MXPA99000885A - Steroids as neurochemical stimulants of the vomeronasal organ for mitigating symptoms of the pre-menstrual syndrome and ansie - Google Patents

Abstract

The present invention relates to a method for mitigating the symptoms of pre-menstrual syndrome (PMS) and anxiety. The method comprises administering nasally a steroid, which is a human vomeropherin, so that vomomeroferin binds to a specific neuroepithelial receptor. The steroid or steroids is / are preferably administered in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable carriers.

Description

STEROIDS AS NEUROQUAL ICONS OF THE VOMERONASAL ORGAN TO MITIGATE SYMPTOMS OF THE PRE-MENSTRUAL AND ANXIETY SYNDROME CROSS REFERENCE TO RELATED APPLICATIONS This is a continuation in part of United States Series No. 08 / 725,862, filed on October 4, 1996, which is a continuation in part of the series No. of the United States. No. 08 / 686,092, filed July 23, 1996, which is a continuation in part of the United States Application Series No. 08 / 6245,268, filed March 29, 1996, which is a continuation in part of the United States Application Series No. 08 / 286,073, filed on August 4, 1994. This application is related to the United States Application Series No. 08 / 127,908, filed September 28, 1993 , which is a continuation in part of the United States Application Series No. 08 / 903,604, filed June 24, 1992, which in turn is a continuation in part of the United States Application Series No. 07 / 708,936, filed on May 31, 1991, which in turn s a continuation in part of U.S. Application Serial No. 07 / 638,185, filed January 7, 1991, now abandoned. The application also relates to the United States Application Series No. 08 / 127,980, filed September 28, 1993, which is another continuation in part of the United States Application Series No. 07 / 903,604, Application for U.S. Patent Series No. 08 / 077,359, filed June 15, 1993, and the co-pending commonly assigned United States Patent Application Series No. 07 / 903,525, filed June 24, 1992 (a Partial continuation of United States Application Series No. 07 / 707,862, filed May 31, 1991, which in turn is a continuation in part of United States Application Series No. 07 / 638,743, filed on January 7, 1991, now abandoned) entitled "Estrene Steroids as Neurochemical Initiators of Change in Human Hypothalamic Function and Related Pharmaceutical Compositions and Methods" (Premiere Steroids as Neurochemical Initiators of Change in Human Hypothalamic Function and Pharmaceutical Compositions and Related Methods); and the co-pending portion commonly assigned from 07 / 903,525, U.S. Patent Application Serial No. 08 / 077,140. The aforementioned US patent applications are incorporated herein by reference. Finally, this request can be related to the U.S. Patent 5,278,141, issued January 11, 1994, entitled "Fragrance Compositions Containing Human Pheromones" Fragrance Compositions Containing Human Feronomas), and U.S. Patent 5,272,134, issued December 21, 1993, entitled "Fragance Compositions and Other Compositions which Contains Human Pheromones" (Fragrance Compositions and Other Compositions containing Human Pheromones).

TECHNICAL FIELD This invention relates generally to methods for mitigating symptoms of PMS (pre-menstrual syndrome) and anxiety.

DESCRIPTION OF THE RELATED TECHNIQUE The present invention relates to certain steroids and methods for using these steroids as human vomeropherins in order to alter the hypothalamic function, thus affecting certain consequent behavior and physiology, for example, the reduction of anxiety. Ohloff, G. et al., (Helv. Chim. Acta (1983) 66: 192-217), which is incorporated herein by reference, has shown that several steroids (androstenes) have an odor that varies with different isomeric forms and stereomeric and enantiomeric. It has been reported that some members of this group act as a pheromone in some mammalian species, for example, 5a-androst-16-en-3-one and 5a-androst-16-en-3a-ol in pigs (Melrose, DR, et al .. Br. Vet. J. (1971) 127: 497-502). These 16-androstenes produced by wild boar induce mating behavior in sows in estrus (Claus, et al., Experimentia (1979) 35: 1674-1675). It has been observed that some species, several characteristics of certain 16-androstenes (including 5a-androst-16-en-3a-ol and 5 -Androst-16-en-3-one), such as concentration, metabolism and localization, are sexually dimorphic (Brooksbank et al .. J. Endocr. (1972) 52 .: 239-251; Claus, et al. Endocr. (1976) 68.:483-484; Kwan, et al. Med. Sci. Res. (1987) 1_5: 1443-1444). For example, 5a-Androst-16-en-3-ol and 5a-Androst-16-en-3-one, as well as Androsta-4,16-dien-3-one have been found in different concentrations in the peripheral blood , saliva and axillary secretions of men and women (Kwan, TK, et al., Med. Sci. Res. (1987) 15: 1443-1444), and its function has been suggested as a human pheromone, to the extent of affecting the selection and judgment, (Go, see also Gower, et al, "The Significance of Odorous Steroids in Axillary Odour," in, Perfumery, pp. 68-72, Van Toller and Dodds, Eds., Chapman and Hall, 1988 ); Kirk-Smith, D.A., et al., Res. Comm. Psvchol. Psychiat. Behav. (1978) 3_: 379). It has been claimed that androstenol (5a-androst-16-en-3a-ol) exhibits a pheromone-like activity in commercial men's cologne and perfume for women (Andron ™ for men and Andron ™ for women by Jovan). Japanese application Kokai No. 2295916, relates to perfume compositions containing androstenol and / or its analogs. Androstadien-ß-ol (and perhaps 3a-ol) have also been identified in human axillary secretion (Gower, et al., Supra, at 57-60). On the other hand, there is a small agreement in the literature that whether or not a putative pheromone actually plays a role in the sexual or reproductive behavior of mammals, particularly humans. See: Beauchamp, G.K., et al., "The Pheromone Concept in Mamalian Chemical Communication: A Critique", In: Mammalian Olfaction, Reproductive Processes and Behavior. Doty, R.L., Ed., Academic Press, 1976). See also: Gower, et al., Supra 68-73. The properties of the pheromone of some premier steroids for some mammalian species have been described. Michael, R.P. et al. Nature (1968) 218: 746 refers to estrogens (particularly estradiol) as an attractive pheromone product of male rhesus monkeys (Parrot, RF, Hormones and Behavior (19756) 7_: 207-215, reports that the injection of estradiol benzoate induces mating behavior in ovariotomized rats, and the role of the estradiol level in the blood to present a sexual response (Phoenix, CH, Physiol. and Behavior (1976) 16305: 310) and a female sexual response (Phoenix , CH, Hormones and Behavior (1977) 8: 356-362) in Rhesus monkeys has also been described, on the other hand, there is a small agreement in the literature that if pheromones as such play an important role in the reproductive behavior and interpersonal communication of mammals (Beuchamp, GK, et al .. The Pheromone Concept in Mammalian Chemical Communication: A Critique ', In: Mammalian Olfaction, Reproductive Processes and Behavior.

R.L., De., Academic Press, 1976).

The present invention refers to the non-systemic administration to the vomeronasal organ (VNO) of certain steroids to mitigate the symptoms of PMS and anxiety, as well as for the treatment of high temperature in the body and paroxysmal tachycardia (high pulse rate). The administration provides contacting neurochemical receptors in the WNV (also known as "Jacobson's organ"), with one or more steroids or compositions containing the steroids. This organ is accessed through the nostrils of most higher animals, from vipers to humans, and has been associated, inter alia, with the reception of pheromones in certain species (see generally Muller-Schwarze & Silvesrstein, Chemical Signáis, Plenum Press, New York (1980)). The axons of the neuroepithelium of the vomeronasal organ, located supra palatal, form the vomeronasal nerve and have a direct synaptic connection to the accessory olfactory bulb and an indirect entry from there to the anterior basal amygdaloid-cortical brain and hypothalamic nuclei of the brain. Axons distant from nerve nerve terminals can also serve as neurochemical receptors in WNV. Stensaas, L.J., et al., J. Steroid Biochem. and Molec. Biol. (1991) 39.:553. This nerve has direct synaptic connection with the hypothalamus. Johnson, A. et al .. (J. Otolarvnology (1985) 14: 71-79) reports evidence of the presence of the vomeronasal organ in most adult human beings, but concludes that the organ is probably nonfunctional. Contradictory results suggesting that WNV is a functional chemosensory receptor are reported by Stensaas, L., et al., Supra.; and by Moran, D.T., et al., Garcia-Velasco, J. and M. Mondragon; Monti-Bloch, L., and B. Grosser all in J. Steroid Biochem. and Molec. Biol. (1991) 3_9. This invention relates to the unexpected discovery that, when administered to human WNV, certain neurochemical ligands, particularly steroids, and related compounds, specifically bind to chemoreceptors of certain nasal neuroepithelial cells and this binding generates a series of neurophysiological responses resulting in in the mitigation of PMS symptoms and anxiety. An effect through WNV in the hypothalamus can affect the function of the autonomic nervous system and a variety of behavioral or physiological phenomena that include, but are not limited to the following: anxiety, premenstrual tension, fear, aggression, hunger, blood pressure , and other behavioral and physiological functions normally regulated by the hypothalamus. See, Otto Appenzeller, The Autonomic Nervous System. An Introduction of basic and clinical concepts (1990); Korner, P.l. Central nervous control of autonomic cardiovascular function, and Levy, N.M. and Martin, P.J. Neural control of the heart, both in Handbook of Physiology; Section 2; Cardiovascular System - the heart, Vol. I., Washington DC, 1979, American Physiological Society; Fishman, A.P., et al. editors, Handbook of Physiology, section 3; Respiratory System. Vol. II. Control of breathing, Bethesda MD, 1986, American Physiological Society. Patients with the diagnosis of pre-menstrual dysphoric disorder (PMDD, commonly referred to as premenstrual syndrome or PMS), show negative changes in mood along with physical symptoms, during the luteal phase of the menstrual cycle (see Table I). The symptoms are severe enough to cause physical or emotional disorders, and decrease shortly after the onset of menstruation. However, they are not unique or diagnostic for this disease. Several investigations show that 30% of women have symptoms of classic pre-menstrual dysphoric disorder, from 2% to 10% being severely affected (Woods et al., Am. J. Pub. Health, 72: 1257-62, 1982; Van Keep et al., "The Premenstrual Syndrome - An Epidemiologic and Statistical Exercise", Van Keep, PA and Utian, WH, Eds., The Premenstrual Syndrome, MTP Press Ltd., Lancaster, England, 1981; and Andersch et al. ., J. Psychomsom, Obstet, Gyn 5: 39-46, 1986). It has also been reported that PMDD is not a disease only of older women, since adolescents and young women have symptomatology as frequently as older women (Rivera-Tovar et al., Am. J. Psychiatry, 147: 1634- 43, 1990). Many patients seeking treatment for PMDD can be found to suffer from a generalized psychiatric disorder. However, the main characteristic that distinguishes PMDD from chronic psychiatric disorders is the presence of at least one asymptomatic week in the follicular phase of each menstrual cycle. A list of the common symptoms of this syndrome is presented in Table I. Most women report a variety of emotional, physical and behavioral changes associated with the luteal phase of the menstrual cycle. But only those women who report symptoms of cyclical luteal phase that remit during menstruation and that significantly affect their level of psychological or occupational functioning have PMDD.

Table I Table I. Common symptoms of PDD Emotional Physics Behavior Anxiety Headache Craving eating Irritability Migraine Increased appetite Labile mood Breast sensitivity Consumption Increased alcohol Depression Swelling of limbs Motivation reduced Courage Inflammation Reduced efficiency Sadness Fatigue Avoid activities Easiness of crying Abdominal cramps Stay at home Nervous tension Pains and discomfort Changes in sleeping Sensitive Weight gain Changes in livid Skin problems Reduced knowledge function Hot flashes Social hold Symptoms Low concentration Faintness Lack of memory Palpitation Recent studies have found that picogram amounts of some vomeroferins locally supplied in the form of vapor to WNV of normal women (20 to 60 years of age), produce significant changes in behavior and autonomy. Monti-Bloch et al., J. Ster. Biochem. Molec. Biol., 39 (4B): 573-582 (1991); Monti-Bloch et al., Psvchoneuroendocrinology. 19: 673-686 (1994). The subjects show changes in mood characterized by a reduced negative aspect. There is a clear reduction in the negative and negative aspects, and patients feel relaxed. These changes correlate with increased parasympathetic tone in all individuals (moderate bradypnea and bradycardia, increased but small body temperature [0.7 ° C + 0.5], change in skin conduction and also increased alpha-cortical activity) . Also, the latency of these effects that correlate well with the latency of polysynaptic reflexes is notorious. The conclusion is that those vomeropherins stimulate receptors in the vomeronasal organ that in turn has influence in the hypothalamus through the vomeronasal terminal system. The present invention also provides attenuation of anxiety symptoms in general, which are characterized by the Hamilton-A standard.

COMPENDIUM OF THE INVENTION The method of the invention has the following advantages: 1) the direct administration to the chemoreceptors in the nasal passage and the vomeronasal organ, without pills or needles, that is, non-invasively; 2) a mode of drug action through the system of the invention and not through the circulatory system, in this way the brain function can be affected without consideration of the blood-brain barrier; 3) direct means to affect the hypothalamus, there is only one synaptic junction between the pheromone receptors and the hypothalamus, and 4) to provide a highly specific drug effect, thus greatly reducing the potential for unwanted side effects, this since the nerves Sensory tests are directed to a specific site in the brain. Objects, advantages and additional novel aspects of the invention will be set forth in part in the description that follows, and in part will be apparent to those skilled in the art, after examination of the following, or can be learned through the practice of the invention . Among the compositions, a preferred class contains a pharmaceutically acceptable carrier and a pregnane steroid having the formula: wherein PT is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propionoxy, a- (ß-) methoxy, a- (ß-) , lower acyloxy a- (β-), lower alkyloxy, and a- (β-) benzoyloxy; P2 is selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acyloxyalkyl and alkoxyalkyl; P3 is selected from the group consisting of hydrogen, oxo, halo, hydroxy, alkoxy and acyloxy; P a P12 each can be, independently, hydrogen, halogen, methyl or halo-, dihalo-, or perhalomethyl and when P2 is methyl and P3 is β-hydroxy, P2 and P3 can be joined to form a cyclic ether; P13 is hydrogen, methyl, methylene, substituted halomethyl, substituted halomethylene, ethyl, ethynyl, acetylenyl, methyl-methylenyl, methyl-methynyl; and "a", "b", "c", "d", "e", "h", "y" and "j" are alternative sites for optional double bonds, and "j" or "k" may be triple links. The halogen substituents include fluorine, bromine, chlorine and iodine atoms. A class of preferred steroids has "b" as a double bond, particularly where "d" or "e" is also a double bond. Another preferred class has "a" and "c" as double bonds, and only "c" as a double bond. Yet another preferred class contains "h" as a double bond, with i and j being absent (ie, individual bonds), j being a double bond, or j being a triple bond. In another class, "h" is absent, and j or i is a double bond, or i, j are absent, or j and y are double bonds, or j is a triple bond. The term lower alkyl, lower alkoxy, etc., represents carbon chains of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. A second class of compositions contains a pharmaceutically acceptable carrier and a pregnane steroid having the formula: wherein Pi is oxo, a- or β-hydroxy, α or β-acetoxy, α or β-propionoxy, α or β-acetoxy, α or α-acyloxy, or α or β-benzyloxy; a, b, c, d, e, f, g, h,? , j, m and n are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms, or halogen; P4 is methyl or ethyl; P5 is hydrogen, methyl or halogen; P6 is hydrogen or methyl. A subgroup of the second preferred class of steroid compositions contains steroids wherein "d" is a double bond, and optionally "b" is present as a double bond. Another preferred class has "a", "d" and "e" and g or h are optionally present. If "g" is present in this class, then "n" is optionally present. Another preferred class has a "c" present with "f" optionally present. A third class of compositions contains steroids with the formula: wherein it is selected from the group consisting essentially of one or two hydrogen atoms, methyl, methylene and one or two halogen atoms; R2 is absent or selected from the group consisting essentially of hydrogen and methyl; R3 is selected from the group consisting essentially of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, cyproionyl, glucuronide and sulfonyl; R 4 is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy, oxo and halo; R5 is absent or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6 is a hydrogen or a halogen; and "a" represents an optional aromatic unsaturation of ring A of such a steroid, or "b", "c" and "d" are each optional double bonds; "e", "f", "g", "h", "i" and "j" are each optional double bonds; and "e" can also form an epoxy ring with C16 and C17. In this embodiment, the steroid is preferably administered in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable carriers. A preferred subgroup of the third class of steroids are those in which "a" is present and "g", "h" or "i" are optional double bonds. Another preferred class contains "b", "c" or "j" as a double bond. Another class contains "c" and "d" as double bonds. Another class contains R2 as methyl and "e" as a double bond. The term "lower alkyl, lower alkoxy, etc." embraces carbon chains of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Halogen includes I, Br, F and C1. A fourth class of preferred compositions contains a pharmaceutically acceptable carrier and an androstane steroid having the formula: wherein Pi is selected from the group consisting of oxo, - (ß-) hydroxy, a- (ß-) acetoxy, oc- (ß-) propionoxy, α- (β-) methoxy, α- (β-) acyloxy lower, a- (ß-) lower alkyloxy and a- (ß-) benzoyloxy; P2 is selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acyloxyalkyl and akoxyalkyl; P3 is absent or selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acyloxyalkyl and alkoxyalkyl; P4 is selected from the group consisting of hydrogen, oxo, halogen, hydroxy, alkoxy and acyloxy; P5 represents one or two substituents, wherein P5 comprises one or two hydrogen atoms, methyl, methylene or one or two halogen atoms; P6 is hydrogen or halogen; and "a", "b", "c", "d", "e", "f" and "h" are alternative sites for optional double bonds. A subgroup of the fourth preferred class of steroids as "b" as a double bond, particularly where "c" or "d" is also a double in lace. Another subgroup has "a" and "c" as double bonds. Yet another subgroup contains P3 as a methyl group, "h" as an optional double bond and P5 as methylene or one or two hydrogen atoms. A subset of steroids where "a" or "b" is a double bond is also preferred. By halogen, it is meant, F, Cl, Br, or I. The term lower alkyl, lower alkoxy, etc. encompass carbon chains of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. A fifth class of compositions comprises a pharmaceutical carrier and a 19-nor-colane of the formula: where P ^ is oxo, a- or β-hydroxy, α- or β-acetoxy, α- or β-propionoxy, α- or β-acetoxy, β- or β-acyloxy, or β-benzyloxy; a, b, c, d, e, f, g, h,? , j, m, s and n are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms or halogen; P is methyl or ethyl; each of P5 and P7 independently is hydrogen, methyl or halogen; P6 is hydrogen or methyl; R 'and R "independently are hydrogen or halogen, are absent, or together form = CH2; q is an integer from 0 to 2. Preferably, q = 1. A preferred class of 19-nor-colane steroid compositions contains steroids where "d" is a double bond, and optionally "b" is present as a double bond.Another preferred class has "a", "d" and "e" present, andgoh are optionally present.If "g" is present in this case, then "n" is optionally present.Another preferred class has "c" or "s" present.The novel class of 19-nor-colanos are those of the above formula, excluding the compounds in the cases where P3. PT, s, P7, R 'and R "are hydrogen, P4 is methyl, e, a, d are present, b, c, f, g, h, i, j, k, n and s are absent, q = o, P. is hydroxy and m is present or absent The term lower alkyl, lower alkoxy, etc. encompasses carbon chains of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.A class of novel steroids is also provides having oxygen atoms attached to ring D. Such steroids have the formula: wherein R- is selected from the group consisting essentially of one or two hydrogen atoms, alkyl of 1 to 10 carbon atoms; R2 is absent or selected from the group consisting essentially of hydrogen, methyl and oxygen to form an epoxy ring with C17; R3 is selected from the group consisting essentially of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, cyproionyl, glucuronide and sulfonyl; R 4 is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy and halogen; R5 is absent or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6 is a hydrogen or a halogen; and "a" represents optional aromatic unsaturation of ring A of such steroid, or "b", "c" and "d" each are optional double bonds; "g", "h", "i" and "j" are each optional double bonds; and "e" can form an epoxy ring with C16 and C17; "f" can form an epoxy ring with C 3 and C 17; and "k" can form an epoxy ring with C17 and C20. Other objects of this invention are achieved by providing a method for altering the hypothalamic function and / or autonomous function in an individual. A ligand is provided for a chemoreceptor presented on the surface of a nasal neuroepithelial cell, wherein the cell is a piece of tissue different from the olfactory epithelium; and, the ligand is administered within a nasal passage of the individual so that the ligand binds specifically to the chemoreceptor, resulting in alteration of the hypothalamic function of the individual. All embodiments of this application relate to, and include the functional equivalents of the steroidal structures described in these embodiments and those modified steroids that demonstrate such functional equivalence, if the modified steroids are or are not explicitly described.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the integrated EG, GSR and ST data for compounds A1-P1 in men as tested in accordance with Examples 16 and 17. Figure 2 is the data for integrated EVG for compounds A1-P1, A2 -P1, A4-P1, A3-P1, A1-P4, A2-P4 in women.

Figure 3 is the data for the ST measurements of the compounds A1-P1, A2-P1, A4-P1, A3-P1, A1-P4, A2-P4 in women. Figure 4 is the data for the GSR measurements in women of the compounds A1-P1, A2-P1-A4-P1, A3-P1, A1-P4, A2-P4. Figure 5 is the data for ST, GSR and EVG measurements in women of compound A1-P3. Figure 6 is the data for RF and EKG measurements in women of compound A1-P3. Figure 7 is the data for EEG measurements in women of compound A1-P3. Figure 8 is the data for ST, GSR and EVG measurements in men of compound A1-P3. Figure 9 is the data for RF and EKG measurements in men of compound A1-P3. Figure 10 is the data for measurements on EEG in men of compound A1-P3. Figures 11 and 12 show the data of ST, GSR and EVG measurements in men and women respectively, for compound A2-P3. Figures 13 and 14 show the data of the EEG measurements in men and women, respectively, for the compound A2-P3. Figures 15 and 16 show the data for RF and EKG measurements in men and women, respectively, for compound A2-P3. Figures 17 and 18 show the data of the ST, GSR and EVG measurements in men and women, respectively for compound A8-P1. Figures 19 and 20 show the data of ST, GSR and EVG measurements in men and women, respectively, for compound A8-P1. Figures 21 and 22 show the data for EEG measurements in men and women, respectively, for compound A8-P1. Figures 23 and 24 show the data for ST, GSR and EVG measurements in men or women, respectively, for compounds A6-P1. Figures 25 and 26 show the data for RF and EKG measurements in men and women, respectively, for compound A6-P1. Figures 27 and 28 show the data for EEG measurements in men and women, respectively, for compound A6-P1. Figures 29, 30 and 31 show the data for ST, GSR, EVG, RF, EKG and EEG measurements in 20, 21-dimethylpregna-5,20-dien-3ß-ol men. Figures 32, 33 and 34 show the data for measurements of ST, GSR, EVG, RF KEG and EEG in women of 20,21-dimethylpregna-5,20-dien-3ß-ol.

Figures 35, 36 and 37 show the data for measurements of ST, GSR, EVG, RF KEG and EEG in men of 20,21-dimethylpregna-5,20-dien-3-one. Figures 38, 39 and 40 show the measurements of ST, GSR, EVG, RF EKG and EEG in women of 20,21 -dimethylpregna-5, 20-dien-3-one. Figures 41, 42 and 43 show the measurements of ST, GSR, EVG, RF EKG and EEG in men of compound A14-P2. Figures 44, 45 and 46 show ST, GSR, EVG, RF, EKG and EEG measurements in women of compound A14-P2. Figures 47, 48 and 49 show ST, GSR, EVG, RF, EKG and EEG measurements in men of compound A7-P2. Figures 50, 51 and 52 show ST, GSR, EVG, RF, EKG and EEG measurements in women of compound A7-P2. Figures 53 and 54 show ST measurements, GSR, EVG, EEG in men of compound A11-P1. Figure 55 shows the data of EEG measurements in men of compound A13-P1. Figures 56, 57 and 58 show the data of ST, GSR, EVG, RF, EKG and EEG measurements in women of compound A13-P1. Figure 59 shows the data of the EVG, EDA and BT measurements in women of the A3 / P1 compound. Figure 60 shows the data of the EVG, EDA and BT measurements in women of the A4 / P1 compound.

Figures 61 and 62 show data of measurements in men and women, respectively of compound A8 / P1. Figures 63 and 64 show data of measurements in men and women, respectively of compound A13 / P8. Figures 65 and 66 show measurement data in men, and women, respectively of compound A6 / P1. Figures 67 and 68 show data of measurements in men and women, respectively, of the 20-methyl derivative of compound A6 / P1. Figures 69 and 70 show measurement data in men and women, respectively, of the 20,21-dimethyl derivative of compound A1 / P1. Figures 71 and 72 show data of measurements in men and women respectively, of the 20,21-dimethyl derivative of compound A6 / P1. Figures 73 and 74 show the measurement data in men and women, respectively, of compound A14 / P2. Figures 75 and 76 show the measurement data in men and women, respectively, of compound A12 / P1. Figures 77 and 78 show the measurement data in men and women, respectively, of compound A7 / P2. Figures 79 and 80 show the measurement data in men and women, respectively, of compound A13 / P1. Figures 81 and 82 show the measurement data in men and women, respectively, of the compound A2 / P7.

Figures 83 and 84 show the measurement data in men and women, respectively, of compound A3 / P5. Figures 85-96 refer to the checks in Chapter II. Figures 85 and 86 show the data of measurements in men and women, respectively, of compound A8 / C1. Figures 87 and 90 show the measurement data in men and women, respectively, of compound A2 / C1. Figures 89 and 90 show the measurement data in men and women, respectively, of the acetate of the compound A2 / C1. Figures 91 and 92 show the measurement data in men and women, respectively, of compound A1 / C1. Figures 93 and 94 show the measurement data in men and women, respectively, of the A3 / C1 compound. Figures 95 and 96 show the measurement data in men and women, respectively, of compound A13 / C1. Figures 97 and Figure 98 show EVG and the frequency of discharge of the vomeronasal nerve, respectively, from steroid E2 / P4 and control, in female rats. Figures 99 to 120 show the data of EVG, EDA, RF, CF, EMG, BT and EEG (alpha-V, alpha-T, beta-V and beta-T) of the administration of 19-nor-steroids designated in the WNV of women. Figures 121 to 142 show the EVG, EDA, RF, CF, EMG, BT and EEG data of the administration of 19-nor-steroids designated in the WNV of men. Figure 143 illustrates the synthesis of 1,3,5 (10). 16-estratetraen-3-ol. Figures 144A, 144B and 144C are graphical representations of the electrophysiological effect on the receptor potential of the localized administration of particular steroids to the vomeronasal organ of male subjects (Figure 144A) and to the olfactory epithelium (Figure 144C). Figure 144B is a graphical comparison of the effect of a Premiere on the potential VNO receptor of male and female subjects. Figure 145 is a graphical representation of the electrophysiological effect of localized administration of particular steroids to the vomeronasal organ of men (145A) and women (145B). Figure 146 illustrates several responses of autonomy of men to acetate of 1,3,5 (10), 16-estratetraen-3-yl A = potential receptor of the vomeronasal neuroepithelium, B = change in the response of galvanic skin (K-ohms) ); C = change in skin temperature (degrees C). Figure 147 illustrates comparative changes in the WNV potential after exposure to 5-methyl ether and acetate of 1, 3,5 (10), 16-estratetraen-3-ol. Figure 148 represents sexual dimorphism in local responses and autonomy to the stimulation of WNV with vomeropherins. Several vomeropherins (200 10 fmoles) and diluent control were administered to 30 men and 30 women (aged 20 to 45 years) as described. The bars indicate the average response of the population. Figures 148A and 148B: EVG responses were measured as 15 described in men (A) and women (B). Figures 148C and 148D: The electrodermal activity was measured as described. Changes (measured in> (0) in response due to the supply of vomeropherins to the WNV of each subject are shown in men C) and women (D). Figures 148E and 148F: The alpha-cortical activity was measured as described. Changes in the response due to the supply of vomeropherins to the WNV of men (E) and women (F). Figures 148G and 148H: The skin temperature (ST) was measured as described. Changes in responses due to the supply of vomeropherins to the VNO of each subject are shown in men (G) and women (H). A = acetate of 1, 3, 5 (10), 16-estratetraen-3-yl B = Androsta-4,16-dien-3-one C = 1,3, 5 (10), 16-estratetraen-3 ol D = 3-methoxy-estra-1,3,5 (10), 16-tetraene E = Androsta-4, 16-dien-3a-ol F = Androsta-4,16-dien-3ß-ol Figure 149 illustrates electro-olfatograms of men and women induced by the stimulation of EO with olfactory agents and vomeropherins A: 400 fmol of the olfactory agents 1-carvone and cineole as well as 200 fmol of the vomeropherins A, B, C, D and F; and 10 stereoisomers E were applied separately as second pulses to EO of 20 subjects (both male and female) and recorded as each EOG response was described. Olfactory agents as well as E and B produced a significant local response (p <0.01), B: 400 fmol of olfactory agents 1-carvone and cineol induce a significant EVG response when supplied to the WNV of men and women. Figure 150 represents the electrophysiological effect of the following vomeropherins in the vomeronasal organ of 20 women: G = Androst-4-en-3-one H = Androsta-4, 16-dien-3,6-dione J = 10.17 -dimethylgone-4,13 (17) -dien-3-one K = ether 1, 3,5 (10), 16-estratetraen-3-ol-methyl L = propionate of 1, 3,5 (10), 16 -stratetraen-3-ilo EVG = electro-vomeronasogram GSR = Galvanic skin response = Electrodermal activity (EDA) ST = Skin temperature Figure 151 illustrates the electrophysiological effect of vomeropherins in the vomeronasal organ of 20 men. M = 1,3,5 (10) -Estratrien-3-ol Figure 152 illustrates the synthesis of Estra-1, 3,5 (10), 6-tetraen-3-ol and Estra-4, 16-dien- 3-ol Figure 153 illustrates the synthesis of the compounds described in Examples 63 to 66. Figure 154 illustrates the synthesis of the compounds described in Examples 67 to 71. Figure 155 illustrates the synthesis of the compounds described in Examples 72 to 75. Figure 156 illustrates the synthesis of the compounds described in Examples 76 to 77. Figure 157 illustrates the synthesis of the compounds described in Examples 78 to 83. Figure 158 illustrates the synthesis of the compounds described in Examples 84 to 86. Figure 159 illustrates the synthesis of the compounds described in Examples 87 to 93. Figure 160 illustrates the synthesis of the compounds described in Examples 94 to 96. Figure 161 illustrates the synthesis of the compounds described in Examples 97 to 98. Figures 162A, 162B and 162C illustrate the EVG, GSR and ST data, in m Women, respectively, for 13 estranos in Diagram 1. Figures 163A, 163B and 163C illustrate the data of EVG, GSR, and ST, in men, respectively, for 13 estranos in Diagram 1. Figures 164A and 164B to the 176A and 176B illustrate the EEG data of men (A) and women (B) for the 13 estrana, respectively, identified in Figures 163A-163C. Figure 177 illustrates the synthesis of Androsta-4,16-dien-3βol. Figure 178 illustrates the synthesis of Androsta-5, 16-dien-3a-ol and Androsta-5,16-dien-3ß-ol. Figure 179 illustrates an alternate synthesis of Androsta-4,16-dien-3-one. Figure 180 is a graphical representation of the electrophysiological effect on the receptor potential of localized administration of steroids particularly to the vomeronasal organ of women (180A) and the olfactory epithelium (180C). Figure 180B is a graphical comparison of the effect of an Androstane on the potential WNV receptor of men and women. Figure 181 is a graphical representation of the electrophysiological effect of localized administration of particular steroids in the vomeronasal organ of men (182A) and women (182B). Figure 182A to 182F represent several responses of women's autonomy to an Androstane. A = potential receptor of the vomeronasal neuroepithelium; B = change in cortical alpha activity of an electroencephalogram (%); C = change in galvanic skin response (K-ohms); D = change in the peripheral arterial pulse (counts / minutes); E = change in skin temperature (degrees C); and F = change in respiratory rate (counts / minute). Figure 183 represents the changes in the potential WNV receptor after exposure of 5 women to two different Androstanes. Figure 184 illustrates sexual dimorphism in local responses and autonomy to VNO stimulation with vomeropherins. Several vomeropherins (200 fmol) and diluent control were administered to 30 men and 30 women (aged 20 to 45 years) as described. The bars indicate the average response of the population. Figures 184A and 184B: EVG responses were measured as described in men (A) and women (B). Figures 184C and 184D: the electrodermal activity was measured as described. The changes (measured in xo) in response due to the supply of vomeropherins to the WNV of each subject are shown in men (C) and women (D). Figures 184E and 184F: Alpha-cortical activity was measured as described. Changes in the response due to the supply of vomeropherins to the WNV of men (E) and women (F). Figures 184G and 184H: The skin temperature ST) was measured. Changes in response due to the supply of vomeropherins to WNV in each subject are shown in men (G) and women (H). The compounds in the graphs are: A = Acetate of 1, 3, 5 (10), 16-estratetraen-3-yl B = Androsta-4, 16-dien-3-one C = 1,3, 5 (10), 16-estratetraen-3 ol D = 3-methoxy-estra-1,3,5 (10), 16-tetraene E = Androsta-4,16-dien-3a-ol F = Androsta-4, 16-dien-3ß-ol Figure 185 illustrates electro-olfatograms of men and women induced through the stimulation of EO with olfactory agents and vomeropherins. Figure 185A: 400 fmoles of olfactory agents 1-carvone and cineole as well as 200 fmoles of vomeropherins A, B, C, D and F; and Esteroisomer E were supplied separately as second pulses at EO of 20 subjects (both male and female) and each EOG response was recorded as described. The olfactory agents as well as E and B produced a significant local response (p <0.01). Figure 185B: 400 fmol of 1-carvone and cineole olfactory agents did not induce a significant EVG response when supplied to the WNV of men and women. Figure 186 illustrates the electrophysiological effect of the following vomeropherins in the vomeronasal organ of 20 women: G = Androst-4-en-3-one H = Androsta-4, 16-dien-3,6-dione J = 10.17 -dimethylgone-4,13 (17) -dien-3-one K = ether 1, 3,5 (10), 16-estratetraen-3-ol-methyl L = Propionate of 1, 3,5 (10), 16 -estratetraen-3-ilo EVG = Electro-vomeronasogram GSR = Galvanic Skin Response = Electro-thermal Activity, EDA ST = Skin temperature Figure 187 illustrates the electrophysiological effect of vomeropherins on the vomeronasal organ of 20 men. M = 1.3.5 (10) -Estratrien-3-ol Figure 188 illustrates the steps of the synthesis for Examples 108 to 112. Figure 189 illustrates the steps of the synthesis for the Examples 1113 to 118. Figure 190 illustrates the steps of the synthesis for Examples 120 to 121. Figure 191 illustrates the steps of the synthesis for Examples 123 to 124. Figure 192 illustrates the steps of the synthesis for Examples 125 to 126. Figure 193A shows respiratory rate and EKG data in women for tests of androsta-5, 16-dien-3β, 19-diol in WNV. Figure 193B shows respiratory rate and EKG data in women for tests of androsta-5, 16-dien-3β, 19-diol in WNV. Figures 194A, 194B and 194C show the EVG, GSR, and ST data in women for four androstanes in the graph and androsta-5,16-dien-3β, 19-diol. Figures 195A, 195B and 195C show the EVG, GSR and ST data in men for the five androstanes identified in Figure 194. Figures 196A and 196B show the EEG data in men and women for androstane A4 / N3. Figures 197A and 197B show the EEG data in men and women for androstane A3 / N3. Figures 198A and 198B show the EEG data in men and women for androstane A13 / N1. Figures 199A and 199B show the EEG data in men and women for androst-5, 16-dien-3β, 19-diol. Figures 200A and 200B show the EEG data in men and women for androstane A6 / N3. Figures 201A and 201B are tracks of EVGs in a man's WNV, tested with two vomeropherins (Figure 201A), and electrograms of the nasal respiratory mucosa (Figure 201B) when the same vomeropherins. Figure 202 shows the dose-dependent effect of two vomeropherins in men. Figure 203 shows the reflex response of the central nervous system of two vomeropherins. Figure 204 shows the difference in testosterone levels in a subject who was administered in one visit a placebo (curve B) to WNV, and in a second visit (curve A), the compound pregna-4,20-3,6 -Diona. Figures 205, 206 and 207 show the data for the testosterone tests in three additional subjects who were given a placebo, in case B, and pregna-4,20-dien-3,6-dione in case A. Figure 208 and Figure 209 show the amplitudes of the steroids E2 / NC2, E1 / NC2, E2 / NC3, E1 / NC3, E2 / NC2 methylated, E2 / NC3 methylated and E8 / NC3 in diagram VI, in the WNV of men and women respectively. Figure 210 shows the results of eleven symptoms of PMDD in women who were given a placebo or estra-4, 16-dien-1 Oß-ol-3-one. Figure 211 shows electromyogram results in women who were given a placebo or estra-4,16-dien-10ß-oI-3-one. Figure 212 shows the frequency of cases of electrodermal activity in women who were given placebo or estra-4,16-dien-10ß-ol-3-one. Figures 213, and 214 show the results of Hamilton-A anxiety tests for the treatment in the WNV of anxious patients with androsta-4, 16-dien-3ß-ol. Figure 215 shows the results of the effect on the respiratory rate and heart rate for the treatment in the WNV of anxious patients with androsta-4, 16-dien-3ß-ol. Figure 216 shows the results in the parasympathetic tone for the treatment in the WNV of anxious patients with androsta-4, 16-dien-3ß-ol. Figure 217 shows the results in the electrodermal activity for the treatment in the WNV of anxious patients with androsta-4,16-dien-3ß-ol. Figure 218 shows the results on changes in body temperature for the treatment in the WNV of anxious patients with androsta-4,16-dien-3ß-ol. Figure 219 shows the results of EVG tests in women who were administered the compounds of Examples 133, 134 and 134A. Figure 220 shows the results of the alpha-brain wave test in women who were administered the compounds of examples 133, 134 and 134A. Figure 221A is a summary of the electrophysical effects due to WNV stimulation in men through eight steroids having epoxy groups in the D ring. Figure 221B is a summary of the electrophysical effects due to the stimulation of WNV in women by eight steroids having epoxy groups in ring D.DETAILED DESCRIPTION OF THE INVENTION I. Definitions An "alteration" is a state of passing feeling.

The typical negative alterations are feelings of nervousness, tension, shame, anxiety, irritability, anger, anger and the like. "Moods" are longer states of feeling such as guilt, sadness, despair, lack of courage, remorse, misery, unhappiness and the like. "Character traits" are more permanent aspects of an individual's personality. Typical negative character traits are sensitivity, regret, guilt, stubbornness, resentment, bitterness, shyness, laziness and the like. The vomeropherins according to the present invention can be used to stimulate, through contact with the WNV, one or more of the hormonal, behavioral, and autonomic functions of the hypothalamus. Due to the predominant role played by the hypothalamus in a wide variety of internal body functions and the neural function between the VNO and the hypothalamus, the vomeropherins according to the present invention are in a position to stimulate such functions as exit control endocrine, for example, the control of the production of vasopressin and oxytoxin by the pituitary as well as a number of other peptides. Vasopressin is an anti-diuretic hormone due to its action in the kidney to increase water consumption and to concentrate urine. In addition, it has the action within the body of regulating blood pressure through its action on the arterial smooth muscle and an action on the metabolism through its increase in the conversion of glycogen to glucose in the liver. Oxytocin, receptors of which are found in the smooth muscle of the uterus and in the mammary smooth muscle, can cause the decrease of milk through the contraction of the mammary smooth muscle and can cause uterine contractions during childbirth. The hypothalamus also controls the release of hormones from the anterior pituitary gland such as ACTH, prolactin, LH (Luteinizing Hormone), GH (Growth Hormone), TSH (Thyroid stimulation hormone), FSH (Follicle Stimulation Hormone), and beta-endorphin. Thus, for example, the ability to control the secretion of LH can lead to the control of fertility, in women, or the production of testosterone in men. The production of testosterone can be used for the treatment of conditions such as low livid in men or for the treatment of diseases or conditions that wear down the muscle, such as aging. The reduction of testosterone can be used for the treatment of conditions such as cancer in the prostate. The control of hypothalamic functions of behavior is also convenient through the use of the vomeropherins according to the present invention. It is known that the hypothalamus controls behavioral productions such as fear, anger, pleasure and circadian rhythms, which regulate sleep and insomnia. Other functions controlled by the hypothalamus include appetite, thirst, sympathetic functions such as booting and fighting, and functions such as cardiovascular control, thermoregulation and visceral functions, such as control of the muscle of the intestines and the secretion of acid for digestion . Thus, although there is a multitude of sensory inputs to the hypothalamus from various parts of the anatomy, it is believed that the vomeropherins of the present invention provide, for the first time, a form to stimulate through the nasal cavity through inhalation to make contact with the epithelial cells in WNV, a method to stimulate functions of the hypothalamus described above. "Pregnane steroids" are aliphatic polycyclic hydrocarbons characterized by a four-ring steroidal structure with methylation at positions 10 and 13 and ethylation (including unsaturated groups) at position 17. A pregnane is a subgroup of pregnanes commonly understood to represent the compound that has at least one double bond. further, all derivatives having the structural characteristics described above are also generically referred to as pregnane steroids. A "colane steroid" is an aliphatic polycyclic hydrocarbon, characterized by a four-ring steroidal structure, with methylation at positions 10 and 13 and a 2-pentyl group (including unsaturated groups) at position 17. A "chemoreceptor" is a receptor molecule presented on the surface of a "chemosensory" neuroepithelial cell, which binds in a stereospecific manner to a particular ligand or ligands. This specific binding initiates a signal transduction that initiates an impulse of the afferent nerve. The chemoreceptors are found, among others, in the taste buds, olfactory epithelium and vomeronasal tissue. The "pregnen steroids" as the term is used herein, are polycyclic aliphatic hydrocarbons with a four-ring steroidal structure, at least one double in ring A, methylation in position 10 and in position 13, ethylation ( including unsaturated groups) at position 17 and an oxo, hydroxyl or hydroxyl derivative such as alkoxy, ester, benzoate, cypionate, sulfate or glucuronide, at position 3. Derivatives containing these structural characteristics are also generically referred to as pregneno steroids . The following structure shows the four-ring steroidal structure common to steroids. For illustration purposes, a side chain on the D-ring for pregnane is shown. To describe the location of the groups and substituents, the following numbering system will be used: "Sexually dimorphic" refers to a difference in the effect of, or response to, a pharmaceutical agent between males and females of the same species. An "effective amount" of a drug is a quantity and / or concentration scale that provides a desired physiological and / or psychological effect when administered to an individual in need of the drug. In the case of the present, an individual with the need is someone with a physiological or behavioral trait, which is normally regulated through the hypothalamus and where it is desirable to alter the function of the hypothalamus or trait. The effective amount of a given drug may vary depending on the function that will be altered, the desired effect, route of administration, and the like. For example, when the steroid is administered as a solution applied to the skin in the facial form of a subject, an effective amount is from 1 microgram / ml to 100 μg / ml preferably, 10 to 50 μg / ml and more preferably 20 at 30 μg / ml. When the steroid is introduced directly into the WNV, an effective amount is from about 1 picogram to about 1 nanogram, more preferably about 10 picograms to about 50 picograms. When the steroid is administered to the nasal passage, through an ointment, cream or spray, or the like, an effective amount is from about 100 pg to about 100 micrograms, preferably about 1 pg to about 10 micrograms. It is continued that some drugs can be effective when administered through some routes, but not effective when they are administered through other routes. The "hypothalamus" is the portion of the diencephalon that comprises the ventral wall of the third ventricle below the hypothalamic sulcus and includes structures that form the floor of the ventricle, including the optic chiasm, cornea, infundibulum, and mamillary bodies. The hypothalamus regulates the autonomic nervous system and controls various physiological and behavioral functions such as so-called flee and share responses, sexual motivation, water balance, sugar and fat metabolism, hunger, regulation of body temperature, endocrine secretions and others. The hypothalamus is also the source of vasopressin, which regulates blood pressure and oxytocin, which induces childbirth and milk release. All the hypothalamic functions are potentially modulable through the therapy with vomeropherin described here. A "ligand" as used herein, is a molecule that acts as a chemical signal by specifically binding to a receptor molecule presented on the surface of a receptor cell, thereby initiating a signal transduction through the surface of the cell . The binding of ligands to chemosensory receptors can be measured. Chemosensory tissue, such as the vomeronasal neuroepithelium or olfactory neuroepithelium, contains a multitude of neuroreceptor cells, each having at least one cell surface receptor. Many of the receptor molecules have a specific character of identical ligand. Therefore, when the tissue is exposed to a ligand for which it has a specific character (for example, a VNO exposure to a vomeropherin), a summed change in cell surface receptor potential can be measured. As used herein, "lower alkyl" means a branched or unbranched saturated hydrocarbon chain of 1 to 4 carbon atoms t such as, for example, methyl, ethyl, n-propyl, i-butyl and the like. "Alkoxy" as used herein, is used in its conventional sense and represents the group -OR where R is alkyl as defined herein. A "pheromone" is a substance that provides chemical means of communication between members of the same species through peripheral secretion and chemoreception. In mammals, pheromones are usually detected by receptors in the vomeronasal organ of the nose. Commonly, pheromones effect related development, reproduction and behavior. A "vomeropherin" is a more general term, which includes pheromones and describes a substance from any source that functions as a chemosensory messenger, binds to a specific vomeronasal neuroepithelial receptor, and induces a physiological or behavioral effect. The physiological effect of a "vomeropherin" is mediated through the vomeronasal organ. A picogram (pg) is equal to .001 nanogram (ng). An ng equals .001 micrograms (μg). One μg equals .001 mg.

II. Modes for Carrying Out the Invention A. Steroids Useful in the Invention The invention is directed to a group of certain steroids. The syntheses are described in the following for the following compounds and are designated in the diagrams: Diagram 1 includes pregnanes to which the invention is directed, but does not limit its scope. The synthesis diagrams that follow represent synthesis of intermediaries and substructures for the preparation of these pregnans: ?? Gon &iuaei-? WE ASK Continuation PREGNAN • CONTINUATION PREGNAN SYNTHESIS OF SUBSTRUCTURE Referring to the preceding table, the following are illustrative summaries for intermediaries in a row (A1 to A13) or given column (P1 to P8).

SYNTHESIS OF SUBSTRUCTURE: TYPE A To the: AKOPr'K C-ctohßxanone HJJJ »* - J ZJ Percy L. Julian, Edwin W. Meyer and Helen C. Printy, J. Amer. ctiem Soc., 1948.70, 3, 887.

Also a commercially available substructure, for example 17a-ethynyltestosterone.

A2: This is a commercially available substructure, for example, dehydroepiandrosterone, pregnenolone.

A3: David G. Loughhead, J. Org. Chem., 1985, Vol. 50, No. 20, p 3931.

A4: I.Z. Kabore, Q. Khuong-Huu, and A. Pancrazi, Tetrahedron, 1978, Vol. 34, p. 2807.

I. Dory, G. Szabo and P. Opoczky, Acta Chim, Exxng. , Vol. 20, p. 67 (1959).

Be nhard Krieger, Egbert BlanKß, and Ep-anußl Kaspar, Germ n Patßnt 1,297,603 (1969).

A6: Alan M. Krubiner, Norman Gottfield, and Eugene P. Oliveto, J. Org. Chem., 1969, 34, 11, 3502.

Roberto Sciaky and Alberto Consonni, Gazz. Chim. Ital. 1962, 92, 730.

A7 (A2 Acetate) (A7) A8: Meo See an example. Vladimir Petrow, Yueh-sha Wang, Leon Lack, Avery Sandberg, Nobuyuki Kodohama, and Keith Kendle, J. Steroid Biochem., 1983, 19, 1491.

A9: -xi Ho CrOs / HpS? t ~ x Hb (A10) (A9) Steven R. Schow and Trevor C. McMorris, Steroids, 1977, Vol. 30, No. 3, p. 389 Also a commercially available substructure, for example, 17a-ethynyldihydrotestosterone.

A10: This is a commercially available substructure, for example, pregnanolone, androsterone. As well: J.M. Kohli, A Zaman and A.R. Kidwai, Phytochemistry 1971, Vol. 10, p. 442 All:) f_T j DICLORODICIANOBENZOQUINQNA S] < A1) (A11) See an example.

Frederick Brown and Cari Djerassi, J. Amer. Chem. Soc, 1980, 102, 2, 807.

A12: HCf < J A13: SYNTHESIS OF SUBSTRUCTURE: TYPE B Pl: Ajay K. Bose and N.G. Steinberg, Synthesis, 1970, p. 595 Steven R. Schow and Trevor C. McMorris, Steroids, 1977, vol, 30, No. 3, p. 389 P2: Ronald Breslow and Louis M. Maresca, Tetrahedron Letters, 1977, No. 7, p. 623 Braja G. Hazra, Vandana S. Pore, Padmakar L. Joshi, J. Chem Soc., Perkin Trans I, 1993 (15), 1819-22.

Also a commercially available substructure, for example, 5a-pregn-17 (20) -in 3ß-ol (Esteraloides): P3: This is a commercially available substructure, for example, pregna-5, 16-dien-3ß-ol (Esteraloides). When it is commercially available, the synthesis proceeds as follows: John P. Dusza and Werner Bergman, J. Org. Chem., 1960, 25, 79.

P4: C.W. Shoppee, Ruth E. Lack, and B.C. Newman, J. Chem. Soc, 1964, p. 3388 Also a commercial substructure available, for example, 5a-pregnan-3ß-ol (Esteraloides): P5: the ^ t3N Alan M. Krubiner, Norman Gottfried, and Eugene P. Oliveto, J. Org. Chem., 1969, Vol. 34, No. 11, p. 3502.

P.6; Eugene P. Oliveto, Corrine Gerold, and Lois Johnson, J. Am. Chem. Soc. 1951, 73, 5073.

P7: Pierre Crabble and Esperanza Valarde, Patent of E.U.A. 3,681,410, 1972.

P8: Maya Dvolaitsky Anna M. Giroud, and Jean Jacques, Bull. Soc. Chim. France, 1963, 62.

French Patent 1,536,034, 1968. 17a-PREGNAN For substructures P1, P4 and P5, the normal configuration at position 17 is ß. However, the corresponding analogue 17 can also be prepared using 17a -prentolone as the starting material. For example: Alan M. Krubiner, Norman Gottfried and Eugene P. Oliveto, J. Org. Chem. 1969, Vol. 34, No. 11, p. 3502.

METILPREGNANQS The following methodology allows a methyl group to be placed in the 20 position whenever it is allowed, mainly P1, P2, P3, P4 and P6: J. Bryan Jones and Keith D. Gordon, Can. J. Chem., 1972, vol. 50, p. 2712 Cr? H2S04 John P. Dusza and Werner Bergmann, J. Org. Chem., 1960, 25., 79.

David G. Loughhead, J. Org. Chem., 1985, 50, 3931. The Patent of E.U.A. 3,681,410 teaches the preparation of 6a-methyl analogues: The patent of E.U.A. 3,492,318 teaches the preparation of 18- and 21-methyl analogues: Certain pregnenolone methylated precursors are commercially available, vis 6, 16a (ß) -methyl: • In addition, 17a-methylpregnenolone is readily available: French patent 1,363,191: Therefore, compounds synthesized from pregnenolone can also be prepared with methyl groups at positions 6, 16 or 17, using the appropriate methylpregnenolone precursor. The dimethyl compounds, such as the 18,21-dimethylpregna-4,16-dien-20-yn-3-one described, can be prepared by any of the three general methods: The first method combines a methylated precursor, such as those in positions 6, 16 or 17, with methodology that introduces a methyl group, such as in position 20. The second method uses a dimethylated precursor, such as 6, 16a-dimethylpregnenolone commercially available. The syntheses of other pregnenolone dimethylated precursors have been described, as in the following examples: Sylvestre Julia, Colette Neuville, and Pierre Simón, Bull. Soc. Chim. France, 1969, 1495.

Aoßtao of 16,16- in? Tilpr? Gn? T? Olona Elliot Shapiro, Theodore Legatt, Lois Weber, Merl Steinberg, A. Watnick, M. Eisler, Marilyn Gilmore Hennessey, C.T. Coniglio, W.

Charney, and Eugene P. Oliveto, J. Med. Pharm. Chem. 1962, 5, 975. 16a.17a ----- meHpregr-ßn - of-a James Cairns, Colin L. Hewett, Robert T. Logan, George McGarry, Donald F.M. Stevenson, and Gilbert F. Woods, J.C.S. Perkin I. 1976, 1558. 17a, 21 --- MmetUpregneno-ona R. Deghenghi and R. Gaudry, J. Amer. Chem. Soc, 1961, 4668.

British Patent 927,515: Romano Deghenghi and Roger Gaudry, Tetrahedron Letters, 1962, No. 11, p. 489 4. 4-Dimethyl-pregnenolone W.J. Adams, D.K. Patel, V. Petrow, I.A. Stuart-Webb and B. Sturgeon, J. Chem. Soc, 1956, 4490. The third method starts with a non-methylated precursor, such as pregnenolone, and uses methodology, which introduces two methyl groups, as in the following example: . 21-dim? Ti] p? Gno-ona-5ÍO < l-? n3ß-c-- The 20, 21-dimethyl pregnanes are also known as 24-Norcolanes. The 24-norcolans can alternatively be prepared through the degradation of a colane precursor, as in the following example: Yutaka Hirano, Tadashi Eguchi, Masaji Ishigmo, and Nubuo Ikakawa, Chem. Pharm. Bull., 1983, 31 (2), 394.

HALOPREGNANOS The Patent of E.U.A. 3,681,410 teaches the preparation of: Derek H. R. Barton, George Bashiardes and Jean-Louis Fourrey, Tetrahedron Letters, 1983, vol. 24, 1605.

Biao Jiang and Yuanyao Xu, Tetrahedron Letters, 1992, vol. 33, 511. Certain pregnenolone methylated precursors are commercially available, vis 6, 16a (ß) -methyl: In addition, 17a-methylpregnenolone is readily available: French patent 1,363,191: Therefore, compounds synthesized from pregnenolone can also be prepared with methyl groups at positions 6, 16, or 17, using the appropriate methylpregnenolone precursor.

SYNTHESIS OF SUBSTRUCTURE Referring to the preceding table, the following are illustrative syntheses for the substructures in a row (A1 to A13) or column (C1 to C7) given.

SYNTHESIS OF SUBSTRUCTURE: TYPE A See an example.

A2: Jo This is a commercially available substructure, for example, PREGNENOLONE, ESTIGMASTEROL, COLONIC ACID.

A3: See an example. A6: See an example.

A8: See an example.

All; D.H.R. Barton, J. Boivin, D. Crich, and C.H. Hill, J. Chem. Soc. Perkin Trans. I, 1986, p. 1805 See an example. SYNTHESIS OF SUBSTRUCTURE: TYPE C J.P. Schmit, M. Piraux, and J.F. Pilette, J. Org. Chem. 1975, Vol. 40, No. 11, p. 1586 C2 . Bergmann and J.P. Dusza, J. Org. Chem., 1958, Vol. 23, p. 1245 C3: J.E. van Lier and L.L. Smith, J. Org. Chem., 1970, Vol. 36, No. 8, p. 2631 C4 A. Burger, F. Colobert, C Hetru, and B. Luu, Tetrahedron, 1988, Vol. 44, No. 4, p 1141.

C5: A.B. Turner, Chemistry and Industry, 1979, p. 385 C6: Stoeck and H. Stein, German Patent No. 854,517, 1952.

(Usß U C7) A. Burger, J-P. Roussel, C. Hetru, J.A. Hoffmann, and B. Luu, Tetrahedron, 1989, Vol. 45, No. 1, p. 155 24-NORCOLANOS AND 24-METTILCOLANOS Structures with the side chain shortened or elongated by a carbon atom in position 24 can be prepared using analogous methodology. The 23-methyl-chromans are also available through similar means. The examples are the following: 23- METHYL 24-METHYL J.P. Schmit, M. Piraux, and J.F. Pilette, J. Org. Chem., 1975, Vol. 40, No. 11, p. 1586 24-METHYL Y.M. Sheikh and C. Djerassi, Steroids, 1975, Vol. 26 (1), p. 129 M. Morisaki, M. Shibata, C. Duque, N. Imamura, and N. Ikekawa, Chem. Pharm. Bull., 1980, Vol. 28 (2), p. 606 24-NOR D.H.R. Barton, J. Boivin, D. Crich, and C.H. Hill, J. Chem. Soc. Perkin Trans. I, 1986, p. 1805 A. Burger, F. Colobert, C. Hetru, and B. Luu, Tetrahedron, 1988, Vol. 44, No. 4, p. 1141 B.M. Trost, R.J. Kulawiec, and A. Hammes, Tetrahedron Letters, Vol. 34, No. 4, p. 587 A. Burger, J-P. Roussel, C. Hetru, J.A. Moffmann, and B Luu, Tetrahedron, 1989, Vol. 45, No. 1, p. 155 C. Synthetic Methods 1. Preparation of the derivatives of position 3-, 6-, 19-, 20-, and 21-. The compounds used in the methods of this invention are pregnane steroids substituted in the 3-, 6-, 19-, 20- and 21- positions. Many of the 3-substituted steroids are known compounds, which can be derived from 3-oxo-steroids. As shown in Figure 1, pregna-4,20-dien-3-one (1_) can be converted to an ether 3, 5, 20-trienic (2_) or 1, 4, 20-trien-3-one (3_), which are respective starting materials for 6- and 3-substituted hydroxy derivatives. Alkoxy derivatives are prepared from their corresponding hydroxy steroids through reaction with an alkylating agent such as trimethyloxonium fluoroborate, triethyloxonium fluoroborate or methyl fluorosulfonate in an inert chlorocarbon solvent such as methylene chloride. Alternatively, alkylating agents such as NaH, KM or KOBut, silver oxide or barium oxide in polar, aprotic solvents, such as, for example, DMF, DMSO and hexamethylphosphoramide. General procedures for synthetic steroid reactions are known to those skilled in the art. The time and temperature of the reactions must be determined, and these can be determined through routine methodology. After the addition of the required reagents, the mixture is stirred under an inert atmosphere and the aliquots are stirred at intervals every hour. The aliquots are analyzed through chromatography to verify the disappearance of the starting material, at which point the processing procedure is initiated. If the starting material is not consumed in twenty-four hours, the mixture is heated to reflux and every hour the aliquots are analyzed, as before, until the starting material disappears. In this case, the mixture is allowed to cool before the processing process is started. The purification of the products is achieved through chromatography and / or crystallization, as is known to those skilled in the art. 2. Preparation of 19-OH Derivatives. Synthesis of 19-OH-pregna-4,17-dien-3-one. In SCHEME 3 a method is provided to synthesize this compound. In the following diagram III, particularly preferred 19-nor-pregnanes are shown. 19-NEOPREGNANOS CO SYNTHESIS OF SUBSTRUCTURE: TYPE E The: Frank B. Colton, Leonard N. Nysted, and Riegel, and Albert L. Raymond, J. Amer. Chem. Soc, 1957, 79., 1132. Also a commercially available substructure, for example, 17a-ETINYL-19-NORTESTOSTERONE.

E2: This is a commercially available substructure, for example, ESTRONA, ETINILESTRADIOL.

E3: H Bu'O ^ IH Pierre Crabble, patent of E.U.A. 3,492,318, 1970x.? E4: rn ^^ X ^ This is a commercially available substructure, for example, 6-DEHYDROESTRONE.

E5: Ooo See an example. E6 See an example.

E7: See an example.

O.l. Fedorova, O.S. Anisimova, an G.S. Grinenko, Khim. Prir. Soedin., 1976, 2, 180.

Frank B. Colton, Leonard H. Nysted, Byron Riegel, and Albert L. Raymond, J. Amer. Chem. Soc., 1957, 79, 1123.

E9: This is a commercially available substructure, for example, EQUILINE. E10: This is a commercially available substructure, for example, EQUYLENIN.

Ell i HO ^^^ See an example. E12: (E6 acetate) (E12) See an example.

E13 XO MeO XX (Eß)) -J = Ü- 0J0 (E103) See an example.

SYNTHESIS OF SUBSTRUCTURE: TYPE P Pl: O.l. Fedorova, O.S. Anisimova, and G.S. Grinenko, Khim. Prir. Soedin., 1976, 2, 180.

Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, 1642. Also see example.

P2: > Frank B. Colton, Leonard N. Nysted, Bryon Riegel, and Albert L. Raymond, J. Amer. Chem. Soc., 1957, 79 1123.

Richards H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, 1642.

P3: - H. Kaufmann, P. Wieland, and J. Kalvoda, Helv. Chim. Acta., 1972 ', 55 (2), 381.

P4: O.l. Fedorova, O.S. Anisimova, and G.S. Grinenko, Khim. Prir. Soedin., 1976, 2, 180.

Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, 1642.

P5: Peter Kaspar and Herbert Witzel, J. Steroid Biochem., 1985, Vol. 23, No. 3, p. 259 Richard H. Peters, David R. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32. 1642.

P6: Y Frank B. Colton, patent of E.U.A. No. 2,840,582, 1958. P7: Pierre Crabble and Esperanza Velarde, patent of E.U.A. 3,681,410, 1972.

Peter Kaspar and Herbert Witzel, J. Steroid. Biochem., 1985, Vol. 23, No. 3, P. 259.

P8 Pierre Crabble, patent of E.U.A. 3,492,318, 1970.

Klaus Prezewowsky and Rudolf Wiechert, patent of E.U.A. 3,682,983, 1972.

METILNORPREG ANOS The 19-norpregnanes in this series can be prepared with a methyl group at positions 6a, 7a, 18, 20 or 21. The US patent. 3,681,410 teaches the preparation of 6-methyl analogs.

The patent of E.U.A. 3,682,983 teaches the preparation of 18-methyl analogues.

M? The patent of E.U.A. 3,492,318 teaches the preparation of 7a, 18 and 21-methyl analogues. 21-methyl analog.

THE. Van Dijck, B.J. Lankwerden, J.G. C.M. Vermeer, and A. J.M. Weber, Recl. Trav. Chim. Pays-Bas Belg., 1971, 90, 801.

Analogs 7a, 18, 20 and 21-methyl.

Richard H. Peters, David F. Crowe, Mitchell A. Averey, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, 1642.

In addition, certain methylated precursors are commercially available, for example: 7a-METILESTRONA NORGESTREL From these, 7α-methyl or 18-methyl analogs of substances can be made, wherein estrone or 17α-ethynyl-19-nortestosterone (norethindrone) are the precursors, respectively.

HALONORPRÉG NANOS The patent of E.U.A. 2,840,582 teaches the preparation of: The patent of E.U.A. 3,681,410 teaches the preparation of: Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, 1642. Alkoxy derivatives are prepared from their corresponding hydroxy steroids through reaction with an alkylating agent such as trimethyloxonium fluoroborate., triethyloxonium fluoroborate or methyl fluoromethyl sulfonate in an inert chlorocabon solvent such as methylene chloride. Alternatively, alkylating agents such as alkyl halides, alkyl tosylates, alkyl mesylates and dialkyl sulfate can be used, with a base such as NaH, KM or KOBut, silver oxide or barium oxide in polar, aprotic solvents, as for example, DMF, DMSO and hexamethylphosphoramide. General procedures for the synthetic reactions of steroids are known to those skilled in the art. The time and temperature of the reactions must be determined, and these can be determined through routine methodology. After the addition of the required reagents, the mixture is stirred under an inert atmosphere and the aliquots are stirred at intervals every hour. The aliquots are analyzed through chromatography to verify the disappearance of the starting material, at which point the processing procedure is initiated. If the starting material is not consumed in twenty-four hours, the mixture is heated to reflux and every hour the aliquots are analyzed, as before, until the starting material disappears. In this case, the mixture is allowed to cool before the processing process is started. The purification of the products is achieved through chromatography and / or crystallization, as is known to those skilled in the art.

SYNTHESIS OF SUBSTRUCTURE Referring to the preceding table, the following are illustrative syntheses for intermediaries in a row (E1 to E12) or column (N1 to N4) given. Type E (E2 methyl ether) (El) E2: The commercially available substructure, for example ESTRONA.

E3: H H0 ?? Jam R. Bull and Jan FLoor, J. Chem J. SocP. Perkin I, 1977 (7), 724.

E4 The commercially available substructure, for example, 6-DEHYDROESTRONE.

E5: V.l. Mel'nikova and K.K. Pivnitskii, Zhurnal Organickeskoi Khisnii, 1974, Vol. 10, No. 5, pp. 1014-1019).

E6: O Hidetoshi Takagi, Ken-ichi Komatsu, and Itsuo Yoshisawa, Steroids, 1991, Vol. 56, p. 173.

E7: OH (E8) (E7) Michel Mauney and Jean Rigaudy, Bull. Soo Chien, 1976, Ño 11-12, 2021.

E8: (Methyl ether d? E2) (E8) I K.J. San, R.H. Blank, R.H. Evans, Jr., L.I. Feldman, and CE. Holmbund, J. Org. Chem., 1964, 29, 2351.

E9: HO OO The substructure commercially available, as in EQUILINA.

E10: The substructure commercially available, as in EQUYLENIN.

(E8) (The l) I A.N. Cherkasov, A.M. Ponomarev, and K.K. Pivnitskii, Zhurnal Organiskeskoi Khimii, 1971, Vol. 7, No. 5, pp. 940-947.

E12: OH Hidetoshi Takagi, Ken-ichi Komatsu, and Itsuo Yoshisawa, Steroids, 1991, Vol. 56, p. 173. 'Ti po N NI: N2: 1. Robert H. Shapiro and Cari Djerassi, J. Am. Chem. Soc., 1964, 86 »2825. 2. Pilar Lupon, French C. Cañáis, Arsenio Iglesias, Joan C Ferrer, Albert Palomar, and Juan- Julio Bonet, J. Org. Chem. 1988, 53, 2193-2198.

N3: 1. Gunther Drefahl, Kurt Ponold and Hans Schick, Berichte, 2. Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masako Tanabe, J. Med. Chem., 1989, 32. 1642.

N4: Ó OTt COLIDINA (N4) * »m 1. Franz Sonheimer, O. Moncera, M. Viquiza & G. Rosenkranz (1955) J. Am. Chem. Soc. 77: 4145. 2. William F. Johns, J. Org. Chem., 1961, 26/4583.

Methylbrakes Harold J. Nicholas, J. Org. Chem., 1958, 23., 1747.

Richard H. Peters, David F. Crows, Mitchell A. Avery, Wesley K. M. Chong, and Masako Tanabe, J. Med. Chem., 1989, 32. 1642.

(RACE ICO) M.B. Green and F.J. Zeelen, Tetrahedron Letters, 1982, Vol. 23, No. 35, p. 3611-3614. The compounds that can be synthesized, therefore, include these, together with those derived therefrom; that is, 17-methyl-N1, 17β-methyl-N2, or 14a-methyl-N4, in combination with E1, E2, E3, E5, E6, E7, E8, E11 or E12. 10 Halo releases H George A. Boswell in the patent C.A. 70: 58140g, next.

G. Michael Blackburn, Brian P. Taylor and Andrew F. Worrell, Journal of Labelled Compounds and Radiopharmaceuticals, 1986, Vol. XXIII, No. 2, p. 197. The compounds that can be synthesized, therefore, include these, together with those derived therefrom; that is, 17-fluoro-N1 in combination with E1, E2, E3, E5, E6, E7, E11 or E12. In addition, 17-iodine-N1 in combination with E2, E6 or E12.

Br European Patent Application EP 208,497. Synthesizable compounds therefore include these, together with those derived therefrom, ie., (4-chloro, 4-bromo, 6a-chloro, 6a-bromo, 6β-chloro, 6β-bromo, or 6β-iodo , Al in combination with N1, N2, N3 or N4 In addition, (17-fluoro, 17-chloro, 17-bromo or 17-iodo) -N1 in combination with Al, A2, A3, A4, A5, A6, A8 , A9, A10 or A11. 1. Preparation of the Derivatives of the 3-, 5-, 6- position. 18-. and 19. The compounds used in the methods herein are substituted androstane steroids at positions 3-, 5-, 6-, 18-, and 19-. Many of the 3-, and 5- substituted steroids are known compounds, which can be derived from 17-hydroxy and 17-oxo steroids (commercially available from, for example, Aldrich Chemical Co.) through elimination or reduction to the homologue ? 16 The synthesis of most of these compounds is described by Ohloff (supra). As shown in Figure 1, 17β-hydroxy-5-androstan-3-one (I) and methyl chloroformate (a) in pyridine gives the methyl carbonate (17β-methoxycarbonyloxy-5α-androstan-3-one (II ) which provides a starting material for 5a-androst-16-en- (3-one and 3-ol) (Ohloff, supra a page 200). The alkoxy derivatives are prepared from their corresponding hydroxy steroids through reaction with an alkylating agent such as trimethyloxonium fluoroborate, triethyloxonium fluoroborate or methyl fluorosulfonate in an inert chlorocarbon solvent, such as methylene chloride. Alternatively, alkylating agents such as alkyl halides, alkyl tosylates, alkyl mesylates and dialkylsulfate can be used as a base such as NaH, KM or KOBut, silver oxide or barium oxide in polar or aprotic solvents, such as for example, DMF, DMSO and hexamethylphosphoramide. General procedures for the synthetic reactions of steroids are known to those skilled in the art. The time and temperature of the reactions must be determined, and these can be determined through routine methodology. After the addition of the required reagents, the mixture is stirred under an inert atmosphere and the aliquots are stirred at intervals every hour. The aliquots are analyzed through chromatography to verify the disappearance of the starting material, at which point the processing procedure begins. If the starting material is not consumed in twenty-four hours, the mixture is heated to reflux and every hour the aliquots are analyzed, as before, until the starting material disappears. In this case, the mixture is allowed to cool before starting the process process. The purification of the products is achieved through means such as chromatography and / or crystallization, as is known to those skilled in the art. 2. Preparation of the 19-OH derivatives. Synthesis of 19-OH-androsta-4,16-dien-3-one. This compound has been described as an intermediate in the synthesis of 19-oxo-3-aza-A-homo-5B-androstane (Habermehl, et al. Z. Naturforsch. (1970) 25b .: 191-195). A method for synthesizing this compound is provided.

DIAGRAM V. ANDROSTANOS ANDROSTANOS NOVEDOSOS 17-methylenandrost-4-en-3a-ol (A4 / N3) 17-methylenandrost-4-en-3ß-ol (A3 / N3) 6β-hydroxyandrosta-4,16-dien-3-one (A13 / N1) 6β-hydroxy-17-methyl-18-norandrosta-4,13 (17) -dien-3-one (A13 / N4) Androsta-5,16-dien-3β, 19-diol (19-hydroxy derivative of A2 / N1) 17-methylenandrost-4-en-3,6-dione (A6 / N3) 17-methyl-18-norandrosta- 4.13 (17) -dien-3a-ol (A4 / N4) 17-methyl-18-norandrosta-4,13 (17) -dien-3-β-ol (A3 / N4) 17β-metilandrost-4- en-3,6-dione (17β methyl derivative of A6 / N2) 3-methoxy-17-methylenandrosta-3,6-diene (A8 / N3) 6β-hydroxy-17-methylenandrost-4-en-3-one (A13 / N3) 17-methylenandrosta-1,4-dien-3- ona (A11 / N3) 6β-hydroxyandrosta-1, 4,16-trien-3-one (6β-hydroxy derivative of A11 / N1) 6β-hydroxy-17-methylenandrosta-1,4-dien-3-one (6β-hydroxy derivative of A11 / N3) 17β-methylarost-4-en-3a-ol (17β-methyl derivative of A4 / N2) 17β-methylandrost-4-en-3β-ol (17β-methyl derivative of A3 / N 2) 3-methoxy-17-methyl-18-norandrosta-3,5,13 (17) -triene (A8 / N4) Substructure synthesis Referring to the preceding diagram V, the following are illustrative syntheses for intermediaries in a row (A1 to A11) or column (N1 to N4) given. Type A Al: (A2) (Al) OR A2"J > This is a commercially available substructure, for example, DEHIDRO EPI ANDROSTERONA. A3: (Michio Matsui and David K. Fukushima, J. Ora, Chem .. 1970, Vol.35, No. 3, pp. 561-564).

A4 HO xb Ohloff, G. et al. (Heyl, Chim. Acta (1983) 66: 192-217) A5: (A1) (A5) Germán Off. 2,631,915.

A6 * O (A2) < A6) ° J. Romer, H. Wagner, and W. Sihade, Steroids, 1988, 51 / 5-6, p. 577-581.

A7: (A2 acetate) (A7) (Habermehl, et al., Z. Naturforsch. (1980) 256: 191-195) A8 (A1) (A8) See example 15.

A9: f j "^ DICLORODICIANOBENZOQUINQNAt ^ l (Al) (A9) Ohloff, G. et al. (Helv. Chim. Acta (1983) 66: 192-217) V.l. Mel'nikova and K.K. Pivnitskii, Zhurnal Organickeskoi Khisnii, 1972, Vol. 8, No. 1, pp. 68-74).

All: See example 19 • 10 15 Type N NI: to O N-NKTs N2: 1. Robert H. Shapiro and Cari Djerassi, J. Am. Chem. Soc., 1964, 86. 2825. 2. Pilar Lupon, French C. Cañáis, Arsenio Iglesias, Joan C. Ferrer, Albert Palomar and Juan-Julio Bonet, J Org. Chem. 1988, 53, 2193-2198. 1. Gunther Drefahl, Kurt Ponold and Hans Schick, Berichte, 1965, 98., 604. 2. Richard H. Peters, David F. Crows, Mitchell A. Avery, Wesley K.M. Chong and Masako Tanabe, J. Med. Chem., 1989, 32., 1642.

OH * ?? J £ ¡X > £ p. * 1. 1. Franz Sondheimer, O. Mancera, M. Urquiza &G. Rosenkrnaz, J. Am. Chem. Soc, 1955, 77, 4145. 2. William F. Johns, J. Org Chem., 1961, 26, 4583.

Metiland Germán Off. 2,631,915 teaches the preparation of: with a methyl group in any of the following positions: 1a, 2a, 4, 6a, 6β, 7a and 16. 6-METHYLANDROSTA-4.6-DIEN-3-ONE Germán Off. 2,428,679.

Daniel Bertin and Lucien Nedelac, Memoires Presents to the Societe Chimique, 1964, No. 345, p.2140. The compounds that can be synthesized, therefore, include these, together with those derived therefrom; that is, N1 with methyl in 1a, 2a, 4, 6a, 6ß, 7a, 16 or 17 combined with A1, A3, A4, A5, A8, A9, A10 or A11, as well as A2 or A6 with a 17-methyl .

Haloand Réstenos Patent of E.U.A. 3,413,321 Germán Off. 2,631,915.

DIAGRAM VI. 19-NORCOLAN SYNTHESIS OF SUBSTRUCTURE: TYPE E He: See an example.

E2 This is a commercially available substructure, for example, ESTRONA.

E3: Pierre Crabbe, patent of E.U.A. 3,492,318, 1970.

E4; This is a commercially available substructure, for example, 6-DEHYDROESTRONE.

E5: V.l. Melnikova and K.K. Pivnitskii, Zhurnal Organischeskoi Khimii, Vol. 10, No. 5, p. 1014, 1974.

E6: Hidetoshi Takagi, Ken-ichi Komatsu, and Hsuo Yoshizawa, Steroids, 1991, 56, 173.

E7: J. Pérez Ruelas, J. Iriarte, F. Kinel, and Cari Djerassi, J. Org. Chem., 1958, 23, 1744.

E8: UNH, M? O M? O (Cetyl ether of O E2) JO (EOB) See an example.

E9: This is a commercially available substructure, for example, EQUILINE.

E10: H0 ^ ^ This is a commercially available substructure, for example, EQUYLENIN.

Ell: A.N. Cherkasov, A.M. Ponomarev, and K.K. Pivnitskii, Zhurnal Organicheskoi Khimii, Vol. 7, No. 5, p. 940, 1971.

E12: E13: , JOO E14: Elie Stephan, Regine Zen, Laurent Authier, and Gerard Jaouen, Steroids, 1995, £ 0, 809.

SYNTHESIS OF SUBSTRUCTURE: TYPE NC NCl: Gerard A. Potter, S. Elaine Barrie, Michael Jarman, and Martin G. Rowlands, J. Med. Chem., 1995, 38., 2463.

Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Másate Tanabe, J. Med. Chem., 1989, 32. 1642.

NC3 Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Másate Tanabe, J. Med. Chem., 1989, 32., 1642.

NC4 Gerard A. Potter, S. Elaine Barrie, Michael Jarman, and Martin G. Rowlands, J. Med. Chem., 1995, 3., 2463.

NC5: Pierre Crabbe, patent of E.U.A. 3,492,318, 1970.

METILNORCOLANOS The 19-norcolanes in this series can be prepared with a methyl group in positions 1 or 7a. The precursor of the 1-methyl analogs can be prepared as follows: The starting material was prepared according to Cari Djerassi, G. Rosenkanz, J. Iriarte, J. Berlin, and J. Romo, J. Amer. Chem. Soc. 1951, 73, 1523. The 7α-methyl analogues can be prepared from commercially available 7α-methylstrone.

D. Methods of Use. The methods of the invention are achieved through the nasal, non-systemic administration of certain steroids and steroid combinations. This particular mode of administration is distinguished from alternative modes, such as ingestion or injection, in several important ways, these by virtue of direct contact with the WNV provided by the nasal administration of the steroidal ligand. In the methods of this invention, the appropriate ligand is administered directly to the chemoreceptors in the nasal passage and the vomeronasal organ, without pills or needles, i.e., non-invasively. The action of the drug is mediated through the binding of the ligands, as described herein, to specific receptors presented by neuroepithelial cells in the nose, preferably in the WNV. In addition to this, the mode of action of the drug is through the nervous system and not through the circulatory system, in this way the function of the brain can be altered without consideration of the blood-brain bar. These methods of treatment provide direct means to alter the hypothalamus through the nervous system since there is only a synaptic junction between the pheromone receptors and the hypothalamus. Because the sensory nerves are directed to a specific site in the brain, this method has a highly specific drug effect, greatly reducing the potential for unwanted side effects. VNO contact is important since WNV is associated with the chemoreceptive / pheromonal function. The WNV consists of a pair of blind tubular diverticula, which are located in the lower margin of the nasal septum. The WNV contains neuroepithelia, the axons of which have direct synapses to the tonsils and from there, to the hypothalamus. The existence of WNV has been well documented in most terrestrial vertebrates including the fetus of the human being; however, in adult humans, it is generally believed to be rudimentary. (See Johnson, et al., Supra.) The ligand substances described herein, or their sulfates derivatives, cipiones, benzoatados, propionados or glucuronados, can be administered directly, but preferably are administered as compositions. They are prepared in a liquid dosage form such as, for example, liquids, suspensions or the like, preferably in unit dosage forms suitable for the individual administration of precise doses. The doses in liquid form can be administered such as nose drops or as an aerosol. Alternatively, the active compound can be prepared as a cream or an ointment composition and applied topically within the nasal cavity. In addition, a vomeropherin can be administered as a vapor contained in a breath of air delivered to the nasal cavity. As another alternative, delivery may occur through controlled release of these agents by encapsulation, either in bulk or at a microscopic level, using synthetic polymers, such as silicone, and natural polymers such as gelatin and cellulose. The rate of release can be controlled by own choice of the polymeric system used to control the diffusion rate (Langer, R.S. and Peppas, N.A., Biomaterials 2,201, 1981). Natural polymers, such as gelatin and cellulose, slowly dissolve in a matter of minutes to hours, since the silicone remains intact for a period of months. The compositions will include a conventional pharmaceutical carrier or excipient, one or more of the active compounds. In addition, the compositions may include other medicinal agents, pharmaceutical agents, vehicles, auxiliaries, etc. The most convenient means of communication of a semi-chemical ligand is the inhalation of a pheromone of natural existence present in the skin of another. Since these compounds are relatively non-volatile, it is estimated that, even during intimate contact, a human being could inhale amounts of picogram of one naturally occurring steroid from the skin of another. Of the inhaled amount, it is estimated that only about 1% could reach the receptors of the vomeronasal organ. The amount of vomeroferin administered will, of course, depend on the subject being treated, the severity of the affliction, the manner of administration, the frequency of administration and the judgment of the attending physician. However, an individual dose of at least 10 picograms, delivered directly to the lumen of the vomeronasal organ, is effective to produce a transient autonomous response. When administered to the nasal cavity, the dose is from about 100 picograms to about 100 micrograms, preferably from about 1 nanogram to about 10 micrograms, more preferably about 10 nanograms to 1 microgram. The frequency of administration is desirably in the scale of one dose every hour at a dose every month, preferably 8 times / day, every other day, more preferably 1 to 3 times a day. Ointments containing one or more optional pharmaceutical active and auxiliary compounds in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, can be prepared using a base such as, for example, jelly of oil, lard or lanolin. The liquefied pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, etc., an active compound as previously dissolved in optional pharmaceutical auxiliaries in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol , and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH regulating agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine acetate sodium, triethanolamine oleate, etc. Current methods for preparing such dosage forms are known, or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 15th Ed., 1975. The composition or formulation to be administered will, in any case, contain an amount of one or more of the active compounds in an effective amount. to mitigate the symptoms of the subject being treated. For aerosol administration, the active ingredient is preferably delivered in finely divided form together with a surfactant and a propellant. The typical percentages of active ingredients are from 0.001 to 2% by weight, preferably from 0.004 to 0.10%. The surfactants must, of course, be non-toxic and preferably soluble in the propellant. Representative examples of such agents are the partial esters and esters of fatty acids containing from 6 to 22 carbon atoms, such as caprope, octanoic, lauric, palmitic, stearic, linoleic, eleostearic and oleic acids with an aliphatic polyhydric alcohol or its anhydride cyclic such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol and hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the tradename "Spans" and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides, may also be employed The preferred surfactants are sorbitan oleates, for example, those sold under the trademarks of "Arlacel C" (sorbitan sesquioleate), "Span 80" (monooleate of sorbitan) and "Span 85" (sorbitan trioleate) The surfactant may constitute 0.1-20% by weight of the composition, preferably 0.25-5% The rest of the composition is ordinarily a propellant. The liquefied propellants are typically gases at ambient conditions, and they condense under pressure. Among the suitable liquefied propellants are lower alkanes containing up to five carbons, such as butane and propane; Fluorinated or fluorinated alkanes, such as those sold under the trade name "Freon". Mixtures of the above can also be used. In production the aerosol, a container equipped with a suitable valve is filled with an appropriate propellant, containing the finely divided active ingredient and the surfactant. The ingredients of this form are maintained at a high pressure, until they are released through the action of the valve. Other means of administration are topical application of a volatile liquid composition to the skin, preferably the skin of the face, of an individual. The composition will usually contain an alcohol such as ethanol or isopropanol. A pleasant deodorant can also be included in the composition.

E. Anti-Fertility Activity The steroid 19-norpregna-1, 3,5, (10) -trien-3-ol (compound E2 / P4 in the 19-norpregnane diagram) was tested in the WNV of female rats. The EVG and the discharge frequency of the vomeronasal nerve (VNn) are shown in Figures 97 and 98, respectively. These data show the VNO stimulation. Steroid E2 / P4 is shown to have postcoital anti-fertility activity, when administered orally to female rats, while having low hormonal activity (measured through estrogen-receptor binding) (Peters, et al., J. Med. Chem., 1989, 32., 1642-52). The data in Figures 97 and 98 suggest that this anti-fertility activity is explained since E2 / P4 is not a hormone, but acts as a vomeropherin through the stimulation of WNV, which in turn alters the hypothalamus. Consistent with the rat model data, compound E2 / P4 also shows WNV stimulation in women (see Figure 118), and to a lesser degree, in men (see Figure 140), and thus it is expected that vomeropherins have anti-fertility activity in humans. The stimulation of the hypothalamus through the VNO allows to suppress the release of LH and FSH. This can provide a clinical method for the treatment of prostate cancer, precocious puberty (in men and women) endometriosis, uterine leiomyoma, breast cancer, pre-menstrual syndrome and dysfunctional uterine bleeding.

F. Measurement of Attack, Humor, and Character Traits Feeling states associated with attacks, moods, and character traits are usually measured through the use of a questionnaire. For example, questionnaires that comprise a number of adjectives that refer to feeling states can be administered to an individual. The individual evaluates the state of feeling described by the adjective and classifies the intensity of the feeling on a numerical scale. The grouping of the related adjectives and the statistical analysis of the evaluation of a subject of each adjective provides a basis for the measurement of the various feelings states. Alternatively, feeling states can be measured through autonomous changes, such as those used in polygraph evaluations (galvanic skin response, pulse rate and the like). Cabanac, M. Annual Review of Physiology (1975) 37_: 41; Hardy, J.D., "Body Temperature Regulation", Chapter 59, page 1417. In: Medical Physiology, Vol. II Ed .: VB Mountcastle (1980); Wolfram Bouscein. Electrodermal Activity (Plenum Press 1992). In addition, non-verbal cues such as facial expressions and body posture can be evaluated.

Treatment of Pre-Menstrual Syndrome Patients entered in the study (women 20-45 years of age) participated in a registration session that was presented on the day when the symptoms of PMDD were at the highest level (day 24 to 28). of the menstrual calendar). The entire procedure lasted approximately one hour in a quiet room with the subject being in a supine form. The active ingredient used in the study was 16a, 17a-epoxiestra-1, 3,5 (10) -trien-3-ol. The opening of the vomeronasal organ towards the nose was identified on both sides of the nasal septum and a nasal tube (vomeronasal applicator) was placed in a nostril, with its exit orifice pointing towards the VNO opening. A pulse of active substance or placebo was given to the WNV. Afterwards, the same procedure was repeated in the other nostril. The bilateral puff of the vomeronasal organ was repeated 30 minutes after the first application. Activation of the device provides pulses of 200 μl, lasting 1 second. The amount of active substance delivered in a pulse is 100 pg. The total amount of the active substance delivered to a WNV of a patient during the entire session is 400 pg (Table II).

Table II. Experimental protocol for random VNO stimulation CLASSIFICATION DAY 24 TO 28 OF THE MENSTRUAL CALENDAR Menstrual Calendar Interview Est. VNO Est. VNO Est. WNV bilateral Without stimulation Bilateral bilateral clinical diagnosis Blind double of WNV Blind ind. Blind double (randomized) (placebo) (random) (as before) Test Psychometric- Psychometric Test- Psychic Test 'Trica Trica Psychic Test Trica Electrophysiology Electrophysiology Electrophysiology (answer at home) -10 0 30 - + - - // - + - Time (minutes) 5 hours The candidates were tested while they had a clear symptomatology of PMDD. This usually happens during the 24th to the 28th day of your menstrual calendar. The psychometric test (Table III) was presented ten minutes before, and thirty minutes after the bilateral VNO stimulation with the test substance or placebo (also, see Table II). After completing the 30-minute questionnaire, both VNOs were again stimulated with the same substance (vomeroferin or placebo) and the patient was again given a similar psychometric test, to respond at home 5 hours after leaving the registration laboratory . The patients' interviews the day after the study session indicated changes in mood, feelings, and how they were perceived by other people, after the second puff in the VNO.

Reflections of Autonomy and EEG Several peripheral electrode cables were attached to the patient's skin to study the autonomy function of the electroencephalogram (EEG). The records were produced 15 minutes before and 30 minutes after the VNO stimulation. The electrodermal activity (EDA) was recorded, using two silver dectrodus discs in the skin of the palm of the major and ring finger (right hand). The electrocardiogram (ECG) of cable I (standard frontal plane I) was verified. Respiratory frequency (RF) was recorded using a strain gauge placed around the lower chest. The respiratory physiological arrhythmia of the breast was obtained from the correlation of the RF frequency and the ECG. To determine changes in parasympathetic tone. The body temperature (BT) of the external ear canal was taken using a thermistor miniprobe. A bipolar electromyographic record (EMG) was performed with two electrodes placed on the beard. The electroencephalogram was recorded from CzA1 and T3A1 of the standard 10/20 system. All signals were amplified and digitized (Biopac Systems) and continuously verified and stored using a computer (Macintosh LC-III). The autonomy function and EEG were recorded during the classification session and again in both double blind sessions, after the VNO stimulation (see Table II). Changes in mood were evaluated on a scale of zero to four, using questionnaires. The autonomy function registered before, and 30 minutes after the administration of the placebo or the test substance to the VNO, was processed using "knowledge" software (Biopac Systems). The importance of the results was determined using t tests and variation analysis. Fourteen patients were classified with the diagnosis of PMDD. Two patients responded to the placebo and were excluded from the study. Six of the patients received the steroid in their VNOs, and the other six received placebo. A summary of the results is shown in Table III. The patient was asked to rank a list of eleven symptoms of PMDD before, and 30 minutes after the stimulation of WNV with the steroid (total dose = 200 pg), or placebo. The bilateral stimulation of the WNV with placebo did not significantly change the magnitude of the symptoms, from the control level (Figure 210, darkened bars). However, 30 minutes after the bilateral stimulus of WNV with the steroid (total dose = 200 pg), there was a significant reduction of most of the PMDD symptoms (p = or <0.03). For some symptoms such as "I would like to throw things" and "I am angry", the improvement was significant at p = 0.01. Classification for other symptoms such as "I feel depressed," and "I feel like the world would be better without me," was no different from the control after steroid administration (p >; 0.05). The analysis of the autonomy function 30 minutes after the stimulus of the WNV with the steroid shows changes of some reflexes, which correlate with the improvement of mood in the patient. Skeletal muscle activity was measured through the electromyogram (EMG), and was reduced thirty minutes after the steroid was delivered to the WNV, but not after the administration of the placebo (Figure 211). Also, the frequency of cases of electrodermal activity was reduced after the administration of vomeropherin, but not after placebo (Figure 212). Other reflows of autonomy did not show significant changes. The electroencephalographic pattern did not change substantially from baseline, after administration of the steroid to WNV. However, in four patients treated with vomeropherin, there was an increase in cortical alpha activity. Classification of PMDD symptoms was also studied five hours after the second application of vomeropherin to WNV. At this time, there was no significant difference with the control. However, during the telephone interview the morning after the registration session, patients felt better after leaving the registration laboratory and this effect lasted from one to two hours. Small amounts of the steroid (200 pg) delivered in the form of vapor to the WNV of patients with PMDD, produced a significant improvement. As shown in Figure 210, most symptoms were reduced after 30 minutes of administration of the substance. This effect was not seen after the administration of placebo to WNV. The reduction of symptoms was accompanied by relaxation, measured by the reduction of EMG and the reduction of the EDA frequency. Finally, the improvement of the patients was substantiated by the verbal reports (telephone interview), obtained the morning after the registration session.

Table lll. Summary of the effects of vomeropherin in patients with PMDD. n = 12 Symptom Improvement I feel like I want to escape + + I feel like I want to throw things + + + + I'm angry + + + + I feel cocky + + + My chest hurts + + I feel like crying + + I feel overwhelmed + + Me I am easily moved + + + I explode with small things + + + My mind is imaginary I feel that the world would be better without me Skeletal muscle relaxation + + Electrodermal activity relaxation + + Alpha brain wave activity Anxiety Tests Eight patients were treated in the WNV with placebo and eleven were treated with androsta-4,16-dien-3ß-ol. Classifications were taken in the symptoms of anxiety, using Hamilton-A convention anxiety tests which measure the following: HAMILTON-A TOTAL HAMILTON-A HAMILTON-A PRESTIGE STATIC humor anxious humor anxious fears tension tension insomnia fear intellectual mood depressed somatic insomnia (muscular) gastrointestinal symptoms somatic (sensory) mental genitourinary symptoms depressed mood cardiovascular symptoms somatic (muscular) respiratory symptoms somatic ( sensory) symptoms of autonomy cardiovascular symptoms behavior in interview respiratory symptoms gastrointestinal symptoms genitourinary symptoms autonomy symptoms behavior in the interview The results are summarized in Figures 213 to 218. In Figure 213, the treated subjects (T) show an improvement over the control (c) in the present, static and total Hamilton-A results. Referring to Figure 214, only 25% of the subjects with placebo showed a fall in the Hamilton-A classification of 45% or more, but 64% of the treated subjects showed a classification drop of 45% or more. Figure 215 shows a significant reduction in respiratory rate (RF) and heart rate (CF) in treated anxious subjects compared to control. Figure 216 shows an improved parasympathetic tone in anxious subjects treated as compared to the control. This characteristic was measured through the standard test for physiological sinus arrhythmia. Figure 217 shows an improvement (reduction) in the electrodermal activity (EDA) in treated anxious subjects as compared to the control. Figure 218 shows an improvement (increase) in body temperature in treated anxious subjects compared to the control.

Electrovomerogram (EVG). Figure 201A shows superimposed tracks of recorded EVGs of a male subject of 25 years of age. The stimulation with ETA (estratotraenil acetate) produced an EVG significantly different from the control. The mean amplitude of the EVGs produced in all the subjects studied was M = 1.95mV, S.D. = + 0.8mV, n = 10. A pulse of air carrying the same amount of PDD induced a higher EVG. The mean amplitude for the same dose of PDD in all the subjects registered was M = 3.6V, S.D. = 0.7mV, n = 10. The action results of vomeropherins in the electrogram of the nasal respiratory mucosa are shown in Figure 201B. Studies show that the respiratory mucosa responded neither to ETA nor to PDD (pregnadiendione) (p> 0.1, n = 10). The same vomeropherins when tested in the olfactory epithelium (unpublished observation) also showed no electrogram response. Figure 202 illustrates dose effect curves of ETA and PDD obtained in male subjects. Note that for vomeropherins, the EVG amplitude was increased as a function of the concentration, and the dose-effect relationship for intervals between stimuli of 5 minutes is sigmoidal. The curve for ETA is not significantly different from that of PDD (p> 0.02, n = 20).

Reflections of autonomy produced by vomeropherins. Studies of the central nervous system (CNS) reflex response to the VNO stimulus with pulses of air containing ETA (5x10-9M), and PDD (5x10-9M) are shown in Figure 203, and are discussed below.

Electro-thermal activity (EDA). Both vomeropherins induced increased conductance in the skin as compared to the control (p <0.001). The effect of an individual air pulse containing vomeropherin, either ETA or PDD, consisted of a transient single-phase wave, with a duration of XLat = 520 ms, SD = 110 ms. The mean peak amplitude of the effect for PDD was XPDD = 21.1 S, SD = 19 μS, and for ETA was XETA = 22.01 μS, SD = 13.6 μS. The average duration of the wave was 32 seconds. Vomeroferins ETA and PDD also changed the frequency of spontaneously occurring cases of EDA. After the application of ETA or PDD, the frequency of the probe was reduced from 4.1 to 0.9.

Body Temperature (BT). A pulse of individual air containing ETA produced a small but significant temperature increase (XLTA = 0.24 ° C, SD = 0.1 ° C, p <0.02), which lasted approximately 2 minutes and then returned to the baseline.

Heart Rate (CF). The heart rate was measured from the R intervals of EKG. The effect induced by both vomeropherins is significantly different in men (p <0.01) (see Figure 215). Compared with control values, ETA reduced the heart rate by XETA = 3.3 beats / minute, SD = 1 beats / minute, while PDD reduced the heart rate by XPDD = 3.8 beats / minute, SD = 1.5 beats / minute. These changes developed approximately 10 seconds after the VNO stimulation with vomeropherins, and after approximately 2 minutes, the heart rate returned to the control values.

Respiratory frequency (RF). PDD induced a small, but significant increase in the respiratory rate (XRF = -2 cycles / min SD = 1 cycle / min n = 10) that appeared approximately 5 seconds after the VNO stimulation and lasted for 1 minute.

Electroencephalogram (EEG). The electroencephalograms were recorded from the vertex (CzA ^ and temporal region (TsA ^, and periods with a duration of four minutes were analyzed offline using the Fast transformation of Fourier Then, the ratio of brain wave activity alpha to beta (alpha / beta) was calculated in one period occurring before and another after the administration of a vomeropherin to WNV. PDD changed the alpha / beta ratio of control subjects 0.11 to treated subjects 1.85, while ETA changed the ratio of control subjects 0.14 to treated subjects 1.71. These effects were significantly different from the control values (p < 0.02). Measurements of autonomy reflexes as described show that stimulation of human VNO with vomeropherins triggers reflex activity in the central nervous system.

Levels of Pituitary and Testosterone Hormones in Plasma. The effect of VNO stimulation with vomeropherins on the levels of pituitary hormones in the plasma is shown in Tables II and III. Table II shows the characteristics of the pulsatile release of TSH, PRL, FSH, and LH in 10 subjects of Group B, before and during treatment with ETA. In 10 normal male volunteers treated with Eta, no significant differences were detected for TSH, PRL, and FSH when compared to normal placebo controls, (p> 0.05). However, the subjects treated with ETA showed an increase in the mean peak and peak width measurements, control 79 against treated subjects 92 and control 45 against treated subjects 54, respectively (p < 0.05). The number of LH peaks for the treated subjects was significantly reduced from 5.2 compared to the control value of 6.8 (p <0.05). In 10 men and 10 women (group C) PDD was administered at a concentration of 5 x 10"9 M, every 10 minutes for 6 hours, and a pulsatile analysis was applied to the concentrations of LH and FSH in the serum obtained over time. As shown in Table III, the mean area under the peaks (concentration / time) and the increase above the baseline were significantly reduced during PDD treatment for both gonadotropins, but only in men without evident changes in the subpopulation of women. In men treated with PDD, the FSH values were significantly reduced for both the M and basal area and point to point measurements: Treaties 12.7 against control 17.6, and treated 0.63 against control 0.89, respectively. Likewise, for the same group, the LH values were significantly reduced for both the M and basal area and point to point measurements: Treat 44 against control 77 and treat 1.4 against 2.0, respectively. For all the measurements described, no statistically significant changes could be detected in women treated with PDD. (Picture III). The main change was observed in the reduction of the increases above the baseline values, particularly for LH (2.0 versus 1.4 p <; 0.009). Similarly, the findings during the administration of ETA, other pituitary hormones analyzed (PRL and TSH) did not show statistically significant changes either in their absolute concentrations or in the pulsatile characteristics. The vomeropherins ETA and PDD appear to be of a specific gender both in their effect on WNV and on hypothalamic responses. Significantly, they reduce the pulsatile appearance of gonadotropin in men, but not in women (see Table III). This specific effect of gender in WNV (electrovomerogram) has been previously reported using naturally occurring vomeropherins (pheromones) of human skin: Estra-1, 3,5 (10), 16-tetraen-3-ol specifically stimulates human WNV in men, but not in women, however, Androsta-4,16-dien-3-one specifically stimulates human WNV in women, but it is not men. The data provide support for the functional connection between the VNO and the basal forebrain. In addition, the stimulation of human VNO in men with ETA (3x10 ~ 9 M) significantly changes the pulsatile appearance of LH, but not of FSH. PDD (5x10"9 M) significantly changes the pulsatile appearance of LH and FSH only in men.These findings open up the opportunity to use a specific vomeropherin (chemically synthesized and not found in nature), which can be used in the treatment of certain diseases that are gender specific The release of LHRH and gonadotropins through exposure to co-specific semiochemicals of the opposite genus has been reported in several mammalian species (Beltramino et al, Neuroendocrinology 36 (1983): 53-58, Coquelin , et al., J. Neuroscience 4 (1984): 2230-2236) It has also been shown in laboratory animals that VNO receptors are essential for activating this neuroendocrine reflux (Johns 1978, Wysocki 2979, Meredith 1994). presented here show that this neuroendocrine reflux is functional in humans and that it can be modulated through the VNO receptor sites that are sensitive to vomerof erins, see Tables II and lil, since there is a reduction in the peak height of LH and FSH and the frequency and increase in the peak interval. Therefore, ETA and PDD must be altered vomeronasal afferent signals that modulate the combination of hypothalamic LHRH neurons. Experimental studies in several animal species have shown a close correlation between the pulsatile nature of LH and the release of episodic GnRH in portal blood from the hypothalamic pituitary (Veldhuis et al., J. Clin. Endocr. Metb., 64. (1987) : 1275-1282). The pulsatile release of LH in normal men, post-menopausal women and young women studied through the menstrual cycle reflects an action of endogenous endogenous episodic gonadotrophic hormone (GnRH). Although variations in the bioactive LH pulse amplitude of the changes in the amplitude of the endogenous GnRH pulse signal and / or changes in pituitary gonadotropic cell sensitivity may occur, significant alterations in the LH pulse frequency may be taken for reflect the corresponding modulation of the hypothalamic pulse GnRH (Knobil, E. 1980, Recent Prog Horm Res 36:53). The changes observed in the amount and pattern of release of gonadotropins in men during the administration of femtomolar amounts of vomeropherins to WNV result in a neuropharmacological effect at the hypothalamic / pituitary level. The pulsatile release of LHRH from the preoptic hypothalamus activates the release of both gonadotropins (LH and FSH) from the pituitary (Yenand Jaffe, Textbook of Reproductive Endocrinology). Data in several patients are shown for the level of testosterone in the blood (subjects 1, 2, 4 and 8, respectively, shown in Figures 204, 205, 206 and 207). The "A" visit shows the levels after the administration of pregna-4,20-dien-3,6-donates to the WNV. Visit "B" shows testosterone levels after the administration of a placebo. The inclinations of the curves for the levels after the treatment with the pregnadiendione are statistically different from the inclinations of the control curves. As well, in most cases testosterone levels are lower after the treatment of pregnadiendione compared to the control. This shows the ability to affect the level of testosterone in the blood through the administration of a vomeropherin to WNV. lll. EXAMPLES The following examples are intended to illustrate but not limit the invention. The abbreviations used in the examples are the following: ac. = aqueous; RT = room temperature; PE = petroleum ether (e.g., 50.70 °); DMF = N, N = dimethylformamide; DMSO = dimethyl sulfoxide; THF = tetrahydrofuran.

SCHEME 1 SCHEME 2 Preqna-5.20-dien-3ß-of SCHEME 3 17a- Etinilandrostenodiol 1-2 22 11 SCHEME 4 lf 15 20 SCHEME 5. Oxidation of pregnanes SCHEME 6. Synthesis of 21-methylene-20 (R) -methylpreknanos twenty SCHEME 7. Synthesis of pregnanes SCHEME 8. Synthesis of a colatriene SCHEME 9. Synthesis of Planos 27 28 EXAMPLES Example 1 - Pregna-4, 20-dien3a-f R) -ol To a 1M solution of lithium trisiamilborohydride (5.0 ml, 5.0 mmol) at -78 ° C under argon was added a solution of pregna-4.20- dien-3-one (1.10 g, 3.70 mmol) in dry THF (14 ml) with stirring, and the mixture was allowed to warm to room temperature. After 3 hours, the mixture was cooled to -78 ° C and the following reagents were added sequentially: water (2 ml), ethanol (6 ml), an aqueous solution of 12% KOH (10 ml) and hydrogen peroxide at 3% (50 ml). The mixture was allowed to warm to room temperature with stirring. After 2 hours, ethyl acetate (200 ml) was added and stirring is continued. The organic layer was separated and washed with a saturated solution of NaHSO 3, a saturated solution of NaHCO 3 and a saturated solution of NaCl, dried (Na 2 SO 4) and evaporated in vacuo to give 2.1 g of the crude material. This was purified via flash chromatography on 210 g of silica gel (230-400 mesh), eluting with EtOAc / CH2Cl2 (5:95 7:93) to give three fractions. Fraction 1 (0.8 g) contained the impure 3a-alcohol. Fraction 2 (0.1 g) was a mixture of the 3a- and 3β-alcohols. Fraction 3 (0.25 g) was 3β-pure alcohol (23%). Fraction 1 was re-purified through flash chromatography on 80 g of silica gel (230-400 mesh), eluting with EtOAc / hexane (10:90 15:85) to give 0.15 g of the pure 3a-alcohol (14%) Example 2 - Pregna-3,5-trien-3-yl methyl ether, 2. Referring to Scheme 1, compounds 2, 3, 4 and 5 were prepared as follows. A solution of pregna-4,20-dien-3-one (1_, 1.00 g, 3.35 mmol) in 2,2-dimethoxypropane (5.0 M1, 41 mmol), dimethylformamide (5.0 ml) and methanol (0.2 ml) was taken up reflux with catalytic p-toluenesulfonic acid monohydrate (26.9 mg, 0.141 mmol) for 2 hours. After cooling, sodium bicarbonate (153.6 mg, 1828 mmol) was added and the reaction mixture was partitioned between 75 ml of hexanes and 50 ml of ice water. The organic phase was washed twice with 50 ml portions of water and once with 50 ml of brine, after which it was filtered through a column of silica gel 60 with a height of 17 mm and a diameter of 30. mm. The product was further eluted with 100 ml of hexanes. Concentration of the combined eluates and recrystallization from acetone / methanol gave very light yellow platelets glossy (828.7 mg, 2.652 mmol, 79%), m.p. 111-114 ° C.

Example 3 - Pregna-1, 4,20-trien-3-one. Pregna-4,20-dien-3-one (1_, 1.19 g, 3.99 mmol) was refluxed for 24 hours with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.72 g. , 12.1 mmoles) in 40 ml of low benzene Argon. The cooled suspension was diluted with ether and washed with two 100 ml portions of 5% sodium hydroxide (w / wt, two 100 ml portions of water and one with 100 ml of brine.) Ether (100 ml) was added. to the resulting emulsion, which was dried over sodium sulfate and then filtered through a column of sodium sulfate (20 g) After washing the residue twice with 50 ml portions of ether, the combined filtrates were concentrated under reduced pressure and then chromatographed by flash (25% ethyl acetate / hexanes on silica gel) to give a slightly yellow crystalline solid (0.26 g, 0.88 mmol, 22%).

Example 4 - Pregna-1, 4,20-trien-3-ol, 4. Pregna-1,4,20-trien-3-one (3_, 0.26 g, 0.88 mmol) in 25 ml of anhydrous ether was reduced under an argon atmosphere with lithium aluminum hydride (250.5 mg, 6.602 mmol) for 2 hours and then extinguished with 2.50 g of Glauber's salt. The resulting suspension was stirred for 70 minutes, filtered and washed twice with 50 ml portions of ether. After concentration of the combined filtrates under reduced pressure, the residue was purified using preparative TLC (35% ethyl acetate / hexanes in alumina to give white needles (26.1 mg, 87.4 μmol, 10%) mp 98- 128 ° C.

Example 5 - pregna-4,20-dien-6ß-ol-3-one, 5. M-chloroperbenzoic acid (MCPBA, 77.4%, 763.4 mg, 3.42 mmol) suspended in 1,2-dimethoxyethane 30 ml (DME), 6 ml of water and 2.4 ml of 5% sodium hydroxide (w / w) was added to a solution of pregna-3,5,20-trien-3-yl methyl ether (2_, 400.3 mg, 1281 mmol) in 20 ml of DME + 2 ml of water for 85 minutes with stirring. The reaction was continued for 5 hours and then it was emptied into 50 ml of saturated sodium bicarbonate. The mixture was extracted three times with 50 ml of ether and the combined organic extracts were washed with 50 g of 5% sodium thiosulfate pentahydrate (w / w) + three 50 ml portions of brine, dried over magnesium sulfate and filtered through Celite. After washing the residue with 10 ml of ether, the combined filtrates were concentrated in vacuo. Flash chromatography (35% ethyl acetate / hexanes on silica gel) and the preparation TLC (35% ethyl acetate / hexanes on silica gel) gave a difficult separable mixture as white crystals (95.5 mg, 0.304 mmol, 24%).

Example 6 - 20.21 - Dimethylpregna-5,20-dien-3ß-ol. 6. Referring to SCHEME 2, compounds 6, 7, 8 and 9 were prepared as follows. Ethyltriphenylphosphonium bromide (25.99 g, 70. 00 mmoles) and potassium t-butoxide with 80 ml of anhydrous DMSO under argon in an oil bath at about 80 ° C for 1 hour, then pre-5-en-3ß.-ol-20-one was added (4.43. g, 14.0 mmol) in 80 ml of hot anhydrous DMSO. The red suspension was stirred for 1 hour, removed from the heat and evacuated in 200 ml of ice-brine. The mixture was then extracted three times with 100 ml of ether and the combined organic extracts were washed with 100 ml of brine, dried over sodium sulfate and filtered through Celite. After washing the residue with 50 ml of ether, the combined filtrates were concentrated under reduced pressure. The yellow residue was taken up in 95% ethanol with heating, briefly boiled with 1 g of carbon, and filtered through Celite. After cooling and filtering the residue, it was recrystallized twice more from ethanol to give white crystals (1746 g, 5.314 mmol, 38%), m.p. 140-145 ° C.

Example 7 - 20.21 - Dimethylpregna-4,20-dien-3,6-dione, 7. Jones Reagent (2.67 M, 2.0 ml, 5.3 mmol) was added to a solution of 20,21-dimethylpregna-5,20-diene. 3ß_-ol (6 ^ 460.1 mg, 1400 mmol) in 50 ml of acetone and the reaction was stirred for 45 minutes. After quenching with 2-priopanol (1.0 ml) the mixture was evacuated in 100 ml of water and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with 50 ml of saturated sodium bicarbonate + 50 ml of brine, dried over magnesium sulfate and filtered through Celite. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (25% ethyl acetate / hexane on silica gel) and recrystallization of the residue from 95% ethanol gave yellow needles (138.2 mg, 0.4059 mmol, 29%), m.p. 172-178 ° C.

Example 8 - 20,21- Dimethylpregna-4,20-dien-3-one, 8. 20,21- Dimethylpregna-5,20-dien-3ß-ol (6- 400.3 mg, 1218 mmol) was oxidized in 5 ml of methylene chloride with pyridinium chlorochromate (525.4 mg, 2,437 mmoles) for 42 hours. Ether (3.5 ml) was added and the suspension was filtered through a column of silica gel with a diameter of 5 mm by a height of 60 mm. The column was further eluted with 3.5 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the resin followed by recrystallization from aqueous ethanol gave color crystals-yellow (43.6 mg, 0.134 mmol 11%). mp 157-165 ° C.

Example 9 - Pregna-4,20-dien-3,6-dione 9. A solution of pregna-5.20-dien-3ß-ol (300.5 mg, 1,000 mmol) in 35 ml of acetone was cooled in an ice-bath. water and Jones 2.67 M reagent (0.71 ml, 1.9 mmol) was added. After stirring for 1 additional hours 0.71 ml of Jones reagent was added and the reaction was continued for 45 minutes, 2-propanol (1.0 ml) was added and the mixture was poured into 100 ml of water. The mixture was then extracted twice with 50 ml of ethyl acetate and the combined organic extracts were washed with 50 ml of saturated sodium bicarbonate + 50 ml of water + 50 ml of brine and filtered through a gel column. silica 60 with a diameter of 21 mm for a height of 22 mm. The column was further eluted with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Crystallization of the residue from 95% ethanol gave a light yellow powder (104.6 mg, 0.3348 mmol, 33%), m.p. 114-120 ° C.

Example 10 - Pregna-5,17,20-trien-3ß-ol, 10. A solution of 17a-ethynylanthrostenediol (439.4 mg, 1397 mmol) in 10 ml of dried THF was added to a suspension of lithium-aluminum hydride ( 106.5 mg, 2 mmol) and aluminum chloride (122.9 mg, 0.9220 mmol) in 10 ml of THF dried under argon. After refluxing for 17 hours, the reaction mixture was quenched by stirring for 2 hours with sodium sulphate decahydrate (1.00 g, 3.10 mmol). The reaction was filtered and the residue was washed with three 10 ml portions of THF. The concentration of the combined filtrates under reduced pressure gave 0.44 g of the white solid, which was purified by flash chromatography (30% ethyl acetate / hexanes on silica gel) and a double recrystallization from aqueous ethanol. giving lustrous white crystals (92.0 mg, 0.303 mmol, 22%), mp 144-149 ° C.

Example 11 - 5a-chloro-6β, 19-epoxypreg n-17-en-3β-ol. 11. Referring to SCHEME 3, compounds 1_1_, 1_2_, 1_3 and 1_4 were prepared as follows: Ethyltriphenylphosphonium bromide (3.05 g, 8.22 mmol) and potassium t-butoxide (0.92 g, 8.2 mmol) were reacted under argon in anhydrous DMSO (9.2 ml) for 1 hour in a 76-86 ° C bath, after which was added 5-chloro-6β, 19-epoxyandrostan-3β-ol-17-one (555.9 mg, 1640 mmol) in 9.2 ml of hot anhydrous DMSO and the mixture was stirred for a further 1 hour. The reaction was then poured into 25 ml of ice-brine and extracted three times with 10 ml portions of ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and filtered through Celite. The residue was washed twice with 5 ml of ether and the combined filtrates were dried in vacuo. The residual yellow oil was purified by flash chromatography (60% ethyl acetate / hexanes on silica gel) to give a solid as a white syrup (0.34 g, 0.97 mmol, 59%).

Example 12 - 5a-chloro-6β-, 19-epoxipregn-17-en-3-one, 12. A solution of 5-chloro-6β, 19-epoxypregn-17-en-3ß-ol (11, 0.34 g, 0.97 mmoles) in 35 ml of acetone was cooled in an ice-acetone bath and 0.47 ml of Jones 2.67M reagent was added. After stirring for 40 minutes, the reaction was quenched with the addition of 0.5 ml of 2-propanol. Water (15 ml) was added, the volatile components were removed under reduced pressure, and the mixture was extracted three times with 15 ml portions of methylene chloride. The combined organic extracts were washed with 15 ml of saturated sodium bicarbonate + 15 ml of brine, dried over magnesium sulfate, and filtered through Celite. After washing the residue twice with 5 ml of methylene chloride, the combined filtrates were dried in vacuo. The residue is flash chromatographed on silica gel, using 30% ethyl acetate / hexanes as eluent to give a white crystalline solid (0.34 g, 0.97 mmol, quantitative).

Example 13 - 6β, 19-epoxypregn-4.17-dien-3-one, 13. 5a-chloro-β, 19-epoxypregn-17-en-3-one (12, 0.34 g, 0.97 mmol) was dissolved with heating in 10 ml of anhydrous methanol, potassium acetate (0.60, 6.1 mmol) was added and 6.5 ml of the solvent was distilled at ambient pressure. The residue was concentrated under reduced pressure, taken up in 21 ml of water, and extracted three times with 10 ml portions of methylene chloride. The combined organic extracts were dried over magnesium sulfate and filtered through Celite. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure to give a white crystalline solid (290.0 mg, 0.9281 mmol, 96%) homogeneous to TLC (60% ethyl acetate / hexanes on silica gel; Rf 0.61).

Example 14 - pregna-4.17-dien-19-ol-3-one, 14. To a solution of 6β, 19-epoxypregne-4, 17-dien-3-one (290.0 mg, 0.9281 mmole) in 10 ml of acid glacial acetic acid was added zinc powder (1.12 g, 17.1 mg-atoms) activated by stirring for 2 minutes with 10% hydrochloric acid followed by washing with water and acetone. The suspension was stirred vigorously for 10 minutes at 99-102 ° C and then filtered through Celite. The residue was washed 4 times with 10 ml of acetic acid and the combined filtrates were concentrated in vacuo. The residue was taken up in 50 ml of ethyl acetate, washed with 50 ml of water + 50 ml of saturated sodium bicarbonate + 50 ml of brine, dried over magnesium sulfate, and filtered through Celite. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were dried in vacuo. The residue was recrystallized from ethyl acetate to give white crystals (46.4 mg, 0.148 mmol, 16%), m.p. 192-195 ° C.

Example 15 - Pregn-4-en-3ß-ol-29-ino. 15. Preg-4-en-3ß-ol-20-ino, 15: Pregna-4-en-on-20-ino (200.1 mg, 0.6750 mmol) and lithium-aluminum-tri (t-butoxy) hydride were suspended ) (343.8 mg, 1352 mmol) in 3.6 ml of anhydrous ether. After reacting for 4 hours, an additional 343.5 mg (1351 mmoles) of hydride was added and the reaction was allowed to continue for 16 hours. See Scheme 4. After quenching with sodium sulphate decahydrate (3.41 g), the reaction mixture was stirred 15 minutes and then filtered through diatomaceous earth. The residue was extracted 5 times with 10 ml portions of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the residue (25% ethyl acetate / hexanes on silica gel) followed by recrystallization from aqueous ethanol yielded a white powder (85.0 mg, 0.285 mmol, 42%), m.p. 120.5 - 123.5 ° C.

Example 16 - 20,21- dimethylpregna-4.20E-dien-3,6-dione. 16. The Jones reagent (2.67 M_, 1.75 mL, 4.67 mmol) was added to a solution of 20,21-dimethylpregna-5,20E-dien-3ß-ol (400.0 mg, 1281 mmol) in 45 mL of acetone and the reaction was stirred 30 minutes. The mixture was then poured into 85 ml of water and extracted three times with 40 ml portions of ethyl acetate. The combined organic extracts were washed with 40 ml of saturated sodium bicarbonate + 40 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (20% ethyl acetate / hexanes on silica gel) of the residue followed by recrystallization from aqueous ethanol gave light yellow needles (119.1 mg, 0.3497 mmol, 20%), m.p. 171-173 ° C. TLC (20% ethyl acetate / hexanes on silica gel) showed a higher component at Rf 0.17 with a minor contaminant at Rf 0.24.

Example 17 - 20-methylpregna-4,20-dien-3,6-dione, 17. Jones Reagent (2.67 M., 1.83 mL, 4.89 mmol) was added to a solution of 20-methylpregna-5,20-diene. 3β-ol (400.0 mg, 1272 mmol) in 45 ml of acetone and the reaction was stirred for 20 minutes. After quenching with 2-propanol (0.91 ml) the mixture was evacuated in 85 ml of water and extracted three times with 40 ml portions of ethyl acetate. The combined organic extracts were washed with 40 ml of saturated sodium bicarbonate + 40 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization of the solid residue from aqueous ethanol gave yellow crystals (235.0 mg, 0.7928 mmol, 57%), m.p. 148-150 ° C. TLC (20% ethyl acetate / hexanes on silica gel) showed a higher product in Rf 0.24 with a lower impurity at the origin.

Example 18 - Pregna-4.16-dien-3,6-dione, 18. Jones Reagent (2.67 M., 0.23 mL, 0.61 mmol) was added to a solution of pregna-5,16-dien-3ß-ol (45.5 mg, 0.151 mmol) in 5 ml of acetone and the mixture was stirred for 20 minutes. After quenching with 2-propanol (0.11 ml), 10 ml of water was added and the mixture was extracted three times with 5 ml portions of ethyl acetate. The combined organic extracts were washed with 5 ml of saturated sodium + 5 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 5 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. TLC preparation (25% ethyl acetate / hexanes on silica gel) of the residue gave a light yellow solid (10.6 mg, 33.9 μmol, 22%) homogeneous to TLC (Rf 0.41 25% ethyl acetate / hexanes on silica gel; starting material, Rf 0.30).

Example 19 - Pregna-4,17,20-trien-3,6-dione, 19. Jones reagent (2.67 M_, 1.03 ml, 2.75 mmole) was added to pregna-5, 17,20-trien-3ß-ol (214.5 mg, 0.7187 mmoles) in 25 ml of acetone and the mixture was stirred for 20 minutes. After quenching with 2-propanol (0.52 ml), the mixture was evacuated in 50 ml of water and extracted three times with 25 ml portions of ethyl acetate. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization with concomitant treatment with carbon in aqueous ethanol gave light yellow needles (67.7 mg, 0.218 mmol, 30%), m.p. 140-143. TLC (25% ethyl acetate / hexane on silica gel) shows a product in Rf 0.43 with minor contaminants in Rf 0.86, 0.14, 0.08, and 0.00 (pregna-5,17-dien-3ß-ol R 0.32) .

Example 20-21-methylene-20 (R) -methylpregn-4-en-3-one. 20. Aluminum isopropoxide (0.39 g, 1.9 mmol) in 3.6 ml of hot toluene was added to a solution of 21-methylene-20 (R) -methylpregn-5-en-3β-ol (208.2 mg, 0.6337 mmol) in cyclohexanone (3.6 ml, 35 mmol) and 18 ml of toluene, and the mixture was refluxed with the exclusion of moisture for 2 hours. After cooling on ice, 0.92 ml of water and 2.2 ml of 3.6 N_ sulfuric acid were added and the mixture was stirred for 1 minute. More water (4.6 ml) was added, and the mixture was stirred 5 minutes, and the aqueous phase was discarded. The volatile components were removed by azeotropic / steam distillation and the resulting aqueous suspension was extracted three times with 5 ml portions of methylene chloride. The combined organic extracts were filtered through a small column of sodium sulfate resting on a bed of diatomaceous earth, all this was contained in a Pasteur pipette. The residue was washed with 5 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residual film gave white needles (152.7 mg, 0.4677 mmol, 74%), m.p. 138-139 ° C. TLC (25% ethyl acetate / hexanes on silica gel) showed a higher product at Rf 0.54 with a contaminant trace at Rf 0.71 (starting material, Rf 0.36).

Example 21 - 21 -methylene-20 (R) -methylpregn-4-en-3ß-ol, 21. A suspension of 21-methylene-20 (R) -methylpregn-4-en-3-one (5., 100.0 mg, 0.3063 mmol) and lithium tri-t-butoxyaluminohydride (319.4 mg, 1.256 mmol) in 5 ml of anhydrous THF was stirred under argon for 6 hours, after which water (48 μl), 15% ( p / p) of sodium hydroxide (48 μl) and water (143 μl). The mixture was filtered through diatomaceous earth and the residue was extracted four times with 5 ml aliquots of THF. Concentration of the combined filtrates under reduced pressure and double recrystallization from aqueous ethanol gave white platelets (42.6 mg, 0.130 mmol, 42%), m.p. 121-123 ° C. TLC (25% ethyl acetate / hexanes on silica gel) showed a higher product in Rf 0.38 and a lower product in Rf 0.43 (starting material, Rf 0.50).

Example 22-21-methylene-20 (R) -methylpregn-4-en-3,6-dione, 22. Jones reagent (2.67 JW, 0.68 ml, 1.8 mmol) was added to 21-methylene-20 (R) methylpregn-5-en-3β-ol (149.8 mg, 0.4560 mmol) in 15 ml of acetone and the reaction was stirred for 20 minutes. After quenching with 2-propanol (0.34 ml), the mixture was evacuated in 30 ml of water and extracted three times with 15 ml portions of ethyl acetate. The combined organic extracts were washed with 15 ml of saturated sodium bicarbonate + 15 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. TLC preparation of the residue (25% ethyl acetate / hexanes on silica gel GF, 1000 μ) gave a yellow crystalline solid, (49.7 mg, 0.146 mmol, 32%) homogeneous to TLC (25% acetate ethyl / hexanes; Rf 0.47; starting material, Rf 0.35).

Example 23 - Preg-4-en-3ß-ol-20-ino, 23. Lithium tri-t-butoxyaluminohydride (343.8 mg, 1352 mmol) was added to pre-4-en-3-on-20-ino ( 200.1 mg, 0.6750 mmole) was suspended in 3.6 ml of anhydrous ether and the mixture was stirred for 4 hours. Additional hydride (343.5 mg, 1351 mmol) was added and the reaction was stirred for a further 16 hours. Glauber's salt (3.41 g) was added and the suspension was stirred 15 minutes. The mixture was filtered through diatomaceous earth and the residue was extracted five times with 10 ml portions of ether. Concentration of the combined filtrates under reduced pressure followed by flash chromatography (25% ethyl acetate / hexanes on silica gel) and recrystallization from aqueous ethanol gave a white powder (85.0 mg, 0.285 mmol, 42%), pf 120.5-123.5 ° C. TLC (25% ethyl acetate / hexanes on silica gel) showed a product (Rf 0.23) contaminated with traces of what appeared to be the starting material (Rf 0.29).

Example 24 - Pregn - 4,16-dien-6ß-ol-3-on-20-ino. 24. The 3-chloroperbenzoic acid (290.0 mg, 1680 mmol) in 9.4 ml of 1,2-dimethoxyethane + 3.6 ml of water was added to a suspension of methyl ether of pregna-3,5, 16-trien-20-in. 3-yl (471.0 mg, 1527 mmol) in 1,2-dimethoxyethane (9.4 ml) and the reaction was stirred for 30 minutes. The mixture was vacuum in 50 ml of saturated sodium bicarbonate and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with 50 g of 5% sodium thiosulfate pentahydrate (w / w + three aliquots of 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. with 25 ml of ethyl acetate and the combined filtrates were concentrated under residue pressure Flash chromatography (50% ethyl acetate / hexanes on silica gel) of the residue followed by recrystallization from aqueous ethanol gave a solid light yellow (145.9 mg, 0.4700 mmol, 31%), mp> 300 ° C.

Example 25 - Cola-5,16,20 (22) -trien-3ß-ol, 25 A suspension of propyltriphenylphosphonium bromide (12.13 g, 31.48 mmoles) and potassium t-butoxide (3.54 g, 31.5 mmoles) in anhydrous DMSO (35 ml) under an argon atmosphere was placed in an oil bath (72-87 ° C) and then stirred for an hour. Pregna-5, 16-dien-3β-ol-20-one (1.9807 g, 6.298 mmol) was added in 35 ml of hot anhydrous DMSO and the reaction was stirred for 90 minutes. The mixture was then poured into 90 ml of ice-brine and extracted with 3 45 ml portions of ether. The combined organic extracts were washed with 45 ml of brine, dried over sodium sulfate and filtered. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (20% ethyl acetate / hexane on silica gel) of the resulting oil gave an amber resin (103.6 mg, 0.3042 mmol, 4.8%).

Example 26 - Tail-4-20 (22) E-dien-4, 6-diona, 26. Jones Reagent (2.6JM, 1.26 mL, 3.3.6 mmol) was added to glue-5, 20 (22) E-dien-3ß-ol, 25 (300.0 mg, 0.8758 mmol) in 30 mL of acetone and the reaction it was stirred for 20 minutes. After quenching with 2-propanol (0.63 m), the mixture was drained in 60 ml of water and extracted three times with 30 ml portions of ethyl acetate. The combined organic extracts were washed with 30 ml of saturated sodium bicarbonate + 30 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave a yellow solid (139.3 mg, 0.3929 mmol, 45%, mp 109-116 ° C. TLC (25% ethyl acetate / hexane on silica gel) showed a higher product (Rf 0.45) with contaminants in Rf 0.24, 0.1 and 0.08 (tail-4,20 (22) E-dien-3-one Rf 0.45).

Example 27 - Cola-4-20 (22) E-dien-3-one. 27. Aluminum isopropoxide (2.82 g, 13.8 mmol) in 26 ml of hot toluene-5,20 (22) E-dien-3ß-ol (1.5777 g, 4,605 mmol) in cyclohexanone (26 ml, 0.25) was added. ) + 130 ml of toluene and the reaction was refluxed for 4 hours with exclusion of moisture. After cooling, water (6.7 ml) and 3.6 N_ sulfuric acid (16 ml) were added and the mixture was stirred for 1 minute. Additional water (32 ml) was added and the mixture was stirred 5 minutes, and the aqueous layer was discarded. The volatile components were removed by azeotropic distillation / steam and the resulting aqueous suspension was extracted three times with 20 ml portions of methylene chloride. The combined organic extracts were dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol with concomitant treatment with carbon gave light yellow crystals (1.3317 g, 3.9104 mmol, 85%), m.p. 133-135 ° C. TLC (25% ethyl acetate / hexane on silica gel) showed that the product was homogeneous (Rf 0.49, starting material Rf 0.31).

Example 28 - Tail-4-20 (22) E-diene-3ß-ol. 28. A suspension of glue-4, 20 (22) E-dien-3-one (3, 400.0 mg, 1175 mmole) and lithium tri-t-botoxyaluminohydride (1.2250 g, 4.8158 mmole) in 15 mol of anhydrous ether it was stirred under argon for 18 hours. The Glauber salt (6.07 g) was added, and the mixture was stirred 5 minutes and then filtered through diatomaceous earth. The residue was extracted 5 times with 15 ml portions of ether and the combined filtrates were concentrated under reduced pressure. The TLC preparation (5% ethyl acetate / methylene chloride on silica gel, 1000μ) of the residue gave a light yellow solid (49.0 mg, 0.146 mmol, 12%) homogeneous to TLC (5% acetate ethyl / methylene chloride on silica gel, Rf 0.34, pregna-5,20-dien-3β-ol Rf 0.26).

Example 29 - Tail methyl ether-3.5.20 (22) E-trien-3-yl. 29. A mixture-4, 20 (22) E-dien-3-one (808.6 mg, 2374 mmol), 2,2-dimethoxypropane (3.1 m., 25 mmol), dimethylformamide (3.1 ml), methanol (0.13 ml) , and p-toluenesulfonic acid monohydrate (28.9 mg, 0.147 mmol) was refluxed for 4 hours with exclusion of moisture. After cooling, sodium bicarbonate (0.17 g) was added and the mixture was partitioned between 30 ml of water and 50 ml of ether. The organic layer was washed with 30 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Recrystallization of the resulting solid from acetone gave a light yellow solid (453.8 mg, 1280 mmol, 54%), m.p. 94-96 ° C. TLC (10% ethyl acetate / hexane on silica gel) showed a product Rf 0.62 with a trace of the starting material (Rf 0.14).

Example 30 - Cola-4-20 (22) E-dien-6ß-ol-3-one, 30. 3-Chloroperbenzoic acid (183.0 mg, 1060 mmol) in 5.9 ml of 1,2-dimethoxyethane + 2.3 ml was added. of water to methyl ether of cola3, 5.20 (22) E-trien-3-ylo in 5.0 ml of 1,2-dimethoxyethane during 2? hours. After stirring the reaction during VT. one hour later, it was drained in 30 ml of saturated sodium bicarbonate and extracted three times with 30 ml portions of ethyl acetate. The combined organic extracts were washed with 30 g of 5% sodium thiosulfate pentahydrate (w / w) + three 30 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (60% ethyl acetate / hexane on silica gel) of the resulting solid and the TLC of subsequent preparation (50% ethyl acetate / hexane on silica gel) of the resulting solid and the subsequent TLC of Preparation (50% ethyl acetate / hexane on silica gel 100μ), gave a white crystalline solid (114.3 mg, 0.3206 mmole, 33%) consisting of two components through TLC (50% ethyl acetate / hexane on silica gel, higher Rf 0.48, lower Rf 0.41, tail-4.20 (22) E-dien-3-one Rf 0.74.

Example 31 - Measurement of Autonomy Responses to the WNV Stimulus. Several parameters of autonomy were verified as A1-P3 Pregna-4,16-dien-3-one A1-P3 Pregna-5,16-dien-3ß-ol A8-P1 3-Methoxy-pregna-3,5,20- triens A6-P1 Pregna-4,20-dien-3,6-dione 20.21-Dimethylpregna-5,20-dien-3β-01 20.21-Dimethylpregna-5,20-dien-3-one A14-P2 6β, 19-Epoxipregna-4,17-dien-3-one A7-P2 19-Hydroxy-pregna-4,17 (20) -dien-3-one A13-P1 Pregna-4,20-dien-6β-ol -3-one A11-P1 Pregna-1, 4,20-trien-3-one A1-P1 Pregna-4,20-dien-3-one A2-P1 Pregna-5,20-dien-3ß-one A4- P1 Pregna-4,20-dien-3ß-ol A3-P1 Pregna-4,20-3ß-ol A1-P1 Preen-4,20-en-3-one A2-P1 Preen-5-en-3ß-ol they were administered to 24 men and 24 women using the procedure described in example 32. Propylene glycol was also administered as a control. When compared to a propylene glycol control, the test compounds induced a significant change in the receptor potential integrated in the WNV, galvanic skin response (GSR), skin temperature (ST), the percentage of the activity of alpha-cortical wave measured by electroencephalogram (EEG), electrocardiogram (EKG), and respiratory rate (RF). The results are shown in Figures 2 to 58. Additional tests were performed on other pregnano derivatives, the results of which are shown in Figures 59-84. The results of these tests on colane derivatives are shown in Figures 85-96.

SCHEME 10. Synthesis of 19-norpregnans SCHEME 11. Synthesis of additional norpregnanes 2 SCHEME 12. Additional synthesis of Norpregnans 4 SCHEME 13. 17-Ketone ethylenation 12 Id eleven Example 32 - 19 Norpregna-4,20-dien-3ß-ol A suspension of 19 Norpregna-4,20-dien-3-one (0.38 g, 13 mmol) and lithium tri-t-butoxyaluminohydride (1.36 g, 5.35 mmoles) in 20 mol of anhydride ether was stirred at room temperature and the Glauber's salt (6.74 g) was added thereto. The resulting mixture was stirred 5 minutes and then filtered through a glass frit. The residue was washed with 5 portions of 20 ml of ether and the combined filtrates were concentrated under reduced pressure. The crude product was purified by TLC preparation on GF silica gel using 5% ethyl acetate / methylene chloride as eluent to give a yellow resin (39.6 mg, 0.128 mmol) homogeneous to TLC (5% ethyl acetate / methylene chloride on silica gel; Rf 0.29).

Example 33 - 19 Norpregna -1, 3,5. (10) .17,20-pentaen-3-ol To a suspension of lithium-aluminum hydride (LAH, 256.1 mg, 6.748 mmol) and aluminum chloride (296.8 mg , 2227 mmol) in 20 ml of anhydrous ether under argon was added ethinyl estradiol (1,000 g), in 20 ml of anhydrous ether. After refluxing for 20 hours, the reaction was quenched with the addition of Glauber's salt (2.00 g), and stirring was continued for a further 2 hours. The mixture was then filtered through diatomaceous earth and the residue was washed with 3 10 ml portions of ethyl acetate. Concentration of the combined filtrates, flash chromatography on silica gel with 15% ethyl acetate / hexanes, and double recrystallization from aqueous ethanol gave needles with a light tan color (367.5 mg, 1.311 mmol, 39 %), pf 132-133 ° C homogeneous to TLC (20% ethyl acetate / hexanes on silica gel, Rf 0.36, estra-1, 3, S (10), 16-tetraen-3-ol-Rf 0.36).

Example 34 - 19-Norpregna-1, 3,5 (1) -trien-3-ol-20β-ino A cooled solution (dried ice / acetone bath of 19-norpregna-1,3,5 (10), 17 , 20-pentaen-3-ol (2. 280.4 mg, 1,000 mmol) in 28 ml of anhydrous THF under argon was added n-BuLi (2.5 M. in hexane, 1.2 ml, 3.0 mmol) for 10 minutes. the reaction was allowed to warm gradually to room temperature 15. The reaction was quenched with 25 ml of HCl1 N and then extracted with 3 portions of 10 ml of ether.The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the resulting yellow resin on silica gel with 20% ethyl acetate / hexanes, followed by recrystallization from aqueous ethanol gave fine, white needles (150.5 mg, 0.5367 mmol, 54% , mp 148-149 ° C homogeneous to TLC (20% ethyl acetate / hexanes on silica gel; Rf 0.34; starting material Rf 0.37).

Example 35-19 Norpregna -1.3.5. (10), 16.20-pentaen-3-ol 19-norpregna-1, 3.5 (10), 16 tetraen-3-ol-yne (200.0 mg, 07184 mmoles) was added ) in 9 ml of anhydrous THF to about 30 ml of anhydrous ammonia. Sodium (0.07 g, 3 mg-atom) was added in small pieces and the reaction was stirred for 1 hour, during which the color disappeared. Absolute ethanol (3 ml) was added and the mixture was allowed to warm to room temperature overnight. HCl (1N, 20 ml) was added, and the mixture was extracted 3 times with 10 ml portions of methylene chloride. The combined extracts were washed with 10 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. TLC preparation (silica gel GF with 20% ethyl acetate / hexanes) of the resulting amber resin, followed by recrystallization from benzene / hexanes gave an off-white powder, m.p. 123-125 ° C. TLC (20% ethyl acetate / hexanes) showed a higher product (Rf 0.38) with a lower contaminant (Rf 0.04).

Example 36 - 19 Norpregna-5, (10) .20-dien-3-one 19-norpregna-2,5 (10), 20 trien-3-ylo- methyl ether (750.0 mg, 2.513 mmol) was dissolved in 80 ml of acetone and oxalic acid (0.88 g, 7.0 mmol) in 12 ml of water was added. Additional acetone (20 ml) was added to bring most of the precipitate back to a solution and the reaction was stirred for 6 hours. After quenching with saturated sodium bicarbonate (30 ml), the reaction mixture was washed twice with 40 ml portions of ethyl acetate. The combined extracts were washed twice with 50 ml portions of brine, dried over magnesium sulfate, filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (10% ethyl acetate / hexanes on silica gel 15) gave a colorless resin (0.54 g, 1.9 mmol, 76%).

Example 37 - 19 Norpregna -5. (10), 20-dien-3-ol To an ether solution (8.4 ml) of 19 Norpregna-5, (10), 20-dien-3-one (0.42 g, 1.5 mmoles) ) 69.7 mg (1.84 mmol) of LAH was added and the reaction was stirred for 30 minutes. The Glauber's salt (2.79 g) was added and the suspension was stirred 5 in an additional 10 ml. The mixture was then filtered through diatomaceous earth and the residue was extracted with 435 ml portions of ether. The combined filtrates were concentrated under reduced pressure and the resulting oil was chromatographed by flash (20% ethyl acetate / hexanes on silica gel) to give a whitish foam (0.38 g, 1.3 mmol, 88%).

Example 38 - 19-Norpregna-4120-dien-1 Oß-ol-3-one 19-norpregna-5 (10), 20-dien-3-one (5_, 0.45 g, 1. 6 mmole) in DMF (5.7 ml) in an ice-acetone bath and Jones reagent (2.67 M, 0.19 ml, 0.51 mmol) was added. After stirring for 1 hr, an additional 0.19 ml of Jones's reagent was added. Stirring was continued for 45 minutes, after which 0.38 ml of Jones's reagent was added. The reaction was quenched after stirring an additional 1 hour through the addition of 2-propanol (0.38 ml). Ethyl acetate (100 ml) was added and the mixture was washed with 3 portions of 50 ml of water + 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. TLC preparation over alumina with 50% ethyl acetate / hexane gave a white, crystalline filler. (89.2 mg, 0.297 mmol, 19%). TLC (50% ethyl acetate / hexanes on silica gel) showed that it was mostly produced (Rf 0.46), contaminated with little starting material (Rf 0.73) Example 39 - 19-Norpregna-4.9 10) .20-trien-3-one A solution of 19-norpregna-5 (10) 20-dien-3-one (0.34 g, 1.2 mmol) in anhydrous pyridine (4.0 in ml, 49 mmol) was cooled in an ice-salt bath to below -80 ° C and solid pyridinium bromide perbromide (1.26 g, 3.94 mmol) was added at such speed that the reaction temperature did not exceed -2 ° C. After stirring 1 minute, 0.20 g of phenol was added, the cold bath was removed, and the. The reaction was stirred at room temperature for 24 hours. Ethyl acetate 10 (50 ml) was added and the mixture was washed with 50 ml of 1 N HCl + 25 ml of saturated CuSo 4 + 25 ml of 5% sodium hydroxide + 25 ml of water + 25. of brine. The mixture was then dried over sodium sulfate for 4 hours and then filtered through a glass frit. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The resulting dark syrup (512.8 mg) was taken up in 8 ml of absolute ethanol, zinc powder 260.8 mg, 3,990 mg atom was added) and the suspension was refluxed during VT. hour. The reduction mixture was filtered through cotton and the residue was washed with 10 ml of ethanol. The concentration of the combined filtrates and the double purification through TLC preparation, first on GF of silica gel (1000μ, 20% ethyl acetate / hexanes as eluent), then on GF of alumina (1000μ, 20% ethyl acetate / hexanes, gave an almost colorless resin (152.8 mg, 0.5410 mmoles, 45%) homogeneous to TLC (Rf 0.22, 10% ethyl acetate / hexanes on silica gel, pregnaa-4,20-dien-3 -ona Rf 0.25).

Example 40 - 19 Norpregna -1.3.5. (10), 20-tetraen-3-ol Ethinylestradiol diacetate (20004 g, 5.2576 mmoles) in 100 ml of anhydrous THF was added to approximately 140 ml NH3 and sodium was added (1.88). g, 81.8 mg-atom) in strips for 5 minutes. After stirring the dark blue solution for 1 hour, absolute ethanol was added and the reaction was allowed to warm gradually to room temperature overnight. 100 ml of HCl1 N_ were added, the layers were separated, and the aqueous layer was extracted 2 times with 50 ml portions of ether. The combined organic phases were washed with 3 100 ml portions of brine, derived over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 25 ml of methylene chloride, dried over sodium sulfate and filtered through diatomaceous earth. The residue was washed twice with 10 ml portions of methylene chloride and the combined filtrates were concentrated under reduced pressure, flash chromatography (15% ethyl acetate / hexane on silica gel) gave a crystalline, white solid with yellow spots. (0.86 g, 3.0 mmol, 58%).

Example 41 Methyl ether of - 19 Norpregna -, 3,5, (10), 20-tetraen-3-yl A 19 Norpregna -1, 3,5, (10), 20-tetraen-3-ol (9, 0.86 g, 3.0 mmol) crude in 75 ml of 90% ethanol was added potassium carbonate 5 (6.73 g, 55.2 mmol) and the suspension was refluxed for A hour. Dimethyl sulfate) 0.75 ml was added) and the mixture was refluxed for an additional 4 hours. Dimethyl sulfate was added in 3 aliquots of 1.8 ml (total = 6.15 ml, 65.0 mmol) for 1 hour, and the reflux was continued for A hour. Ice-water added (65 ml) and the mixture was cooled in an ice bath and stirred for 2 hours. The suspension was centrifuged and then filtered through a coarse frit. The residue was washed with 50 ml of water + 50 ml of 5% sodium hydroxide + 3 50 ml portions of water. The residue was recrystallized from aqueous ethanol to give fine white needles, m.p. 108.5-110 ° C (lit. p.f. 108.5-110 ° C).

Example 42 - Acetate of 19 Norpregna -1, 3,5, (10), 16-tetraen-3-on-20-in-3-Mo Chromium trioxide (2.68 g, 2.68 mmol) in 40 ml of chloride was suspended of methylene and the suspension was cooled in an ice-salt bath at -8 ° C. 3,5-Dimethylpyrazole (2.58 g, 26.8 mmol) was added and the suspension was stirred for 20 minutes. 19 Norpregna-1, 3,5, (10), 16-tetraen-20-yn-3-ylo acetate (0.86 g, 2.7 mmol) was added over 5 minutes, so that the reaction temperature did not exceed -7 ° C. After stirring a further 2 hours, the reaction mixture was emptied through a 30 mm x 11 mm silica gel column and the elution was continued under pressure with methylene chloride. The concentration of the appropriate fractions gave a brown film (0.16 g, 0.48 mmol 18%).

Example 43 - 19 Norpregna -1,3,5, (10), 16-tetraen-3-6β-diol-20-? No 19-norpregna-1, 3,5, (10), 16-tetraen acetate was suspended -6-on20-in-3-yl (JJ_, O-16, 9.0.48 mmol) in 20 ml of anhydrous ether, LAH (36.7 mg, 0967 mmol) was added and the mixture was refluxed with the exclusion of water during 18 hours. After cooling, 1.22 g of the Glauber's salt was added and the suspension was stirred VT. hour. The mixture was filtered through diatomaceous earth and the residue was washed with 4 portions of 10 ml of the hot concentration of the combined filtrates, ethyl acetate, followed by purification through TLC preparation (50% ethyl acetate hexanes on GF silica gel, 1000μ) and gave a white solid 826.0 mg, 88.3 mmoles, 18%) homogeneous with TLC (50% ethyl acetate / hexanes on silica gel, Rf 0.48).

Example 44 - 19 Norpregna -1, 3.5, (10), 17-tetraen-3-ol Ethyltriphenylphosphonium bromide (1.3947 g, 3.7572 mmol) and potassium t-butoxide (422.5 mg, 3.765 mmol) suspended in anhydrous DMSO were placed. (4.1 ml) under argon, in an ice bath (80-84 ° C) and stirred for 1 hour. Equilin (200.2 mg, 0.7459 mmol) was added in 4.1 ml of anhydrous DMSO and the reaction was stirred for a further 1 hour. After cooling, 25 ml of 1 N ice-HCl was added and the mixture was extracted three times with 20 ml portions of ether. The combined organic extracts were washed with 25 ml of sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (20% ethyl acetate / hexanes on silica gel) followed by preparative TLC (20% ethyl acetate / hexanes on GF silica gel, 1000μ) gave a light yellow resin ( 182.9 mg, 15 0.6523 mmole 87%) homogeneous with TLC (20% ethyl acetate / hexanes Rf 0.42).

Example 45 - 19 Norpregna -1, 3,5, (10), 617-tetraen-3-ol Ethyltriphenylphosphonium bromide (1.3945 g, 3.7561 mmol) and potassium itobutoxide (422.8 mg, 3.768 mmol) suspended in 4.0 ml of anhydrous DMSO under argon, in a 77-79 ° C bath and stirred for 1 hour. 6-Dehydroestrone (200.4 mg, 0.7466 mmol) in 4.1 ml of anhydrous DMSO was added and the reaction was stirred for 1 hour. The reaction mixture was allowed to cool and then was poured into 25 ml of ice-HCl 1N_. The mixture was extracted three times with 20 ml of ether and the combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (15% ethyl acetate / hexanes) and the TLC preparation (15% ethyl acetate / hexanes on GF silica gel, 1000μ) gave an off-white crystalline solid (212.9 mg,> 100). %) homogeneous with TLC (15% ethyl acetate / hexanes on silica gel Rf 0.21).

Example 46 - 19 Norpregna -1, 3,5, (10), 6,8,17-hexaen-3-ol Ethyltriphenylphosphonium bromide (1.3945 g, 3. 7561 mmoles) and potassium t-butoxide (422.3 mg, 3.763 mmol) suspended in 4.1 ml of anhydrous DMSO under argon, in an oil bath (74-83 ° C) and the reaction was stirred for 1 hour. Equilenin (200.2 mg, 0.7518 mmol) in 4.1 ml of anhydrous DMSO was added and the reaction mixture was stirred for a further 1 hour. The mixture was poured into 25 ml of ice-HCl 1 N_ and extracted three times with 20 ml portions of ether. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (20% ethyl acetate / hexanes) and the TLC preparation (20% ethyl acetate / hexanes on GF silica gel, 1000μ) gave a light yellow crystalline wax (180.6 mg , 0.6487 mmoles 86%) homogeneous with TLC.

Example 47. The following study compares the effect of 23 vomeropherins with a structure of 19-norpregnane, and placebo (propyl glycol), on autonomy activity and EEG. Twelve healthy human beings (6 women and 6 men) aged 19 to 29 years participated in this study. All the substances were delivered in the air to the vomeronasal organ (VNO) as a breath lasting 5 seconds. For this purpose, a miniprobe electrode previously described was used, which allowed local stimulation and simultaneous recording of the organ electrovomerogram (EVG). The parameters recorded were: electrodermal activity (EDA), respiratory frequency (RF), electrocardiogram (CF), electromyogram (EMG), body temperature (BT), and EEG from CzA1 and T3A1. The activity of autonomy, EEG and EVG were recorded using surface electrodes; all the techniques used were non-invasive. The procedure was carried out in two registration sessions, each lasting one hour. The electrical records were amplified, digitized and verified and stored in a computer. The processing and analysis of the results were carried out offline. The data in the tests on the women are shown in Figures 99-120, and the data on the men are shown in Figures 121-142. The summary results in the following tables show the total effect of each vomeropherin already removed from the control. An arbitrary classification of Oa 5 was assigned to compare the activity of the compounds relative to each other, but virtually all the compounds tested had some effect. These results show that the effect of some vomeropherins on autonomy activity and EEG is significantly different from placebo. It also shows some substances that do not have significantly different effects in both genders.

Example 48 - Synthesis of Estra-1.3.5 (10) .16-tetraen-3-ol The following synthesis method is illustrated in Figure 1: estrone p-toluenesulfonylhydrazone. Estrone (270 g, 1.00 mol) was heated and toluenesulfonyl hydrazide (232.8 g, 1.25 moles) in dry methanol (2.5 liters) under reflux for 20 hours. The mixture was transferred to a conical flask and allowed to cool. The crystalline product was filtered under suction and washed with methanol (300 ml). Other cultures of the product were obtained by sequentially evaporating the filtrate to 2000 ml, 800 ml and 400 ml and allowing it to crystallize at each moment. The total yield was 433.5 g (99%). 1, 3, 5 (10), 16 -Es tra tet raen -3 -o I Estrone p-toluenesulfonylhydrazone (219.9 g, 500 mmol) in dried tetrahydrofuran (8.0 liters) was cooled in a sodium chloride / ice bath . The mixture was stirred mechanically, while adding n-butyl lithium (800 ml of a 2.5 M solution in hexane, 2.00 mmole) through a double-ended needle. The mixture was stirred at room temperature for 3 days. Ice (250 g) was added, followed by a solution of saturated ammonium chloride (500 ml). The phases were mixed by stirring and then allowed to settle. The aqueous phase was removed by suction with a Teflon tube and extracted with ether (500 ml). The two organic phases were washed sequentially with the same batch of a saturated sodium bicarbonate solution (500 ml) followed by a saturated sodium chloride solution (500 ml). The organic layers were dried (MgSO4) and evaporated in vacuo to give the crude product. This was subjected to flash evaporation filtration on 500 g of silica gel 60, 230-400 mesh, eluting with ethyl acetate / hexane (25.75, 2.5 liters). The filtrate was evaporated in vacuo to give a crystalline material. The product was recrystallized from methanol (300 ml) / water (75 ml) washing with methanol) 80 ml) / water (20 ml). Further recrystallization from * ethyl acetate / hexane (12.5: 87.5) gave the pure product (88.9 g, 70%).

Example 49 - Synthesis of acyl derivatives of 1.3.5 (10), 16-Estratetraen-3-ol A 1,3,5 (10), 16-Estratetraen-3-ol (254 mg, 1.00 mmol) in ether ( 10 ml) was added acetic anhydride (0.25 ml) (or propionic anhydride for propionate) followed by pyridine (0.25 ml) and the mixture was stirred at room temperature for 16 hours. The mixture was emptied in ice / water and extracted with ether (2 x 20 ml). The organic extracts were washed with water, a saturated copper sulfate solution, water and a saturated sodium chloride solution, dried (MgSO) and evaporated in vacuo to give the pure product.

Example 50 - Synthesis Estra-4,16-dien-3-one To ether estra-1, 3,5, (10), 16-tetraen-3-methyl, (551.5 mg, 2,955 mmoles) in 8.6 ml of THF Anhydrous, approximately 30 ml of anhydrous ammonia and 6.76 g of t-butyl alcohol were added lithium cable (0.24 g, 35 mg atom) cut into small pieces. The reaction mixture was refluxed for 4 hours and A under argon, after which methanol (2.3 ml) was added and the ammonia was allowed to boil overnight. The residue was dissolved in 25 ml of methanol and acidified to a pH of 1 with 5N HCl. After heating in an oil bath between 55 and 70 ° C for 15 minutes, the cooled hydrolysis mixture was precipitated between 25 ml of water and 50 ml of ethyl acetate and the aqueous phase was extracted with 25 ml of ethyl acetate. ethyl. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate and 25 ml of brine, dried over magnesium sulfate and filtered. Removal of the solvent under reduced pressure yielded 0.57 g of the oily residue, which was purified by flash chromatography on silica gel (eluent 2: 15% ethyl acetate / hexane) followed by recrystallization from pentane for give crystals (206.1 mg, 39%) homogeneous to TLC, mp 67-71 ° C.

Example 51 - Ether synthesis Estra-2, 5H 0), 16-tpene-3-methyl-ether To ether -1,3,5, (10), 16-tetraen-3-methyl, (1.22 mg, 4.54 mmol) in 19 ml of anhydrous THF, 14.99 g and approximately 70 ml of ammonia was added lithium cable (0.53 g, 76 mg atom) cut into small pieces. After refluxing under argon for 6 hours, the mixture was quenched with 5 ml of methanol and the ammonia was allowed to boil overnight. A suspension of the residue in 100 ml of water was extracted twice with 100 ml portions of ethyl acetate and the combined organic extracts were washed with brine, and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residue was flash chromatographed on silica gel using 1% ethyl acetate / hexane as eluent and then recrystallized from absolute ethane to give viny white crystals (884.1 mg, 3.269 mmole, 72%), homogeneous to TLC.

Example 52 - Synthesis of Estra-5 (10), 16-dien-3-one Ester estra-2,5, (10), 16-trien-3-methyl (2) (646.3 mg, 2390 mmol) was hydrolysed, dissolved in 50 ml of acetone, for 6 hours at room temperature using oxalic acid dihydrate (0.84 g 6.7 mmoles). The reaction mixture was quenched with 25 ml saturated sodium bicarbonate and then extracted twice with 25 ml portions of ethyl acetate. The combined organic extracts were washed twice with 25 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from hexane for the product (462.5 mg, 1.804 mmol 75%), m.p. 112-116 ° C.

Example 53 - Synthesis of Estra-5 (10), 16-d-ene-3-oles (4) Estra-5, (10), 16-dien-3-one (3) (301.1 mg, 1,174 mmol) was reduced ), in 6 ml of anhydrous ether for 1 hour at room temperature using lithium aluminum hydride (50.0 mg 1.32 mmol). After quenching with sodium sulfate decahydrate (2.00 g) for 10 minutes, the suspension was filtered through Celite and the residue was washed with 4 portions of 21 ml of ether. The combined filtrates were concentrated under reduced pressure and purified by flash chromatography (silica gel, 5% ethyl acetate / hexanes, as eluent) with the subsequent TLC preparation of the mixed fractions. The more polar product could be recrystallized with a considerable loss from aqueous ethanol to give 4.8 mg of solid. The less polar product was recrystallized from methanol to yield white crystals (59.5 mg), m.p. 98-100 ° C the total yield was 64.3 mg (0.249 mmol, 21%) Example 54 - Synthesis of Estra-4,9,16-trien-3-one Estra-5, (10), 16-dien-3-one (3) (0.38 g, 1.5 mmol) was cooled in pyridine (5.0 ml, 62 mmol) in an ice-salt bath at -13 ° C and pyridinium bromide perbromide (1.58 g, 4.94 mmol) was added in small portions so that T < 4 ° C. After stirring for 1 minute, phenol (0.25 g, 2.7 mmol) was added and the mixture was continued for 24 hours at room temperature. Ethyl acetate (50 ml) was added and the reaction mixture was washed with 25 ml of 1N HCl, 2 portions of 25 ml of saturated copper sulfate, 25 ml of 5% sodium hydroxide and 25 ml of brine. After drying over magnesium sulfate, filtering and concentrating under reduced pressure, the residue was taken up in 10 ml of absolute ethanol, granulated zinc (0.33 g, 5.0 mg-atom) was added, and the mixture was brought to reflux. hour. The supernatant was removed, the residue was washed with 10 ml of absolute ethanol and the combined supernatants were extracted under reduced pressure. The resulting resin was flash chromatographed on silica gel using 15% ethyl acetate / hexane as eluent. The appropriate fractions were combined, concentrated and then recrystallized from hexane to give the solid product (117.5 mg, 0.4619 mmol, 31%), m.p. 87-92 ° C.

Example 55 - Synthesis of 3-Acetate of Estra-1.3.5 (10), 16-tetraen-β-one Chromium trioxide (13.40 g, 0.1340 mmol) was suspended in 200 ml of methylene chloride and then cooled to - 10 ° C in an ice-salt bath. 3,5-Dimethylpyrazole (12.90 g, 0. 1342 mmoles) and the mixture was stirred for 20 minutes. Estra-1, 3,5, (10), 16-tetraen-3-yl acetate (4.0 g, 13.5 mmol) was added in a cooled solution of 20 ml of methylene chloride, and the reaction was stirred for 2 hours , during which T < -8 ° C. The mixture was then filtered through 200 g of silica gel and the product was eluted with additional methylene chloride. After combining and concentrating the appropriate fractions, the crude product was flash chromatographed on silica gel using 15% ethyl acetate / hexane as eluent. Combination of the appropriate fractions and concentration under reduced pressure yielded a white solid (0.92 g, 3.0 mmol, 22%), m.p. 87-103 ° C.

Example 56 - Synthesis of Estra-1, 3,5 (10), 16-tetraen-3-ol-6-one Saponified 3-acetate estra-1, 3,5, (10), 16-tetren-6 -one (203.1 mg, 0.6543 mmol) in 30 ml of methanol with 1.5 ml of 5% sodium hydroxide (w / w) for 40 minutes. The reaction mixture was concentrated under reduced pressure, taken up in 50 ml of water, neutralized with 1N HCl, and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated to give a white solid, which was purified through recrystallization from benzene / hexane and TLC preparation to give a white crystalline solid (52.8 mg, 0.197 mmol 30%), mp 188-191 ° C.

Example 57 - Synthesis of Acetate of Estra-1.3.5 (10), 16-tetraen-3-ßa-ol-3-yl Acetate of estra-1, 3,5, (10), 16-tetraen-6 was reduced -one-3-yl (421.4 mg, 01,358 mmoles) suspended in 35 ml of 95% ethanol, with sodium borohydride (98.8 mg, 2.61 mmoles) for 100 minutes at room temperature. After concentrating under reduced pressure, the residue was suspended in 25 ml of water, neutralized with 1N HCl, and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts were washed with 25 ml of brine, dried over magnesium sulfate, filtered and concentrated. The resulting white foam was flash chromatographed on silica gel using 25% ethyl acetate / hexane as eluent. The combined fractions and the concentrations gave a white solid (0.12 g, 3.8 mmol, 28%), m.p. 209-212 ° C.

Example 58 - Synthesis of Estra-1, 3,5 (10), 16-tetraen-3-6-diol To a solution of lithium-aluminum hydride (LAH, 95%, 46. 9 mg, 1.17 mmoles) in 5 ml of anhydrous THF was added estra-1, 3, 5 (10), 16-tetraen-6-one-3-yl acetate (6) (422.9 mg, 1360 mmoles) in 25 ml of anhydrous THF, dropwise, with stirring. The reaction was stirred 50 minutes, after which more LAH (46.5 mg, 1.16 mmol) was added and the reaction was stirred for 22 hours. After refluxing for 4 hours, TLC continued to show the starting material. The reaction was quenched with 0.5 ml of water + 0.5 ml of 20% sulfuric acid (w / w) and concentrated under reduced pressure. The residue was extracted four times with 10 ml portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice via flash chromatography to give the solid product. (0.05 g, 0.2 mmol, 10%), m.p. 150-157 ° C.

Example 59 - Synthesis of Estra-1, 3,5 (10) .7-tetraen-3-ol To a solution of equilin (100.2 MG, 0.3733 mmol) in 2 ml of diethylene glycol was added hydrazine (59 μL 1.9 mmol) ) and potassium hydroxide (0.04 g, 0.7 mmol). The mixture was stirred in an oil bath of 200 to 214 ° C for 2 hours, after which the cooled reaction was diluted with 10 ml of water, neutralized with 1 N HCl and extracted three times with 25 ml of ether. . The combined organic extracts were washed with 10 ml of brine, dried over magnesium sulfate, filtered and concentrated, and purified by preparative TLC (silica gel, 15% ethyl acetate / hexane as eluent) to give a yellow resin. The product was further purified by decolorization with carbon and recrystallization from aqueous ethanol to give tan crystals (13.2 mg, 51.9 μM, 14%), m.p. 130-134 ° C.

Example 60 - Synthesis of 20 Homoestra-1, 3,5, (10), 6,8,17-hexaen-3-ol A solution of triphenylmethylphosphonium bromide (671.0 g, 1. 878 mmoles) and potassium t-butoxide (212.1 mg, 1.8905 mmoles) in 2.1 ml anhydrous DMSO was heated in a bath at 76-86 ° C under argon for 1 hour, after which equilenin (100.1 mg, 0.3579) was added. mmoles) in 2.1 ml of anhydrous DMSO and the green solution was stirred for 1 hour. After cooling10 ml of ice-HCM were added ii and the mixture was extracted with three 10 ml portions of ether. The combined organic extracts were washed with 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over magnesium sulfate, filtered through Celite and concentrated under reduced pressure. The residual orange oil was purified through TLC preparation (silica gel, 25% ethyl acetate / hexanes) to give the product (75.5 mg, 0.286 mmol, 76%) homogeneous at TLC, pf113-121 ° C.

Example 61 - Synthesis of 20 Homoestra-1,3.5, (10) .6,8.17-hexaen-3-ol Estra-1, 3,5, (10), 6-tetra-3-ol-17-one (91.1 mg. , 0.339 mmoles), hydrazine (54 μL, 1.7 mmol), and potassium hydroxide (0.06 g) in 1.8 ml of diethylene glycol in a bath at 200 ° C under argon for 2 hours. After cooling to room temperature, 10 ml of water was added and the solution was acidified to pH = 2 with 1N HCl. The resulting suspension was extracted three times with 10 ml of ether and the combined organic extracts were washed with 10 ml of brine, dried over magnesium sulfate, filtered through Celite and concentrated under reduced pressure. The crude solid was purified by preparative TLC (25% ethyl acetate / hexane on silica gel) to give the homogeneous product to TLC (5.9 mg, 23 mmol, 7%).

Example 62 - Synthesis of Estra-4 16-dien-3-ol To estra-4 16-dien-3-one, in 1.7 ml of anhydrous ether was added lithium-aluminum hydride (15.0mg, 0.395mmol) and the suspension was stirred for 17 minutes. The reaction was then stirred 10 minutes, with 0.50 g of sodium sulfate decahydrate and filtered through Celite. The residue was washed with 3 portions of 10 ml of ether and the combined filtrate was concentrated under reduced pressure. The working TLC (5% ethyl acetate / dichloromethane on silica gel) gave the crude product (50.0 mg as a yellow resin) which could be rechromatographed until it became sufficiently pure.

Example 63 Estra-4, 16-dien-3-one This synthesis is presented in Figure 153. 19-Nor-testosterone (XIX) is commercially available, for example, from Chemical Dynamics Corp. Provides the starting material for 19-Nor-16-androstene derivatives. 19-Nor-testosterone (XIX) was converted to acetate (Hartam, J.A. et al., J. Am. Chem. Soc. (1956) 78: 5662) with acetanhydride and pyridine. (a) A solution of this acetate (4.8 g, 15.17 mmol) in toluene (10 ml) was hydrolyzed, (b) A 540 ° C (200 Torr, slow current of N2) in a glass tube packed with quartz pieces. Chromatography of the crude pyrolisate (3.1 g) on silica gel (150 g) with CH 2 Cl 2 yielded 1.1 g (28%) of the homogeneous oily ketone 9; + 57.9 ° (C1) ((27): p.f. 71-73 °). -GO. (CHCl3): 1660s, 1615m, 1585w, -1H-NMR. (90 MHz): 0.84 (s, 3 H); 5.82 (m, 2 H); 5.87 (br.s, 1 H).

Example 64 Estr-16-en-3-one This synthesis is presented in Figure 153. The 19-Nor-testosterone was reduced to 19-nor-5a-Androstan-17-ol-3-one (XX) with lithium and ammonia (c) according to the method of Villotti, R., et al. (J. Am. Chem. Soc. (1960) 82: 5693). Androsta-5a-17-diol-3-one (XX) was converted to acetate (Hartam, J.A. et al., J. Am. Chem. Soc. (1956) 78: 5662) with acetanhydride and pyridine. (a) A solution 17β-acetoxy-5a-Estran-3-one (8.0 g, 25.1 mmol) in octane / acetone 10: 1 (22 ml) was pyrolyzed, (b) At 550 ° C (200 Torr, current slow of N2) in a glass tube packed with quartz pieces. Chromatography of the crude product (5.4 g) on silica gel (600 g) with CH 2 Cl 2, and recrystallization of the homogeneous fractions from PE gave 3.13 g (48.3%) of the pure ketone 10. Mp 51-54 °, [a] - + 72.8 ° (C 1.0) -IR. (CHCl3): 1705s, 1585w, -1H-NMR. (90 MHz): 0.79 (s, 3 H); 5.71 (m, 1 H); 5.87 (m, 1 H).

Example 65 Estra-16-en-3a-ol This synthesis is presented in Figure 153. L-Selectride (lithium d, tri (sec-butyl) hydroborate, 4 ml of a 1 M solution in THF was added dropwise. , 4 mmol) at 0 ° to a solution of ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml): After stirring for 1 hour at 0 °, water (10 ml) was added. The boranes were oxidized by adding an aqueous solution of 10% NaOH, (5 ml). followed by an aqueous solution of 30% H2O2 (3 ml) and stirred for 3 hours at room temperature. After workup (ether), the crude product (790 mg, approximately 9: 1 mixture 11 and 12) was chromatographed over the crude product (5.4 g) on silica gel with CH2Cl2, to give 700 mg (87%) of pure alcohol 11 .. Pf 119-120 ° -123-124 ° (from PE); [a] D + '40 .6 ° (C = 1.0). -GO. (CHCl3): 3640m, 3500 br., 1585w, -1H-NMR. (90 MHz): 0.78 (s, 3 H); 4.09 (m, w1 / 2 «8.1H); 5.71 (m, 1 H), 5.87 (m, 1H).

Example 66 Estra-16-en-3ß-ol This synthesis is illustrated in Figure 153. A solution of ketone 10 (800 mg, 3.10 mmol) in dried ether (5 ml) was added dropwise at room temperature to a slurry. of LiAIH4 (38 mg, i mmol) in ether (3 ml) (e). After 1 hour, the mixture was hydrolysed with 10% aqueous H2SO4. After processing (ether) the crude product (802 mg, 9: 1 mixture of 11 and 12 was chromatographed on silica gel with Ch 2 Cl 2) A small fraction of 11 (70 mg) was eluted first, followed by the main fraction of 12 (705 mg, 87%), mp 113-115 °, [a] - + 36.3 ° (C = 1.0) -IR. (CHCl3): 3640m 3500br., 1585w, -1H-NMR. (90 MHz): 0.78 (s, 3 H), 3.60 (m, w1 / 2 * (m, 20, 1 H), 5.71 (m, 1 H), 5.87 (m, 1H).

Example 67 - Alternative Synthesis of Estra-4,16-dien-3-one Estra-4,16-dien-3-one: to ether estra-1, 3,5 (10), 16-tetraen-3-methyl ( 551. S mg, 2.055 mmoles) in 8.6 ml of anhydrous THF, approximately 30 ml of anhydrous ammonia and 6.76 g of t-butyl alcohol was added lithium cable (0.24 g, 35 mmoles) cut into small pieces. The reaction mixture was refluxed for 4 hours and A under argon, after which methanol (2.3 ml) was added and the ammonia was allowed to boil overnight. The residue was dissolved in 25 ml of methanol and acidified to approximately pH 1 with 5N HCl. After heating in an oil bath between 55 and 70 ° C for 15 minutes, the cooled hydrolysis mixture was partitioned between 25 ml of water and 50 ml of ethyl acetate and the aqueous phase was extracted with 25 ml of ethyl acetate. ethyl. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate and 25 ml of brine. They were dried over magnesium sulfate and filtered. Removal of the solvent under reduced pressure yielded 0.57 g of the oily residue, which was purified by flash chromatography on silica gel (eluent: 15% ethyl acetate / hexane) followed by recrystallization from pentane to give crystals (206.1 mg, 39% homogeneous at TLC, mp 67-71 ° C).

Example 68 - Estra-2.5 (10) .16-trien-3-methyl ether. 2. To ether estra-1, 3, 5- (10), 16-tetraen-3-methyl (1.22 g, 4. 54 mmoles) in 19 ml of anhydrous THF, 14.99 g of t-butyl alcohol and approximately 70 ml of anhydrous ammonia was added key of lithium (0.53 g, 76 mg-atom) cut into small pieces. See Figure 12. After refluxing under argon for 16 hours, the mixture was extruded with 5 ml of methanol and the ammonia was allowed to boil overnight. A suspension of the residue in 10 ml of water was extracted twice with 100 ml portions of ethyl acetate and the combined organic extracts were washed with brine and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residue was flash chromatographed on silica gel using 1% ethyl acetate / hexane as eluent and then recrystallized from absolute ethanol to give bright white crystals (884.1 mg, 3,269 mmol, 72%), mp 72-73 ° C, homogeneous to TLC.

Example 69 - Estra-5 (10) .16-dien-3-one, 3. Estra-2,5 (10), 16-trien-3-methyl ether, 2 (646.3 mg, 2,390 mmol), hydrolyzed, dissolved in 50 ml of acetone for 6 hours at room temperature using oxalic acid dihydrate (0.84 g, 6.7 mmol). See Figure 12. The reaction mixture was quenched with 25 ml of saturated sodium bicarbonate and then extracted twice with 25 ml portions of ethyl acetate. The combined organic extracts were washed twice with 25 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from hexane to give the product (462.5 mg, 1,804 mmol, 75%), m.p. 112-116 ° C.

Example 70 - Estra-5 (10), 16-dien-3-ols. Estra-5 (10), 16-dien-3-one, 3 (301.1 mg, 1174 mmol), in 6 ml of anhydrous ether was reduced for 1 hour at room temperature using lithium-aluminum hydride (50.0 mg, 1.32 mmol ), See Figure 155. After quenching with sodium sulphate decahydrate (2.00 g) for 10 minutes, the suspension was filtered through Celite and the residue was washed with 4 portions of 25 ml of ether. The combined filtrates were concentrated under reduced pressure and purified by flash chromatography (silica gel, 5% ethyl acetate / hexanes as eluent) with TLC of subsequent preparation of the mixed fractions. The more polar product could be recrystallized with considerable loss from aqueous ethanol to give 4.8 mg of the solid. The less polar product was recrystallized from aqueous methanol to give white crystals (59.5 mg), m.p. 98-100 ° C. Total production was 64.3 mg (0.249 mmol, 21S).

Example 71 - Estra-4.9.16-trien-3-one. Stra-5 (10), 16-dien-3-one, 3 (0.38 g, 1.5 mmol) was cooled in pyridine (5.0 ml, 62 mmol) in an ice-salt bath at -13 ° C and added pyridinium bromide perbromide (1.58 g, 4.94 mmoles) in small portions so that T < -4 ° C. After stirring for 1 minute, phenol (0.25 g, 2.7 mmol) was added and the mixture was continued for 24 hours at room temperature. See Figure 12. Ethyl acetate (50 ml) was added and the reaction mixture was washed with 25 ml of 1N HCl, 2 portions of 25 ml of saturated copper sulfate, 25 ml of 5% sodium hydroxide and 25 ml of brine After drying over magnesium sulfate, filtration and concentration under reduced pressure, the residue was taken up in 10 ml of absolute ethanol, granulated zinc (0.33 g, 5.0 mg-atom) was added, and the mixture was brought to reflux during I saw an hour The supernatant was removed, the residue was washed with 10 ml of absolute ethanol and the combined supernatants were concentrated under reduced pressure. The resulting resin was flash chromatographed on silica gel using 15% ethyl acetate / hexane as eluents. The appropriate fractions were combined, concentrated and then recrystallized from hexane to give the solid product (117. S mg, 0.4619 mmol, 31%), m.p. 87-92 ° C.

Example 72 - 3-Acetate of estra-1, 3, 5 (10), 16-tetraen-6-one. Chromium trioxide (13.40 g, 0.1340 mmol) was suspended in 200 ml of methylene chloride and then cooled to -10 ° C in an ice-salt bath. 3,5-Dimethoxy-pyrazole (12.90 g, 0.1342 mmol) was added and the mixture was stirred for 20 minutes. See Figure 13. Stra-1, 3,5 (10), 16-tetraen-3-yl acetate (4.00 g, 13.5 mmol) was added in a cooled solution of 20 ml of methylene chloride and the reaction was stirred for 2 hours, during which T? 8 ° C. The mixture was then filtered through 200 g of silica gel and the product was eluted with additional methyl chloride. After combining and concentrating the appropriate fractions, the crude product was flash chromatographed on silica gel using 15% ethyl acetate / hexane as eluent. Combination of the appropriate fractions and concentration under reduced pressure yielded a white solid (0.92 g, 3.0 mmol, 22%) m.p. 87-103 ° C.

Example 73 - Estra-1, 3,5 (10), 16-tetraen-3-ol-6-one. 3-Acetate of estra-1, 3.5 (10), 16-tetraen-6-one (203.1 mg, 0.6543 mmol) was saponified in 30 ml of methanol with 1.5 ml of 5% sodium hydroxide (w / w) ) for 40 minutes. See Figure 156. The reaction mixture was concentrated under reduced pressure, taken up in 50 ml of water, neutralized with 1N HCl and extracted 3 times with 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated to give a white solid, which was purified through recrystallization from benzene / hexane and TLC preparation to give a white crystalline solid (52.8 mg, 0.197 mmol, 30%), mp 188-191 ° C.

Example 74 - Acetate estra-1, 3, 5 (10), 16-tetraen-6a-ol-3-yl. Acetate of estra-1, 3,5 (10), 16-tetraen-6-one-3-yl, 6 (421.4 mg, 1,358 mmol), suspended in 35 ml of 95% ethanol, was reduced with sodium borohydride. (98.8 mg, 2.61 mmol) for 100 minutes at room temperature. See Figure 13. After concentrating under reduced pressure, the residue is suspended in 25 ml of water, neutralized with 1N HCl and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts were washed with 25 ml of brine, dried over magnesium sulfate, filtered and concentrated. The resulting white foam was chromatographed on flash over silica gel using 25% ethyl acetate / hexane as eluent. Combination fractions and concentration gave a white solid (0.12 g, 0.38 mmol, 28%), m.p. 209-212 ° C.

Example 75 - Estra-1, 3.5 (10), 16-tetraen-3,6-diol. To a suspension of lithium aluminum hydride (LAH, 95%, 46.9 mg, 1.17 mmol) in 5 ml of anhydrous THF was added estra-1, 3, 5 (10), 16-tetraen-6-one acetate. -3-yl, 6 (422.9 mg, 1360 mmol) in 5 ml of anhydrous THF, dropwise, with stirring. See Figure 156. The reaction was stirred for 50 minutes, after which more LAH (46.5 mg, 1.16 mmol) was added and the reaction was stirred for 22 hours. After refluxing for 4 hours, TLC continued to show the starting material. The reaction was quenched with 0.5 ml of water plus 0.5 ml of 20% sulfuric acid) (w / w) and concentrated under reduced pressure. The residue was extracted four times with 10 ml portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice by flash chromatography to give the solid product (0.05 g, 0.2 mmol, 10%), m.p. 150-157 ° C.

Example 76 - Estra-1, 3.5 (10), 7-tetraen-3-ol. To a suspension of equilin (100.2 mg, 0.3733 mmoles) in 2 ml of diethylene glycol was added hydrazine (50 μl, 1.9 mmol) and potassium hydroxide (0.04 g, 0.7 mmol). See Figure 157. The mixture was stirred in an oil bath at 200-214 ° C for 2 hours, after which the cold reaction was diluted with 10 ml of water, neutralized with 1N HCl and extracted three times with water. ml of ether. The combined organic extracts were washed with 10 ml of brine, dried over magnesium sulfate, filtered, concentrated and purified by preparative TLC (silica gel, 15% ethyl acetate / hexane as eluent to give a yellow resin The product was further purified by decorating with carbon and recrystallization from aqueous ethanol to give tan crystals (13.2 mg, 51.9 μM, 14%), mp 130-134 ° C.

Example 77 - 20-homoestra-1, 3.5 (10), 6,8,17-hexaen-3-ol. A suspension of triphenylmethylphosphonium bromide (671.0 mg, 1878 mg) and potassium t-butoxide (212.1 mg, 1890 mmol) in 2.1 ml of anhydrous DMSO was heated in a bath at 76-86 ° C under argon for 1 hour, after which equilenin was added (100.1 mg, 0.3579 mmoles) in 2.1 ml of anhydrous THF.

See Figure 157. DMSO was added and the green solution was stirred for 1 hour. After cooling, 10 ml of 1N ice-HCl was added and the mixture was extracted with three 10 ml portions of ether. The combined organic extracts were washed with 10 ml of saturated sodium bicarbonate plus 10 ml of brine, dried over magnesium sulfate, filtered through Celite, concentrated and purified.

Example 78 - Estra-1 hydrazone, 3,5 (10), β-tetraen-3-ol-17- (p-toluenesulfonyl). A suspension of 6-dehydrostrone (538.0 mg, 2,004 mmol) and p-toluenesulfonyl p-hydrazide (pTsNHNH2, 466.6 mg, 2.506 mmol) in anhydrous methanol (5.4 ml) was refluxed for 25 hours with the exclusion of moisture. See Figure 15. After concentrating under reduced pressure, the reaction residue was flash chromatographed (50% ethyl acetate / hexane on silica gel) to give a whitish foam (942.5 mg, representing a > 100% Example 79 - Estra-1, 3,5 (10), 6-tetraen-3-ol-17- (p-toluenesulfonyl) hydrazone. To a cooled solution (low ice-water) of estral hydrazone, 3, 5 (10), 6-tetraen-3-ol-17- (p-toluenesulfonyl) crude (1, 942.5 mg, < 2,004 mmoles) in tetrahydrofuran (THF) under argon, n-butyl lithium (2.5 M_ in hexane, 3.2 ml, 8.0 mmol) was added dropwise with stirring, over a period of 7 minutes. See Figure 158. Stirring was continued for 48 hours, during which the reaction was allowed to warm gradually to room temperature. 50 ml of 1N hydrochloric acid were added and the reaction mixture was extracted with three 25 ml portions of ether. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. The crude product was purified by flash chromatography (20% ethyl acetate / hexanes on silica gel) and preparation TLC (20% ethyl acetate / hexanes on silica gel GF., thickness 1000μ) to give a white crystalline film (134.5 mg, 0.5331 mmoles, 27%) homogeneous to TLC (20% ethyl acetate / hexanes on silica gel Rf 0.39).

Example 80 - Acetate estra-1.3.5 (10), 6,16-pentaen-3-yl. A solution of estra-1, 3.5 (10), 16-pentaen-3-ol (2.97.9 mg, 0.388 mmol) in anhydrous pyridine (1.3 ml, 16 mmol) and acetic anhydride (0.18 ml, 1.9 mmol) The mixture was stirred for 24 hours, after which ethyl acetate (15 ml) was added and the mixture was washed with three aliquots of 5 ml of 1N hydrochloric acid + 5 ml of saturated sodium bicarbonate + 5 ml of brine. dried over magnesium sulfate and filtered through diatomaceous earth. See Figure 15. The residue was washed with 5 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. TLC preparation (10% ethyl acetate / hexanes on GF silica gel, thickness 1000) of the residue gave a slightly yellow crystalline solid 874.9 mg, 0.254 mmol, 66%) homogeneous to TLC (10% acetate) of ethyl / hexanes on silica gel, R, 0.40).

Example 81 - Estra-1, 3, 5 (10), 7-etraen-3-ol-17- (p-toluenesulfonyl) hydrazone Equilin (500.1 mg, 1863 mmol) and p-TsNHNH2 (433.7 mg) were refluxed. , 2.329 mmoles) suspended in anhydrous methanol (5.0 ml) for 24 h. with the exclusion of humidity. See Fig. 15. After concentration under reduced pressure, the residual reaction mixture was flash chromatographed (35% ethyl acetate / hexane on silica gel) to give a white foam (99.9 mg) representing a production of > 100% Example 82 - Estra-1, 3.5 (10), 7,16-pentaen-3-ol To a cooled solution (ice-water bath) of estra-1, 3, 5 (10) hydrazone, 7 - crude tetra-3-ol, -17- (p-toluensul fonyl) (4,899.9 mg, < 1,863 mmol) in anhydrous THF (20 ml) under argon was added n-butyl lithium (2.5M in hexane, 3.0 mol, 7.5 mmol) dropwise with stirring for a period of 3 min. See Fig. 15. Stirring was continued 48 h. during which the reaction was allowed to warm gradually to room temperature. The reaction was poured into 50 ml of 1 N hydrochloric acid and the mixture was extracted with three 25 ml portions of ether. The organic extracts were washed with 50 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were filtered under reduced pressure. The product was chromatographed by flash (20%) ethyl acetate / hexanes on silica gel) and decolorized with carbon to give a crystalline / yellow solid (274.8 mg, 1089 mmol, 58%).

Example 83 - Acetate estra-1, 3,5 (10), 7,16-pentaen-3-yl A solution of estra-1, 3,5 (10), 7,16-pentaen-3-lo (5,192.1 mg, 0.7612 mmoles) in anhydrous pyridine (2.6 ml, 32 mmol) and acetic anhydride (036 ml, 3.8 mmol) was stirred for 6 h, after which 30 ml of ethyl acetate was added. The mixture was washed with three 10 ml portions of 1N hydrochloric acid + 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The TLC preparation (5% ethyl acetate / hexanes on GF silica gel) thickness 1000μ) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 9.267 mmol, 35%) mp 77- 80 ° C) TLC (4% ethyl acetate / hexanes on silica gel) showed 2 spots in Rf 0.21 and 0.24.

Example 84 - Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol-17- (p-toluenesulfonic acid) hydrazone Equilenin (0.6559 mg, 2.463 mmol) and p-TsNHNH2 were refluxed ( 573.6 mg 3080 mmol) suspended in anhydrous methanol (8.2 ml) for 24 h. with the exclusion of humidity. See Fig. 16. After cooling and concentrating under reduced pressure, the reaction mixture was chromatographed by flash (35-40% ethyl acetate / 57% hexane), m.p. 95-96 ° C. TLC (2% ethyl acetate / hexanes on silica gel) showed that the product (Rf 0.1) contained a contaminant trace at the origin.

Example 85 - Estra-1, 3.5 (10) .6,8,16-hexaen-3-ol. To a cooled solution (ice-water hydrazone of (estra-1, 3, 5 (10), 6, 8-pentaen-3-ol 17- (p-toluenesulfonyl) crude (7.1.0887 g, < 2463 mmoles) in anhydrous THF (25 ml) under argon was added n-butyl lithium (2.5M in hexane, 3.9 ml, 9.8 mmoles) dropwise with stirring for 2 min, see Fig. 159. Agitation was continued. three days, during which the reaction was allowed to warm gradually to room temperature 50 ml of 1N-ice hydrochloric acid was added and the mixture was extracted three times with 25 ml portions of ether.The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth, the residue was washed with 10 ml of ether and the combined filtrates were filtered under reduced pressure.Short flash chromatography (20% ethyl acetate / hexanes on silica gel) and recrystallization from aqueous ethanol with acrylic discoloration rbono gave cinnamon-colored platelets (245.8 mg, 0.9819 mmol, 40%) m.p. 162-163 ° C.

Example 86 - estra-1 acetate, 3,5 (10), 6,8,1 ß-hexaen-3-yl A solution of estra-1, 3,5 (10), 6,8, 16-hexaen- 3-ol (8, 148.8 mg, 0.5944 mmol) in anhydrous pyridine (2.0 mL, 25 mol) and acetic anhydride (0.28 mL, 3.0 mol) was stirred for 6 h, after which 20 mL of ethyl acetate was added. . See Fig. 159. The mixture was washed with three 10 ml portions of 1 N hydrochloric acid + 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over sodium sulfate, and filtered. The residue was washed with 5 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from ethanol gave lustrous white platelets (99.4 mg, 0.340 mmol, 55%) mp 95-96 ° C) TLC (2% ethyl acetate / hexanes on silica gel) showed that the product (Rf 0.1) contained a contaminant at the source.

Example 87 - 17-methylenenestra-1, 3,5 (10) -trien-3-ol A suspension of methyltriphenylphosphonium bromide (100.03 g, 0.28001 mol) and potassium t-butoxide (31.42 g, 0.2800 mol) in sulfoxide of Anhydrous dimethyl (DMSO, 320 ml) under argon was stirred in an oil bath (68-81 ° C) for 1 h, after which, estrone (15.14 g, 55.99 mmol) in DMSO was added via syringe. anhydrous (320 ml). See Fig. 160. Stirring was continued 1 h. and the reaction was allowed to cool. The mixture was drained in 800 ml of ice-1N hydrochloric acid and then extracted three times with aliquots of 400 ml of ether. The combined organic extracts were washed with 350 ml of saturated sodium bicarbonate + 400 ml of brine, dried over sodium sulfate, and filtered by flash-flashing through a column of silica gel with a height of 58mm x diameter 84 mm (200-40 mesh). The product was further eluted with additional ether. Concentration of the appropriate fractions under reduced pressure and triple recrystallization from aqueous ethanol gave very fine white needles (11.47 g, 42.73 moles, 76%), m.p. 134-136 ° C), homogeneous to TLC (20% ethyl acetate / hexanes on silica gel 0.45).

Example 88 - 17-methylene-tetra-1, 3.5 (10) -trien-3-yl acetate A solution of 17-methylene-tetra-1, 3,5 (19), - trien-3-ol (10, 5.84 g, 21.8 mmoles) in pyridine and acetic anhydride (32 ml, 0.40 moles) was stirred for 24 h, after which ethyl acetate (250 ml) was added. See Fig. 160. The mixture was washed with three 100 ml portions of 1 N hydrochloric acid + 100 ml of saturated sodium bicarbonate + 100 ml of saturated copper sulfate + 100 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave lustrous white platelets (6.84 g, 18.8 mmol), mp 77-79 ° C) Example 89 - Methylene-1-Acetate, 3,5 (10) -trien-6-on-3-yl To a suspension of chromium trioxide (6.19 g, 61.9 mmol) cooled to -8 ° C (ice-salt bath) in methylene chloride (100 ml) was added 2,4-dimethylpyrazole (5.95 g, 61.9 mmol) See Fig. 17. After stirring 20 min., a solution of 17-methylene-tetra-1, 3,5 (10) -trien acetate was added. -3-yl (1 _, 20001 g, 6.4428 mmoles) in 10 ml of cold methylene chloride for a period of 2 min, so that the temperature did not reach -6 ° C. The stirring was continued for two hours and the mixture was then passed through a column of 100 g of silica gel (200-400 mesh). The product continued to elute with additional methylene chloride. The combination and concentration of the appropriate concentrations under reduced pressure gave a product, which was further purified through double recrystallization from aqueous ethanol to give glossy whitish crystals (344.0 mg, 1030 mmol, 16%), m.p. 91-94 ° C. TLC (25% ethyl acetate / hexanes on silica gel) showed the product (Rf 0.47) with two minor contaminants in Rf 0.30 and 0.39.

Example 90 - 17-methylenenestra-1, 3,5 (10) -trien-3-6B-diol To a suspension of lithium-aluminum hydride /53.6 mg, 1.41 mmol) in anhydrous THF (3.0 ml) under argon cooled in a dried ice / acetone bath was added 17.35 methylenenestra-1, 3,5 (10) -trien-6-on-3-yl acetate (1_2, 251.7 mg, 0.7758 mmole) in anhydrous THF (3.0 ml) Drop by drop with shaking for 8 min. See Fig. 160. After stirring 2 h, the bath was removed and the stirring was continued for an additional hour. The reaction was quenched by stirring for half an hour with Glauber's salt (1.78 g). The resulting mixture was applied to a short pad of diatomaceous earth and extracted four times with 10 ml portions of ethyl acetate. Extraction was continued with five 10 ml portions of hot ethyl acetate and the concentration of all the extracts under reduced pressure gave a colorless film. TLC preparation (40% ethyl acetate / hexanes on GF silica gel, thickness 1000 || _) and a white foam (15.3 mg, 53.8 mmol, 7%). TLC (40%) ethyl acetate / hexanes on silica gel) showed major (Rf 0.29) and minor (Rf 0.37) components.

Example 91 - 17-Methylenestra-1, 3,5 (10) -trien-3-ylmethyl ether To a stirred suspension of 17-methylenenestra-1, 3,5 (10) -trien-3-ol (5.37 g, 20.0 mmol) and potassium carbonate (50.82 g, 0. 3678 moles) at reflux in 90% ethanol (500 ml) was added dimethyl sulfate (5.0 ml, 53 mmol). After half an hour at reflux, additional dimethyl sulfate (36 ml, 0.38 moles, in three aliquots of 12 ml) was added over a period of 1 h, See Fig. 160. The reaction was refluxed for an additional hour, after which 360 ml of water was added and the mixture was placed in the refrigerator overnight. The resulting suspension was filtered and washed with 80 ml of 60% methanol + three 80 ml portions of 5% sodium hydroxide (w / w) + three 80 ml portions of water. The residue was crystallized from aqueous methanol to give white crystals (3.88 g, 13.7 mmol, 69%), m.p. 59-62 ° C. TLC (20% ethyl acetate / hexanes on silica gel) showed the product (Rf 0.63) with trace contaminants at Rf 0.37 and at the origin.

Example 92 - 17-methylenestra-2,5, (10) -dien-3-yl methyl ether Approximately 70 ml of anhydrous ammonia were destined through a KOH tower in a flame-dried 250 ml three-necked flask. equipped with an inlet adapter, a magnetic stir bar, a dried ice / acetone condenser, and a V-shaped ground glass stopper. See Fig. 160. A solution of 17-methylenestra-1 ether, 3.5 (10) -trien-3-yl methyl (ü, 1-1297 g, 4,0001 mmol) and t-butyl alcohol (13.21 g, 0.1782 mol) in 17 ml of dry THF was added, followed by lithium wire (0.47 g). , 68 mg-atom) cut into small pieces. After refluxing under argon for 6 h, 6.6 ml of methanol was added and the suspension was stirred overnight, while the ammonia was allowed to boil. 100 ml of water was added and the suspension was extracted three times with 50 ml portions of methylene chloride. The combined organic extracts were washed with 100 ml of brine, dried over sodium sulfate and dried. The residue was washed with 25 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. The resulting yellow oil was crystallized from aqueous ethanol to give lustrous white crystals (815 mg, 2865 mmol, 72%), m.p. 77-78 ° C, homogeneous to TLC (Rf 0.60, 10% ethyl acetate / hexane on silica gel).

Example 93 - 17-Methylene-4-en-3-one Concentrated hydrochloric acid (6.0 ml) and water (6.0 ml) were added to a solution of 17-methylene-tetra-2,5, (10) -dien-3 ether. Methyl (1_5., 702.8 mg, 2471 mmol) in 6 ml of methanol and 20 ml of acetone. See Example 160. After stirring 1 h, 7.50 g of sodium bicarbonate was added cautiously. The mixture was concentrated under reduced pressure once the effervescence ceased and 50 ml of water was added. The mixture was extracted three times with 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were filtered under reduced pressure. The product was purified through carbon decolorization, flash chromatography (20% ethyl acetate / hexanes on silica gel), and recrystallization from aqueous ethanol to give a white powder (302.8 mg 1120 mmol, 45 g. %), mp 83-89 ° C.

Example 94-17-Methylenetr-4-en-3ß-ol Lithium tri-t-butoxyaluminum hydride (766.6 mg, 3. 015 mmoles) to a solution of 17-methylenenestra-4-en-3-one (16, 203.7 mmol) in 10 ml of anhydrous ether and the reaction was stirred 420 h. See Fig. 161. Glauber's salt 83.80 g) was added and the suspension was stirred for a further half hour. The mixture was stirred through diatomaceous earth and the residue was washed five times with 10 ml portions of ether. The combined filtrates were concentrated under reduced pressure and then subjected to TLC preparation (5% ethyl acetate / methylene chloride on GF silica gel, thickness 1000) to give white needles (60.2 mg 0.221 mmol, 29%) homogeneous to TLC (Rf 0.37, 5% ethyl acetate / methylene chloride on silica gel).

Example 95 - 17-methylenenestra-1, 3,5 (19), 7-tetraen-3-ol Methyltriphenylphosphonium bromide (1.9967 g, 5.5892 mmol) and potassium t-butoxide 8627.2 mg, 5.589 mmol) suspended in 6.1 were stirred. ml of anhydrous DMSO under argon for 1 h. in an oil bath (71-83 ° C), after which equiline (300.0 mg, 1118 mmol) in 6.1 ml of anhydrous DMSO was added via syringe. See Fig. 161. After stirring for 70 min. Further, the reaction mixture was poured into 40 ml of ice-water and extracted three times with 25 ml portions of ether. The combined organic extracts were washed with 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (15% ethyl acetate / hexanes on silica gel) followed by preparative TLC (20% ethyl acetate / hexanes GF silica gel, 1000μ thick) gave a white film opaque (162.3 mg, 0.6093 mmol, 54%).

Example 96 - 17-methylene-tetra-1, 3,5 (19), 7-tetraen-3-yl acetate Methyltriphenylphosphonium bromide (3.33 g, 9.32 mmol) and potassium t-butoxide (1.05 g, 9.36 mmol) were stirred. suspended in 10 ml of anhydrous DMSO under argon for one hour in an oil bath (77-79 ° C), after which equilin (500.0 mg, 1863 mmol) in 10 ml of anhydrous DMSO was added via a syringe. . See Fig. 161. After stirring 1 h. more the cold reaction mixture was poured into 50 ml of ice-1N hydrochloric acid and extracted three times with 25 ml portions of ether. The combined organic extracts were washed with 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. The resulting light yellow syrup was collected in anhydrous pyridine (6.3 mL, 78 mmol), acetic anhydride (0.88 mL, 9.3 mmol) was added, and the reaction mixture was stirred for 16 h. The mixture was then poured into 100 ml of 1 N hydrochloric acid and extracted three times with 50 ml portions of ether. The combined organic extracts were washed with 100 ml of saturated sodium bicarbonate + 100 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. The crude acetate was chromatographed by flash evaporation (5% ethyl acetate / hexanes on silica gel) to give a yellow resin 494.7 mg, 1.604 mmol, 86%).

Example 97 - 16a, 7-epoxystr-4-en-10ß-ol-3-one To a frozen suspension (dried ice / acetone) of estra-5810), 16-dien-3-one (1, 115.7 mg, 0.4513 mmoles) in 3 ml of chloroform was added m-chloroperbenzoic acid (MCPBA), 77.4%, 420. 8 mq, 1.89 mEquiv, peracid) suspended in 4.3 ml of ether and the mixture was stirred for 2 h. The reaction was then stored in a refrigerator for 18 h, after which sodium thiosulfate pentahydrate (5% (w / w), 25 g) was added. After stirring for 5 min., The mixture was extracted three times with 10 ml portions of ether. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. The TLC suggested that intermediate 5B, 1 OB-epoxide underwent a partial elimination. Removal was completed by refluxing the white crystalline residue for one hour in 20 g of potassium hydroxide (w / w) in anhydrous methanol. The reaction mixture was poured into 50 ml of ice water and extracted with 50 ml of ether. The organic extract was washed twice with 50 ml portions of water, dried over sodium sulfate and dried through diatomaceous earth. The residue was washed with 20 ml of ether and the combined filtrates were concentrated under reduced pressure. The residue was subjected to TLC preparation (50% ethyl acetate / hexanes on silica gel, thickness 1000μ) to give a colorless resin (19.7 mg, 72.3 μmol 16%).

Example 98 - 18-Nor-17-methylestra-4.13 (17) -dien-3-ol To a cooled solution (ice-water bath) of 18-nor-17-methylestra-4,13 (17) -dien- 3-one (3, 0.23 g, 0.90 mmol) in anhydrous methanol (2.3 ml) was added to sodium borohydride (0.23 g, 6.1 mmol) and the reaction was stirred for 2 h. See Fig. 162. The solvent was removed under reduced pressure and 10 ml of water was added to the residue. The mixture was then extracted three times with 10 ml portions of methylene chloride. The combined organic extracts were washed with 10 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed twice with 5 ml of methylene chloride and the combined filtrates were filtered under reduced pressure. The resulting light yellow-colored solid was purified through preparative TLC (5% ethyl acetate / methylene chloride in GF silica gel, thickness 1000) to give a yellow solid (53.6 mg, 0.207 mmol, 23%) homogeneous to TLC (5% ethyl acetate / methylene chloride on silica gel, Rf 0.32).

Example 99 - Androsta-4,16-dien-3-one This synthesis is illustrated in Figure 178. Several methods are recognized for the conversion of testosterone to Androsta-4,16-dien-3-one (Brooksbank et al., Biochem. J. (1950) AZ: 36). Alternatively, the thermolysis (460 °) of the methyl carbonate 15 of testosterone gives Androsta-4,16-dien-3-one in a 90% yield. 17B-MethoxyCarbonyloxy-andorst-4en-3-one (IV) was prepared from testosterone (III Fluka) with methyl chloroformate / pyridine (a) in a 76% yield (after recrystallization from MeOH. Mp 140-141 ° C, [a] D = + 95.4 ° (c = 1.10) - IR. (CDCI3): 1740s, 1665s, 1450s, 1280s, - 1H-NMR. (360 MHz): 0.87 (s, 3 H), 1.20 (s, 3 H), 3.77 (s, 3 H), 4.53 (br.t, J (, 1 H), 5.75 (s, 1 H), a solution of methyl carbonate IV in toluene pyrolysed (b) as described for I. Recrystallization of the crude product from acetone at room temperature gave pure ketone 4 in a 90% yield Pf127-129.5 °, (a) D + 118.9 ° (C = 1.32 ) ([3]: mp 131.5-133.5 ° (hexane), [a] D16 = + 123 + 3.5 ° (C = 1.03)). -IR. (CDCI3): 3050w, 1660s, 1615m - 1H-NMR. (360 MHz): 0.82 (s, 3 H), 1.22 (s, 3 H), 5.70 (m, 1 H), 5.73 (s, 1 H), 5.84 (m, 1 H).

Example 100 - Androsta-4,16-dien-3a-ol (5) and -3ß-ol These syntheses are represented in Figure 178. Androsta-4, 16-dien-3-one (4) was reduced to -55 ° C with lithium tris- (1,2-dimethylpropyl) borohydrate 5 in THF (c) as described for the preparation of 2 (Figure 1). Chromatography on silica gel CH2Cl2 / ethyl acetate 9: 1 gave pure axial alcohol (48% yield) and pure equatorial alcohol 6 (yield 48%). The analytical samples were further purified through recrystallization (from PE at -30 ° C to 5, from cyclohexane at room temperature to 6). Data of 5. P.f. 77-79 °, [a] D + 120.6 ° (C = 1.26) - IR. (CDCl 3): 3620m, 3440m br., 1660m, 1595w.-1 H-NMR. (360 MHz): 0.79 (s, 3 H); 1.02 (s, 3 H); 4.07 (m, W? 2 * 10, 1 H); 5.48 (d x d, J 5 and 2, 1 H); 5.71 (m, 1 H); 5.85 (m, 1 H). Data of 6. P.f. 116-119 °, [a] D + 53.9 ° (C = 1.28) ([47): p.f. 116-118 °, [8) D + 59.3 ° (C = 0.4) - IR. (CDCI3): 3610m, 3420m br., 3050m, 1660m, 1590w. -1H-NMR. (360 MHz): 0.78 (s, 3 H); 1.08 (s, 3 H); 4.15 (m, w? * 20, 1 H); 5.30 (m, w? «5, 1 H); 5.71 (m, 1 H); . 85 (m, 1 H).

Example 101 - androsta-5,16-d ien-3 -ol This synthesis is shown in Figure 179. To a solution of alcohol 8 (545 mg, 2.0 mmol) in acetone (100 ml) at 0 ° C under N2 he quickly added Jones Reagent (i, 1.5 ml ca. 4 mmoles). After 5 min., The reaction was poured into dilute phosphate pH buffer (pH 7.2, 1200 ml) and extracted with ether. The extracts were washed with a saturated aqueous NaCl solution, dried (Na 2 SO 4) and dried to give mainly Androsta-5,16-dien-3-one as an oil (567 mg). The crude product was dissolved in 7 ml of THF and reduced with lithium tris (1, 2-dimethylpropyl) borohydrate (c) at 55 ° C as described for the preparation of 2. The crude product (530 mg) was chromatographed on silica gel (100 g) with CH2Cl2 / ethyl acetate 4: 1 to give 280 mg (51%) of pure a-alcohol 7 (eluted first) and 13 mg of the starting alcohol 8. A small sample of 7 was recrystallized from acetone / water at room temperature. P.f. 1380, [8] D -7705 ° (c = 1.2. - IR. (CDCI3): 3580m, 3430m, 1665w, 1590w, - 1H-NMR. (360 MHz): 0.80 (s, 3 H); 1.06 (s) , 3 H), 4.02 (m, w1 / 28, 1 H), 5.44 (m, 1 H), 5.72 (m, 1 H), 5.86 (m, 1 H).

Example 102 - Androsta-5,16-dien 3B-ol This compound was prepared in a 73% yield by a known method (Marx, A: F: et al., Ger. Offen, 2631.915, Chem. Abst. 87: 23614p (1977)) from commercial 3B-hydroxy-androst-5-en-17-one (Vil) (Fluka). P.f. 137 °, [a] D = -71.9 ° (c = 1.5) ([48]: mp 140-14 °, [a] D = 68 °. - IR. (CDCI3): 3600m, 3420m br., 1670w, 1590w, -1H-NMR. (360 MHz): 0.80 (s, 3 H), 1.05 (s, 3 H), 3.53 (m, w1 / 2"22.1H), 5.38 (m, 1H), 5.72 (m, 1 H); 5.86 (m, 1H).

This synthesis is presented in Figure 4.

Example 103 - Alternate synthesis of Andorsta-4,16-dien-3-one The following synthesis method is illustrated in Figure 180: dehydroepiandrosterone p-toluenesulfonylhydrazone Dehydroepiandrosterone (VII) (14.4 g, 50.0 m moles) and hydrazide of p toluenesulfonyl (12.75 g, 68.5 mmoles) in 300 ml of dried methanol were heated under reflux for 20 hours. The mixture was transferred to a conical flask and allowed to cool. The crystalline product was filtered under suction and washed with methanol (50 ml). Other cultures of the product were obtained by sequentially evaporating the filtrate to 75 ml and 20 ml, and allowing crystallization each time. The total production was 21.6 g (95%).

Androsta-5, 16-dien-3ß-ol. Dehydroepiandrosterone p-toluenesulfonylhydrazone (22.8g, 40.0 mmol) was cooled in 1.0 liters of tetrahydrofuran dried in a dry ice / isopropanol bath. The mixture was stirred while adding n-butyl lithium (125 mL of 1.6 M solution in hexane, 200 mmol). The mixture was allowed to warm to room temperature and was stirred for 24 hours. 50 ml of water was added with cooling on ice. The mixture was evacuated in a saturated ammonium chloride / ice solution (500 ml) and extracted with ether twice. The organic layers were washed with a saturated sodium carbonate solution (500 ml) and a saturated sodium chloride solution (500 ml), dried and evaporated in vacuo to give the crude product. This was purified via flash chromatography on 190 g of silica gel 60, 230-400 mesh, eluting with ethyl acetate / hexane (20: 80-> 50:50) to give the crystalline material. The product was recrystallized from ethanol (45 ml) / 3% hydrogen peroxide - (8 ml) by washing with methanol (30 ml) / water (8 ml) to give the pure product (6.75 g, 50%) . • 10 Androsta-4, 16-dien-3-one A solution of 10 g of Androsta-5, 16-dien-3ß-ol in 475 ce of toluene and 75 ce of 30-cyclohexanone was distilled (approximately 50 ce of distillate was collected) to eliminate the moisture, 5 g of AI (OPr1) 3 in 50 g of toluene was added and the solution was refluxed for 1 hour. After water was added, the volatile components were removed by steam distillation and the residue was extracted with chloroform. The evaporation of the dried extract followed by the crystallization of the residue from chloroform-hexane, produced 7.53 g of Androsta-4, 165-dien-3-one (25). Another 0.97 g (total, 8.5 g, 86%) was obtained through mother liquor chromatography on neutral alumina.

Example 104 - Synthesis of ether Androsta-3,5,16-trien-3-yl methyl To a partial solution of androsta-4, 16-dien-3-one (1.00 g, 3.70 mmol) in 2,2-dimethoxypropane (5.0 ml, 41 mmol) and 5 ml of DMF was added 0.2 ml of methanol and p-toluenesulfonic acid monohydrate 826.4 mg, 0.139 mmol). The mixture was refluxed for 5 h, after which it was cooled and 152.5 mg of sodium bicarbonate was added. The suspension was divided between 50 ml ice-water and 50 ml ethyl acetate. The organic layer was washed with two 50 ml portions of water + 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residual oil was taken up in 50 ml of hot hexane and filtered through a column of silica gel 60 of 12 mm x 30 mm using 150 ml of hot hexane. The combined filtrates were concentrated under reduced pressure and recrystallized from acetone / methanol to give white crystals (468.9 mg, 1645 mmol, 44%), m.p. 83-92 ° C.

Example 105 - Synthesis of 17-methylene-Androst-4-en-oles To 20-homoandrosta-4,17-dien-3-one (119.0 mg, 0.4184 mmol) in 5 ml of methanol was added sodium borohydride (6.0 mg, 0.16 mmole) and 77μL of water. After stirring 2 h, more sodium borohydride 832.0 mg, 0.846 mmol) was added and the mixture was stirred overnight. After concentrating under reduced pressure (5% ethyl acetate / hexane on silica gel), a more polar product (59.8 mg) and a less polar product (1.7 mg) were present.

Example 106 - Synthesis of 17-methylene-6-oxo-Androsta-4-en-3-one To a cooled solution of 20-homoandrosta-5, 17-dien-3-lo (399.4 mg, 1394 mmol) in 50 ml of acetone was added Jones Reagent 2.67M (2.0 ml, 5.3 mmol). After stirring for 1 h, the reaction was quenched with isopropanol (1.0 mL, 13 mmol) and was poured into 100 mL of water. The mixture was extracted three times with 50 ml portions of ethyl acetate and the combined organic extracts were washed with 50 ml of saturated sodium bicarbonate + 50 ml of brine. The organic phase was then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from 95% ethanol to give an almost white powder (177.8 mg, 0.5958 mmol, 43%), m.p. 113-115 ° C.

Example 107 - Synthesis of 6β-OH-Androsta-4,16-dien-3-one To a solution of 3.5, 16-trien-3-yl-methyl androstather, (12) (200.5 mg, 0.7049 mmoles), in 5 ml of 1,2-dimethoxyethane (DME) and 1 ml of water was added m-chloroperbenzoic acid (MCPBA, 77.4%, 173.2 mg, 0.776 mmoles) suspended in 5 ml. ml of DME + 1 ml of water + 0.40 g of 5% NaOH (w / w) dropwise, with stirring for a period of 90 min. After stirring 18 h, additional MCPBA (247.0 mg, 1.11 mmol) suspended in 10 ml of DME + 2 ml of water + 0.8 g of 5% NaOH (w / w) was added dropwise, with stirring, for 1 h. ? A h. the reaction mixture was stirred V * h and then was poured into 25 ml of saturated sodium bicarbonate. The aqueous mixture was extracted three times with 25 ml of ether and the combined organic extracts were washed with 50 g of 5% sodium thiosulfate (w / w) + three 50 ml portions of brine, dried over magnesium sulfate, they were filtered through Celite®, and concentrated under reduced pressure. The resulting crystalline residue was purified through preparative TLC (35% ethyl acetate / hexane on silica gel) followed by double recrystallization from aqueous ethanol to give white glossy platelets (102.3 mg, 0.3571 mmol, 51%), pf 165-166 ° C.

Example 108 - 18-Nor-17-methilandrosta-4,13 (17) -dien-3-ol Refer to Fig. 189. To a solution of 18-nor-17-metilandrosta-4,13 (17) - dien-3-one (1, 378.2 mg, 1399 mmol) in 7.5 ml of anhydrous ether was added 59.7 mg (1.57 mmol) of lithium-aluminum hydride (LAH). After stirring the resulting suspension for 30 minutes, 2.00 of the Glauber's salt was added and the mixture was stirred for an additional 30 minutes. The mixture was filtered and extracted with four 25 ml portions of ether. The combined filtrates were concentrated under reduced pressure and then subjected to TLC preparation (GF silica gel, 1000μ, 5% ethyl acetate / methylene chloride as eluent) to give a less polar fraction (Rf 0.63, 34.5 mg , 0.127 mmoles, 9%) and a more polar fraction (R 0.45, 273.8 mg, 1.005 mmoles, 72%).

Example 109 - 18-Nor-17-methilandrosta-3,5,13 (17) -trien-3-yl methyl ether. Refer to Fig. 189. A solution of 18-nor-17-metilandrosta-4,13 ( 17) -dien-3-one (1_, 0.86 g, 3.2 mmol) in 2,2-dimethoxypropane (4.3 ml, 35 mmol) and dimethylformamide (DMF, 4.3 ml) containing 0.17 ml of anhydrous methanol and 21.3 mg of monohydrate p-Toluenesulfonic acid was refluxed for 4 h. and then let it cool. 0.13 g of sodium bicarbonate was added and the mixture was divided between 65 ml of hexanes and 40 ml of ice-water. The organic phase was washed with two 40 ml portions of water + 40 ml of brine and then filtered by flash-evaporation through a column of silica gel with a height of 17 mm by a diameter of 30 mm (200-400). tights). Concentration of the combined filtrates followed by recrystallization from acetone / 95% ethanol gave bright yellow crystals (489.6 mg, 1721 mmol, 54%, mp 95-101 ° C). TLC (10% or ethyl acetate / hexane on silica gel) showed a higher product in Rf 0.69 with a contaminant trace at the origin.

Example 110 - 18-Nor-17-methilandrosta-4,13 (17) -d »en-6β-ol-3-one Refer to Fig. 189. The reaction was carried out in a manner similar to the procedure of DN Kirk and J. M. Wiles, J. Chem. Soc, Chem. Commun. 1974, 927. To a stirred solution of 18-nor-17-methilandrosta-3,5, 13 (17) -trien-3-ylmethyl ether (477.0 mg, 1677 mmol) in 1,2-dimethoxyethane (DME, 20 26 ml) was added 77% m-chloroperbenzoic acid (MCPBA, 999.7 mg, 4.48 mEq) suspended in 39 ml of DME, 8 ml of water and 5% sodium hydroxide (w / w) (7.1 ml), for a period of 88 min. After stirring 20 h, the reaction mixture was poured into 50 ml of saturated sodium bicarbonate and extracted with three 50 ml portions of ether. The combined organic extracts were washed with 50 g of sodium thiosulfate pentahydrate at 55 (w / w) + 3 50 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure to give a yellow syrup. Purification through TLC preparation (silica gel GF, 1000μ, 35% ethyl acetate / hexane as eluent) gave an off-white crystalline film (132.1 mg, 0.4612 mmol, 28%) whose TLC (35% ethyl acetate) ethyl / hexanes on silica gel) showed that it contained a major component (Rf 0.23) and a minor component (Rf 0.18).

Example 111 - 17ß-Metilandrost-4-en-3,6-dione Refer to Figure 189. Reagent was added Jones (2.67 M., 0.88 ml, 2.3 mmol) to a solution of 17β-metilandrost-5-en-3β-ol (5. 135.5 mg 0.4697 mmol) (JB Jones and KD Gordon, Can J. Chem. 1972 , 50, 2712-2718) in 15 ml of acetone and the mixture was stirred for 45 min. The reaction was quenched with the addition of 0. 44 ml of 2-propanol. After stirring for a further 10 minutes, the reaction mixture was emptied into 30 ml of water and extracted with three 15 ml portions of ethyl acetate. The combined organic extracts were washed with 15 ml of saturated sodium bicarbonate + 15 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10%) ethyl acetate and the combined filtrates were concentrated under reduced pressure. TLC preparation (silica gel GF, 1000 μ, 25% ethyl acetate / hexanes as eluent) and recrystallization from aqueous ethanol gave glossy whitish crystals (37.5 mg, 0.125 mmol, 27%) m.p. 94-95 ° C, homogeneous to TLC (25% ethyl acetate / hexanes on silica gel, Rf 0.39).

Example 112 - 17ß-Metilandrost-4en-3-ol Refer to Fig. 189. LAH (21.3 mg, 0. 561 mmoles) to a solution of 17β-methylandrost-4-en-3-one (7, 143.2 mg, 0.4999 mmoles) (JB Jones and KD Gordon, Can. J. Chem. 1972, 50, 2712-2718) in 2.8 ml of anhydrous ether. After stirring the suspension for 30 minutes, 0.76 g of the Glauber's salt was added and the mixture was stirred during V? h. plus. 10 ml of ether were added and the suspension was filtered through diatomaceous earth. The residue was washed with three 10 ml portions of ether and the combined filtrates were concentrated under reduced pressure. The crude product was separated through TLC preparation (GF silica gel, 1000 μ, 5% d4e ethyl acetate / methylene chloride as eluent) in a more polar component (Rf 0.30, 77.9 mg, 0.270 mmol, 54% ) and a less polar component (Rf 10 0.43, 10.3 mg, 0.0357 mmol, 7%).

Example 113- 17-Methylenandrost-3,5-dien-3-yl-methyl ether Refer to Fig. 190. To 17-methylenandrost-4-en-3-one (9, 2.0000 g, 7.0314 mmoles) in 2 , 2-dimethoxypropane (9.4 ml, 76 mmol) and 9. 4 ml of DMF were added 0.37 ml of anhydrous methanol and 47.0 mg of p-toluenesulfonic acid. After refluxing for 4 h, the reaction mixture was allowed to cool and then partitioned between 140 ml of hexanes and 90 ml of water. The organic phase was washed with two 90 ml portions of water + 90 ml of brine, dried over magnesium sulfate and filtered by flash-flashing through a silica gel column 30 mm in diameter by 37 mm in height (200-400 meshes). The product continued to elute with 200 ml of hexanes. Concentration of the combined filtrates under reduced pressure and recrystallization of the residue from acetone / methanol gave very light yellow platelets (1.5291 g, 5.1231 mmol, 73%), m.p. 97-99 ° C, homogeneous to TLC (25% ethyl acetate / hexane on silica gel Rf 0.72).

Example 114 - 17-Methylenandrost-4-en-6β-ol-3-one Refer to Fig. 190. To a stirred solution of 17-methylenandrosta-3,5-dien-3-yl methyl ether (1_0, 500.1 mg, 1676 mmol) in 10 ml of DME was added MCPBA (318.6 mg, 1846 mmol) in 10 ml of DME and 4 ml of water for a period of 15 min. After stirring for 30 minutes, the mixture was emptied into 50 ml of saturated sodium bicarbonate and extracted with three 50 ml portions of ether. The combined organic extracts were washed with 50 g of 5% sodium thiosulfate pentahydrate (p-p) + three 50 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (45% ethyl acetate / hexanes on silica gel) followed by recrystallization from aqueous ethanol gave slightly yellow crystals (187.1 mg, 0.6228 mmol, 37%), m.p. 192-194 ° C, whose TLC (355 ethyl acetate / hexanes on silica gel showed major components (Rf 0.17) and minor components (Rf 0.13).

Example 115 - 17-Methylenandrosta-1,4-dien-3-one Refer to Fig. 190. A solution of 17-methylenandrost-4-en-3-one (9, 1,0001 g, 3.5160 mmoles) and 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.43 g, 10.7 mmol) in 60 ml of dioxane, freshly distilled after refluxing overnight over sodium, was refluxed 6 h and then it was cooled with stirring in tap water. 50 ml of methyl t-butyl ether (MTBE) were added and the suspension was filtered through diatomaceous earth. The residue was washed with two 50 ml portions of MTBE and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the residue (20%) of ethyl acetate / hexanes on silica gel) followed by recrystallization from 95% ethanol gave off-white crystals (498.9 mg, 1767 mmol, 50%, mp 155-157 ° C.

Example 116- 17-Methylenandrosta-1, 3,5-trien-3-yl benzoate Refer to FIG. 190. The reaction was carried out in a procedure adapted from R.W. Draper et al., Arzneim.-Forsch. 1982, 32, 317-322, as follows: Under argon, 17-methyleneadrosta-1,4-dien-3-one (2, 389.9 mg) was stirred for 18 hours in an oil bath (68-73 ° C). 1378 mmole), anhydrous pyridine (4.7 ml, 58 mmol), and benzoyl chloride (1.2 ml, 10 mmol). After cooling on ice, the reaction mixture was poured into 40 ml of 1N ice-HCl and extracted with three 20 ml portions of methylene chloride. The combined organic extracts were washed with 40 ml of cold 1N HCl + 40 ml of saturated sodium bicarbonate + 40 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Flash chromatography (4% ethyl acetate / hexane on silica gel) gave a yellow solid (0.43 g, 1.1 mmol, 81%).

Example 117-17-Methylenandrosta-1,4-dien-6-ol-3-one Refer to Figure 190. The reaction was carried out in a procedure adapted from R.W. Draper et al., Arznoim.-Forsch. 1982, 32, 317-322, as follows: MCPBA (211.4 mg, 1225 mmoles) in DME 86.6 ml) and 2.7 ml of water 30 were added to 17-methylenandrosta-1, 3,5-trien-3-yl benzoate (1_3, 0.43 g, 1.1 mmol) in 6.6 ml of DME over a period of 20 minutes with shaking. Stirring was continued for 30 minutes, and the reaction mixture was then poured into 35 ml of saturated sodium bicarbonate. The mixture was extracted with three 35 ml portions of ethyl acetate. The combined organic extracts were washed with 35 g of 5% sodium thiosulfate pentahydrate + three 35 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparation TLC (silica gel GF, 1000μ, 50% ethyl acetate / hexanes as eluent) gave a yellow crystalline solid (83.7 mg, 0.280 mmol, 25%) homogeneous to TLC (50%) ethyl acetate. hexanes on silica gel, Rf 0.50).

Example 118 - Androsta-1,4,16-trien-6ß-ol-3-one Refer to Fig. 190. Argon, Androsta-1, 4, 16-trien-3-one (15., 500.0 mg, 1863 mmol), anhydrous pyridine (6.4 ml, 79 mmol) and benzoyl chloride (1.6 ml, 14 mmol) in an oil bath / 70-73 ° C) and stirred for 18 h.

After cooling on ice, the mixture was emptied into 50 ml of 1 N ice-HCl and extracted with three 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of cold 1 N HCl + 50 ml of saturated sodium bicarbonate + 50 ml of brine. They were dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Flash chromatography (2% ethyl acetate / hexane on silica gel) gave yellow crystals (0.47 g, 1.3 mmol, 68%) of intermediate benzoate. This was taken up in 30 ml of chloroform with MCPBA (240.0 mg, 1391 mmol). After stirring for 1 h, more MCPBA (239.5 mg, 1388 mmol) was added and the reaction was stirred for another hour. The mixture was then washed with 30 g of 5% sodium thiosulfate pentahydrate (w / w) + 30 ml of saturated sodium bicarbonate + 30 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. . The residue was washed with 10 ml of chloroform and the combined filtrates were concentrated under reduced pressure. Flash chromatography (40-45% ethyl acetate / hexane on silica gel) gave a yellow resin (106.1 mg, 0.3731 mmol, 29%), which TLC (40% ethyl acetate / hexanes on silica gel) showed that it contained major (Rf 0.34) and minor (Rf 0.40) components.

Example 119 - Androsta-4,16-dien-6ß-ol-3-one To a solution of androsta-3,5, 16-trien-3-yl methyl ether, 12 (200.5 mg, 0.7049 mmoles), in 5 ml of 1, 2-dimethoxyethane (DME) and 1 ml of water was added m-chloroperbenzoic acid (MCPBA, 77.4%, 173.2 mg, 0.776 mmol) suspended in 5 ml of DME + 1 ml of water + 0.40 g of NaOH at 5% (w / w), drop by drop with stirring, for a period of 90 min. After stirring 18 h, more MCPBA (247.0 mg, 1.11 mmol) suspended in 210 ml of DME + 2 ml of water + 0.8 g of 5% NaOH (w / w) was added dropwise, with stirring, for 1 hour. Goes h. The reaction mixture was stirred 14 h. and then it was emptied into 25 ml of saturated sodium bicarbonate. The aqueous mixture was extracted three times with 25 ml of ether and the combined organic extracts were washed with 50 g of 5% sodium thiosulfate (w / w) + three portions of 50 ml brine, dried over magnesium sulfate, filtered through Celite® and concentrated under reduced pressure. The resulting crystalline residue was purified through TLC (35%) preparation of ethyl acetate / hexane on silica gel) followed by double recrystallization from aqueous ethanol to give glossy white platelets (102.3 mg, 0.3571 mmol, 51%). %), pf 165-166 ° C.

Example 120- 20-Homoandrosta-4,17-dien-3-one Refer to Fig. 191. To a partial solution of 20-homoandrosta-5,17-dien-3-ol (1,0001 g, 3.4911 mmol) in 100 ml of toluene and 20 ml (0.19 moles) of cyclohexanone was added to aluminum isopropoxyl 82.00 g, 9.79 mmoles) in 20 ml of hot toluene. After refluxing for 4 h. The cooled reaction mixture was stirred for one minute, with 5 ml of water and 12.5 ml of 3.6N sulfuric acid. The organic layer was washed with 50 ml of brine, dried over magnesium sulfate, filtered through Celite® and concentrated under reduced pressure. After steam distillation to remove the cyclohexanone, the non-volatile residue was taken up in two 10 ml aliquots of dichloromethane, dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by flash chromatography (15% ethyl acetate / hexane on silica gel) and recrystallization from aqueous acetone to give colorless needles (238.8 mg, 0.8400 mmol, 24%), m.p. 130-134 ° C [lit. (B. S. Macdonald et al., Steroids 1971, 18, 753-766) p.f. 129-131 ° C].

Example 121 - 20-Homoandrosta-4,17-dien-3-oles Refer to Figure 191. A 20-homoandrosta-4,17-dien-3-one (119.0 mg, 0.4184 mmole) in 5 ml of methanol was added. they added sodium borohydride (6.0 mg, 0.16 mmol) and 77 ml of water. After stirring for 2 h, more sodium borohydride (32.0 mg, 0.846 mmol) was added and the mixture was stirred overnight. After concentrating under reduced pressure, the residue was purified through TLC preparation (5% ethyl acetate / hexane on silica gel) to give a more polar product (59.8 mg) and a less polar 81.7 mg).

Example 122 - 20-Homoandrosta-4,17-diene-3,6-dione Refer to Figure 191. To a cooled solution of 20-homoandrosta-5, 17-dien-3-ol (399.4 mg, 1,394 mmol) in 50 ml of acetone, Jones 2.67M reagent (2.0 ml, 5.3 mmol) was added. After stirring for one hour, the reaction was quenched with isopropanol (1.0 mL, 13 mmol) and was poured into 100 mL of water. The mixture was extracted three times with 50 ml portions of ethyl acetate and the combined organic extracts were washed with 50 ml of saturated sodium bicarbonate + 50 ml of brine. The organic phase was then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from 95% ethanol to give an almost white powder (177.8 mg, 0.5958 mmol, 43%). P.f. 113-115 ° C.

Example 123 - 6β, 19-Epoxy-17-vodoandrosta-4,16-dien-3-ethylene ketal Refer to Fig. 192. A mixture of 6β, 19-epoxy-5β-chloro-17-iodoandrost-16- crude ene (VL, 1.38 g, 3.09 mmol) (G. Habermehl and A. Haaf, Z. Naturforsch, 1970, 25b, 191-195), ethylene glycol (0.97 g, 16 mmol), 50 ml of toluene and monohydrate of p-Toluenesulfonic acid (20.3 mg, 0.107 mmol) was refluxed 19 h with the azeotropic removal of water (Deen-Stark). After cooling, 100 ml of ethyl acetate was added and the reaction mixture was washed with 100 ml of saturated sodium bicarbonate + 100 ml of brine. The organic phase was dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure to give a tan crystalline solid (1.47 g). This residue was suspended in 40 ml of anhydrous methanol, potassium acetate 82.44 g, 24.9 mmol) was added and approximately 26 ml of methanol was distilled. The remainder was concentrated under reduced pressure, 50 ml of water was added and the mixture was extracted three times with 25 ml aliquots of methylene chloride. The dried extracts (sodium sulfate) were filtered through diatomaceous earth and the residue was washed with 10 ml of methylene chloride. Concentration of the combined filtrates under reduced pressure gave a yellow solid, which was further purified by flash evaporation chromatography (5-7.5-10% ethyl acetate / methylene chloride on silica gel) and recrystallization from from methanol to give light yellow needles (914.6 mg, 2.013 mmol, 65%), mp 187-189 ° C. 1 H-NMR: 6.13 d, 1 H, dd, 16-H; 5.82 d, 1H, s, 4-H; 4.71 d, 1H, d, 6a-H; 4.22 d and 3.53 d, 2H, AB, 19-H's; 4.10-3.28 d,? U, mult., 3-ketal H's; 0.83 d, 3 H, s, 18-Me.

Example 124 - Androsta-4,16-dien-19-ol-3-one Refer to Fig. 192. Approximately 75 ml of anhydrous ammonia were distilled through a KOH tower in a flame-dried 3-necked flask. of 250 ml equipped with an inlet adapter, a magnetic stir bar, a dried ice / acetone condenser, 35 and stoDPer. A solution of 6β, 19-epoxy-17-iodoandrosta-4,16-dien-3-ethylene ketal (1_8, 880.4 mg, 1938 mmol) 45 ml of tetrahydrofuran (THF) was added, followed by sodium metal (0.20 g, 8.7 mg-atom) cut into small pieces. After stirring under argon pressure for 30 minutes, the reaction was quenched with the addition of 1.0 ml of absolute ethanol. The ammonia was allowed to boil overnight, 50 ml of water was added and the mixture was extracted with 3 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. After washing the residue with 10 ml of methylene chloride, the combined filtrates were concentrated under reduced pressure. The cetal intermediary proved to be remarkably non-reactive, but was finally hydrolyzed under reflux for 18 hours in 5 ml of chloroform and 2.5 ml of 4 N hydrochloric acid. To the cold hydrolysis mixture was added 50 ml of ethyl acetate and the layers separated. The organic layer was washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The resulting brown foam was purified by flash evaporation chromatography (50% ethyl acetate / hexane on silica gel) followed by preparation TLC (50% ethyl acetate / hexanes on GF silica gel, thickness 1000μ) to give a partially crystalline film. (66.7 mg, 0.233 mmol, 12%). 1 H-NMR: 5.92 d, 1 H, s, 4-H; 5.87-5.64 d, 2H, mult., 16.17-H's; 4.109 and 3.94 d, 2H, AB, 19-H's; 0. 79 d, 3 H, s, 18-Me.

Example 125 - Hydrostone of Androst-5-en-3β, 19-diol-17- (p-toluenesulfonyl) Refer to Fig. 193. A suspension of androst-5-en-3β, 19-diol-17-one (1_, commercially available from Research Plus, 512.5 mg, 5 1684 moles) and p-toluenesulfonyl hydrazide (p-TsNHNH2, 392.1 mg, 2.105 mmol) in 6.0 ml of 2-propanediol was brought to reflux for 24 hours. To the cold reaction mixture was added 20 ml of ether and the solvent was removed under reduced pressure. The residue was taken up in 10 ml of ether and the solution was filtered through diatomaceous earth. 10 ml of hexanes were added to the filtrate and the suspension was concentrated under reduced pressure. The residue was taken up in 10 ml of hot benzene and the cold suspension was filtered. The filtrate was concentrated under reduced pressure and then flash chromatographed (40% > ethyl acetate / hexane on silica gel) to give an opaque resin (0.69 g, 1.5 mmol, 87%).

Example 126 - Androsta-5,16-dien-3β, 19-diol Refer to Fig. 193. A hydrazone solution of androst-5-en-3β, 19-diol-17- (p-toluenesulfonyl) (2 , 0.69 g, 1.5 mmol) in 35 ml of anhydrous THF was cooled in an ice / acetone bath under argon and n-butyl lithium (2.5 in hexanes, 3.7 ml, 9.3 mmol) was added dropwise, with stirring, during a period of 1 min. The reaction mixture was stirred 4 days, during which time it was allowed to warm gradually to room temperature. The reaction was then poured into 50 ml of saturated ammonium chloride-ice and the layers were separated. The aqueous layer was extracted twice with a 25 ml portion of ethyl acetate. The combined organic phases were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The residual yellow resin was flash chromatographed (50-55-60% ethyl acetate / hexane on silica gel) and recrystallized from methyl t-butyl ether / benzene to give viny white crystals ( 92.5 mg, 0.361 mmol, 24%), mp 169-171 ° C.

SCHEME 14. Synthesis of bisnorcolenes Example 127 - Ether 19.21-Bisnorcola-1, 2.5 (10), 17Z-tetraen-3-yl methyl, 2 (Scheme 14) To a suspension of 19,21 -bisnorcola-1, 3.5 (10), 17Z-tetraen-3β-ol (1, 1.0000 g, 3.2208 mmol) in 50 ml of acetone was added potassium carbonate (0.67 g, 4.8 mmol), and the resulting suspension was heated to reflux with the exclusion of moisture. Dimethyl sulfate (0.76 ml, 8.0 mmol) was added and the reaction was continued for 22 h. The mixture was then poured into 50 ml of 5% sodium hydroxide (w / w) and extracted three times with 50 ml portions of ether. The combined organic extracts were washed three times with 50 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Crystallization of the residual tan solid from 95% ethanol with the treatment of the carbon intermediate produced white glossy platelets (753.1 mg, 2.321 mmol, 72%) m.p. 80.5-82 ° C, homogeneous to TLC (10% ethyl acetate / hexane on silica gel, product Rf 0.69, ether estra-1, 3.5 (10, 17Z-trien-3-yl methyl Rf 0.66.

Example 128 - Ether 19. 21 -Bisnocola-2.5 (10) .17Z-trien-3-yl methyl, 3 (Scheme 14) A solution of ether 19.21 - bisnorcola-1, 3.5 (10) 17Z -tetraen-3-yl methyl (2, 450.0 mg, 1387 mmol) in 13 ml of anhydrous THF + 4.60 g (62.1 mmol) of t-butanol was added to approximately 50 ml of anhydrous ammonia followed by 0.20 g (29 mg- atom) of lithium wire cut into small pieces. The reaction was continued for 7 h, after which 1.6 ml of methanol was added and the ammonia was allowed to boil overnight. 40 ml of water were added and the mixture was extracted three times with 40 ml portions of ether, and extracted three times with 50 ml portions of ether. The combined organic extracts were washed three times with 40 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Instantaneous evaporation filtration of the resulting white platelets (hexanes-1% ethyl acetate / hexanes-2% ethyl acetate / hexanes) followed by recrystallization from 95% ethanol gave white, fine, glossy platelets (329.7 mg, 1010 mmol, 73%), mp 76-77 ° C. The FTA (1% >; ethyl acetate / hexane) showed that this is a mixture of the desired Birch product (Rf 0.15) and the starting material (Rf 0.09).

Example 129 - 19,21-Bisnorcola-4,17Z-dien-3-one, 4 (scheme 14): To a solution of ether 19,21 -bisnorcola-2, 5 (10), 17Z-trien-3-il Methyl (3,130 mg, 0.3981 mmol) in 35 ml of acetone was added with 1.3 ml of methanol and 1.3 ml of concentrated HCl (12.1 M_). After stirring for 1 h, 1.33 g of sodium bicarbonate + 10 Ml of water were added and the mixture was extracted three times with 5 Ml portions of methylene chloride. The combined organic extracts were washed with 5 Ml of brine, dried over sodium sulfate and filtered through Celite® 503. The residue was washed with 5 Ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. The TLC preparation (10%> ethyl acetate / hexane on GF of alumina 1000μ) of the resulting yellow syrup produced a slightly yellow resin (293 mg, 93.7 μmol, 24%) homogeneous to TLC (10% ethyl acetate / hexanes on silica gel, product Rf 0.1, estra-4,16-dien-3-one Rf 0.1) Example 130 - Ether 19.21 -Bisnorcola-1, 3,5 (10) -trien-3-yl methyl, 6 (Esguema 14): To a solution of 19,21 -bisnorcola-1, 3,5 (10) -trien-3-ol (5, 460.0 mg, 1472 mmol) in 25 mL of acetone was added potassium carbonate (0.31 g, 2.2 mmol), and the suspension was heated to reflux with the exclusion of moisture. Dimethyl sulfate (0.34 Ml, 3.6 mmol) was added and the reaction was continued for 20 h. The mixture was then poured into 25 Ml of 5% sodium hydroxide (w / w) and extracted three times with 25 Ml portions of ether. The combined organic extracts were washed three times with 25 Ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (10% ethyl acetate / hexanes on silica gel) gave a colorless syrup (0.43 g, 1.3 mmol, 89%).

Example 131 - Ether 19,21 - Bis-norcola-2, 5 (19) -dien-3-yl methyl, 7 (Scheme 14): A solution of ether 19,21 -bisnorcola - 1, 3,5 (10) -trien -3-yl methyl (6, 0.36 g, 1.1 mmol) in 10 Ml of anhydrous THF + 3.68 g (49.6 mmol) of t-butanol was added to approximately 35 Ml of anhydrous ammonia, followed by 0.16 g (23 mg atom) of lithium cable cut into small pieces. The reaction was continued for 8 h and then quenched with 1.3 Ml of methanol. After the ammonia was boiled overnight, 30 Ml of water was added and the mixture was extracted three times with 30 Ml portions of ether. The combined organic extracts were washed three times with 30 Ml portions of brine, dried over sodium sulfate and filtered through Celite® 503. The residue was washed with 25 Ml of ether and the combined filtrates were concentrated under reduced pressure. to give a colorless syrup (0.33 g, 1.0 mmol, 91%) homogeneous to TLC (5% ethyl acetate / hexanes on silica gel, Rf 0.69, starting material Rf 0.56 0.49).

Example 132 - 19,21 -Bisnorc4-en-3-one, 8 (Scheme 14): A solution of ether 19,21-bisnorcola-2,5 (10) -dien-3-yl methyl (7, 0.27 g, 0.82 mmoles) in 7.2 Ml of acetone were added 2.3 Ml of methanol and 2.3 Ml of concentrated HCl (12.1 M_). After stirring for 1 h, 2.75 g of sodium bicarbonate and 20 Ml of water were added and the mixture was extracted three times with 10 Ml portions of methylene chloride. The combined organic extracts were washed with 10 Ml of brine, dried over sodium sulfate and filtered through Celite® 503. The residue was washed with 10 Ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. The TLC preparation (20% ethyl acetate / hexanes on GF of alumina 1000μ) gave a light yellow syrup (125.6 mg, 0.3994 mmoles, 49%) homogeneous to TLC (20% ethyl acetate / hexanes on silica gel). silica, product R 0.38, estra-4,16-dien-3-one Rf 0.-34).

Example 133 - 16a, 17a-Epoxiestra-1, 3.5 (10) -trien-3-ol, 2 (Scheme 15): To a solution of, 3.5 (10), 16-estratetraen-3-ol (2, CAS No. [1150-90-9], 636.0 mg, 2,500 mmol) in 15 ml of 1,2-dimethoxyethane (DME) was added m-chloroperbenzoic acid (862.9 mg, 5,000 mmol) in 25 mL of DME for 3 minutes and the reaction was stirred for 6 h. The mixture was poured into 140 g of 5% sodium thiosulfate pentahydrate (w / w) and extracted three times with 100 Ml portions of ethyl acetate. The combined organic extracts were washed with 100 Ml of saturated sodium bicarbonate + 3 aliquots of 100 Ml of saturated sodium chloride, dried over magnesium sulfate and filtered through Celite® 503. The residue was washed with 50 Ml. ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (820% ethyl acetate / hexanes on silica gel) of the resulting residue, followed by recrystallization from ethyl acetate gave white platelets (349.9 mg, 1294 mmol, 52%), mp 217- 219 ° C lit. [Prelog, V., Ruzicka, L., and Wieland, P., (1945), "Steroids and Sexualhormone", (111. Mitteilung). Uberein neues Steroisomeres des Oestriols., Helv. Chem. Acta. 28: 250-256] p.f. 215 ° C, homogeneous to TLC (20% ethyl acetate / hexanes on silica gel; Rf 0.32, starting material Rf 0.50).

Example 134 - Estra-4,16-dien-10ß-ol-3-one, 4 (Scheme 15): To a solution of estra-5 (10), 16-dien-3-one (3, 256.4 mg, 1,000 mmoles) in 6 ml of 1,2-dimethoxyethane (DME) was added MCPBA (189.8 MG, 1100 mmol) and 6 ml of DME + 2.4 ml of water. After stirring 14 h. The reaction mixture is poured into 30 g of 5% sodium thiosulfate pentahydrate (w / w) and extracted three times with 30 ml aliquots of ethyl acetate. The combined organic extracts were washed with 30 ml of saturated sodium bicarbonate + 3 30 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. To the resulting crystalline film was added 45 ml of 5% (w / v) potassium hydroxide in methanol and the mixture was refluxed with the exclusion of moisture for 1 h. After which it was drained in 100 ml of ice-water and extracted three times with aliquots of 70 ml of ether. The combined ether extracts were washed three times with 70 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml ether and the combined filtrates were concentrated under reduced pressure. TLC preparation (50% ethyl acetate / hexane on 1000μ alumina GF) of the residual resin, followed by recrystallization from aqueous ethanol gave light yellow needles (62.4 mg, 0.229 mmol, 23%), pf 156-166 ° C. TLC (50% ethyl acetate / hexanes on silica gel, estrone Rf 0.59) showed a higher product (Rf 0.44) with minor contaminants in Rf 0.62 and 0.73.

Example 134A-16a, 17a-Epoxiestr-4-en-1 Oß-ol-3-one, (Scheme 15) A solution of estra-5 (10), 16-dien-3-one was treated with MCPBA as in Example 134, except that four equivalents of MCPBA were used instead of a slight excess of one equivalent. After refluxing, the resulting product in 5% (w / v) potassium hydroxide in methanol, and after processing and purification as in Example 134, was obtained 16a, 17a-epoxystr-4-en- 1 Oß-ol-3-one.

SCHEME 15 Example 135 - Estra-5 (10), 16-dien-3-one, 2 (Scheme 16): To approximately 200 ml of anhydrous ammonia was added ether estratetraenol methyl (2.20 g, 8.20 mmoles) in 27.07 g (.3652 mol) of t-butyl alcohol and 34 ml of anhydrous THF, followed by 1.o1 g (0.146 g-atom) of lithium wire cut into small pieces. After refluxing for 4 h, 9.2 ml of methanol was added and the ammonia was allowed to boil overnight. 200 ml of water were added and the mixture was extracted 3 times with 100 ml of aliquots of ether. The combined organic extracts were washed twice with 100 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. The resulting crystalline syrup (presumably raw ether 1) was dissolved in 200 ml of acetone and 2.88 g of oxalic acid dihydrate in 38 ml of water was added. After stirring for 7 h, the mixture was drained in 100 ml of saturated sodium bicarbonate and extracted three times with 100 ml aliquots of ether. The combined organic extracts were washed three times with 100 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Double recrystallization of the resulting white solid from hexane yielded white crystals (1.2931 g, 5. 0435 mmol, 62%), m.p. 117-119 ° C. TLC (10% ethyl acetate / hexane on silica gel; estratetraenol methyl ether Rf 0.61); showed the product (Rf 0.34) with a contaminant trace (R 0.14).

Example 135A-16oc, 17a-Epoxiestr-4-en-10ß-ol-3-one, 3 (Scheme 16): Estra-5 (10) was cooled, 16-dien-3-one (2, 270.4 mg, 1055 mmol) in 6.7 ml of chloroform in a dried acetone / ice bath and 3-chloroperbenzoic acid (724.8 mg, 4200 mmol) in 7.4 ml of ether was added. After stirring for 2 h, the mixture was placed in the refrigerator. After 18 h, the mixture was poured into 60 g of 5% sodium thiosulfate pentahydrate (w / w) and extracted three times with 25 ml of aliquots of ethyl acetate. The organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. To the resulting white solid was added 50 ml of 5% (w / w) potassium hydroxide in methanol and the mixture was refluxed for one hour with the exclusion of moisture. After cooling, the mixture was drained in 100 ml of ice-water and extracted three times with aliquots of ether. The combined organic extracts were washed three times with 70 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. The resulting yellow resin was chromatographed twice on TLC plates of GF preparation of alumina (1000 μ) to give a white crystalline solid (55.1 mg, 0.191 mmol, 18%).

SCHEME 16 Methyl ether oxalic acid / H2O Estratetraenol Example 136 - Electrophysiology of Androstane Stimulation of Human VNO v Oligatory Epithelium. A non-invasive method was used to record the local electrical potentials of the human vomeronasal organ (VNO) and the olfactory epithelium (OE). Localized gas stimulation was applied to both nasal structures in different cases using specially designed catheter / electrodes connected to a multi-channel drug delivery system. This electrode and delivery system have been described by Monti and Grosser (J. Steroid Biochem and Molec. Biol. (1991) 39: 573) and in the patent of E.U.A. copending, commonly assigned 07 / 771,414, incorporated herein by reference. The local response of VNO and OE showed a relationship with the correlation of the ligand stimulus. The study was conducted on ten clinically normal volunteers (classified), 2 men and 8 women, aged 18 to 85 years. The studies were conducted without general or local anesthetics. The catheter / electrodes were designed to deliver a localized stimulus and simultaneously record the response. In the case of WNV recording, the right nostril of the subject was explored using a nasoscope (nasal speculum) and the vomeronasal opening was located near the intersection of the anterior edge of the vomero and the nasal floor. The catheter / electrode was moderately slid through the VNO opening and the tip of the electrode was placed in the lumen of the organ 1 to 3 mm from the opening. The nasoscope was then removed. In the case of OE, the registration procedure was similar, except for the placement of the catheter / electrode that was placed moderately deep in the lateral part of the middle nasal bridge, reaching the olfactory mucosa.

Localized gas stimulation was performed through the catheter / electrode. A constant stream of moist, clean, odorless air at room temperature was continuously passed through a channel of the stimulation system. The stimulating ligand substances were diluted in propylene glycol, mixed with the moistened air, and applied as a 1 to 2 second puff through the catheter / electrode. It was estimated that this administration provides approximately pg of the steroid-ligand to the nasal cavity. The results of this study are presented in Figures 180A, 180B and 180C. The response was measured in minivoltios-seconds (mV x s). Androsta-4, 16-dien-3-one produced a significantly stronger VNO response in women than in the other compounds tested (Fig. 180A). In addition, the response of WNV to Andorsta-4, 16-dien-3-one is sexually dimorphic, twice as strong in women as in men (Fig. 180B). In contrast, the OE response in both men and women is low compared to a strong deodorant such as nail (Fig. 180C).

Example 137 - Measurement of the Change in the WNV Neuroepithelial Receptor Potential in Response to Several Steroids The change in the potential receptor in the response of five different ligands was measured in 40 women (Fig. 181A) and 40 men (Fig. 181B) . Each subject was administered 60 pg of each of the seven substances indicated in the figure. The substances were administered separately for 1 second. The change in WNV neuroepithelial potential was recorded over time and the integral change in potential for each of the fourteen subjects was averaged. The results are shown in the figure. The comparison of Figures 181A and 181B shows that each steroid is sexually dimorphic in its activity, and that some ligand substances are stronger in men while others are stronger in women.

Example 138 - Measurement of Autonomy Responses to VNO Stimulation with 16-Androstene Several parameters of autonomy were verified as Androsta-4, 16-dien-3-one was administered to 40 women. Propylene glycol was also administered as control. The ligand was administered as a pulse of one second. The change in the autonomy function was first observed in 2 seconds and lasted at least up to 45 seconds. As shown in Fig. 182, when compared to a propylene glycol control, androstane induced a significant change in the receptor potential integrated in the VNO (182A), galvanic skin response (182B), skin temperature (182 C), the percentage of alpha-cortical wave activity as measured by electroencephalogram (182D), peripheral arterial pulse (182E) and respiratory rate (182F).

Example 139 - Comparison of the Change in Receptor Potential Induced by Two Androstane Steroids 60 picograms of each ligand steroid and the propylene glycol control were administered to 5 women. As shown in Fig. 183, Androsta-4,16-dien-3ß-ol induced a greater change in receptor potential than did Androsta-4, 16-dien-3-one.

Example 140 - Psychophysiological effect of VNO Stimulation with Androstane The psychophysiological effect of WNV stimulation with Androstane was measured through the coordinated administration of pheromone and evaluation of the questionnaire of the subject before and after the administration. The questionnaire included a panel of adjectives used as part of the standard Sexual Evaluation of Derogatis. The subjects were 40 women in an age between 20 and 45 years, and all in good health. The women were randomly assigned, 20 were exposed to placebo and 20 were exposed to approximately 20 picograms of Androsta-4, 16-dien-3-one. The subjects were given a questionnaire of 70 articles to evaluate the states of feeling immediately before and 30 minutes after the administration of either placebo or the experimental substance. The 70 adjectives of the questionnaire were randomly administered and subsequently gathered for evaluation based on their importance for mood, feeling or character trait. The results were as follows: Changes in feelings of social, personal warmth, arousal excitation / excitement and aggression, before administration at 30 minutes after administration, were not important in those exposed to 16-Androstene compared to the changes that result of the administration of control, however, the reduction in negative affect (nerves, attention, embarrassment, anxiety, irritability, anger, anger, test T: p <0.0001, Anova: p <0.04), humor and character negative (sensitive, repentant, reprehensible, guilty, remorse, sad, desperate, resentful, useless, miserable, unhappy, bitter, shy-proof T: p <0.0004, Anova: p <0.06), and total negative character (the combination of affect and character-test T: p <0.0003, Anova: p <0.05) were highly significant after the administration of 16-Androstene as compared to the administration of the control. In summary, these results suggest a sedative and / or anti-anxiety effect, and / or antidepressant of Androsta-4, 16-dien-3-one when administered intranasally.

Example 141 - Electrophysiological Studies The following electrophysiological studies were performed on 60 volunteers, clinically healthy humans of both sexes (30 men and 30 women), whose ages ranged from 20 to 45 years of age. No anesthetics were used and women were excluded if they were pregnant.

The stimulation and registration system consists of a "multifunctional miniprobe" described on either side (Monti-Blonch, L. and Grosner, Bl (1991) "Effect of putative pheromones on the electrical activity of human vomeronasal organ and olfactory 35 epithelium," J. Steroid Biochem, Molec, Biol. 3_9: 573-582 The registration electrode is a 0.3 mm plate ball attached to a small silver cable (0.1 mm) insulated with Teflon ©, the surface of the electrode was first treated to produce a silver chloride interface and then covered with gelatin, which was placed inside a small-bore Teflon® catheter (day = 5 mm) so that the tip of the electrode exits approximately 2 mm Teflon® catheter It has a length of 10 cm and constitutes the terminal extension for a multi-channel supply system, which supplies a continuous air stream carrying discrete pulses of chemosensory stimuli. r to a small chamber and bubbled through a solution containing either a vomeropherin or an olfactory agent in a diluent or diluent alone. A solenoid was used to quickly redirect the airflow from the chamber to a path that veers into the chamber. This created a discreet pulse of stimulant in the air stream. A second Teflon © external tube with a diameter of 2 mm encircled the catheter / electrode assembly, and its central end was connected to a vacuum cleaner that provided continuous suction of 3 mm / s. The concentric arrangement of the external suction tube allowed the chemosensory stimuli emitted to be located in an area that was called a "minicamp" (approximate diameter of 1 mm), and the diffusion of substances was avoided either outside the stimulation site destined or towards the respiratory system. The entire stimulation and registration assembly was placed either on the neurosensory epithelium with the WNV or on the surface of the olfactory or respiratory epithelium.

Electro-vomeronasogram (EVG): Recorded in a quiet room with the supine subject, the multifunctional miniprobe was initially stabilized inside the nasal cavity using a nasal retractor placed in the vestibule. The reference and ground electrodes consisted of silver discs (8 mm), both were placed on the glabella. The entrance to the VNO or vomeronasal cavity was identified by first dilating the nasal opening and the vestibule. A 6x magnification binocular loupe with halogen illumination was then used to introduce the tip of the Teflon © catheter and the registration electrode assembly into the VNO opening, where it was stabilized at a depth of approximately 1mm within the vomeronasal passage. . Optimal placement of the recording electrode is signaled after testing an adequate depolarization in response to a test substance. The electrical signals of the recording electrode were fed to a DC amplifier after which they were digitized, checked by computer and stored. The peak-to-peak amplitude of the signals was measured, and the area under the depolarization wave was integrated, while the signal was continuously monitored both on the computer screen and on a digital oscilloscope. Artifacts produced by respiratory movements were eliminated by training subjects to practice breathing with velopharyngeal closure.

Chemosensory Stimulants: The olfactory test substances are cineol, and 1-carvone; the vomeropherins are A, B, C, D, E and F in Figs. 180-184. Vomeroferin samples at a concentration of 25-800 fmoles were supplied in the continuous air stream for 300 milliseconds at 1 second. Usually, intervals of 3 to 5 minutes separated each series of short test pulses. All the components of the lines that carry the test stimuli were made of Teflon® glass, glass or stainless steel and cleaned and sterilized carefully before each use.

Electro-olfatograma (EOG): The olfactory readings used the same multifunctional stimulation and registration minison as the one used for the VNO. The tip was introduced slowly until the recording electrode touched the olfactory mucosa. Proper placement was signaled through a depolarization in response to a pulse of the deodorant test substance.

The cortical evoked activity was measured through the stimulation of VNO with vomeropherins, and the olfactory stimulation with deodorant supplied in air pulses of 300 ms. It was recorded using standard electroencephalographic electrodes (EEG) placed at positions Cz-A1 and Tz-A1 of the international system 10120; the ground electrode was placed in the mastoid process. The electrodermal activity (EDA) was recorded using standard 8 mm plate electrodes in contact with the skin of the middle and annular palm, respectively, through a conductive gel interface. The temperature of the skin (ST) was recorded through a small thermistor probe (1.0 mm) placed in the lobe of the right ear. The peripheral arterial pulse (PAP) was verified with a plethysmograph attached to the tip of the index finger. The respiratory frequency (RF) was measured with an adjustable tension gauge placed around the lower thorax. All electrical signals were DC amplified, digitized (MP-100, Biopac Systems) and continuously verified using a computer.

Statistical Analysis: EVGs or EOGS, peak-to-peak changes and frequency changes of other parameters were measured and analyzed statistically. The importance of the results was determined using either t-tests in pairs or variation analysis (ANOVA).

Effect of Vomeroferins on EVG: It was found that each of the vomeropherins produces a sexually dimorphic receptor potential (Figs 184A and 184B). The EVG records were made on 30 men and 30 women (aged 20 to 45 years). The vomeropherins were diluted and applied as pulses of a second to the WNV with intervals of 1 minute between the pulses when they were questioned, the subjects could not "smell" or otherwise consciously detect any of the vomeropherins. This finding is in accordance with previously reported results (Monti-Bloch, L. and Grosser, Bl (1991) Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory 5 epithelium ", J. Steroid Biochem. Molec. Biol. 39: 573-582) which indicated that neither the olfactory test nor vomeropherin stimulus delivered to the WNV produced a perceptible sensation at the concentration given.Figure 184A shows the average response of average male subjects (average ages 20 to 38 years) to the diluent, and to equimolar amounts (100 fmoles) of five vomeropherins (A, B, C, D, and F), and to E, a steroisomer of F. The profile of the response to each of the substances was similar in each of the subjects without considering the age, and no significant difference was revealed through the tests through the variation analysis, for example, A, C and D produced significant effects (M15 = 11.4 mV, SD = 3.6 mV; M76 = 6.4 mV, SD 2.5 mV, and M8 = 15.1 mV, SD = 4.9 mV; p < 0.01), which were consistent in all individual cases. Other vomeropherins depolarized the VNO receptors to a much lesser degree, but with consistent mean response amplitudes from individual to individual. Active vomeropherins in men produced greater responses than the diluent (p <0.001). B, F and similar concentrations of olfactory agents induced significantly reduced responses in the WNV of men (Fig. 184A and Fig. 185). A similar experimental protocol was followed with the 30 women (ages 20 to 45 years). Among the vomeropherins, F (100 fmoles) produced the most significant differences within the group (Fig. 184B). Here, A induced an effect that was significantly different from F (p <0.01). In both populations of subjects, the active vomeropherins induced receptor responses having large standard deviations (Fig. 184). When the frequency distribution of the effects of A and F was studied in men and women respectively, a bimodal distribution was found. The importance of this observation is being studied at this point. E, a stereoisomer of F, did not stimulate WNV in women while f did so (Fig. 184B). This is a demonstration of the specific character of VNO recognition to vomeropherins. In this regard, it is interesting to note that F is a superior vomeropherin, E generates a stronger olfactory effect than does F (Fig. 184B and Fig. 185).

The results in the EVG amplitude tested in the WNV of men (Fig. 208) and women (Fig. 209) are shown for steroids E2 / NC2, E1 / NC2, E2 / NC3, E1 / NC3, E2 / NC2 methylated , E2 / NC3 methylated, and E8 / NC3 in Diagram VI.

Effects of Vomeroferins on EOG: The aggregate receptor potential of the olfactory epithelium (EO) was recorded in 20 subjects: 10 men and 10 women. In contrast to the sensitivity of VNO to vomeropherins, OE is less sensitive to these substances. This is true for both men and women (Fig. 185A). The average receiver potential amplitude varied from 2.3 mV to 0.78 mV. In this study, B was the only vomeroferin having a significant effect on OE (p <0.02). Of the subjects questioned regarding odor sensations following each stimulus presentation, 16 reported no olfactory sensation, while three men and one woman described B as an unpleasant odor. This finding reveals that at the concentrations used in the study, most vomeropherins are not effective stimulants of olfactory receptors, but have a clear effect on vomeronasal reflectors.

Effects of Olfactory Agents on EVG and EOG: In contrast to vomeropherins, olfactory agents 1-carvone and cineole produced only a minor local response in WNV (Fig. 185B). This was true for both men and women. As expected, these olfactory agents produced a strong response in both men and women (p <0.01) when applied locally to the EO (Fig. 185A). The diluent depolarized the olfactory receptors to a degree less than cineole or 1-carbone (p <0.01), and did not produce an olfactory sensation.

Reflex Effects of Vomeroferins: Studies were conducted to determine the reflex responses of the central nervous system (CNS) to the stimulation of VNO by vomeropherins. The sexually dimorphic local responses induced by vomeropherins (Fig. 184A and Fig. 184B) were mirror images in the autonomy response of male and female subjects. In men (Fig. 184C) A and C reduced the resistance of the skin (electrodermal activity = EDA) (p <0.01, n = 30). In women (Fig. 184B), F and B produced a greater reduction in EDA than A or C (p <0.01, n = 30). Vomeroferins A and C induced a significant increase in skin temperature (ST) (Fig. 184G) in 30 men (p <0.01); however, d induced a significant reduction in temperature (p <0.01). In the 30 women (Fig. 184H) B and F evoked a significant increase in skin temperature (ST) (p <0.01) compared to A and C. In women, vomeropherins produced changes in EDA and ST with a standard deviation higher than in men. Cortical activity was recorded from Cz and Tz in men and women during the application to the WNV of air pulses (300 ms to 1 second) containing 200 fmol of vomeropherin (Fig. 184G and 184H). In men (Fig. 184E) A, C and D significantly increased alpha-cortical activity with a latency of 270-380 ms. D and A evoked the strongest effect (p <0.01). The EEG synchronization was sustained for 1.5 to 2.7 minutes after the application of an individual pulse of active substance. In women (Fig. 184F), an individual pulse (200 fmoles) of B or F applied to the VNO increased the alpha-cortical independently of the response of the olfactory receptors. Characteristic specific characters were found in the response of the human WNV and the olfactory epithelium, which suggests that there are independent functional systems are separate connections to the CNS (Brookover, C. (1914), The nervus terminalis in adult man, J. Comp. Neurol. 24: 131-135). There is also preliminary evidence that EVG is not associated with trigeminal noreceptor terminations, since the application of a local anesthetic (2% lidocaine) to the respiratory epithelium of the nasal septum neither blocks nor diminishes the EVG (Monti-Bloch, L. and Grosser, B.1. (1991) Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory epithelium ", J. Steroid Biochem, Molec. Biol. 39: 573-582), also, the subjects failed to report sensations of pain as a consequence of Any of the stimulation procedures We conducted additional tests using androsta-5,16-dien-3ß, 19-diol and four other androstanes, identified by their positions in the diagram.The results are shown in Fig. 193 to 200 The response of EEG, RF and EKG to androsta-5, 16-dien-3ß, 19 diol) is stronger in women compared to men, while the response of ST, GSR and EVG is stronger in men. those who were given the compound reported feelings of happiness, which is unusual since the reports are usually accompanied by RF and GSR data much greater than those shown in Figs 194B and 194 C. VNO recipients are clearly more sensitive to vom eroferins than any of the olfactory agents tested; the opposite is true for olfactory receptors. Since the EO may have receptor sites for some vomeropherins, the specific nature of the VNO response is clearly different. Sex differences were observed in the specific characters and effects of the two groups of vomeropherins A, C, and D; and B and F. This suggests a possible sexual dimorphism related to the receptor. The findings suggest the activation of components of the autonomic nervous system in the adult human being through the stimulation of VNO with vomeropherins. In addition, the results suggest that the stimulation of VNO with vomeropherins produces EEG synchronization (Fig. 184G and 184H). In this way, the evidence from the present indicates that the vomeronasal system responds to a variety of chemosensory stimuli, and that some are capable of inducing reflex autonomous activity.

Example 142 - Electrophysiological Studies Electrophysiological studies were performed as described in Example 141 in volunteers of clinically normal human subjects of both sexes whose ages ranged from 20 to 45 years. No anesthetics were used, and women were excluded if they were pregnant.

Electro-vomeronasogram (EVG): The EVG is shown integrated in Figs. 1 and 2 for the compounds A1-PA, A2-PA, A4-PA, A3-P1, A1-P4, A2-P4 (referring to Diagram I). Artifacts produced through respiratory movements were eliminated by training subjects to practice mouth breathing with velopharyngeal closure. Vomeroferin mixtures at a concentration of 25-800 fmoles were administered in the continuous air stream for 300 milliseconds to 1 second.

Example 143 - Electrophysiological studies were performed on the compounds of Examples 133, 134 and 134A in clinically normal adult women. The following diagram summarizes the results. The results for the EVG and a-CA are shown in Figs. 219 and 220, respectively.

Summary of the effects of debut vomeropherins on WNV of females, autonomic activity, electromyogram and alpha brain waves Example 133: 16a, 17a-Epoxiestra-1, 3,5 (10) -trien-3-ol Example 134: Estra-4,16 dien-1 Oß-ol-3-one Example 134A: 16a, 17 -Epoxiestr- 4-in-1 Oß-ol-3-one EVG = Electrovomeronasogram RF = Respiratory frequency CF = Heart rate EDA = Electrodermal activity BT = Body temperature EMG = Electromyogram a-CA = Alpha waves of brain 0 Compound that showed an effect that is not significantly different from the control + Arbitrary scale of effects + + Better than control, correlated + + + Unimportant differences between + + + + Data (p-value) SUMMARY OF THE EFFECTS OF VOMEROFERINAS OF 19-NQR-PREGNANO IN EEG AND AUTONOMOUS ACTIVITY IN WOMEN n = 6 EVG EDA RF CF EMG BT a-CA ßCA SCALE FUNCTION Metallic ether +25 +100 .5 .5 0 -2.5 -10 -35 EDA + .RF-.CF-.β- 5 of E2 / P8 E9 / P2 +5 -10 -2.5 +10 +5 -2.5 +5 - 35 CF +, a +, ß- 3 E4 / F2 +2.5 -10 -2 +5 -5 0 +2.5 +2.5 EDA-.EMG- 3 E7 / PI +30 -70 -5 -5 0 0 -5 -2 EDA + RF-CF- 4 Acetate +50 + 130 0 0 0 +6 0 -15 EDA +, BT + ß- 4 E2 / P8 E3 / P1 +20 +70 -2.5 -2.5 0 +3 -10 -30 EDA + 2 E10P2 +3 -10 0 +10 -5 0 +10 +10 EDA-.CF + EMG- 5 a + E2 / P7 +25 -50 +5 -5 0 -10 -15 -30 EDA + .BT * 3 E2 / P5 +25 -30 0 0 0 0 -10 -40 0. 0 E2 / P6 +20 +50 0 .5 0 0 -15 -30 EDA + .CF- 3 Pl -45 -110 +5 0 or 0 -5 -10 0 0 E2 / P1 +40 +95 +3 -5 0 0 0 -15 EDA + .RF-.CF-r 4 Metheric ether +20 +85 -2.5 -5 0 0 -6 -20 EDA + .CF- 3 of E2 / P8 E13 / P1 + 1 -10 0 0 -5 0 0 -40 EDA-, EMG-.ß- 4 Ell Pl +20 -10 0 -5 -2.5 -1 0 -25 0 0 E5 / P1 0 -10 0 0 0 0 0 -40 0 0 Acetate of +2.5 -10 -2.5 +2.5 -5 -3 +10 -20 EMG-, BT-, a + ß- 5 E2 / P8 E2 / P8 +25 +110 0 0 0 +10. +7 -20 EDA +, BT + .a + .6 + 5 E2 / P2 +20 +20 -2.5 .5 0 -2.5 +7 -25 CF-.BT-, a +, 6- 5 E2 / P4 +50 +110 +2.5 0 0 0 +30 -10 EDA +, a +, 6- 4 E12 / P8 +35 +100 0 -5 0 -3 -10 -25 EDA +, CF-, BT- 4 E8 / P9 +35 +105 +2.5 0 0 -1 -10 -40 0 0 SUMMARY OF EFFECTS OF VOMEROFERINES OF 19-NOR-PREGNAN IN EEG AND AUTONOMOUS ACTIVITY IN MEN n = 6 EVG EDA RF CF EMG BT a-CA ßCA SCALE FUNCTION Metheric ether +12 -95 0 -5 -2.5 -2.5 +2.5 -10 EDA +, CF-3 (+) of E2 / P8 E9 / P2 +20 -20 0 +2.5 -2.5 -5 -7 +40 BT- 2 E4 / P2 +15 -20 0 +2.5 0 -2.5 -2.5 -20 0 0 E7 / P1 + 18 +70 0 0 0 +7 -2.5 -30 EDA +. BT + ß- 4 Acetate of -40 +80 0 0 0 +2.5 -10 -20 EDA + 2 E2 / P8 E3 / pl + 15 +50 0 +2.5 0 -5 -10 -30 EDA +, BT-ß- 4 E10 / P2 -20 -20 0 +2.5 -2.5 -1 0 +40 0 0 E2 / P7 -30 + 120 0 +2.5 0 0 -10 -20 0 0 E2 / P5 -10 -.- 90 0 0 0 - 10 -5 -30 EDA-BT-.ß 4 E2 / P6 +12 -100 0 0 0 -2.5 0 -20 EDA- 2 The / Pl -35 + 120 -2.5 0 0 +2.5 -2.5 -20 EDA + 2 E2 / P1 -30 + 120 0 0 0 -7 -10 -20 EDA-.BT- (EEG ±) 4 Metallic ether + 15 +110 -5 0 0 0 0 -20 EDA +. RF- 3 of E2 / P8 E13 / P1 +20 -20 0 0 -2.5 0 -5 -15 0 0 Ell PI +18 -20 +2.5 0 0 -2.5 -5 -t5 0 0 E5 / P1 +10 -20 0 -2.5 -2.5 0 -5 -10 0 0 Acetate of +2.5 -20 0 -2.5 -2.5 -2.5 -5 -15 0 0 E2 / P8 E2 / P8 +30 +100 0 0 0 0 -10 -20 0 0 E2 / P2 +15 +80 0 0 0 +2.5 -5 -25 0 0 E2 / P4 +30 +80 -2.5 0 0 -5 -10 -20 EDA +, BT -, (EEG ±) 4 E12 / P8 +25 + 120 0 0 0 +2.5 -10 -25 EDA + 2 E8 / P1 +30 + 130 0 0 0 +2.5 -5 -20 EDA + 2 SCHEME 17. Synthesis of steroidal D ring oxides SCHEME 18. Synthesis of oxide of more steroidal D rings • 11 Example 144 - 17a, 20a-Epoxy-19-norpregna-1, 3,5 (10) -trien-3-ol, 1 To a solution of 19-norpregna 1, 3,5 (10), 17Z-tetraen -3-ol (282.4 mg, 0.9999 mmol) in 6 ml of 1,2-dimethoxyethane (DME) was added 3-chloroperbenzoic acid (92.2%, 207.1 mg, 1200 mmole) in 6 ml of DME and the reaction was stirred for 5 h. The mixture was poured into 50 g of 5% sodium thiosulfate pentahydrate (w / w) and extracted in three 20 ml portions of ethyl acetate. The combined organic extracts were washed with 20 ml of saturated sodium bicarbonate + 20 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 5 ml of ethyl acetate and the combined filtrates they were concentrated under reduced pressure. The double crystallization of the resulting white solid, first from methyl t-butyl ether (MTBE) / hexane and then from aqueous ethanol, gave thin glossy white plates (160.0 m, 0.5320 mmoles, 54%), mp 154-159 ° C, homogeneous to TLC (25% ethyl acetate / hexanes on silica gel, product Rf 0.42, starting material Rf 0.57, 0.42 (fingerprints)).

Example 145 - 3-Methoxypyr [estra-1, 3,5 (10) -17,2'-oxetane] 2: A 3-methoxy-19-norpregna 1, 3,5 (19) -trien-17ß-ol- 21 -tosylate (168.1 m, 0.3469 mmoles) and potassium t-butoxide (168.1 m, 1498 mmoles) under argon were added with 8 ml of anhydrous dimethyl sulfoxide (DMSO) and the reaction was stirred in a hot oil bath ( 77-99 ° C) for 3 [deg.] C. 20 ml of MTBE were added after cooling and the mixture was washed with three 5 ml portions of water +5 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 5 ml of MTBE and the combined filtrates were concentrated under reduced pressure.The preparation TLC (10% ethyl acetate / hexanes on GF silica gel, (1000 μ) produced crystals whitish (72.2 mg, 0.231 mmol, 67%): TLC (10% ethyl acetate / hexanes on silica gel; estra-1, 3,5 (10), 16-tetraen-3-yl-methyl ether ( Rf 0.70) showed the product (Rf 0.33) with a contaminant of footprint (R = 0.42).

Example 146. - 16a, 17a-Epoxipregn-4-en-3-one, 3: To a solution of pregna-4.16-dien-3-one (31.0 m, 0.104 mmoles) in 0.6 ml of DME was added acid 3 -chloroperbenzoic acid (92%, 21.5 m, 0.125 mmole) in 6 ml of DME and the reaction was stirred for 5 h. The mixture was subjected directly to TLC preparation (30% ethyl acetate / hexanes on GF silica gel, 1000μ) to give a white crystalline solid (13.1 mg, 41.7 μmol, 40%). TLC (30% ethyl acetate / hexanes on silica gel, starting material Rf 0.53, 0.00 (trace)) showed the product (Rf 0.33) with a trace contaminant (Rf 0.38).

Example 147 - 13,17-Epoxy-10,17-dimethylgona-4-en-3-one, 4: To a solution of 10, 17-dimethylgona-4-13 (17) -dien-3-one (342.1 ma , 1,265 mmoles) in 7.6 ml of DME was added 3- chloroperbonzoic acid (92%, 262.0 m, 1518 mmoles) in 7.6 ml of DME. After stirring for 5 h, the reaction mixture was poured into 60 g of 5% sodium thiosulfate pentahydrate (w / w) and then extracted three times with 30 ml portions of ethyl acetate. The combined organic extracts were washed with 30 ml of saturated sodium bicarbonate +30 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 10 ml of ethyl acetate and the combined filtrates they were concentrated under reduced pressure. Flash chromatography (30% ethyl acetate / hexanes on silica gel) of the resulting yellow resin, followed by preparation TLC (30% ethyl acetate / hexanes on silica gel GF, 1000μ) gave a solid light yellow (87.2 m, 0.304 mmoles, 24%) showing three spots (Rf 0.23, 0.29, and 0.32) on TLC (30% ethyl acetate / hexanes on silica gel; (pregna-4-16-dien-3 -ona Rf 0.54).

Example 148 - Ether 19,21-Bis-norcola-1,3,5 (10), 16-tetraen-3-yl-methyl, 5: A-ether 17-iodoestra 1, 3,5 (10), 16-tetraen-3 methyl-lime (788.6 m, 2000 mmoles) 15% NaOH (w / w) (2.0 ml), and a complex of [1, 1 '-bis (diphenylphosphonium) ferocene] palladium (ii) methylene chloride (1: 1) (40.8 m, 50.0 Camel) under argon 8.0 ml of anhydrous THF and tributylborane (1.0 M in THF, 2.2 ml, 2.2 mmoles) were added. After refluxing for 24 h, 20 ml of benzene were added to the mixture. the cold reaction. The mixture was washed with 10 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 5 ml of benzene and the combined filtrates were concentrated under reduced pressure. Flash chromatography (1% ethyl acetate / hexane on silica gel) of residual dark syrup, followed by crystallization from 95% ethanol with intermediate carbon treatment gave white platelets (425.4 mg, 1311 mmol, 66%). %), pf 50-52 ° C, homogeneous to TLC (5% ethyl acetate / hexanes on silica gel, Rf 0.48, ether estra-1, 3.5 (10), 16-tetraen-3-yl methyl Rf 0.45).

Example 149 - 19,21 -Bisnorcola-5 (10), 16-dien-3-one, 6: Approximately 30 ml of anhydrous NH3 were distilled through KOH to a flame-dried three-necked flask with an inlet adapter , magnetic stirring bar, dried ice / acetone condenser and glass stopper. Ether 19,21-Bisnorcola-1,3,5 (10), 16-tetraen-3-yl-methyl (5, 300.0 m, 0.9245 mmol) in 8 ml of anhydrous THF and 3.09 g (41.7 mmoles) were added. t-butyl alcohol, after which, lithium cable (high sodium content, 0.13 g, 19 mg-atom) cut into small pieces was added. The reaction mixture was stirred 6 hours and then quenched with 1.0 ml of methanol. After allowing NH3 to boil overnight, 25 ml of water was added and the reaction mixture was extracted three times with 25 ml aliquots of MTBE. The combined organic extracts were washed three times with 25 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 10 ml of MTBE and the combined filtrates were concentrated under reduced pressure. The resulting syrup was taken up in 25 ml of acetone, 0.35 g of oxalic acid dihydrate in 5 ml of water was added and the suspension was stirred 4 h. The evasion hydrolysis mixture 10 ml of saturated sodium bicarbonate was extracted three times with 10 ml aliquots of MTBE. The combined organic extracts were washed three times with 10 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 5 ml of MTBE and the combined filtrates were concentrated under reduced pressure. The residual syrup was taken up in 5 ml of hexanes, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 2 ml of hexanes and the combined filtrates were boiled in about 2 ml. The resulting solution was applied to a preparation TLC plate (GF silica gel, 1000p) and developed with 10% ethyl acetate / hexanes. Extraction and concentration of the appropriate band gave a colorless syrup (226.4 ma, 0.7245 mmol, 78%). TLC (10% ethyl acetate / hexanes on silica gel) showed the product) Rf 0.34) with a contaminant trace (Rf 0.14).

Example 150 - 16 17a-Epoxy-19,21-bisnorcol-4-en-10ß-ol-3-one, 7: To a cooled solution (dry ice / acetone) 19,21-bisnorcola-5 (10), 16-dien-3-one (6,270.2 m, 0.8647 mmoles) in 1.6 ml of methylene chloride was added 3-chloroperbenzoic acid (97.4%, 328.2 mg, 1.902 mmol) in 6.3 ml of methylene chloride for 3 minutes. The remaining peracid was rinsed in the vessel with 1.8 ml of methylene chloride and the reaction was stirred for 5 hours. The cooling bath was removed and the bath was stirred for 1 h more. The reaction was then filtered through Celite 503 and the residue was washed with 1 ml of methylene chloride. The combined filtrates were washed with 5 g of 5% sodium thiosulfate pentahydrate (w / w) +5 ml of saturated sodium bicarbonate + 5 ml of brinewere dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 1 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. The resulting light yellow solid was taken up in 22 ml of methanol with heating, 3.6 ml of triethylamine was added thereto and the reaction was stirred for 2 h. The mixture was then concentrated under reduced pressure to give an amber colored syrup. This was purified by TLC preparation (50% ethyl acetate / hexanes on GF silica gel, 1000μ) to produce a white crystalline solid (133.0m, 0.3861mmol, 45%. ethyl / hexanes on silica gel; 16a, 17a-epoxystr-en-1 Oß-ol-3-one Rf 0.26) showed the product (Rf 0.38) with a contaminant trace (Rf 0.30) Example 151 - Estra-5 (10), 16-dien-3- ona, 8: Approximately 2.4 liters of anhydrous ammonia were distilled through KOH to a flame-dried four-neck round bottom flask equipped with two dried acetone / ice condensers, a mechanical stirrer and a glass stopper. Ether Estra-1, 3,5 (10), 16-tetraen-3-yl methyl (27.45 g, 0.1'23 mol) in 260 ml of anhydrous THF +133.24 g (1,798 moles) a t-butyl alcohol was added, followed by four portions of 3.12 g (12.49 g total, 1.79 g atom) of lithium wire cut into small pieces, one portion every half hour. Mechanical agitation was sometimes interrupted to avoid over boiling. After stirring for 3 h. Further, 100 ml of methanol was added and the reaction was stirred overnight while allowing the ammonia to boil. 600 ml was added and the mixture was extracted three times with 300 ml portions of MTBE. The combined organic extracts were washed with 300 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 50 ml of MTBE and the combined organic extracts were concentrated under reduced pressure. The resulting light yellow oil was turned and 7.16 g of oxalic acid dihydrate in 95 ml of water was added. After stirring 8 h, the hydrolysis mixture was vacuum in 250 ml of saturated sodium bicarbonate and extracted three times with 250 ml portions of MTBE. The combined organic extracts were washed three times with 250 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 50 ml of MTBE and the combined filtrates were concentrated under reduced pressure. Double recrystallization from hexanes (intermediate drying over magnesium sulphate is necessary to remove the residual water gave white crystal harvests) Total production was 12.18 g (47.51 mmoles, 46%) First crop mp 117.5-119.5 ° C , second harvest pf 115-119 ° C.

Example 152 - 5β, 10β, 16, 17a-Bisepoxiestran-3-one, 9: A solution of estra-5 (10), 16-dien-3-one (8, 12.02 g, 46. 88 mmoles) in 70 ml of methylene chloride cooled to 0 ° C, was added 3-chloroperbenzoic acid (97.4%, 17.80 g, 0.1031 mol) suspended in 340 ml of methylene chloride for 58 minutes, so that the temperature of reaction was maintained for 2 minutes at 0 ° C. 100 ml of additional methylene chloride was added to rinse the peracid adhered in the reaction vessel and the mixture was stirred 5 h. The resulting suspension was filtered through Celite 503 and the residue was washed with 50 ml of methylene chloride. The combined filtrates were washed with 250 g of 5% sodium thiosulfate perhydrate (w / w) + 250 ml of saturated sodium bicarbonate + 250 ml of brine, dried over magnesium sulfate and filtered through Celite 503 The residue was washed with 50 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Recrystallization of the light yellow solid resulting from 95% methanol with carbon intermediate treatment gave bright white platelets (11.38 g, 39.46 mmoles, 84%), m.p. 168-173 ° C.

Example 153 - 16a, 17a-Epoxiestr-4-en-10ß-ol-3-one, 10: 5ß, 10β, 16a, 17a-Bisepoxiestran-3-one (9, 11. 30 g, 39.18 mmoles) in 1 L of methanol with heating and triethylamine (166 ML, 1.19 mmol) was added. After stirring for 6 h, the solution was concentrated under reduced pressure and the resulting yellow-colored solid was taken up in 250 ml of 95% hot ethanol. Carbon was added (Darco G-60, 0.58 g 9 and the mixture was heated to boiling.) The hot suspension was filtered through Celite 503 and the residue was washed with 50 ml of hot ethanol.The combined filtrates were boiled at approximately 250 ° C. ML and then cooled in tap water with stirring The solution was seeded with "by-product" crystals and then refrigerated overnight after the start of recrystallization.The "by-product" was filtered and washed with 10 ML cold ethanol (after drying the residue weight 3.2762 g and had a mp of 262-269 ° C.) The combined filtrates were boiled to approximately 50 ML and then cooled in tap water with stirring.The solution was seeded with authentic product and then it was cooled overnight after the start of crystallization, the suspension was filtered and the residue was dried over P205 under vacuum to give white, flat crystals (4.6827 g, 16.283 mmol, 41%), mp. 193-195 ° C, homogeneous to TLC (50% ethyl acetate / hexane on silica gel; product Rf 0.47; authentic sample Rf 0.47).

Example 154 - 16a, 17a-Epoxiestra-1, 3,5 (10) -trien-3-ol, 11: To a solution of 1, 3,5 (10), 16-estratetraen-3-ol (CAS No. 11150-90-91, 636.0 m, 2,500 mmoles) in 15 ml of DME was added 3-chloroperbenzoic acid (862.9 m, 5,000 mmoles) in 25 ml of DME for 3 min., And the reaction was stirred 6 h. The mixture was poured into 140 g of 5% sodium thiosulfate pentahydrate (w / w) and extracted three times with 100 ml portions of ethyl acetate. The combined organic extracts were washed with 100 ML of saturated sodium bicarbonate +3 aliquots of 100 ML of saturated sodium chloride, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 50 ML of acetate ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (30% ethyl acetate / hexane on silica gel) of the resulting residue followed by recrystallization from ethyl acetate gave glossy white platelets (349.9 ma, 1294 mmol, 52%) m.p. 217-219 ° C (lit. [Prelog, V., Ruzicka, L., and Wieland, P. (1945): Steroid und Sexualhormone (111. Mitteilung) Über ein neues Stereoisomeres des Oestriols, Helv, Chim. Acta 28, 250-256.1 mp 215 ° C, homogeneous to TLC (20% ethyl acetate / hexane on silica gel, R 0.32, starting material Rf 0.50).

Example 155 - Electrophysical studies were performed on the compounds of Examples 144, 146, 147, 150, 153, and 154, as well as two other epoxy steroids gint-D in clinically normal adult men and women. The results are summarized in Figs. 221A and 221B. The preparation of 17,20-EPOXIPREGN-4-EN-3-ONA is described by J. Hader and E. Blanke in British Patent 1,049,988 (1966). The preparation of 16B, 20B-EPOXIPREGN-4-EN-3B-OL is described by M. Matsui and D. Fukushima, J. Org. Chem. 35 (3), 561 (1970). The preparation of 18,20-EPOXIPREGN-4-EN-3-ONA is described by G. Cainelli, B. Kamber, J. Keller, M.Lj. Michailovic, D. Arigoni and O. Jeger, Helv. Chim. Acta, 62., 518 (1961). 16a, 17a-EPOXIANDROST-4-EN-3-ONA (OXIDE OF ANDROSTEINE) was prepared according to the literature procedure: F. Sondheimer, O. Mancera, M. Urquiza and G. Rosenkranz, J. Chem. Soc. 77, 4145 (1955). 17B, 21-EPOXY-3-METOXY-19-NOR-17a-PREGNA-1, 3,5, (10) -TRIENE was prepared according to the literature procedure: B. Singh and R.G. Christiansen, J. Pharm, Sci 60., 491 (1971).

SCHEME 19. Synthesis of ether 17-iodoestra-1, 3.5 (10), 16-tetraen-3-yl methyl Estrone methylene ether SCHEME 20. Synthesis of additional steroidal D-ring oxides § Example 156 - Estrone Hydrazone, 1_: A suspension of estrone (20.00 g, 73.97 mmoles) in 150 Ml of absolute EtOH, 34 Ml (0.24 mols) of triethylamine, and 64 Ml (2.0 mols) of hydrazine was brought to reflux 1 1 / 2h, with the exclusion of humidity. The reaction mixture was added to 580 Ml of water with mixed stirring, and then refrigerated overnight. The crude hydrazone was filtered, washed with 100 Ml of water and P205 was dried in vacuo to give an off-white solid (22.57 g,> 100%).

Example 157 - 17-Iodoestra-1, 3,5 (10), 16-tetraen-3-ol, 2: To a cooled mixture (ice-water bath) of crude estrone hydrazone (1, 22.45 g) with 200 Ml of anhydrous tetrahydrofuran (THF) and 50 Ml (0.36 moles) of triethylamine under argon was added iodine (44.31 g, 0.1746 moles) in 150 Ml of anhydrous THF for 33 minutes, until gas evolution ceased (remaining solution: 8 ml). After stirring for 20 minutes, the reaction mixture was poured into 300 ml of 1 N HCl and extracted three times in 100 ml aliquots of ether. The combined organic extracts were washed with three portions of 100 g of 5% sodium thiosulfate pentahydrate (w / w) +100 ml of saturated sodium bicarbonate +100 ml of brine, dried over sodium sulfate and filtered at room temperature. through a thick glass frit. The residue was washed twice with 50 ml portions of ether and the combined filtrates were concentrated under reduced pressure, the resulting red foam was crystallized twice from aqueous methanol with the carbon intermediate treatment so many times to give off white platelets. fine (18.70 g, 49.18 mmoles, 66% of total estrone) pf 134-135 ° C.

Example 158 Ether 17-iodoestra-1, 3,5 (10), 16-tetraen-3-yl-methyl, 3, 17-iodoestra-1,3,5 (10), 16-tetraen-3-ol: A suspension of 17-iodoestra-1, 3.5 (10), 16-tetraen-3-ol (2, 17.11 g, 44.99 mmol) and potassium carbonate (9.33 g, 67.5 mmol) in 600 ml of acetone was heated at reflux with the exclusion of moisture, and dimethyl sulfate (11 ml, 0.12 mol) was added. After stirring for 24 hours, the cold reaction mixture was poured into 500 g of sodium hydroxide at 55 (w / w) and extracted three times in 250 ml of aliquots of methyl t-butyl ether (MTBE). The combined organic extracts were washed with 250 ml of brine, dried over sodium sulfate and filtered through Celite 503. The residue was washed with 50 ml of MTBE and the combined filtrates were concentrated under reduced pressure. Crystallization of the resulting tan solid gave pink-to-purple needles 814.85 g, 37.66 mmol, 84%), m.p. 14-147 ° C.

Example 159 - estra-1, 3, 5 (10) -triene-17-hydroxy-3-yl methyl ether, 4: A suspension of estrone-3-methyl ether (1.0000 g, 3.5162 mmol) in 7 ml of absolute EtOH , triethylamine (1.6 ml, 11 mmol), and hydrazine (3.1 ml, 99 mmol) was refluxed with the exclusion of moisture for 90 minutes, during which the reaction became homogeneous. 28 ml of water were added with stirring and the mixture was refrigerated overnight. Filtration and drying of the residue on P205 in vacuo yielded brittle, thin white platelets (1.0437 g, 3.4973 mmol, 99%), m.p. 166-169 ° C.

Example 160 - Ether 17-iodoestra-1, 3,5 (10), 16-tetraen-3-yl methyl, 3, from ether estra-1, 3, 5 (10) -triene-17-hydrazone-3 methyl-1-methyl: To a mixture of estra-1, 3,5 (10) -triene-17-hydrazone-3-yl methyl ether (4.1000 g, 3.3509 mmol) in 18 ml of anhydrous THF and under argon was added. he added iodide (2.01 g, 7.92 mmol) in 10 ml of anhydrous THF for 30 minutes until a yellow color persisted (remaining solution: 3 ml). After stirring for an additional 15 minutes, the reaction mixture is evacuated in 35 ml of 1N HCl. and it was extracted three times in aliquots of 15 ml of ether. The combined organic extracts were washed with 15 g of 5% sodium thiosulfate pentahydrate (w / w) + 15 ml of saturated sodium bicarbonate, dried over sodium sulfate and filtered through a thick glass frit. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. The resulting yellow / orange solid was crystallized from absolute EtOH with the intermediate treatment with carbon to give a light yellow crystalline solid (764.5 m, 1939 mmole, 58%) m.p. 145-146 ° C.

Example 161 - Estra-5 (10), 16-dien-3-one, 5 from ether estra-1, 3,5810), 16-tetraen-3-yl-methyl: Approximately 2.4 L of anhydrous ammonia alloyed through KOH to a flame-dried four-neck round bottom flask with two acetone / ice condensers • dried, a mechanical agitator and a glass stopper. Ether estra-1, 3, 5 (10), 16-tetraen-3-yl methyl (27.45 g, 0.1023 moles) in 5 260 ml of anhydrous THF +133.24 g (1798 moles) of t-butyl alcohol was added, followed for four portions of 3.12 g (12.49 g total, 1799 g-atom) of lithium wire cut into small pieces, one portion each A h. At times, mechanical agitation was interrupted to avoid excess foam formation. After shaking 3 h. Further, 100 ml of methanol was added and the reaction was stirred overnight while the ammonia was allowed to boil. 600 ml of water was added and the mixture was extracted three times with 300 ml portions of MTBE. The combined organic extracts were washed with 300 ml of brine, dried over sodium sulfate and filtered through Celite 503. The residue was washed with 50 ml of MTBE and the combined filtrates were concentrated under pressure. • reduced. The resulting light yellow oil was taken up in 500 ml of acetone, and 7.19 g of oxalic acid dihydrate in 95 ml of water was added. After stirring 8 h, the hydrolysis mixture is emptied in 250 ml of saturated sodium bicarbonate and extracted three times with 250 ml portions of MTBE. The combined organic extracts were washed three times with 250 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 50 ml of MTBE and the The combined filtrates were concentrated under reduced pressure. Double recrystallization from hexanes (intermediate drying over magnesium sulfate is necessary to remove residual water) gave two crops of white crystals. The total production was 12.18 g (47.51 mmoles, 46%). First harvest p.f. 117.5-119.5 ° C, second harvest p.f. 115-119 ° C.

Example 162 - Estra-5 (10), 16-dien-3-one, 5, from 17-iodoestra -1,3, 5 (10), 16 -tet raen -3 -i I methyl: Approximately 1.2 L NH3 anhydrous were distilled through KOH to a three-liter three-necked round bottom flask equipped with two dried acetone / ice condensers and a mechanical stirrer, and containing ether 17-iodoestra-1, 3.5 (10) , 16-tetraen-3-yl methyl (14.71 g, 37.31 mmoles) in 200 ml of anhydrous THF. Lithium cable (high sodium content, 5.18 g, 0.7469 g-atom) connected in small pieces in portions was added to control foaming, and the reaction was stirred one h. 40 ml of methanol was added for 3 h, during which the reaction was discolored and the mixture was stirred overnight, while the NH3 was allowed to boil. 400 ml of water was added and the mixture was extracted three times with 200 ml aliquots of MTBE. The combined organic extracts were washed with 200 ml of brinewere dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 5 ml of MTBE and the combined filtrates were concentrated under reduced pressure. The resulting pale yellow syrup was collected in 175 ml of acetone, oxalic acid dihydrate (2.51 g) in 33 ml of water was added, and the hydrolysis mixture was stirred 6 h, the mixture was emptied into 65 ml of sodium bicarbonate. saturated and extracted three times with aliquots of 65 ml of MTBE. The combined organic extracts were washed three times with 65 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 25 ml of MTBE and the combined filtrates were concentrated under reduced pressure. Double and triple recrystallization from hexanes (intermediate over magnesium sulfate necessary to remove residual water) gave two residual cultures of light yellow to yellow. The total production was 4.7217 g (18,416 mmoles, Limo). First crop p.f. 116-118 ° C. second crop p.f. 117-118 ° C.

Example 163 - Purification and titration of 3-chloroperbenzoic acid: Commercially available 3-chloroperbenzoic acid (MCPBA, 57-86%, 50.00 g) was added to 1 L of aqueous phosphate pH regulator (0.5 M_ monobasic, 0.5 M dibasic. ) and the suspension was mechanically stirred for 5 min. The mixture was filtered through a thick glass frit and the residue was washed with 200 ml of water. The residue was dried in vacuo over P205 to give a white solid (33.50 g, 67% mass recovery). Approximately 0.25 g samples of purified peracid were titrated in triplicate as follows: 1.5 g of sodium iodide was dissolved in water, and 5.0 ml of acetic acid and 5.0 ml of chloroform were added followed by the peracid sample. The mixture was stirred rapidly, while titrating against standard 0.1 N sodium thiosulfate (available from Aldrich) to a colorless endpoint. The following equations were used to calculate the MCPBA percentages in the samples: Apparent molecular weight = 2 (sample mass, g) / [thiosulfate volume, L) (standard thiosulphate concentration)] Percentage of MCPBA = 172.57 / apparent molecular weight.

The triplicate readings were averaged to give a percentage of 92.2% MCPBA.

Example 164 - 5β, 10β, 16a, 17a-Bisepeciestran-3-one, 6 .: To a solution of estra-5 (10), 16-dein-3-one (5, 12.02 g, 46.88 mmoles) in 70 ml of methylene chloride cooled to 0 ° C was added 3-chloroperbenzoic acid 897.4%, 17.80 g, 0.1031 mol) suspended in 340 ml of methylene chloride for 58 min., so that the reaction temperature remained within 2 degrees of 0 ° C. 100 ml of additional methylene chloride was added to rinse the peracid adhered in the reaction vessel, the cooling bath was removed and the mixture was stirred 5 h. The resulting suspension was filtered through Celite 503 and the residue was washed with 50 ml of methylene chloride. The combined filtrates were washed with 250 g of 5% sodium thiosulfate pentahydrate 8p / p) + 250 ml of saturated sodium bicarbonate + 250 ml of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 50 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Recrystallization of the resulting light yellow solid from 95% ethanol with the intermediate treatment with carbon gave bright white platelets (1.38 g, 39.46 mmol, 84%), mp 168-173 ° C.

Example 165 - 16a, 17a-Epoxiestr-4-3n-10ß-ol-3-one, 7 from estra-5 (10), 16-dien-3-one: To a solution of estra 5, (10) , 16-dien-3-one (5_, 331.8 ma, 1294 mmole) in 6 ml of 1,2-dimethoxyethane (DME) was added 3-chloroperbenzoic acid (95.6%>, 491.3 ma, 2847 mmole) in 16 ml of DME. After stirring 24 h, the reaction mixture was poured into 15 g of 5% sodium thiosulfate pentahydrate (w / w) and extracted three times in 30 ml aliquots of ethyl acetate. The combined organic extracts were washed with 30 ml saturated sodium bicarbonate + three 30 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 15 ml of ethyl acetate and the Combined filtrates were concentrated under reduced pressure. The resulting white solid was taken up in 20 ml of anhydrous THF under argon and cooled in a dried acetone / ice bath. Lithium diisopropylamide (LDA, 1.5 JM in cyclohexane, 0.86 ml, 1.3 mmol) was added over 2 minutes, and the reaction mixture was stirred for a further 25 minutes. 0.5 ml of saturated ammonium chloride and 30 ml of ether were added and the mixture was washed three times with 10 ml portions of brine, dried over magnesium sulfate and filtered through Celite 503. The residue was washed with 5mL of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (50% ethyl acetate / hexanes on silica gel 150) of the resulting wet yellow solid followed by preparation TLC (50% ethyl acetate / hexanes on OF of silica gel, 1000 p) and recrystallization from methylene chloride and hexanes gave white crystals (47.0 m, 0.163 mmoles, 13%), mp 192-194 ° C, homogeneous to TLC (50% ethyl acetate / hexanes on silica gel; Rf product 0.32; estrone Rf 0.59). UV:? Mass 236 nm, e = 13,000. IR: 3508 cm "1 (OH str.), 1661 cm-1 (unsaturated C = 0 str.), 1620 cm" 1 (C = C str). 1 H-NMR (in acetone): 5.6.d (1H, s, H-4), 4.1 d (1H, s, 10β-OH), 3.1-3.3 (2H, AB q, 160-H &17, OH ), 0.82 d (3H, s 18-H). Anal.; Calculated for C18H2403: 74.96%, H 8.33%). It was found: C 74.94 ± 0.06%, H 8.33 + 0.07%. HR-EIMS: 5ß, 1 Oß, 16a, 17a-Biseoxiestr-3-one (6, 11.30 g, 39.18 mmol) was dissolved in 1L of methanol with heating, and triethylamine (166 mL, 1.19 mmol) was added. After stirring for 6 h, the solution was concentrated under reduced pressure and the resulting yellow-colored solid was taken up in 250 ml of 95% hot ethanol. Carbon (Darco G-60, 0.58 g) was added and the reaction mixture was heated to boiling. The hot suspension was filtered through Celite 503 and the residue was washed with 50 ml of hot ethanol. The combined filtrates were boiled to approximately 150 ml and then cooled in tap water with stirring. The solution was seeded with by-product crystals and then refrigerated overnight after the start of recrystallization. The by-product was filtered and washed with 10 ml of cold ethanol (after drying the by-product residue weight 3.2762 g and tube a p.f of 262-269 ° C). The combined filtrates were boiled to approximately 50 ml and then cooled in tap water with stirring. The solution was seeded with the authentic product and then refrigerated overnight after the start of recrystallization. The suspension was filtered and the residue was dried over P2O5 under vacuum to give flat white crystals (4.6827 g, 16.283 mmol, 41%), mp 193-195 ° C, homogeneous to TLC (50% ethyl acetate / hexanes on gel of silica, product Rf 0.47, authentic sample Rf 0.47).

Claims (83)

1. - A method for treating premenstrual dysphoric disorders in an individual, said method comprising: providing a steroid, which binds to receptors on the surface of nasal neuroepithelial cells of the individual, wherein the cells are part of tissue different from the olfactory epithelium; and administering said effective amount of the steroid within the nasal passage of the individual, such that the steroids come together Specifically to the recipients and results in the mitigation of the symptoms of the disorder in the individual.

2. The method according to claim 1, wherein the neuroepithelial cell is located within a vomeronasal organ of said individual.

3. The method according to claim 2, wherein it: wherein P- is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (β-) propionoxy, a- (β-) methoxy, a- (β -), lower acyloxy a- (β-), lower alkyloxy, and a- (β-) benzoyloxy; P2 is selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acyloxyalkyl and alkoxyalkyl; P3 is selected from the group consisting of hydrogen, oxo, halo, hydroxy, alkoxy and acyloxy; P4 to P12 each can independently be hydrogen, halogen, methyl or halo-, dihalo-, or perhalomethyl; P13 is hydrogen, methyl, methylene, substituted halomethyl, or substituted halomethylene, ethyl, ethynyl, acetylenyl, methyl-methylenyl, methyl-methynyl; and "a", "b", "c", "d", "e", "h", "i" and "j" are alternate sites for optional double bonds, and "j" or "k" may be triple links; and when P2 is methyl and P3 is β-hydroxy, P2 and P3 can be joined to form a cyclic ether.

4. A method according to claim 3, wherein "b" is a double bond.

5. A method according to claim 4, wherein "e" or "d" is a double bond.

6. A method according to claim 3, wherein "a" and "c" are double bonds.

7. A method according to claim 3, wherein "h" is an optional double bond, "i" and "j" are absent.

8. A method according to claim 3, wherein "j" is a double bond.

9. A method according to claim 3, wherein "j" is a triple bond.

10. - The method according to claim 2, wherein the steroid comprises a 19-nor-pregnane of the formula: where P-? is oxo, a- or β-hydroxy, a or β-acetoxy, α or β-propionoxy, α or β-acetoxy, α or α-acyloxy, or α or β-benzyloxy; a, b, c, d, e, f, g, h, i, j, m and n are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms, or halogen; P is methyl or ethyl; P5 is hydrogen, methyl or halogen; P6 is hydrogen or methyl; R 'and R "are independently hydrogen or halogen, or are absent.

11. - A method according to claim 10, wherein "a", "e" and "d" are double bonds.

12. A method according to claim 11, wherein "h" is a double bond.

13. A method according to claim 11, wherein "g" is a double bond.

14. A method according to claim 13, wherein "n" is a double bond.

15. A method according to claim 10, wherein "d" is a double bond.

16. A method according to claim 15, wherein "b" is a double bond.

17. A method according to claim 15, wherein "c" is a double bond.

18. A method according to claim 17, wherein "f" is a double bond.

19. The method according to claim 2, wherein the steroid is a premiere, which has the formula: wherein Ri is selected from the group consisting essentially of one or two hydrogen atoms, methyl, methylene and one or two halogen atoms; R2 is absent or selected from the group consisting essentially of hydrogen and methyl; R3 is selected from the group consisting essentially of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, cyproionyl, glucuronide and sulfonyl; R 4 is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy, oxo and halo; R5 is absent or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6 is a hydrogen or a halogen; and "a" represents an optional aromatic unsaturation of ring A of such a steroid, or "b", "c" and "d" are each optional double bonds; "e", "f", "g", "h", "i" and "j" are each optional double bonds; and "e" can also form an epoxy ring with C16 and C17.

20. A method according to claim 19, wherein "a" is present and "g", "h" or "i" are optional double bonds.

21. A method according to claim 20, wherein "h" and "i" are both double bonds.

22. A method according to claim 19, wherein "b" is a double bond.

23. A method according to claim 19, wherein "j" is a double bond.

24. A method according to claim 19, wherein "c" is a double bond.

25. - A method according to claim 19, wherein "c" and "d" are double bonds.

26. A method according to claim 19, wherein R2 is methyl and "e" is a double bond.

27. A method according to claim 19, wherein the steroid is selected from the group consisting of estra-4,16-dien-3-one; estra-1, 3.5 (10), 16-tetraen-3-ol; 10-estra-4, 16-dien-3a-ol; estra-4.9 (10), 16-trien-3-one; estra-1, 3.5 (10), 16 -tet raen -3-ol-6-one; 3-methoxyl-estra-2,5 (10), 16-triene; estra-5 (10), 16-dien-3a-ol; and estra-1, 3, 5 (10), 16-tetraen-3,6a-diol.

28. A method according to claim 19, wherein R5 is methyl.

29. A method according to claim 28, wherein the steroid is selected from the group consisting essentially of estra-1, 3, 5 (10) -trien-3-ol; estra-1, 3.5 (10), 6-tetraen-3-ol; and estra-1,3, 5 (10), 7-tetraen-3-ol.

30. A method according to claim 19, wherein Ri is methylene.

31. A method according to claim 30, wherein the steroid is 17-methylene-estra-1, 3.5 (10), 6.8 (9) hexaen-3-ol.

32. A method according to claim 19, wherein Ri is methylene or an individual hydrogen and R2 is methyl.

33. A method according to claim 19, wherein "f" is a double bond and R2 is methyl.

34. The method according to claim 33, wherein at least one Premiere steroid is selected from the group consisting of ether 1, 3.5 (10), 16-estratetraen-3-methyl, 1, 3.5 (10), 16-estratetraen-3-ol, acetate of 1, 3,5 (10), 16-estratetraen-e-ilo, and propionate of 1, 3,5 (10), 16-estratetraen-3-yl .

35. The method according to claim 33, wherein the steroid Premiere is 1, 3.5 (10), 16-estratetraen-3-ol.

36. A method according to claim 19, wherein the premiere is estra-4, 16-dien-1 Oß-ol-3-one.

37. A method according to claim 19, wherein "e" forms an epoxy ring with C16 and C-? 7.

38. A method according to claim 37, wherein the premiere is 16a, 17a-epoxy-estra-1, 3,5 (10) -trien-3-ol.

39. A method according to claim 37, wherein the premiere is 16a, 17a-epoxystr-4-en-1 Oß-ol-3-one.

40. The method according to claim 2, wherein said steroid is an androstane of the formula: wherein P ^ is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propionoxy, a- (ß-) methoxy, a- (ß-) ) lower acyloxy, a- (β-) lower alkyloxy and a- (β-) benzoyloxy; P2 is selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acyloxyalkyl and alkoxyalkyl; P3 is absent or selected from the group consisting of methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acyloxyalkyl and alkoxyalkyl; P4 is selected from the group consisting of hydrogen, oxo, halogen, hydroxy, alkoxy and acyloxy; P5 represents one or two substituents, wherein P5 comprises one or two hydrogen atoms, methyl, methylene or one or two halogen atoms; P6 is hydrogen or halogen; and "a", "b", "c", "d", "e", "f" and "h" are alternative sites for optional double bonds.

41. A method according to claim 40, wherein "b" is a double bond.

42. A method according to claim 41, wherein "c" or "d" is a double bond.

43. A method according to claim 40, wherein "a" and "c" are double bonds.

44.- A method according to claim 40, wherein P3 is methyl, "h" is an optional double bond, and P5 is methylene or one or two hydrogen atoms.

45. A method according to claim 40, wherein P3 is methyl and "h" is a double bond.

46. A method according to claim 45, wherein said steroid is selected from the group consisting of androsta-5,16-dien-3a-ol, androsta-4,6,16-trien-3-one; androsta-4,16-dien-3,6-dione; 19-hydroxy-androsta-4,16-dien-3-one; 3-methoxy-androsta-3,5,16-triene; and 6-hydroxy-androsta-4-16-dien-3-one.

47.- A method according to claim 40, wherein P3 is methyl.

48. A method according to claim 47, wherein said steroid is androst-4-en-3-one.

49. A method according to claim 40, wherein P5 is methylene.

50. A method according to claim 49, wherein said steroid is selected from the group consisting of 20-homo-androsta-4, 17-dien-3-ol; 20-homo-androsta-4, 17-dien-3ß-ol; and 20-homo-androsta-4,17-dien-3,6-dione.

51.- A method according to claim 40, wherein P5 is methyl and "f" is a double bond.

52. A method according to claim 40, wherein "a" or "b" is a double bond.

53. The method according to claim 40, wherein at least one androstane steroid is selected from the group consisting of androsta-4,16-dien-3-one, androsta-4, 16-dien-3a-ol and androsta-4,16-dien-3ß-ol.

54. The method according to claim 53, wherein said steroid is androsta-4,16-dien-3-one.

55.- A method according to claim 53, wherein said steroid is androsta-4, 16-dien-3ß-ol.

56.- A method according to claim 2, wherein said steroid is a 19-nor-collagen of the formula: wherein Pi is oxo, a- or β-hydroxy, α- or β-acetoxy, α- or β-propionoxy, α- or β-acetoxy, α- or α-β-acyloxy, or α- or β-benzyloxy; Or a, b, c, d, e, f, g, h,? , j, m, s and n are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms or halogen; P4 is methyl or ethyl; each of P5 and P7 independently is hydrogen, methyl or halogen; • P6 is hydrogen or methyl; R 'and R "independently are hydrogen or halogen, are absent, or together form = CH2; and q is an integer from 0 to 2 on the surface of the nasal neuroepithelial cell of said individual, wherein the cell is a part of tissue different from the olfactory epithelium, and 10 administering the 19-nor-colane derivative within a nasal passage of the individual, such that said 19-nor-colane derivative binds specifically to said receptor and results in an alteration of Hypothalamic function of the individual

57. A method according to claim 56, wherein 15"a", "e" and "d" are double bonds

58. A method according to claim 57, wherein • "h" is a double bond.

59. A method according to claim 57, wherein "g" is a double bond.

60.- A method according to claim 59, wherein "n" is a double bond.

61.- A method according to claim 56, wherein "d" is a double bond.

62. A method according to claim 61, wherein 25"b" is a double bond.

63. - A method according to claim 56, wherein "c" is a double bond. 64.- A method according to claim 51, wherein "s" is a double bond. The method according to any of claims 1 to 64, wherein the amount of said steroid that is administered is at least about 100 picograms, but not more than about 100 micrograms. 66. The method according to claim 65, wherein the amount of said steroid that is administered is at least about 1 nanogram, but not more than about 10 microgram. 67.- The method according to claim 66, wherein the amount of said steroid that is administered is at least about 10 nanograms, but not more than about 1 microgram. 68.- The method according to claim 65, wherein said steroid is administered in an ointment. 69. The method according to claim 65, wherein said steroid is administered in a liquid. The method according to claim 65, wherein said steroid is administered through an aerosol. 71.- A method to treat anxiety disorders in an individual, said method comprises: providing a steroid, which binds to receptors on the surface of nasal neuroepithelial cells of the individual, where the cells are part of tissue different from the olfactory epithelium; and administering said effective amount of the steroid within the nasal passage of the individual, such that the steroids bind specifically to the receptors and result in the mitigation of the symptoms of the disorder in the individual. 72.- A method according to claim 71, wherein said individual is a woman. 73.- A method according to claim 71, wherein said individual is a man. 74. A method for altering the temperature of the body in an individual, said method comprises: providing a steroid, which binds to receptors on the surface of nasal neuroepithelial cells of the individual, where the cells are part of tissue other than the epithelium olfactory; and administering said effective amount of the steroid within the nasal passage of the individual, such that the steroids bind specifically to the receptors and result in the alteration of the body temperature in the individual. 75.- A method to treat paroxysmal tachycardia in an individual, said method comprises: providing a steroid, which binds to receptors on the surface of nasal neuroepithelial cells of the individual, where the cells are part of tissue different from the olfactory epithelium; and administering said effective amount of the steroid within the nasal passage of the individual, such that the steroids bind specifically to the receptors and result in the mitigation of the symptoms of the disorder in the individual. 76.- A steroid according to the formula: wherein R ^ is selected from the group consisting essentially of one or two hydrogen atoms, alkyl of 1 to 10 carbon atoms; R2 is absent or selected from the group consisting essentially of hydrogen, methyl and oxygen to form an epoxy ring with C17; R3 is selected from the group consisting essentially of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, cyproionyl, glucuronide and sulfonyl; R 4 is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy and halogen; R5 is absent or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6 is a hydrogen or a halogen; and "a" represents optional aromatic unsaturation of ring A of such steroid, or "b", "c" and "d" each are optional double bonds; "g", "h", "i" and "j" are each optional double bonds; and "e" can form an epoxy ring with C16 and C17; "f" can form an epoxy ring with C 3 and C 17; and "k" can form an epoxy ring with C17 and c20. 77.- A steroid according to claim 76, 16a, 17a-epoxy-estr-4-en-10β-ol-3-one. 78. A steroid according to claim 76, estra-4,16-dien-1 Oß-ol-one. 79. A steroid according to claim 76, 17a, 20a-epoxy-19-norpregna-1, 3,5 (10) -trien-3-ol. 80.- A steroid according to claim 76, 16a, 17a-epoxipregn-4-en-3-one. 81. A steroid according to claim 76, 13,17-epoxy-10,17-dimethylgon-4-en-3-one. 82.- A steroid according to claim 76, 16a, 17a-epoxy-19,21-bisnorcol-4-en-10β-ol-3-one. 83.- A method for altering a hypothalamic function of an individual, said method comprises providing a steroid for a chemoreceptor of a nasal neuroepithelial cell of said individual, wherein the cell is part of tissue different from the olfactory epithelium of the following formula: wherein Ri is selected from the group consisting essentially of one or two hydrogen atoms, alkyl of 1 to 10 carbon atoms; R2 is absent or selected from the group consisting essentially of hydrogen, methyl and oxygen to form an epoxy ring with C17; R3 is selected from the group consisting essentially of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, cyproionyl, glucuronide and sulfonyl; R 4 is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy and halogen; R5 is absent or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6 is a hydrogen or a halogen; and "a" represents optional aromatic unsaturation of ring A of such steroid, or "b", "c" and "d" each are optional double bonds; "g", "h", "i" and "j" are each optional double bonds; and "e" can form an epoxy ring with C6 and C17; "f" can form an epoxy ring with C13 and C17; and "k" can form an epoxy ring with C17 and C20; and administering said steroid within a nasal passage of the individual so that the steroid specifically binds to the chemoreceptor and results in an alteration of the hypothalamic function of said individual.