efficiently 40 milliliters of a solution of 91.9 grams (383 mmol) of 1- (4-bromophenyl) piperidine in 333 milliliters of THF was added. After heating the mixture at reflux for about 5 minutes, the color of the iodine rapidly dissolved to colorless, and at this time the mixture was allowed to cool to near ambient temperature. The rest of the bromide solution was added dropwise over a period of 1.5 hours. The mixture was cooled in an ice-water bath for 1.8 hours, then 15.1 grams. (153 mmol) of finely powdered CuCl was added in one portion.

After the mixture was stirred efficiently for 60 seconds, a solution of 50.6 grams (153 mmol) of 3-, 3- [1,2-ethanedi-ylbis (oxy)] -5c.-10a.-oxidoestr-9 (11) - In -7-one in 380 milliliters of THF was added (poured in) for 30 seconds, causing the formation of a voluminous light yellow precipitate. After 10 minutes, 250 milliliters of saturated aqueous NH 4 Cl solution was added slowly, followed by 630 milliliters of EtOAc. After stirring for 30 minutes, the mixture was diluted and stirred with 300 milliliters of water. The aqueous layer was separated and extracted three times with 250 milliliters of EtOAc. The combined organic solutions were washed three times with 250 milliliters of brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The resulting material (116 grams) was combined with an analogously prepared batch of crude product (11.3 grams) in 55 milliliters of CH2C12, then chromatographed on silica gel (elution of the piperidinophenyl reagent by-product with CH2C12, elution of the product with 60 percent EtOAc in hexanes) to produce the desired product, in which some fractions contained a minor amount of bisaduct in which the Grignard reagent was added to the 17-carbonyl group. In this way, another chromatography of the contaminated fractions of concentrate on silica gel (60 percent EtOAc in hexanes) with combination of the resulting pure fractions with the pure fractions of the first chromatographic separation produced product without contaminants (65.2 grams, 79 percent adjusted yield). )]. lE NMR (250 MHz, CDC13) d 7.07 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.7 Hz), 4.53 (1H, s), 4.30 (1H, d, J = 6.8 Hz ), 4.02-3.92 (4H, m), 3.13-3.08 (4H, m), 0.50 (3H, s). 3,3- [1,2-Ethanedi-ylbis (oxy)] -5a-hydroxy-110- [4- (N-piperidino) phenyl] estr-9-en-17-one. A solution of 65.1 grams (132 mmol) of 3,3- [1,2-ethanedi-ylbis (oxy)] -5c-hydroxy-110- [4- (N-piperidino) phenyl] estr- 9-en-17 -one in 450 milliliters of anhydrous pyridine at room temperature under nitrogen was added 15.2 grams (218 mmol) of hydroxylamine hydrochloride. After stirring for 19.5 hours, 1.50 liters of water and 475 milliliters of EtOAc were added. After stirring for 10 minutes, the aqueous layer was separated and extracted three times with 275 milliliters of EtOAc. The combined organic solutions were washed twice with 275 milliliters of brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The resulting foam was rotatively evaporated iteratively under reduced pressure three times with 275 milliliters of toluene at 40 ° C, during this time 4.93 grams of analogously prepared material was combined. More solvent was removed in vacuo, yielding the desired oxime in a yellow foam (81.7 grams) free of pyridine by H-RM analysis. The material was carried out without further purification. H RM? (250 MHz, CDC13) d 8.37 (1H, br s), 7.08 (2H, d, J = 9.0 Hz), 6.81 (2H, d, J = 8.6 Hz), 4.37 (1H, s), 4.22 (1H, d, J = 6.6 Hz), 4.08-3.89 (4H, m), 3.12-3.08 (4H, m), 0.54 (3H,, s). 3,3- [1,2-Ethanedi-ylbis (oxy)] -5-ar-hydroxy-110- [4- (N-piperidino-N-oxide) phenyl] estr-9-en-17-oxime. To a solution of 81.7 grams (148 mmol) of 3, 3- [1,2-Ethanedi-ylbis (oxy)] -5a.-hydroxy-110- [4- (N-piperidino) phenyl] estr-9-en-17-oxime in 290 milliliters of CH2C12 at 0 ° C were added 10.3 milliliters (73.7 mmol) of hexafluoroacetone trihydrate. With vigorous stirring, 17.8 milliliters (310 mmol) of 50 percent H202 was added dropwise. The mixture was stirred vigorously for 14.5 hours during this time the mixture was gradually warmed to ambient temperature. Water (414 milliliters) and EtOAc (1.65 liters) were added, and the resulting mixture was stirred well for 20 minutes. The organic layer was separated and extracted five times with 125 milliliters of water. The combined aqueous solutions were taken to the next step without further manipulation. A small aliquot was concentrated in vacuo for characterization: H RM? (250 MHz, CDC13) d 10.7 (1H, br s), 7.96 (2H, d, J = '8.6 Hz), 7.36 (2H, d, J = 8.6 Hz), 4.39-4.32 (1H, m), 4.05 -3.97' (4H, m), 3.68-3.56 (2H, m), 3.44-3.39 (2H, m), 0.49 (3H, s). 17-Bromo-3, 3 - [1,2-Ethanedi-ylbis (oxy)] - 5a-hydroxy-17-nitro-110- [4- (N-piperidino) -phenyl] estr- 9 -one [A- l (R * = 4 - (? -piperidino) -, R7 = Br, R6 = R12 = H)]. To a solution of 65. 9 grams (369 mmol) of N-bromosuccinimide (NBS) in 375 milliliters of 1,4-dioxane at room temperature was added a solution of 37.Q grams (369 mmol) of KHC03 in 375 milliliters of water. After 5 minutes, the above aqueous solution of 3, 3- [1,2-Ethanedi-ylbis (oxy)] -5? '-hydroxy-110- [4- (N-piperidino-N-oxide) feriyl] estr - 9-in-17-oxime at room temperature was diluted with 720 milliliters of 1,4-dioxane, then slowly added to the solution of? BS-KHC03 at such a rate to avoid excessive evolution of gas and formation of excessive foam. After stirring the solution at room temperature for 16 hours, 262 grams (994 mmol) of FeS04.7H20 was added, causing a large brown precipitate, then 375 milliliters of EtOAc and 250 milliliters of water were added. After stirring efficiently for 30 minutes, the aqueous layer was separated and extracted four times with 300 milliliters of EtOAc. The combined organic solutions were washed twice with 300 milliliters of brine, dried over? A2S04, filtered, and the solvent was removed under reduced pressure to produce A-1 (R1 = 4- (? -piperidino) -, R7 = Br, R6 = R12 = H) as a brown foam (69.3 grams), which was used directly in the next step without purification. lE RM? (250 MHz, CDC13) d 7.07 (2H, d, J = 7.5 Hz), 6.87 (2H, m), 4.42 (1H, s), 4.32 (1H, d, .J = 6.0 Hz), 4.03-3.93 (4H, m), 3.43-3.28 (1H, m), 3.12 (4H, br s), 0.48 (3H, s). 3,3- [1,2-Ethanedi-ylbis (oxy)] -5a-hydroxy-170-nitro-110- [4- (N-piperidino) -phenyl] estr-9-one [Al (R * = 4 - (? -piperidino) -; R6 = R7 = R12 = H)]. To a well-stirred solution of 69.3 grams of the above crude bromide [A-1R1 = 4- (α-piperidino) -, R = Br, R ° = R1 - '= H)] in 1.17 liters of THF and 230 milliliters of Water at room temperature was added 14.4 grams (380 mmol) of? aBH4 in small portions over a period of 1 hour. After an additional hour, a solution of 84.3 grams (1.21 mol) of hydroxylamine hydrochloride in 585 milliliters of water was added carefully. After 15 minutes, the aqueous layer was separated and extracted three times with 116 milliliters of EtOAc. The combined organic solutions were washed three times with 116 milliliters of brine, dried over? A2SO4, filtered, and the solvent was removed under reduced pressure to produce a yellow foam (56.2 grams). The material was collected in a minimum amount of CH2C12 and chromatographed on silica gel (55 percent EtOAc in hexanes) to produce nitro intermediate Al (R1 = 4- (? -piperidino) -, R6 = R7 = R12 = H) (33.3 grams, 45 percent yield produced for 5 steps) as a solid yellow. * H RM? (250 MHz, CDC13) d 7.04 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.8 Hz), 4.38 (1H, s), 4.33 (1H, t, J = 11 Hz), 4.23 (1H, d, J = 6.6 Hz1), 3.12-3.07 (4H, m), 2.71 (1H, d, J = 13 Hz), 0.36 (3H, s). 17a- (2-Carbomethoxyethyl) -3,3- [1,2-ethanedi-iIbis (oxy)] -5o; -hydroxy-170-nitro-110- [4- (N-piperidino) phenyl] estr-9- eno [Al (R1 = 4- (? -piperidino) -, R7 = - (CH2) 2COOCH3, R6 = R12 = H)]. To a mixture of 12.0 grams (23.0 mmol) of nitro intermediate Al (R1 = 4- (? -piperidino) -, R6 = R7 = R12 = H) in 65 milliliters of ü- BuOH at room temperature was added 41.2 milliliters (460 mmol) of methyl acrylate, followed by the dropwise addition of 13.2 milliliters (30.0 mmol) of 40 weight percent weight Triton B in MeOH. After one hour at room temperature, 132 milliliters of saturated aqueous H 4 Cl solution and 132 milliliters of EtOAc were added. The aqueous layer was separated and extracted three times with 30 milliliters of EtOAc. The organic solutions were washed twice with 132 milliliters of brine, dried over? A2SO4, filtered, and the solvent was removed under reduced pressure. Chromatography on silica gel (60 percent EtOAC in hexanes) presented nitroester A-1 (R = 4- (? -piperidino) -, R7 = - (CH2) 2COOCH3, R6 = R12 = H) 11.8 grams (85 percent yield). * H RM? (250 MHz, CDC13) d 7.04 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.7 Hz), 4.35 (1H, s), 4.30 (1H, d, J = 6.1 Hz), 4.03-3.93 (4H, m), 3.68 (3H, s), 3111-3.07 (4H, m), 0.38 (3H, s). 3,3- [1,2-Ethanedi-ylbis (oxy)] -5a-hydroxy-17a- (3-hydroxypropyl) -170-nitro-110- [4- (N-piperidino) -phenyl] estr-9- ona [Al (R1 = 4- (? -piperidino) -, R7 = - (CH2) 3OH, R6 = R12 = H)]. To a solution of 8.13 grams (13.3 mmol) of Al ester (R1 = 4- (N-piperidino), R7 = - (CH2) 2COOCH3, R6 = R12 = H) in 145 milliliters of THF at 0 ° C were added 67.0 milliliters (67.0 mmol) of 1.0 M DIBAL-H in hexanes. After 15 minutes, 55 milliliters of saturated aqueous sodium-potassium tartrate solution was added, causing a gel to form. After stirring the mixture at room temperature for 2 hours, the gel was dissipated, giving a clear mixture. The aqueous layer was separated and extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure to produce nitropropanol Al (R 1 = 4- (N-piperidino), R = - (CH 2) 3 OH, R6 = R12 = H) as a yellow foam (7.83 grams, 100 percent yield). lH NMR (250 MHz, CDC13) d 7.05 (2H, d, J = 8.6 Hz), 6.81 (2H, d, J = 8.7 Hz), 4.38 (1H, s), 4.29 (1H, d, J = 6.4 Hz), 4.02-3.93 (4H, m), 3.68-3.50 (2H, m), 3. 11-3.07 (4H, m), 2.90-2.75 (1H, m), 0.37 (3H, s). 170-Amino-3, 3- [1,2-Ethanedi-i-bis (oxy)] -5a-hydroxy-17a- (3-hydroxypropyl) -110- [4- (N-piperidino) -phenyl] estr-9- ona [A-4 (R = 4- (? -piperidino) -, R7 = - (CH2) 3OH, R6 = R12 = H)]. To a solution of 7.25 grams (12.5 mmol) of nitropropanol Al (R1 = 4- (? -piperidino) -, R7 = - (CH2) 3OH, R6 = R12 = H) and 13.4 grams (250 mmol) of? H4C1 in 70 milliliters of EtOH, 70 milliliters of water, and 140 milliliters of THF at 70 ° C were carefully added 49.0 grams (749 mmol) of zinc powder (-325 mesh) for about 3 minutes. After the resulting mixture was stirred efficiently for 18 hours, it was allowed to cool to room temperature then filtered through a pad of Celite with the aid of EtOAc. The filtrate was washed twice with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure to produce aminopropanol A-4 (R 1 = 4- (N-piperidino) -, R 7 = - (CH 2) 3 OH , R6 = R12 = H) as a white amorphous solid (9.16 grams), which was taken to the next step without purification. lH NMR (250 MHz, CDC13) d 7.15 (2H, d, J = 8.2 Hz), 6.85 (2H, d, J = 8.3 Hz), 4.40-4.20 (2H, m), 4.05-3.82 (4H, m), 3.46 (2H, br s), 3.10 (4H, br s), 0.54 (3H, s). 170 -Amino-17a- (3-hydroxypropyl) - 110 - [4 - (N-piperidino) -phenyl] estra-4, 9-diene-3 -one [A- 6 (R1 = 4 - (? -piperidino ) -, R7 = - (CH2) 3OH, R6 = R12 = H)]. To a vigorously stirred milky white mixture of 9.45 grams (13.0 mmol) of ketal A-4 (R1 = 4- (? -piperidino) -, R7 = - (CH2) 3OH, R6 = R12 = H), 575 milliliters of CH2C12, and 12 milliliters of water at 0 ° C were added by dripping 16.6 milliliters (215 mmol ) of trifluoroacetic acid, which gradually caused a light blue color to turn pale yellow for about 15 minutes. After stirring vigorously for two hours, saturated aqueous aHC03 was carefully added and the mixture was allowed to stir gently at room temperature for 1J4 hours. The mixture was extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered and the solvent was removed under reduced pressure to produce dienone A-6 (R 1 = 4- (N-piperidino) -, R 7 = - (CH 2 ) 3OH, R6 = R12 = H) as a yellow foam (6.18 grams, 74 percent adjusted yield over 3 steps) in a high purity state by nuclear magnetic resonance analysis [H. lE NMR (250 MHz, CDC13) d 7.04 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.7 Hz), 5, .76 (1H, S), 4.36 (1H, d, J = 6.1 Hz), 3.62-3.42 (2H, m), 3.13-3, .09 (4H, m), 0.54 (3H, s). MS / z (reí inten) 488 (M +, 21), 470 (37), 387 (100), 320 (25), 162 (52), 96 (35). Example 7. Synthesis of 170-Hydroxylamino l7a- (3-hydroxypropyl) -110- [4- (N-piperidino) phenyl] estra-4,9-dien-3-one [A-3 (R1 = 4- (? -piperidino) -, R7 = - (CH2) 3 OH, R6 = R12 = H)]. 3,3- [1,2-Ethanedi-ylbis (oxy)] -5a-hydroxy-170-hydroxylamino-17o.- (3-hydroxypropyl) -110- [4- (N-piperidino) -phenyl] estr-9 -one [A-2 (R1 = 4- (? -piperidino) -, R7 = - (CH2) 3OH, R6 = R12 = H)]. To a solution of 4.34 grams (7.47 mmol) of nitropropanol Al (R1 = 4 - (? - piperidino), R7 = - (CH2) 3OH, R6 = R12 = H) and 840 milligram s (15.7 mmol) of? H4C1 in 49 milliliters of EtOH, 49 milliliters of water, and 99 milliliters of THF at room temperature were added 4.40 grams (67.2 mmol) of zinc powder (-325 mesh). After shaking efficiently for 2.5 hours, the mixture was filtered through a pad of Celite with the aid of EtOAc. The filtrate was washed twice with brine, dried over NaSO 4, filtered, and the solvent was removed under reduced pressure. Chromatography on silica gel (6 percent MeOH in EtOAc) produced initial nitropropanol Al (R1 = 4- (N-piperidino), R = - (CH2) 3OH, R6 = R12 = H) (420 milligrams, 10 percent recovery) and the desired hydroxylamine propanol A-2 (R = 4- (N-piperidino), R7 = - (CH2) 3OH, R6 = R12 = H) (2.95 grams, 70 percent yield). lE NMR (250 MHz, CDC13) d 7.07 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.7 Hz), 5.29 (1H, br s), 4.35 (1H, s), 4.18-4.16 (1H, br s), 4.01-3.92 (4H, m ), 3.75-3.75 (1H, m), 3.60-3.51 (1H, m), 3.10-3.05 (4H, m), 1.04-0.93 (1H, m), 0.57 (3H, s). 170-Hydroxylamino-17oi- (3-hydroxyprop i) -110- [4- (N-piperidino) phenyl] estra-4, 9-dien-3-one [A-3 (R1 = 4- (? -piperidino ) -, R = - (CH2) 3 OH, R "= R = H)]. To a vigorously stirred mixture of 2.95 grams (5.20 mmol) of hydroxylamine A-2 (R1 = 4- (? -piperidino), R7 = - (CH2) 3OH, R6 = R12 = H), 4.80 milliliters of water, and 230 milliliters of CH2C12 at 0 ° C were added dropwise to 6.50 milliliters (84.2 mmol) of trifluoroacetic acid, after vigorously stirring at 0 °. C for 3 hours, the saturated aqueous solution of aHC0 in excess was added carefully, after stirring at room temperature for 30 minutes, the mixture was extracted three times with EtOAc The combined organic solution was washed twice with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure to produce a yellow foam (2.77 grams) This material was combined with analogously prepared material (205 milligrams) in a minimum amount of CH 2 C 12 and chromatographed on silica gel (5.5 percent MeOH in EtOAc) to give a yellow foam (1.99 grams). This was combined with similar additional material (393 milligrams) in a minimum amount of CH2C12 and chromatographed on silica gel (5.0 percent MeOH in EtOAc). The combination of the fractions was determined to be > 97 percent pure by HPLC analysis producing 1 dienone A-3 (R1 = 4- (N-piperidino), R7 = - (CH2) 3OH, R6 = R12 = H) (1.69 grams, 52 percent adjusted yield). The majority of this material (1.68 grams) was dried at 92 ° C to 94 ° C under vacuum for 38 hours to provide product without solvent by H nuclear magnetic resonance analysis and > 97 percent purity by HPLC analysis. H NMR (250 MHz, CDC13) d 7.03 (2H, d, J = 8.6 Hz), 6.84 (2H, d, J = 8.7 Hz), 5.75 (1H, s), 5.21 (1H, br s, exchangeable with D20 ), 4.28 (1H, d, J = 6.0 Hz), 3.78-3.74 (1H, m), 3.64-3.61 (1H, m), 3.10-3.02 (4H, m), 1.08-0.93 (1H, m), 0.64 (3H, s). MS m / z: LC-MS 505 (M + 1); MS-MS 505 (M + l). Anal. Caled. For C32H44N203: 3, 76.15; H, 8.79; N, 5.55. found: C, 75.90; H, 8.77; N, 5.50. Example 8. 170- (N-Formamido) -17o; - [3- (formyloxy) propyl] -110- [4- (N-piperidino) phenyl] estra-4, 9-dien-3-one [A- 8 (RX = 4- (? -piperidino) -, R7 = - (CH2) 3 OH, R10 = R6 = R12 = H)]. To a solution of 10.4 grams (50.6 mmol) of 3-dicyclohexylcarbodiimide in 28 milliliters of CHC1 at room temperature was added 101 milliliters (101 mmol) of 1.00 M formic acid in CHCL3, causing a white precipitate. After 5 minutes, the mixture was added to a solution of 6.18 grams (12.7 mmol) of amino alcohol A-6 (R = 4- (? -piperidino), R7 = - (CH2) 3OH, R6 = R12 = H) and 12.4 milliliters (152 mmol) of pyridine in 55 milliliters of CHC1. After 15 minutes, a spatula tip of 4-dimethylaminopyridine was added. After 2.5 hours, another spatula tip of 4-dimethylaminopyridine was added. An additional amount of a mixture of 2.60 grams (12.7 mmol) of dicyclohexylcarbodiimide and 25.3 milliliters (25.3 mmol) of 1.00 M of formic acid in CHC13 in 10 milliliters of CHC1 was stirred for 5 minutes, then added to the mixture. the reaction. After one hour, the reaction mixture was diluted with 600 milliliters of diethyl ether and stirred efficiently for 12 hours, then filtered through a pad of Celite with the aid of diethyl ether rinse. The filtrate was concentrated by rotary evaporation under reduced pressure then in vacuo. The residue was stirred with 100 milliliters of EtOAc for 45 minutes, then the resulting solids were filtered through a pad of Celite with the aid of EtOAc rinse. The filtrate was combined with a smaller batch of the desired crude product (0.688 mmol, in theory) which had been prepared similarly up to this point. The solvent was removed under reduced pressure. The residue was iteratively diluted three times with 30 milliliters of toluene and concentrated under reduced pressure by rotary evaporation (to remove pyridine) yielding 8.42 grams of an orange / yellow foam. The material was chromatographed twice on silica gel (85 percent EtOAc in hexanes) to yield 4.66 grams of an amorphous yellow solid. A 1.63 gram sample of this material was dried under vacuum for 21 hours at 95 ° C, producing a yellow amorphous solid (1.51 grams, 51 percent adjusted yield). The ester group format was observed to be susceptible to slow dissociation in MeOH solution. Analysis by reverse phase analytical HPLC (column C-18, YMC, inc.) Showed >97 percent purity of the desired product, existing as two balanced forms. Verification of this interconversion was obtained by separating the individual forms by analytical HPLC, followed by their reinjection to provide virtually identical chromatograms. This behavior was also observed by two-dimensional TLC experiments, as well as in lE nuclear magnetic resonance spectra (approximately 2: 1 ratio). [H NMR (250 MHz, CDC13 integration adjusted for proportion of major and minor forms) d 8.03 (1H, s), 7.03 (2H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.6 Hz), 5.75 (1H, s), 5.32 (1H, s), 4.44-4.30 (1H, m), 4.25-4.15 (2H, m), 3.10 (4H, br s), 0.50 (3H, s); minor form: 8.14 (1H, d, J = 12.4 Hz), 6.99 (2H, overlapping doublet), 5.95 (1H, d, J = 12.4 Hz). Anal. Caled. For C34H44N204: C, 74.97; H, 8.14; N, 5.14. Found: C, 74.72; H, 8.26; N, 5.07. MS m / z (reí inten) 544 (M +, 25), 320 (23), 161 (100). Example 9. 170- (N-Formamido) -17a- [3- (hydroxypropyl) -110- [4- (? -piperidino) phenyl] estra-4, 9 -dien-3 -one [A- 8 (R1 = 4- (? -piperidino) -, R7 = - (CH2) 3 OH, R10 = R6 = R12 = H)]. To a mixture of 1.43 grams (2.62 mmol) of ester format A-8 (R1 = 4- (? -piperidino), R7 = - (CH2) 30CH0, R10 = R6 = R12 = H)] and 24 milliliters of MeOH a Room temperature with good stirring was added by dripping 0.48 milliliters of concentrated ammonium hydroxide, gradually causing the formation of a homogeneous solution. After 1.2 hours, 24 milliliters of saturated aqueous ammonium chloride solution, 24 milliliters of water, and 24 milliliters of EtOAc were added. The aqueous layer was separated and extracted three times with EtOAc. The combined organic solutions were washed twice with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure to yield 1.35 grams (100 percent yield) of product. The material was combined with 474 milligrams of crude product analogously prepared in a minimum amount of CH2C12 and chromatographed on silica gel (8 percent MeOH in EtOAc) to yield a yellow foam (1.59 grams). The material was iteratively diluted three times with 15 milliliters of CH2C12 and concentrated under reduced pressure by rotary evaporation to provide material free of any other solvent, by 1 H nuclear magnetic resonance analysis. This material was dried at 95 ° C for 23.5 hours under vacuum to yield 1.36 grams of essentially desired solvent-free formamide propanol A-8 (R = 4- (N-piperidino) -, R7 = - (CH2) 3 OH, R10 = R6 = R12 = H) [1.45 grams, 79 percent yield (adjusted for supplement)] on > 97 percent purity by HPLC analysis. Balancing forms analogous to the former formamide A-8 (R 1 = 4- (N-piperidino), R 7 '= - (CH 2) 3 OCHO, R 10 = R 6 = R 12 = H) were similarly observed by analytical HPLC and * H NMR ( approximately 1: 1 ratio). l NMR (250 MHz, CDC13) integration adjusted for the ratio of shapes) d 8.12 (1H, d, J = 12.3 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.83 (2H, d, 8.6 Hz) , 6.39 (1H, d, J = 12.9 Hz), 5.75 (1H, s), 4.40-4.31 (1H, m), 3.65-3.62 (2H, m), 3.10-3.08 (4H, m), 0.50 (3H , s); another, partial form: 8.01 (1H, s), 7.00 (2H, d, J = 8.6 Hz), 5.39 (1H, s), 0.49 (3H, s). Anal. Caled. For C33H44N203.0.25 H20: C, 76.04; H, 8.61; N, 5.37. Found: C, 75.95; H, 8.62; N, 5.38. MS m / z (reí inten) 516 (M +, 44), 387 (16), 320 (38), 161 (100). Example 10. Synthesis of 5'-Oxo-110- [4- (N-piperidino) phenyl] -spiro [estra-4, 9-dien-170,2'-pyrrolidine] -3- onaCB-SÍR1 = 4- ( N-piperidino) -, R6 = R12 = H)]. 3,3- [1,2-Ethanedi-ylbis (oxy)] -5or-hydroxy-5'-oxo-110- [4- (N-piperidino) phenyl] -spiro [estr-9-ene-170, 2 '-pyrrolidine] [B-2 (R1 = 4- (N-piperidino) -, R6 = R12 = H)]. A solution of nitro ester B-KR1 = 4- (N-piperidino) -, R6 = R12 = H, R = CH3) (3.13 grams, 5.10 mmol) was prepared in 63 milliliters of 50 percent aqueous ethanol and 32 milliliters of THF. To this was added 1.93 grams (73.4 mmol) of ammonium chloride and 20 grams (306 mmol) of zinc powder. The reaction mixture was heated at 70 ° C for 20 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated. The crude product was chromatographed on silica gel eluting with 6: 3: 1 ethyl acetate-hexane-methanol to yield 1.97 grams (70 percent yield) of pure B-2 (R1 = 4- (N-piperidino) -, R6 = R12 = H): IR (solution, CDC13) 3495, 2995, 2855, 1685, 1506, 1438, 1384, 1226 cm "1; lE NMR (250 MHz, CDC13) d 7.03 (d, 2, J = 8.5 Hz, ArH), 6.83 (d, 2, J = 8.8 Hz, ArH), 5.57 (s, 1, NH), 4.39 (s, 1, C5 OH), 4.25 (d, 1, J = 5.9 Hz, CllaH), 3.98-4.02 (m, 4, (OCH2) 2), 3.09 (m, 4, N (CH2) 2), 0.42 (s) , 3, C18 H). 5 '-Oxo-110- [4- (N-piperidino) phenyl] -spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3 -one [B-3 (R1 = 4- (N -piperidino) -, R6 = R12 = H)]. To a solution of 120 milligrams (0.23 mmol) of B-2 (R1 = 4- (N-piperidino) -, R6 = R12 = H) in 2.5 milliliters of CH2C12 was added 0.1 milliliter of water and the mixture was cooled to 0 ° C. To the solution was added about 0.5 milliliters of trifluoroacetic acid (TFA) per drop. The reaction was stirred at 0 ° C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, and extracted with CH2C12. The CH2C12 layer was washed with water, followed by brine and dried over anhydrous MgSO4. The dried solution was then filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 5: 5: 1 methylene chloride-hexane-methanol as eluent to yield 79 milligrams (76 percent yield) of pure B-3 (R1 = 4- (N-piperidino) - , R6 = R12 = H). * H NMR (250 MHz, CDCl3) d 6.99 (d, 2, J = 8.7 Hz, ArH), 6.64 (d, 2, J = 8.8 Hz, ArH), 5.79 (s, 1, NH), 5.77 (s, 1, C4 H), 4.36 (d, 1, J = 6.4 Hz, CUaH), 3.12 (m, 4, N (CH2) 2), 0.49 (s, 3, C18) H); mass spectrum, m / z (intensity of laugh) 484 (75), 374 (5), 320 (16), 213 (6), 174 (17), 161 (100); Anal. Caled for C32H40N2O2; C, 79.30; H, 8.32; N, 5.78. Found: C, 79.12; H, 8.26; N, 5.72.

Example 11. Synthesis of 110- [4- (N, N-Dimethylamino) phenyl] -1'-hydroxy-5'-methyl-spiro [estra-4, 9-diene-170, 2'-pyrrolidine] -3- ona [C-3 (R1 = 4- (Me2N-, R6 = R12 = H, R13 = CH3)]. 1 ', 5a-Dihydroxy-110- [4- (N, N-dimethylamino) phenyl] -3, 3- [1,2-ethanedi-ylbis (oxy)] - 5 '-me il-spiro [estr-9-ene -170, 2'-pyrrolidine] [C-2ÍR1 = 4- (Me 2 N -) -, R 6 = R12 = H, R13 = CH3] To a stirred solution of Cl (R1 = 4- (Me2N-, R6 = R12 = H, R13 = CH3) (200 milligrams 0.38 mmol) and (3.58 mmol) of NaBH 3 CN in 4 milliliters of methanol, 0.5 milliliters of AcOH was added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with a saturated NH 4 Cl solution and extracted with CH 2 C 12. The organic layer was washed with water, followed by brine and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated to yield crude C-2 (R = 4- (Me 2 N-, R6 = R12 =. H, R13 = CH3) which was used without further purification in the next step. lE NMR (250 MHz, CDCl 3) d 7.06 (d, 2, J = 8.7 Hz, ArH), 6.64 (d, 2, J = 8.7 Hz, ArH), 4.35 (s, 1, C5 OH), 4.19 (d , 1, J = 6.2 Hz, CllaH), 3.98-4.02 (m, 4, (OCH2) 2), 2.88 (s, 6, N (CH3) 2), 1.19 (d, 3, J = 6.5 Hz, HONCHCH3), 0.62 (s, 3, C18 H). 110- [4- (N, N-Dimet -lamino) phenyl] -1'-hydroxy-5'-methyl-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3-one [C -3 (R1 = 4-Me2N-, R6 = R12 = H, R13 = CH3)]. To a solution of 200 milligrams (0.38 mmol) of C-2 (R1 = 4- (Me2N-, R6 = R12 = H, R13 = CH3) in 2.0 milliliters of CH2C12, 0.1 milliliter of water was added and the mixture was cooled At 0 ° C. To the cooled solution was added about 0.5 milliliter of TFA by dropping.The reaction mixture was stirred at 0 ° C. for 1 hour.The reaction was quenched with saturated sodium bicarbonate solution, and extracted with CH2C12 The CH2C1 layer was washed with water, followed by brine and dried over anhydrous Na2SO4 The dried solution was filtered and concentrated in vacuo The crude product was chromatographed on silica gel using 3-l of ethyl acetate-hexane as eluent to give 114 milligrams (65 percent yield) of pure C-3 (R1 = 4-Me2N-, R6 = R = H, R13 = CH3). lE NMR (250 MHz, CDCl3) d 7.02 (d, 2, J = 8.6 Hz, ArH), 6.65 (d, 2, J = 8.7 Hz, ArH), 5.74 (s, 1, C4 OH), 4.30 (d, 1, J = 6.8 Hz, CllaH), 2.89 (s, 6, N (C) 2), 1.19 (d, 3, J = 6.4 Hz, H0NCHCH3), 0.69 (s, 3, C18 CH3), mass spectrum, m / z (intensity) 459 (8), 458 (23), 442 (31), 280 (12), 134 (100), 121 (33), 96 (7 ); Anal. Caled, for C30H40N2O2.0.25 H20: C, 77.45; H, 8.83; N, 5.61. Found: C, 77.46; H, 8.78; N, 6.02. Example 12. Synthesis of 110- [4- (N, N-Dimethylamino) phenyl] -1'-hydroxy-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3 -one [C-3 (R1 = 4- (Me2N-, R6 = R12 = H, R13 = H)]. 1 ', 5a-Dihydroxy-110- [4- (N, N-dimethylamino) phenyl] -3,3- [1,2-ethanedi-ylbis (oxy)] -spiro [estr-9-ene-170, 2] '-pyrrolidine] [C-2 (RI = 4- (Me2N -) -, R6 = R12 = H, R13 = H)]. To a stirred solution of Cl (R1 = 4- (Me2N-, R6 = R12 = H, R13 = H) (200 milligrams 0.37 mmol) and 234 milligrams (3.77 mmol) of NaBH3CN in 5 milliliters of methanol was added 0.5 milliliter of AcOH After stirring at room temperature for 2 hours, the reaction was quenched with saturated NH4C1 solution and extracted with CH2C12, the organic layer was washed with water, followed by brine and dried over anhydrous NaS04.The organic layer was filtered and concentrated to give the crude product which was used without further purification in the next step H NMR (250 MHz, CDCl 3) d 7.04 (d, 2, J = 8.7 Hz, ArH), 6.64 (d, 2, J = 8.8 Hz, ArH), 4.37 (s, 1, C5 OH), 4.16 (d, 1, J = 7.4 Hz, CllaH), 3.92-4.02 (m, 4, (OCH2) 2), 2.90 (s, 6, N (CH3) 2), 0.64 (s, 3, C18 H). 110- [4- (N, N-Dimethylamino) phenyl] -1'-hydroxy-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3 -one [C-3 (R1 = 4- Me2N-, R6 = R12 = H, R13 = H)]. To a solution of 200 milligrams (0.39 mmol) of C-2 (R1 = 4-Me2N-, R6 = R12 = H, R13 = H)] in 5.0 milliliters of CH2C12 was added 0.1 milliliter of water and the mixture was cooled to 0 ° C To the cooled solution was added about 0.5 milliliter of TFA per drop. After stirring for 1 hour at 0 ° C, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with CH2C12. The CH2C12 layer was washed with water, followed by brine and dried over Na2SO4. The dried solution was filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 3: 1 ethyl acetate-hexane as eluent to give 115 milligrams (65 percent) of pure C-3 (R1 = 4-Me2N-, R6 = R12 = H, R13 = H). lH NMR (250 MHz, CDCl 3) d 7,004 (d, 2, J = 8.7 Hz, ArH), 6,654 (d, 2, J = 8.8 Hz, ArH), 5.75 (s, 1, C4 H), 4.29 (d , 1, J = 6.7 Hz, CllaH), 2.91 (s, 6, N (CH3) 2), 0.66 (s, 3, C18 H); mass spectrum, m / z (reite intensity) 446 (11), 428 (66), 347 (82), 280 (27), 226 (31), 134 (80), 121 (87), 96 (100), 83 (42); Anal.

Caled for C29H38N202.0.25 H20: C, 77.44; H, 8.84; N, 5.84.

Found: C, 77.20; H, 8.60; N, 6.21. The biological activity of the compounds of this invention was examined by in vitro and in vivo tests. Receptor link The affinity of the compounds for the human progesterone hormone receptor was determined by standard procedures similar to those described in Horwitz, et al., Cell, 28: 633-42 (1982) and Mockus, et al. Endocrinology, 10: 1564-71 (1982). The receptor was obtained in cytosol from human T-47D breast cells and was used [3 H] -R5020 was used as the radioligand. T47D cells (1 billion / milliliters) were homogenized in TEDG buffer (10 mM Tris, 1.5 mM EDTA, 1 mM dithiothreitol, 1 mM sodium molybdate, and 10% glycerol) using a Dounce A mortar, the homogenate was centrifuged 34,000 xg for 1 hour. The supernatant was stored at -80 ° C An aliquot of receptor preparation was combined with test compound, 0.4 nM [3H] -R5020, and TEDG buffer to a final volume of 150 microliters 40 percent polyethylene glycol and 15 microliters 1 percent of human globulin range was added to the incubated and the content of each well was incubated for four hours at 4 ° C in microtiter plates. At the end of the incubation, 40 microliters of 40 percent polyethylene glycol and 15 microliters of 1 percent human gamma globulin were added to the incubation and the contents of each well were harvested on double-thickness filter B mats (Wallac LKB) using a TomTec harvester. A Meltilux scintillating wax film was applied to the dried filter mats and the mats were dried on a scintillation counter to determine the inhibition of the rH] -R5020 linkage. The data are expressed as IC50 values, ie the concentration of compound that inhibits the radioligand binding by 50 percent. Table 1 shows that the compounds of the present invention bind strongly to the progestin receptor but vary in degrees of affinity. Animal tests were also performed to further characterize the biological activity of the compounds of the invention. Determination of progestational and antipro-seasonal activity in vivo: Progestational activity and antiprogestational activity were determined in rabbits by means of the McGinty test (test compound alone, procedure by McGinty et al., Endocrinology-, 24: 829-832 (1939)) or anti-McGinty test (test compound plus progesterone, procedure of Tamara et al, Jpn J. Fertil, Steril 24: 48-81 (1979)). The results were scored according to McPhail (McPhail, J. Physiol, 83: 146 (1934)). These are standard procedures well known to those skilled in the art. The results of these tests are shown in Tables 2 (agonist activity) and 3 (antagonist activity). Most of the compounds shown exhibited antiprogestational activity. Some compounds were extremely potent in this regard. For example, compounds I (R1 = 4-Me2N-C6H4, X = 0, R6 = R8 = R12 = H, R7 = CH3CC, R9 = CHO) the ((R1 = 4-Me2N-C6H4, X = 0, R6 = R8 = R12 = H, R7 = CH3CC, R9 = OH) were completely effective in blocking the action of progesterone at a dose of only 0.3 micrograms in the anti-McGinty test (Table 3), however the last compound also exhibited some activity progestational (agonist) at high doses in the McGinty trial (Table 2) and at the highest dose in the anti-McGinty trial Thus, a variety of agonist and antagonist properties can be found among the compounds of the invention. -estrogenic: Certain compounds exhibited non-competitive anti-estrogenic activity of the type reported for mifepristone, for example by Wolf et al. (Fertil Steril 52: 1055-1060 (1989).) Surprisingly they exhibited this activity despite the fact that they do not have the 170-hydroxyl substituent characteristic of both mifepristone and estrogens such as estradiol, but instead have 170-nitrogen substituents. Thus, when the immature female rabbits were administered 110- [4- (N, N-dimethylamino) phenyl] -170- (N-formamido) - lia- (1-propynyl) is ra-4, 9- dien-3-one orally at 10 milligrams / day along with 5 micrograms of estradiol per day and the uteri were removed and weighed, the uterine weight, which rose from 216.7 + 37.2 (SE) mg without estradiol to 1337 + 105 milligrams with estradiol alone, it was reduced to 716 + 96.6 milligrams.

Table 1. Relation Affinity Relative Link Affinity hPR Structure R 'R12 X R6 R7 R8 R9 • R'3 R14 ICJ0 (nM) Progesterone 3.3 I 4-Me2N HOH -CC-CH3 H OH - - 14.3 I 4-Me2N HOH -CC-CH3 CH3 OH - - 7.1 00 I 4-Me 2 N H O H -CC-CH 3 H H - - 8.3 H I 4-Me 2 N HOH -CC-CH 3 H CH 3 C (= O) - - 1.3 1 4-Me 2 N HOH -CC-CH 3 H HC (= O) - - 0.7 II 4-Me 2 N HOH - H OH CH 3 H 5.2 II 4- Me2N HOH - H OH HH 3.5 Table 2. Progestational activity McGinty assay Dosage (Micrograms) (Agonist) 0.3 3 30 Structure R1 R.2 X R6 R7 R8 R9 R13 MR Indice of McPhail Vehicle 0 Progesterone 2.45 ± 0.14 00 I 4-Me2N H O H -CC-CH3 H OH - - O ± O O ± O 0.7 ± 0.0 I 4-Me2N HOH -CC-CH3 CH3 OH - - O ± OO ± OO ± OI 4-Me2N HOH -CC-CH3 HH - - O ± OO ± OO ± OI 4-Me2N HOH -CC-CH3 H CH3C (= O) - - O ± OO ± OO ± OI 4-Me2N HOH -CC-CH3 H HC (= O) - - O ± OO ± OO ± O II 4-Me2N HOH - H OH CH3 HO ± OO ± OO ± O II 4-Me2N HOH - H OH HHO ± OO ± OO ± O Table 3. Antiprogestational Activity I Anti-McGintj I Dose (Micrograms) tagonist) 0.3 3 30 uctura R1 R12 X R6 R7 R8 R9 R13 R.4 Index of Me Phail icle 0 1719 2.45 ± 0.14 4-Me2N HOH -CC-CH3 H OH - - O ± OO ± O 2.5 ± 0.4 00 4-Me2N HOH -CC-CH3 CH3 OH - - 2.0 ± 0.2 O ± OO ± O 4-Me2N HOH -CC-CH3 HH - - 1.6 ± 0.3 0.2 ± 0.1 O ± O 4-Me2N HOH -CC-CH3 H CH3C (= O) - - 1.8 ± 0.3 0.1 ± 0.1 O ± O 4-Me, NHOH -CC-CH3 H HC (= O) - - O ± OO ± OO ± O 4-Me2N HOH - H OH CH3 H 2.1 ± 0.3 2.4 ± 0.4 0.7 ± 0.4 4-Me2N HOH - H OH HH 2.7 ± 0.0 2.3 ± 0.5 0.07 ± 0.07 Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. Therefore, it will be understood that within the scope of the appended claims, the invention may be practiced otherwise than specifically described herein.

Claims (17)

1. A hormonal or antihormonal steroid compound of structure I, wherein R1 is (R2R3N (0) r) -, wherein r is 0 or 1 and R2 and R3 each is independently H, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, or alkynyl with 2 to 6 carbon atoms, any of which may optionally be substituted; where q is 0 or 1, Y is - (CH2) m- where m is an integer from 0 to 5, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer from 0 to 2, and Z is a heteroatom (optionally substituted) and wherein the CH2 groups may be optionally substituted; or R is N-imidazolyl, -N-pyrrolyl-, H, halo-, HO-, CF3S020-, alkyl with 1 to 6 carbon atoms -0-, alkyl with 1 to 6 carbon atoms -S-, alkyl having from 1 to 6 carbon atoms -S (0) -, alkyl having from 1 to 6 carbon atoms -S (02) -, alkyl having from 1 to 6 carbon atoms -CO-, alkyl having from 1 to 6 carbon atoms -CH (OH) -, NC-, HCC-, C6H5CC-, 2'-furyl, 3 '-furyl, 2'-thiophenyl, 3'-thiophenyl, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl, 2'-thiazolyl, 2'-N-methylimidazolyl, 5'-pyrimidinyl, C6H5-, H2C = CH-, alkyl of 1 to 6 carbon atoms, MeC (= CH2) -; R12 is H or halo; or R1 and R12 combine to form a ring wherein W is CH2, CH, NH, N, 0, or S, and R4 is H or alkyl with 1 to 6 carbon atoms; X is 0 or ÑOR5, wherein R5 is H or alkyl with 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms , aryl having from 6 to 12 carbon atoms, or heteroaryl, any of which may be optionally substituted; or X is (H, H), (H, OH), (H, or Si (alkyl with 1 to 6 carbon atoms) 3), or (H, OCOR 5), wherein R 5 is alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl , heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted; or where Y is - (CH2) m- where m is an integer from 0 to 3, or Y is - (CH2) nZ- (CH2) _- where n is an integer from 0 to 2, p is an integer from 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two alkyl groups with from 1 to 6 carbon atoms; R6 is H, alkyl having 1 to 6 carbon atoms or halogen; R7 is H, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaryl, alkyl, heteroaralkenyl or heteroaralkynyl atoms, any of which can be optionally substituted, CN, COOR10 or CONHR10, wherein R? is H, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 atoms carbon, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may optionally be substituted: s is 0 or 1, - R ° and Ry each is independently is H, alkyl with from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms or alkynyl having from 2 to 6 carbon atoms, R CO, OR, any of which may be optionally substituted, wherein R 10 is H, alkyl having from 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl, with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl , heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which it may be optionally substituted, and wherein R 11 is H, alkyl having from 1 to 6 carbon atoms, Si (alkyl having from 1 to 6 carbon atoms), 2'-tetrahydropyranyl or R 10 CO wherein R 10 is defined as previously where when s is 0, R8 can also be 0"and R 9 es = CH2 or = C (H, q.6), = C (H, aryl) or = C (Cμ6) 2 and the nitrogen attached to position 17 is positively charged; and pharmaceutically acceptable salts thereof.

2. A hormonal or antihormonal steroid compound of structure II, wherein R1 is (R2R3N (0) r) -, wherein r is 0 or 1 and R2 and R3 each is independently H, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, or alkynyl with 2 to 6 carbon atoms, any of which may optionally be substituted; or where q is 0 or 1, Y is - (CH2) m- where m is an integer from 0 to 5, or Y is - (CH2) nZ- (CH2) _- where n is an integer from 0 to 2, p is an integer from 0 to 2, and Z is a heteroatom (optionally substituted) and wherein the CH2 groups may be optionally substituted; or R is N-imidazolyl, -N-pyrrolyl-, H, halo-, HO-, CF3S020-, alkyl with 1 to 6 carbon atoms -0-, alkyl with 1 to 6 carbon atoms -S-, alkyl having from 1 to 6 carbon atoms -S (0) -, alkyl having from 1 to 6 carbon atoms -S (02) -, alkyl having from 1 to 6 carbon atoms -CO-, alkyl having from 1 to 6 carbon atoms -CH (OH) -, NC-, HCC-, C6H5CC-, 2'-furyl, 3 '-furyl, 2'-thiophenyl, 3'-thiophenyl, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl, 2'-thiazolyl, 2'-N-methylimidazolyl, 5'-pyrimidinyl, C6H5-, H2C = CH-, alkyl of 1 to 6 carbon atoms, MeC (= CH2) -; R12 is H or halo; or R1 and Rl? combine to form a ring R4 I < where W is CH2, CH, NH, N, 0, or S, and R4 is H or alkyl with 1 to 6 carbon atoms; X is 0 or ÑOR5, where R5 is H or alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, aryl with 6 to 12 carbon atoms, or heteroaryl, which can be optionally replaced; or X is (H, H), (H, OH), (H, or Si (alkyl with 1 to 6 carbon atoms) 3), or (H, 0C0R5), wherein R5 is alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl , heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted; or where Y is (CH2) m- where m is an integer from 0 to 3, or Y is - (CH2) nZ- (CH2) _- where n is an integer from 0 to 2, p is an integer of 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two alkyl groups having from 1 to 6 carbon atoms; R is H, alkyl having 1 to 6 carbon atoms or halogen; s is 0 or 1; R is H, alkyl having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms or alkynyl having from 2 to 6 carbon atoms, R CO, OR, any of which may be optionally substituted, wherein R10 is H, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl, with 6 to 12 carbon, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl atoms, any of which may optionally be substituted, and wherein R is H, alkyl having 6 carbon atoms, Si (alkyl having 1 to 6 carbon atoms), 2'-tetrahydropyranyl or R 10 CO wherein R 10 is defined as above R 13 and R 14 each independently is H, alkyl with 1 to 18 carbon atoms, alkenyl with 2 to 1.8 carbon atoms , alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms carbon, aryl having from 6 to 12 carbon atoms, aralkyl, aralkenyl or aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted; or R13 R14 is 0; and R15 and R16 cac; to one are H or combine to form a group = CH2, optionally substituted, and pharmaceutically acceptable salts thereof.

3. The steroid having the structure I of claim 1 wherein: R -Ph is 4-aminophenyl, 4- (N-methylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 4- (N-piperidino) ) phenyl, 4- (N-pyrrolidino) phenyl, 4- (N-morpholino) phenyl, l-methylindol-5-yl or l-methyl-2,3-dihydroindol-5-yl or RJ-Ph is the N- 4- (N, N-dimethyl) phenyl oxide, 4- (N-piperidino) phenyl, 4- (N-pyrrolidino) phenyl, 4- (N-morpholino) phenyl; X is 0, NOH, or N0CH3; R6 is H, CH3, F or Cl; R7 is H, methyl, ethinyl, 1-propinyl, 3-propinyl, 3-hydroxypropyl, 3-hydroxy-1-propenyl (E- or Z-), 3,3,3-trifluoropropin-1-yl, 3-hydroxypropin -l-ilo, (CH2) 2COOCH3, (CH2) 2COOC2H5, (CH2) 2COCH3, CC-C6H5, CH2C6H5, CN, or C00CH3; R8 is H, CH3 or CH2C6H5; and R9 is H, OH, 0CH3, CHO, CH3C0, C6H5CO or C6H5CH2CO.

4. The steroid of claim 2, wherein R ^ Ph is 4-aminophenyl, 4- (N-methylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 4- (N-piperidino) phenyl, 4- (N-pyrrolidino) phenyl, 4- (N-morpholino) phenyl, l-methylindol-5-yl or l-methyl-2,3-dihydroindol-5-yl); X is 0, NOH, or N0CH3; R6 is H, CH3, F or Cl; R9 is H, OH, CHO, CH3C0, C6H5CO or C6H5CH2CO; R13 and R14 are 0, (H, H), (H, CH3) or (CH3 CH3); and R15 and R16 (H, H) or combine to form (= CH2).

5. The steroid of claim 1 selected from the group consisting of 110- (4- (N, N-dimethylamino) phenyl) -170- (N-hydroxylamino) -I7a- (l-propio__il.) - f.estra- 4, 9-dien-3-one; 110- (4- (N-piperidino) phenyl) -170- (N-hydroxylamino) -lia- (1-propynyl) -estra-4,9-dien-3-one; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-hydroxy-N-methylamino) -17a- (1-propynyl) estra-4,9-dien-3-one; 110- (4- (N-piperidino) phenyl) -170- (N-hydroxy-N-methylamino) -17o? - (1-propynyl) estra-4,9-dien-3-one; l70-amino-110- (4- (N, N-dimethylamino) phenyl) -yl- (l-propynyl) estra-4,9-dien-3-one; 170-amino-110- (4- (N-piperidino) phenyl) -yl- (1-propynyl) estra-4,9-dien-3-one; 170- (N-acetamido) -110- (4- (N, N-dimethylamino) phenyl) -lia- (1-propynyl) estra-4,9-dien-3-one; 170- (N-acetamido) -110- (4- (N-piperidino) phenyl) -17a- (1-propynyl) estra-4,9-dien-3-one; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-formamido) -17a- (1-propynyl) estra-4, 9-dien-3-one, and N-oxide; 170- (N-formamido) -110- (4- (N-piperidino) phenyl) -I7a- (1-propynyl) estra-4, 9-dien-3-one and N-oxide; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-hydroxylamino) -17o; - (3-hydroxypropyl) estra-4,9-dien-3-one; 110- (4- (N-piperidino) phenyl) -170- (N-hydroxylamino) -17a- (3-hydroxypropyl) -stra-4,9-dien-3-one; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-hydroxylamino) -17a- (3-hydroxypropyl) estra-4,9-dien-3-one; 110- (4- (N-piperidino) phenyl) -170- (N-hydroxy-N-methylamino) -yl- (3-hydroxypropyl) estra-4,9-dien-3-one; 170-amino-110- (4- (N, N-dimethylamino) phenyl) -yl- (3-hydroxypropyl) estra-4,9-dien-3-one; 170-amino-17?! - (3-hydroxypropyl) 110- (4- (N-piperidino) phenyl) -estra-4,9-dien-3-one; 170- (N-acetamido) -110- (4- (N, N-dimethylamino) phenyl) -17a- (3-hydroxypropyl) estra-4,9-dien-3-one; 170- (N-acetamido) -17a- (3-hydroxypropyl) -110- (4- (N-piperidino) phenyl) -estra-4,9-dien-3-one; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-formamido) -yl- (3-hydroxypropyl) estra-4,9-dien-3-one; and 170- (N-formamido) -17a- (3-hydroxypropyl) -110- (4- (N-piperidino) -phenyl) estra-4,9-dien-3-one; 110- (4- (N, N-dimethylamino) phenyl) -170- (N-formamido) -yl- (3-formyloxy-l-propyl) estra-4,9-dien-3-one; and 170- (N-formamido) -17a- (3-hydroxypropyl) -17CÜ- (3-formyl-oxy-1-propyl) -110- (4- (N-piperidino) phenyl) estra-4, 9-dien -3-ona.

6. The steroid of claim 2, selected from the group consisting of 110- (4- (N, N-dimethylamino) phenyl) -l'-hydroxy-5'-methyl-spiro [estra-4, 9-dien- 170, 2 'pyrrolidine] -3-one, - 110- (4- (N-piperidino) phenyl) -l'-hydroxy-5'-methyl-spiro [estra-4, 9-dien-170, 2' pyrrolidine ] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -l'-hydroxy-5'-methyl-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3-one; 110- (4- (N-piperidino) phenyl) -1'-hydroxy-5'-methyl-spiro- [estra-4, 9-dien-l70, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -5'-methyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N-piperidino) phenyl) -5'-methyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N-piperidino) phenyl) -spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one, -101- (4- (N-piperidino) phenyl) - 5'-oxo-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one; 110- (4- (N, N-dimethylamino) phenyl) -1'-formyl-spiro [estra-4, 9-dien-170, 2'-pyrrolidine] -3-one and 110- (4- (N- piperidino) phenyl) -1'-formyl-spiro [estra-4, 9-dien-170, 2 'pyrrolidine] -3-one. A method for therapeutically treating progesterone activity comprising administering a therapeutically effective amount of the compound of claim 1, to a patient in need thereof for a therapeutic purpose. The method of claim 7, wherein the therapeutic purpose is the treatment of endometriosis or uterine fibroids. The method of claim 7, wherein the therapeutic purpose is cervical maturity preparatory to labor and delivery of the product. v r '* 97 10. The method of claim 7, wherein the therapeutic purpose is the control and regulation of fertility. The method of claim 7, wherein the therapeutic purpose is tumors or cancers. The method of claim 7, wherein the therapeutic purpose is hormone replacement therapy. 13. A method for therapeutically treating the activity of progesterone comprising administering a The therapeutically effective amount of the compound of claim 2 to a patient in need thereof for a therapeutic purpose. A method for preparing the compound of claim 1, comprising: i) treating a compound of structure (III) by reducing the nitro group, followed by hydrolysis of X and removal of the hydroxyl group Wherein R1 is (R2R3N (0) r) -, where r is 0 or 1 and R2 and R3 each is independently H, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms , alkenyl with 2 to 6 carbon atoms, or alkynyl with 2 to 6 carbon atoms, any of which may optionally be substituted; where q is 0 or 1, Y is - (CH2) m- where m is an integer from 0 to 5, or Y is - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is an integer from 0 to 2, and Z is a heteroatom (optionally substituted) and wherein the CH2 groups may be optionally substituted; or R is N-imidazolyl, -N-pyrrolyl-, H, halo-, HO-, CF3S020-, alkyl with 1 to 6 carbon atoms -O-, alkyl with 1 to 6 carbon atoms -S-, alkyl having from 1 to 6 carbon atoms -S (0) -, alkyl having from 1 to 6 carbon atoms -S (02) -, alkyl having from 1 to 6 carbon atoms -CO-, alkyl having from 1 to 6 carbon atoms -CH (OH) -, NC-, HCC-, C6H5CC-, 2'-furyl, 3 '-furyl, 2'-thiophenyl, 3'-thiophenyl, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl, 2'-thiazolyl, 2'-N-methylimidazolyl, 5'-pyrimidinyl, C6H5-, H2C = CH-, alkyl of 1 to 6 carbon atoms, '' MeC (= CH2), 12 is H or halo; R and R12 combine to form a ring wherein W is CH2, CH, NH, N, 0, or S, and R4 is H or alkyl with 1 to 6 carbon atoms; where Y is - (CH2) m- where m is an integer from 0 to 3, or Y is 15 - (CH2) nZ- (CH2) p- where n is an integer from 0 to 2, p is a integer from 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two alkyl groups with from 1 to 6 carbon atoms; R is H, alkyl having 1 to 6 carbon atoms or halogen; R is H, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, »* '-pm 100 aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, CN, COOR 10 or CONHR 10, wherein R is H, alkyl with 1 to 18 carbon atoms, alkenyl with 5 2 18 carbon atoms, alkynyl with 2 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, aryl with 6 to 12 carbon atoms, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, of which 10 may be optionally substituted. 15. A method for therapeutically treating progesterone activity comprising administering a therapeutically effective amount of the compound of claim 2 to a patient in need thereof. 15 a therapeutic purpose. 16. The method of claim 7, further comprising administering one or more pharmacologically active compounds. 1

7. The method of claim 15, further comprising administering one or more pharmacologically active compounds. »" »* -. 101 SUMMARY The invention is directed to a novel class of steroids that exhibit potent antiprogestational activity. * * * * *