MXPA98007951A - Steroids as neurochemical initiators of change in the levels in human blood of luteinizing hormone or stimulating hormone of folicu - Google Patents

Abstract

The invention relates to a method for altering the blood levels of luteinizing hormone or follicle-stimulating hormone in an individual. The method comprises administering nasally a steroid, which is a human vomeropherin, such that the vomeropherin binds to a specific neuroepithelial receptor. The steroid or steroids are preferably administered in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable carriers.

Description

STEROIDS AS NEUROOUIMIC INITIATORS OF CHANGE IN THE LEVELS IN HUMAN BLOOD OF UTEINIZING HORMONE OR STIMULATING HORMONE OF FOLLICLES Reference to Related Requests This is a partial continuation of the United States of America Patent Application Serial Number 08 / 286,073, filed on August 4, 1994. This application is related to the Application for Patent of the United States of America with Serial Number 08 / 127,908, filed September 28, 1993, which is a partial continuation of the United States of America Patent Application Serial Number 07- '/ 9Q3. 604, filed June 4, 1992, which in turn is a partial continuation of the United States of America Patent Application Serial Number 07 / 708,936, filed May 31, 1991, which at its once is a partial continuation of the United States of America Patent Application Serial Number 07 / 638,185, filed January 7, 1991, now abandoned. The application also relates to U.S. Patent Application Serial Number 08 / 127,980, filed September 28, 1993, which is another partial continuation of the U.S. Patent Application with Serial Number 07- / 903,604, U.S. Patent Application Serial Number 08 / 077,359, filed June 15, 1993, and the commonly-assigned pending United States Patent Application Number of Series 07 / 903,525, filed June 24, 1992 (a partial continuation of United States of America Patent Application Serial Number 07 / 707,862, filed May 31, 1991, which in turn is a partial continuation of U.S. Patent Application Serial Number 07 / 638,743, filed January 7, 1991, now abandoned), entitled "Estrene Steroids as Neuroc Hemical Initiators of Change in Human Hypothalamic Function and Related Pharmaceutical Compositions and Methods "; and to the pending partial continuation commonly assigned of the United States of America Patent Application Serial Number 07 / 903,525, and the United States of America Patent Application Serial Number 09 / 077,140. The aforementioned US Patent Applications are incorporated herein by reference. Finally, this application can be related to the Patent of the United States of America Number 5-, 278,141, issued on January 11, 1994, entitled "Fragrance Compositions Containing Human Pheroons", and with the Patent of the United States of America Number 5,272,134, issued December 21, 1993, entitled "Fragrance Compositions and Other Compositions which Contains Human Pheromones." Technical Field This invention relates generally to methods for altering the blood levels of luteinizing hormone or follicle-stimulating hormone in humans.

Description of the Related Art The present invention relates to certain steroids, and to methods for using these steroids as human vomerofe-rines, 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 (1993) 66: 192-217), which is incorporated herein by reference, has shown that several steroids (androstenes) have an odor that varies with different isomeric, diastereomeric forms , and enantiomerics. 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) 12.7: 497-502). These 16-androstenes produced by the wild boar induce the coupling behavior in sows in estrus (Claus et al., Experimentia (1979) 35: 1674-1675). Some studies have observed that, in some species, several characteristics of certain 16-androstenes (including the Sof-Androst-lß-en-Sc-ol and the 5th-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. J. Endocr. (1976) 68.:483-484; Kwan, et al., Med. Sci. Res. (1987) 5: 1443-1444). For example, 5a-Androst-16-en-3OÍ-O1 and 5a; -Androst-16-en-3-one, as well as Androsta-, 16-dien-3-one, have been found in different concentrations in the peripheral blood, in the saliva, and in the 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 that it affects choice and judgment (Id., - see also Gower et al., "The Significance of Odorous Steroids in Axillary Odour", In, Perfumery, pages 68-72, Van Toller and Dodds , Eds. Chapman and Hall, 1988); Kirk-Smith, D.A., et al., Res. Comm. Psychol. Psychiat. Behav. (1978) J3.-379). It has been claimed that androstenol (5a-androst-16-en-3a; -ol) exhibits a pheromone-like activity in a men's cologne and in a commercial lady's perfume (AndronMR for men, and Andron for ladies, for Jóvan). Japanese Patent Kokai Number 2295916, relates to perfume compositions containing androstenol and / or its analogs. Androstadien-3/3-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 little agreement in the literature on whether any supposed pheromone actually has any role or not in the sexual or reproductive behavior of mammals, particularly humans. See: Beauchamp. G.K. and collaborators, "The Pheromone Concept in Mammalian 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 pheromone properties of some premiere steroids for some mammalian species have already been described. Michael, R.P. et al., Nature (1968) 218: 746 refers to Estrogens (particularly Estradiol) as a pheromonal attractant of male Rhesus monkeys. Parrot, R.F. Hormones and Behavior (1976) 2 = 207-215, reports that the injection of estradiol benzoate induces copulation behavior in ovariectomized rats; and the role of the blood level of Estradiol in the formation of the sexual response (Phoenix, C.H. Phvsiol. And Behavior (1976) 16 305-310) and in the sexual response of females (Phoenix, C.H., Hormones and Behavior (1977) 8: 356-362) eg the Rhesus monkeys, has already been described. On the other hand, there is little agreement in the literature on whether pheromones as such have any role or not in the reproductive behavior and in the interpersonal communication of mammals (Beuchamp, GK, and collaborators, The Pheromo-ne Concept in Mammalian Chemical Communication : A Critique ', In: Mammalian Olfaction, Reproductive Processes and Behavior, Doty RL, Ed., Academic Press, 1976). The present invention relates to the non-systemic administration to the vomeronasal organ (VNO) of certain steroids to affect the blood levels of luteinizing hormone or follicle-stimulating hormone in human subjects. The administration provides contact of the neurochemical receptors in the vomeronasal organ (also known as the "Jacobson organ"), with one or more steroids, or with compositions containing the steroids. This organ has access through the nostrils of most of the higher animals - from snakes to humans, and has been associated, among other things, with the reception of pheromone in certain species (see in general Muller -Schwarze and Silverstein, Chemical Sign is, Plenum Press, New York (1980)). The axons of the neuroepithelia of the vomerone-salt organ, located supra-palatally, form the vomeronasal nerve, and have a direct synaptic connection with the access olfactory bulb, and an indirect entry from there to the anterior basal-medial amygdaloid-cortical-amyloid brain. the hypothalamic nuclei of the brain. The distal axons of terminal nerve neurons can also serve as neurochemical receptors in the vomeronasal organ. Stensaas, L.J., and collaborators, J. Steroid Biochem. and Molec. Biol. (1991) 39: 553. This nerve has a direct synaptic connection with the hypothalamus. Johnson, A. and collaborators (J. Ótolaryngology (1985) 14 report evidence of the presence of the vomeronasal organ in most adult human beings, but conclude that the organ is probably not functional. The results in contravention that suggest that the vomeronasal organ is a functional chemosensory receptor, are reported by extensive L. et al., Supra; and by Moran, D.T., and collaborators, García-Velazco, J. and M. Mondragón; Monti-Bloch, L. and B.

Grosser, all in J. Steroid Biochem. and Molec. Biol. (1991) 39. This invention relates to the unexpected discovery that, when administered intranasally to human subjects, certain neurochemical ligands, particularly steroids, and related compounds, specifically bind to the chemoreceptors of certain neuroepithelial cells. nasal, and this link generates a series of neurophysiological responses that result in an alteration of the hypothalamic function of an individual. When administered appropriately, the effect of some of these compounds on the hypothalamus, affects autonomic nervous system function, and a variety of behavioral or physiological phenomena, which 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, Volume I, Washington DC, 1979, American Physiological Society; Fishman, A.P., and collaborators, editors, Handbook of Phvsiology. Section 3: Respiratorv System. Vol. II. Control of breathing, Bethesda MD, 1986. American Physiological Society. In some cases, a single steroid, or a related compound, is administered, and in some cases combinations of steroids and / or related compounds are administered.

SUMMARY OF THE INVENTION In accordance with the foregoing, it is an object of this invention to provide methods for using vomeropherins to alter the hypothalamic functions of an individual, in particular to alter the blood levels of luteinizing hormones or of follicle-stimulating hormone. The method of the invention has the following advantages: 1) administration directly to the chemoreceptors in the nasal passage and the vomeronasal organ, without pills or needles - that is, non-invasively; 2) a mode of action of the drug through the system of the invention, and not through the circulatory system - therefore, brain function can be affected without considering the blood-brain barrier, 3) a direct means to affect the hypothalamus - there is only one synaptic junction between the pheromone receptors and the hypothalamus; and 4) provide a highly specific drug effect, thereby greatly reducing the potential for undesirable side effects - this because the sensory nerves are directed to a specific place in the brain.

The objects, advantages, and additional novel features of the invention will be set forth in part in the following description, and will become apparent to those skilled in the art, upon examination of the following, or may be learned by practice of the invention. .

Among the compositions, a preferred class contains a pharmaceutically acceptable carrier, and a pregnane steroid having the formula: wherein P-j_ is selected from the group consisting of oxo, - (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, a- (ß-) methoxy, or; - (ß-) lower acyloxy, - (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, halogen, hydroxy, alkoxy, and acyloxy; P4 to P12 can each be, independently, hydrogen, halogen, methyl, or halo-, dihalo-, or perhalo-methyl, and when P2 is methyl and P3 is β-hydroxy, P2 and P3 can be attached to form an ether cyclic; P13 is hydrogen, methyl, methylene, methyl substituted by halogen, methylene substituted by halogen, ethyl, ethylenyl, 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" "They can also be triple links. 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, or only "c" as a double bond. Still another preferred class contains "h" as a double bond, with i and j absent (ie, single bonds), where j is a double bond, or j is a triple bond. In another class "h" is absent, and j or i is a double bond, or i and j are absent, or j and i are double bonds, or j is a triple bond. The term "lower alkyl", "lower alkoxy", and the like encompasses 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: where ? > 1 is oxo, a- or 3-hydroxy, a- or 3-acetoxy, of- or 3-propionoxy, OIO- lower -acetoxy, a; - or -cyloxy, or o- or 3-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; P4 is methyl or ethyl; P5 is hydrogen, methyl, or halogen; Pg is hydrogen or methyl. A subset 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" present, and g or h are optionally present. If "g" is present in this case, then "n" is optionally present. Another preferred class has "c" present, with "f" optionally present. A third class of compositions contain steroids with the formula: wherein R-_ is selected from the group consisting essentially of 1 or 2 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 halogen; R5 is absent, or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, and lower acyloxy; R6 is hydrogen or halogen; and "a" represents optional aromatic unsaturation of ring A of this steroid, or "b", "c", and "d" are each optional double bonds; and "e", "f", "g", "h", "i" and "j" are each optional double bonds. In this embodiment, the preferred steroid is administered in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable carriers. A preferred subset 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. Still another class contains "c" and "d" as double bonds. Still another class contains R2 as methyl, and "e" as a double bond. The term "lower alkyl", "lower alkoxy", and the like encompasses carbon chains of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Halogen includes I, Br, F, and Cl. A fourth class of preferred compositions contains a pharmaceutically acceptable carrier, and an androstane steroid having the formula: where P? it is selected from the group consisting of oxo, a- (ß-) hydroxy, a - (? -) acetoxy, a-. { ß-) propio-noxi, - (ß-) methoxy, - (ß-) acyloxy, - (ß-) alkyloxy, and o; - (ß-) 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 1 or 2 substituents, wherein P5 comprises 1 or 2 hydrogen atoms, methyl, methylene, or 1 or 2 halogen atoms; P6 is hydrogen or halogen; and "a", "c", "d", "e", "f", and "h" are alternative sites for optional double bonds. A subset of the fourth preferred class of steroids has "b" as a double bond, particularly where "c" or "d" is also a double bond. Other subset has "a" and "c" as double bonds. Still another subset contains P3 as a methyl group, "h" as an optional double bond, and P5 as methylene or 1 or 2 hydrogen atoms. A subset of steroids is also preferred where "a" or "b" is a double bond. Halogen means F, Cl, Br, or I. The term "lower alkyl", "lower alkoxy", and the like encompasses carbon chains of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Other objects of this invention are able to provide a method for altering the hypothalamic function and / or the autonomous function in an individual. A ligand for a chemoreceptor displayed on the surface of a nasal neuroepithelial cell is provided, wherein the cell is a part of the tissue different from the olfactory epithelium; and the ligand is administered inside the nasal passage of the individual, such that the ligand specifically binds with the chemoreceptor, resulting in an alteration of the hypothalamic function of the individual. All embodiments of this application relate to, and include, the functional equivalents of the steroid structures disclosed in these embodiments, and to modified steroids that demonstrate that functional equivalence, whether or not the modified steroids disclosed explicitly.

Brief Description of the Drawings Figure 1 is the data on integrated EVG, GSR, and ST for the compound Al-Pl in males, tested according to examples 16 and 17. Figure 2 is the data for the integrated EVG for the compounds Al-Pl, A2-P1, A4-P1, A3-P1, A1-P4, A2-P4 in females. Figure 3 is the data for the ST measurements of the compounds Al-Pl, A2-P1, A4-P1, A3-P1, A1-P4, A2-P4 in females. Figure 4 is the data for the GSR measurements in females, of the compounds Al-Pl, A2-P1, A4-P1, A3-P1, A1-P4, A2-P4. Figure 5 is the data for ST measurements, GSR and EVG in females, of compound A1-P3. Figure 6 is the data for RF and EKG measurements in females of compound A1-P3. Figure 7 is the data for EEG measurements in females, of compound A1-P3. Figure 8 is the data for measurements of ST, GSR and EVG in males, of compound A1-P3. Figure 9 is the data for RF measurements, and EKG in males, of compound A1-P3. Figure 10 is the data for male EEG measurements of compound A1-P3. Figures 11 and 12 show the data for measurements of ST, GSR, and EVG in males and females, respectively, for compound A2-P3. Figures 13 and 14 show the data of EEG measurements in males and females, respectively, for compound A2-P3. Figures 15 and 16 show the data for RF measurements, and EKG in males and females, respectively, for compound A2-P3.

Figures 17 and 18 show the data of ST, GSR, and EVG measurements in males and females, respectively, for compound A8-P1. Figures 19 and 20 show the data of RF, EKG measurements in males and females, respectively, for compound A8-P1. Figures 21 and 22 show the data for EEG measurements in males and females, respectively, for compound A8-P1. Figures 23 and 24 show the data for measurements of ST, GSR, and EVG in males and females, respectively, for compound A6-P1. Figures 25 and 26 show the data for RF and EKG measurements in males and females, respectively, for compound A6-P1. Figures 27 and 28 show the data for EEG measurements in males and females, respectively, for compound A6-P1. Figures 29, 30, and 31 show the data for ST, GSR, EVG, RF, EKG and EEG measurements in males, of 20, 21-dimethylpregna-5, 20-dien-3? -ol. Figures 32, 33, and 34 show the data for ST, GSR, EVG, RF, KEG and EEG measurements in females of 20, 21-dimethylpregna-5, 20-dien-33-ol. Figures 35, 36, and 37 show the data for the ST, GSR, EVG, RF, KEG and EEG measurements in males of the 20, 21-dimethylpregna-5, 20-dien-3-one. Figures 38, 39, and 40 show ST, GSR, EVG, RF, EKG and EEG measurements in females 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 males of compound A14-P2. Figures 44, 45, and 46 show measurements of ST, GSR, EVG, RF, EKG and EEG in females of compound A14-P2. Figures 47, 48, and 49 show the measurements of ST, GSR, EVG, RF, EKG and EEG in males of compound A7-P2. Figures 50, 51, and 52 show the measurements of ST, GSR, EVG, RF, EKG and EEG in females of compound A7-P2. Figures 53 and 54 show measurements of ST, GSR, EVG, EEG in All-Pl composite cores. Figure 55 shows EEG measurement data in cores of compound A13-P1. Figures 56, 57, and 58 show the data of ST, GSR, EVG, RF, EKG, and EEG measurements in females of compound A13-P1. Figure 59 shows the EVG, EDA, and BT data of the measurements in women of the A3 / P1 compound. Figure 60 shows the EVG, EDA, and BT data, of the measurements in women, of the A4 / P1 compound. Figures 61 and 62 show the data of measurements in men and women, respectively, of compound A8 / P1. Figures 63 and 64, show the data of the measurements in men and women, respectively, of compound A13 / P8. Figures 65 and 66 show the data of the measurements in men and women, respectively, of the compound A6 / P1. Figures 67 and 68 show the data of the measurements in men and women, respectively, of the 20-methyl derivative of compound A6 / P1. Figures 69 and 70 show the data of the measurements in men and women, respectively, of the 20, 21-dimethyl derivative of the compound Al / Pl. Figures 71 and 72 show the data of the measurements in men and women, respectively, of the 20, 21-dimethyl derivative of the compound A6 / P1. Figures 73 and 74 show the data of the measurements in men and women, respectively, of compound A14 / P2. Figures 75 and 76 show the data of the measurements in men and women, respectively, of compound A12 / P1. Figures 77 and 78 show the data of the measurements in men and women, respectively, of compound A7 / P2. Figures 79 and 80 show the data of the measurements in men and women, respectively, of compound A13 / P1. Figures 81 and 82 show the data of the measurements in men and women, respectively, of the compound A2 / P7. Figures 83 and 84 show the data of the measurements in men and women, respectively, of the compound A3 / P5. Figures 85-96, refer to the phalluses of Diagram II. Figures 85 and 86 show the data of measurements in men and women, respectively, of compound A8 / C1. Figures 87 and 88 show the data of the measurements in men and women, respectively, of the compound A2 / C1. Figures 89 and 90 show the data of the measurements in men and women, respectively, of the acetate of the compound A2 / C1. Figures 91 and 92 show the data of the measurements in men and women, respectively, of the compound Al / Cl. Figures 93 and 94 show the data of the measurements in men and women, respectively, of the A3 / C1 compound. Figures 95 and 96 show the data of the measurements in men and women, respectively, of compound A13 / C1. Figure 97 and Figure 98 show the EVG and the discharge frequency of the vomeronasal nerve, respectively, of the steroid E2 / P4 and the control, in female rats. Figures 99 to 120 show the EVG, EDA, RF, CF, EMG, BT, and EEG data (alpha-V, alpha-T, beta-V, and beta-T) of the administration of the 19-nor- Designated steroids in WNV women. Figures 121 to 142 show the EVG, EDA, RF, CF, EMG, BT and EEG data of the administration of the 19-nor-steroids 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 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 graphic comparison of the effect of a release on the potential WNV 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 male subjects (145A) and females (145B). Figure 146 illustrates different autonomous responses of male subjects to acetate of 1, 3, 5 (10), 16-Estratetraen-3-yl. A = potential receptor of the vomeronasal neuroepithelium; B = change in galvanic skin response (K-ohms); C = change in skin temperature (degrees C.). Figure 147 illustrates the comparative changes in the potential of the vomeronasal organ after exposure to 5-methyl ether and acetate 1, 3, 5 (10), 16-Estratetraen-3-ol. Figure 148 illustrates the sexual dimorphism in local and autonomic responses to vomeronasal organ stimulation with vomeropherins. Different vomeropherins (200 10 fmoles) and diluent control were administered to 30 male subjects and 30 females (ages 20 to 45), as described. The bars indicate the average response of the population. Figures 149A and 149B: EVG responses were measured as described in male (A) and female (B) subjects. Figures 149C and 149D: The electrodermal activity was measured as described. The changes (measured in x?) In the response due to the application of vomeropherins to the vomeronasal organ of each subject are shown in male subjects (C) and females (D). Figures 149E and 149F: alpha-cortical activity was measured as described. Changes in response due to the application of vomeropherins to the vomeronasal organ of male (E) and female (F) subjects. Figures 149G and 149H: Skin temperature (ST) was measured as described. Changes in response due to the application of vomeropherins to the vomeronasal organ of each subject are shown in male (G) and female (H) subjects. 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-l, 3, 5 (10), 16-tetraene. E = Androsta-4, 16-dien-3o; -ol. F = Androsta-4, 16-dien-3 / S-ol. Figure 149 illustrates electro-olylograms of male and female subjects induced by the stimulation of OE with olfactants and vomeropherins A: 400 fmol of the olfactory 1-carvone and cineole, as well as 200 fmol of the vomeropherin A; B, C, D, and F; and 10-stereoisomer E, were applied separately as a second pulse to the EO of 20 subjects (both males and females), and each EOG response was recorded as described. The olfactants, as well as E and B, produced a significant local response (p <0.01). B: 400 fmol of 1-carvone and cineole olfactants do not induce a significant EVG response when applied to the vomeronasal organ of male and female subjects.

Figure 150 illustrates the electrophysiological effect of the following vomeropherins on the vomeronasal organ of 20 male subjects: 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-yl EVG = Electro-vomeronasogram GSR = Galvanic Skin Response EDA = Electro-Thermal Activity (EDA) ST = Skin Temperature Figure 151 illustrates the electrophysiological effect of vomeropherins on the vomeronasal organ of 20 male subjects. 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 steps described in Examples 67 to 71. Figure 155 illustrates the synthesis steps described in Examples 72 to 75. Figure 156 illustrates the synthesis steps described in Examples 76 to 77. Figure 157 illustrates the synthesis steps described in Examples 78 to 83. Figure 158 illustrates the synthesis steps described in Examples 84 to 86. Figure 159 illustrate the synthetic steps described in Examples 87 to 93. Figure 160 illustrates the synthetic steps described in Examples 94 to 96. Figure 161 illustrates the synthetic steps described in Examples 97 to 98. Figures 162A, 162B , and 162C illustrate the EVG, GSR, and ST data in women, respectively, for 13 estranos in Diagram 1. Figures 163A, 163B, and 163C illustrate the data from EVG, GSR, and ST in men, respectively, for 13 estranos in Diagram 1. Figures 164A and 164B to 176A and 176B, illustrate the EEG data in men (A) and women (B) for the 13 estranos, respectively , identified in Figures 163A-163C. Figure 177 illustrates the synthesis of Androsta-4, 16-dien-3-one, Androsta-4, 16-dien-3c-ol, and Androsta-4, 16-dien-33-ol. Figure 178 illustrates the syntheses of Androsta-5, 16-dien-3?! -ol and Androsta-5, 16, dien-33-ol.

Figure 179 illustrates an alternative synthesis of Androsta-, 16-dien-3-one. Figure 180 is a graphic representation of the electrophysiological effect on the receptor potential of the localized administration of particular steroids to the vomeronasal organ of female subjects (180A) and to the olfactory epithelium (180C). Figure 180B is a graphical comparison of the effect of an Androstane on the potential receptor of the vomeronasal organ of male and female subjects. Figure 181 is a graphical representation of the electrophysiological effect of localized administration of particular steroids to the vomeronasal organ of male subjects (182A) and females (182B). Figure 182A to 182F illustrates different autonomous responses of female subjects 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 impulse (counts / minute); E = change in skin temperature (degrees C.); and F = change in respiratory rate (counts / minute). Figure 183 illustrates the changes in the potential receptor of the vomeronasal organ after the exposure of 5 females to 2 different Androstanes. Figure 184 illustrates the sexual dimorphism in the local and autonomic response to the vomeronasal organ stimulation with vomeropherins. Different vomeropherins (200 fmoles) and diluent control were administered to 30 male subjects and 30 females (ages 20 to 45), as described. The bars indicate the main response of the population. Figures 184A and 184B: EVG responses were measured as described in male subjects (A) and (B). Figures 184C and 184D: The activity of the electro-mica was measured as described. The changes (measured in x?) In the response due to the application of vomeropherins to the vomeronasal organ of each subject are shown in male (C) and female (D) subjects. Figures 184E and 184F: Alpha-cortical activity was measured as described. Changes in response due to the application of vomeropherins to the vomeronasal organ of male (E) and female (F) subjects. Figures 184G and 184H: Skin temperature (ST) was measured as described. Changes in response due to the application of vomeropherins to the vomeronasal organ of each subject are shown in male (G) and female (H) subjects. The compounds of the graphs are: A = 1, 3, 5 (10), 16-Estratetraen-3-yl acetate. B = Androsta-4, 16-dien-3-one. C = 1.3, 5 (10), 16-Estratetraen-3-ol. D = 3-methoxy-Estra-l, 3.5 (10), 16-tetraene.

E = Androsta-4, 16-dien-3a-ol. F = Androsta-4, 16-dien-3 / S-ol. Figure 185 illustrates electro-olylograms of male and female subjects, induced by the stimulation of OE with olfatantes and vomeropherins Figure 185A: 400 fmol of the olfactory 1-carvone and cineole, as well as 200 fmol of the vomeropherin A; B, C, D, and F; and stereoisomer E, were applied separately as a second pulse to the EO of 20 subjects (both males and females), and each EOG response was recorded as described. The olfactants, as well as E and B, produced a significant local response (p <0.01).

Figure 185B: 400 fmol of 1-carvone and cineole olfactants do not induce a significant EVG response when applied to the vomeronasal organ of male and female subjects. Figure 186 illustrates the electrophysiological effect of the following vomeropherins on the vomeronasal organ of 20 female subjects: G = Androst-4-en-3-one H = Androsta-4, 16-dien-3, 6-dione J = 10, 17-dimethylgona-4, 13 (17) -dien-3-one K = ether 1, 3, 5 (10), 16-Estratetraen-3-ol- methyl L = propionate 1, 3, 5- (10), 16-Estratetraen-3-yl EVG = Electro-vomeronasogram GSR = Galvanic Skin Response EDA = Electro-thermal Activity, EDA ST = Skin temperature Figure 187 illustrates the electrophysiological effect of vomeropherins on the vomeronasal organ of 20 male subjects. M = 1,3,5 (10) -Estratrien-3-ol Figure 188 illustrates the synthesis steps for Examples 108 to 112. Figure 189 illustrates the synthesis steps for Examples 113 to 118. Figure 190 illustrates the synthesis steps for Examples 120 to 121. Figure 191 illustrates the synthesis steps described in Examples 123 to 124. Figure 192 illustrates the synthesis steps for Examples 125 to 126. Figure 193A shows the respiratory rate and EKG data in females , for the tests of androsta-5, 16-dien-3jS-19-diol in the vomeronasal organ. Figure 193B shows the respiratory rate and EKG data in females for the tests of androsta-5, 16-dien-3 / 3-19-diol in the vomeronasal organ. Figures 194A, 194B, and 194C show the EVG, GSR, and ST data in women, for four androstanes, in the diagram, and androsta-5, 16-dien-3 /? -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-3/3, 19-diol. Figures 200A and 200B show the EEG data in men and women for androstane A6 / N3. Figures 2A and 20IB are traces of EVGs in the vomeronasal organ of a male subject, tested with two vomerophermins (Figure 2OY), and electrograms of the nasal respiratory mucosa (Figure 201B) using the same vomeropherins. Figure 202 shows the dose-dependent effect of two vomeropherins in male subjects. Figure 203 shows the central nervous system reflex response of two vomeropherins. Figure 204 shows the difference in testosterone levels in a subject who was administered in a placebo visit (curve B) to the vomeronasal organ, and in a second visit (curve A), the compound pregna-4, 20- dien-3, 6-dione. Figures 205, 206, and 207 show the data for the testosterone tests in three additional subjects who were given a placebo, in the case of a pregna 4,20-dien-3,6-dione in case A .

Detailed description of the invention I. Definitions An "affection" is a state of transient feeling. The typical negative affects are feelings of nervousness, tension, shame, anxiety, irritability, anger, anger, and the like. The "humors" are longer lasting feelings, such as guilt, sadness, hopelessness, worthlessness, 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. Vomeroferins according to the present invention can be used to stimulate, through contact with the vomeronasal organ, one or more hormonal, behavioral, and autonomic functions of the hypothalamus. Due to the predominant role played by the hypothalamus in a wide variety of internal bodily functions, and the neural connection between the vomeronasal organ and the hypothalamus, the vomeropherins according to the present invention are in a position to stimulate these functions such as control of endocrine production, for example the control of pituitary production of vasopressin and oxytocin, as well as a number of other peptides. Vasopressin is an antidiuretic hormone, due to its action inside the kidney to improve water recovery, and to concentrate urine. In addition, it has an action inside the body to regulate the blood pressure through its action on the arterial smooth muscle, and an action on the metabolism through its improvement of the conversion of glycogen into glucose in the liver. Oxytocin, whose receptors are found in the uterine smooth muscle, and in the mammary smooth muscle, they can cause the milk to drop by means of the contraction of the mammary smooth muscle, and they can cause uterine contractions during the birth. 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 Stimulating Hormone), FSH (Follicle Stimulating Hormone), and beta-endorphin. Therefore, for example, the ability to control the secretion of luteinizing hormone may lead to fertility control in females, or testosterone production in males. The production of testosterone can be used for the treatment of conditions such as low livid in males, or for the treatment of diseases or conditions of muscular waste, such as aging. The reduction of testosterone can be used for the treatment of conditions such as prostate cancer. The control of hypothalamic functions of behavior is also feasible 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 the circadian rhythms that regulate sleep and awakening. Other functions controlled by the hypothalamus include appetite, thirst, sympathetic functions such as flight and struggle, and functions such as cardiovascular control, thermoregulation, and visceral functions such as bowel muscle control and bowel control. secretion of acid for digestion. Therefore, although they excite a multitude of sensory inputs into the hypothalamus from different parts of the anatomy, it is believed that the vomeropherins of the present invention provide, for the first time, a way to stimulate through the nasal cavity by inhalation. to make contact with the epithelial cells of the vomeronasal organ, a method to stimulate the functions of the hypothalamus discussed above. "Pregnane steroids" are aliphatic polycyclic hydrocarbons characterized by a four-ring steroidal structure, with methylation in positions 10 and 13, and ethylation (including unsaturated groups) in position 17. A pregnane is a subset of pregnanes commonly understood to mean that the compound has at least one double bond. In addition, 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 steroid 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 displayed on the surface of a" chemosensory "neuroepithelial cell that binds in a stereospecific manner with a particular ligand or ligands. This specific bond initiates signal transduction, which initiates an afferent nerve impulse. Chemoreceptors are found, among other things, in the taste buds, the olfactory epithelium, and the vomeronasal tissue. "Pregnen steroids", as the term is used herein, are aliphatic polycyclic hydrocarbons with a four-ring steroidal structure, at least one double bond on ring A, methylation at position 10 and at 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 illustrative purposes, a side chain is shown on the D ring for the pregnane. In the description of 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 range of quantity and / or concentration that causes a desired physiological and / or psychological effect when administered to an individual in need of the drug. In the present case, an individual who needs it is one with a physiological or behavioral trait that is normally regulated by the hypothalamus, and where it is desirable to affect the function of the hypothalamus or trait. The effective amount of a given drug may vary depending on the function to be affected, the desired effect, the route of administration, and the like. For example, when the steroid is administered as a solution applied to the facial skin of a subject, an effective concentration is from 1 microgram / milliliter to 100 microgram / milliliter, preferably 10 to 50 microgram / milliliter, and more preferably 20 at 30 micrograms / milliliter. When the steroid is introduced directly into the vomeronasal organ, an effective amount is from about 1 picogram to about 1 nanogram, more preferably from about 10 picogram to about 50 picogram. When the steroid is administered to the nasal passage, by ointment, cream, or aerosol, or the like, an effective amount is from about 100 picograms to about 100 micrograms, preferably from about 1 nanogram to about 10 micrograms. It follows that some drugs can be effective when they are administered by some routes, but they are not effective when they are administered by other routes. The "hypothalamus" is the portion of the diencephalon that comprises the ventral wall of the third ventricle below the hypothalamic sulcus, and that includes the structures that form the floor of the ventricle, including the optic chiasm, the tuberous cinerea, the infundibulum, and the mammillary bodies. . The hypothalamus regulates the autonomic nervous system, and controls various physiological and behavioral functions, such as the so-called fight and flight 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 that regulates blood pressure, and of oxytocin that induces labor and milk release. All hypothalamic functions are potentially modulable by the vomerofe-rina therapy described herein. A "ligand", as used herein, is a molecule acting as a chemical signal by specific binding to a receptor molecule displayed on the surface of a recipient cell, thereby initiating signal transduction through the cell surface. The binding of ligands to chemosensory receptors can be measured. Chemosensory tissue, such as neuroepi-telium vomeronasal or olfactory neuroepithelium, contains a multiplicity of neuroreceptor cells, each exhibiting at least one cell surface receptor. Many of the receptor molecules have identical ligand specificity. Accordingly, when the tissue is exposed to a ligand for which it has specificity (eg, an exposure of the vomeronasal organ to a vomeropherin), a summed change in the 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, such as, for example, methyl, ethyl, normal propyl, isobutyl, and the like. "Alkoxy", as used herein, is used in its conventional sense to mean the group -OR, wherein R is alkyl as defined herein. A "pheromone" is a substance that provides a means of chemical communication between members of the same species, through secretion and peripheral chemoreception. In mammals, pheromones are usually detected by receptors in the vomeronasal organ of the nose. Commonly, pheromones effect development, reproduction, and related behaviors. A "vomeropherin" is a more general term that 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) equals 0.001 nanogram (ng). A nanogram is equal to 0.001 micrograms (μg). One microgram is equal to 0.001 milligrams.

II. MODES FOR CARRYING OUT THE INVENTION A. Steroids Useful in the Invention The invention relates to a group of certain steroids. The syntheses for the following compounds are described herein, as designated in the diagram: Diagram I includes pregnanes to which the invention relates, but does not limit its scope. The synthesis diagrams that follow illustrate the intermediate and substructure syntheses for the preparation of these pregnanes.

PREGNANTS SYNTHESIS OF SUBSTRUCTURE Referring to the previous Table, the following are example syntheses for the intermediaries of the given row (Al to A13) or given column (Pl to P8).

SYNTHESIS OF SUBSTRUCTURE: TYPE A Percy L. Julian, Edwin W. Meyer and Helen C. Printy, J. Amer. Chem. Soc., 1948, 70, 3, 887. Also, a commercially available substructure, for example, 17a; -etinyltestosterone.

A2 Hc This is a commercially available substructure, for example, dehydroepiandrosterone, pregnenolone. A3: David G. Loughhead, J. Org. Chem., 1985, vol. 50, No, 20, page 3931.

U I.Z. Kabore, Q. Khuong-Huu, and A. Pancrazi, Tetrahe5 drone, 1978, vol. 34, page 2807. A5: I. Dory G. Szabo and P. Opoczky, Acta Chim, Hung. , vol. 20, page 67 (1959). Bernhard Krieger, Egbert Blanke, and Emanuel Raspar, German Patent Number 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.

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

Steven R. Schow and Trevor C. McMorris, Steroids, 1977, vol. 30, No. 3, page 389. Also, a commercially available substructure, for example, 17a; -etinyldihydrotestosterone.

Hello 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, page 442.

At l: See the example Frederick Brown and Cari Djerassi, J. Amer. Chem. Soc. , 1980, 102, 2, 807. A12: Al 3 SYNTHESIS OF SUBSTRUCTURE; TYPE P Pl Ajay K. Bose and N.G. Steinberg, Synthesis, 1970, page 595.

Steven R. Schow and Trevor C. McMorris, Steroids, 1977, volume 30, No. 3, page 389. P2: Ronald Breslow and Louis M. Maresca, Tetrahedron Letters, 1977, No. 7, page 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, 5o¿-pregn-17 (20) -in-3jß-ol (Esteraloides): P3 This is a commercially available substructure, for example, pregna-5, 16-dien-3? -ol (? Steraloides). When it is not commercially available, the synthesis proceeds as follows: John P. Dusza and Werner Bergman, J. Org. Chem., 1960, , 79. P4: Soc., 1964, page 3388. Also, a commercially available substructure, for example, 5o; -pregnan-3) S-ol. (Esteraloides): ^ P5: 53 l2 ^ t3N Alan M. Krubiner, Norman Gottfried, and Eugene P, Oliveto, J. Org. Chem., 1969, vol. 34, No. 11, page 3502.

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

P7 54 Pierre Crabble and Esperanza Velarde, Patent of the United States of America Number 3,681,410, 1972. P8: Maya Dvolaitsky Anna M. Giroud, and Jean Jacques, Bull Soc. Chem. France, 1963, 62.

French Patent No. 1,536,034, 1968 17a-PREGNANOS For substructure Pl, P4, and P5, the normal configuration at position 17 is ß. However, the analogue 17o; The corresponding one can also be prepared by using 17a; -pregnolone as the starting material. For example: Alan M. Krubiner, Norman Gottfried, and Eugene P. Oliveto, J. Org. Chem., 1969, Vol. 34, No. 11, page 3502.

METTILPREGNA OS The following methodology makes it possible to place a methyl group in position 20 whenever allowed by the structure, ie, with Pl, P2, P3, P4, and P6: J. Bryan Jones and Keith D. Gordon. Dog. J. Chem., 1972, vol. 50, page 2712.

John P. Dusza and Werner Bergmann, J. Org. Chem., 1960, 25, 79 David G. Loughhead, J. Org. Chem., 1985, 50, 3931. U.S. Patent Number 3,681,410 teaches the preparation of 6a-methyl analogues: U.S. Patent Number 3,492,318 teaches the preparation of 18- and 21-methyl analogues: Certain methylated pregnenolone precursors are commercially available, vis 6, 16a (ß) -methyl: H In addition the 17th; -methylpregnenolone is readily available: French Patent No. 1,363,191: Accordingly, 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 18,21-dimethylpregna-4,16-dien-20-yn-3-one, described, can be prepared by one of 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 dimethylated pregnenolone precursors have already been described, as in the following examples: Sylvestre Julia, Colette Neuville, and Pierre Simón, Bull. Soc. Chim. France, 1962, 1495. 16,16-dimethylpregnenolone acetate Elliott 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. 16oc, 17o-dimethylpregnenolone 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 -dimethylpregnenolone R. Deghenghi and R. Gaudry, J. Amer. Chem. Soc., 1961, 4668. British Patent Number 927,515: 6,16 (3-dimethylpregnenolone 6,17o-dimethylpregnenolone acetate Romano Deghenghi and Roger Gaudry, Tetrahedron Letters, 1962, No. 11, page 489.

W. J. Adams, D.K. Patel, V. Petrow, I.. 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 that introduces two methyl groups, as in the following example: ,21-dimethylpregna-5,20-dien-3/3-ol The 20, 21-dimethylpregnanes are also known as 24-Norcolanos. The 24-norcolanes can alternatively be prepared by the degradation of a colane precursor, as the following example: Yutaka Hirano, Tadashi Eguchi, Masaj i Ishigmo, and Nubuo Ikakawa, Chem. Pharm. Bull., 1983, 31 (2), 394.

HALOPREGNANOS The Patent of the United States of North America Number 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 methylated pregnenolone precursors are commercially available, vis 6, 16a (ß) -methyl: In addition 17a-methylpregnenolone is readily available: French Patent Number 1,363,191: Accordingly, 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 previous Tabia, the following are the same as the substructures in a given row (Al to A13) or in a given column (Cl to C7). SYNTHESIS nw gTTBESTRUCTURE- TTD? ? Watch the . eg A2: This is a commercially available substructure, for example, PREGNENOLONE, ESTIGMASTEROL, A3 COLENIC ACID See the example All: Chem. Soc. Perkin Trans. I, 1986, page 1805.

At 3: See the example Cl: ESIS OF SUBSTRUCTURE: TYPE C J.P. Schmit, M. Piraux, and J.F. Pilette, J. Org. Chem. 1975, vol. 40, No. 11 page 1586. C2: W. Bergmann and J.P. Dusza, J. Org. Chem., 1958, vol 23, page 1245.

J.E. van Lier and L.L. Smith, J. Org. Chem., 1970, vol. 36, No. 8, page 2631.

A. Burger, F. Colobert, C. Hetru, and B. Luu, Tetrahedron, 1988, vol. 44, No. 4, page 1141.

A.B. Turner, Chemistry and Industry, 1979, page 385 Stoeck and H. Stein, German Patent No. 854,517, 1952.

C7 (use ü - S5- for C7) (24-N0RC7) A. Burger, J-P. Roussel, C. Hetru, J.A. Hoffmann, and B. Luu, Tetrahedron, 1989, vol. 45, No. 1, page 155. 24-NORCOLANQS AND 24-METTILCOLANES Structures can be prepared with the side chain shortened or elongated by a carbon atom at position 24, using analogous methodology. The 23-methylcolanos are also available by similar means. Follow the examples. 23-METHYL 24-METHYL J.P. Schmit, M. Piraux, and J.F. Pilette, J. Org. Chem., 1975, vol. 40, No. 11, page 1586 '24-METHYL Y.M. Sheikh and C. Djerassi, Steroids, 1975, vol 26 (1), page 129.

M. Morisaki, M. Shibata, C. Duque, N. Imamura, and N. Ikekawa, Chem. Pharm. Bull., 1980, vol. 28 (2), page 606. 24-NOR D.H.R. Barton, J. Boivin, D. Crich, and C.H. Hill, J. Chem. Soc. Perkin Trans. I, 1986, page 1805. 24-METHYL A. Burger, F. Colobert, C. Hetru, and B. Luu, Tetrahe-dron, 1988, vol. 44, No. 4, page 1141 24-N0R B.M. Trost, R.J. Kulawiec, and A. Hammes, Tetrahedron Letters, vol. 34, No. 4, page 587. 24-NOR A. Burger, J-P. Roussel, C. Hetru, J.A. Moffma? N, and B. Luu, Tetrahedron, 1989, vol. 45, No. 1, page 155.

C. Synthetic Methods 1. Preparation of derivatives at positions 3, 6, 19, 20, and 21. The compounds used in the methods of this invention are pregnane steroids substituted at positions 3, 6, 19, 20, and 21 Many of the 3-substituted steroids are known compounds that can be derived from 3-oxo-steroids. As shown in Figure 1, pregna-4, 20-dien-3-one (1) can be converted into an ether of 3, 5, 20-triene (2.), or 1, 4, 20- trien-3-one (3.), which are respective starting materials for the 6- and 3-substituted hydroxy derivatives. The alkoxy derivatives are prepared from their corresponding hydroxysteroids, by their reaction with an alkylating agent, such as trimethylenium oxonium fluoroborate, triethyl oxonium fluoroborate, or methyl fluorosulfonate in an inert chlorocarbon solvent, such as sodium chloride. methylene. Alternatively, alkylating agents, such as NaH, KM or KOBut, silver oxide or barium oxide, in polar aprotic solvents, such as, for example, dimethyl formamide, dimethyl sulfoxide, and hexamethylphospho-ramide. General procedures for the synthetic reactions of steroids are known to those skilled in the art. Where the time and temperature of the reactions must be determined, they can be determined by a routine methodology. After the addition of the required reagents, the mixture is stirred under an inert atmosphere, and aliquots are removed at hourly intervals. The aliquots are analyzed by chromatography to monitor the disappearance of the starting material, at which point, the working procedure is started. If the starting material is not consumed within 24 hours, the mixture is heated to reflux, and aliquots are analyzed for hours, as before, until the starting material disappears. In this case, the mixture is allowed to cool before start the work procedure. The purification of the products is carried out by means of chromatography and / or crystallization, as is known to those skilled in the art. 2. Preparation of 19-OH derivatives.

Synthesis of 19-OH-preqna-4, 17-dien-3-one. In SCHEME 3 a method is provided to synthesize this compound. In the following diagram III, the particularly preferred 19-nor-pregnanes are shown. 19-NORPREGNANOS 00 SYNTHESIS OF SUBSTRUCTURE: TYPE E Frank b. Colton, Leonard N. Nysted, Byron Riegel, - and Albert L. Raymond, J. Amer. Chem. Soc, 1957, 79, 1132. Also, a commercially available substructure, for example, 17a-ETINIL-19-N0RTEST0STER0NA This is a commercially available substructure, for example, ESTRONA, ETINILESTRADIOL.

Pierre Crabble, United States Patent of North America Number 3,492,318, 1970.

This is a commercially available substructure, for example 6-DEHYDROESTRONE. E5: See the example E6 acetate) See the example me .tí-, lico d, e. E2, *) (Eß) M? O TO 0.1. 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, J79, 1123. E9 This is a commercially available substructure, for example EQUILINE. E10: This is a commercially available substructure, for example EQUYLENIN.

O UAH HO ^^^ S ^ (E13) (EH) See the example. E12: (Acetate E6) (E12) See the example.

E13, 00 See the example.

SYNTHESIS OF SUBSTRUCTURE: TYPE P Pl \ N ^ OAc? L Na / NH3 £ "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 the example.

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

Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, H. Kaufmann, P. Wieland, and J. Kalvoda, Helv. Chim Acta., 1972, 55 (2), 381. 0. 1. 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, Peter Kaspar and Herbert Witzel, J. Steroid Biochem., 1985, vol. 23, No. 3, page 259.

Richard H. Peters, David R. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32, 1642 Frank B. Colton, United States Patent of North America Number 2,840,582. 1958. P7: If Zp \ í > (P7) Pierre Crabble and Esperanza Velarde, Patent of the United States of America Number 3,681,410, 1972.

Peter Kaspar and Herbert Witzel, J. Steroid. Biochem., 198 North America Number 3,492,318, 1970.

Klaus Prezewowsky and Rudolf Wiechert, Patent of the United States of North America Number 3,682,893, 1972.

METHYLNORPREGNANTS The 19-norpregnanes of this series can be prepared with a methyl group at positions 6a, la, 18, 20, or 21. US Pat. No. 3,681,410 teaches the preparation of 6a-methyl analogues.

U.S. Patent No. 3,682,983 teaches the preparation of 18-methyl analogues.

U.S. Patent No. 3,492,318 teaches the preparation of 7a, 18, and 21-methyl analogues. 21-methyl analogue: THE. Van Dijck, B.J. Lankwerden, J.G. C.M. Vermeer, and A. .M. Weber, Recl. Trav. Chim. Pays-Bas Belg., 1971, 90, 801. Analogs of 7a, 18, 20, and 21-methyl.

Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 32., 1642. In addition, certain methylated precursors are commercially available, for example: From these, analogues of methyl or 18-methyl can be made of substances wherein estrone or 17α-ethynyl-19-nortestosterone (norethindrone) are the precursors, respectively.

HALONORPREGNANOS The Patent of the United States of North America Number 2,840,582 teaches the preparation of: U.S. Patent No. 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. The alkoxy derivatives are prepared from their corresponding hydroxysteroids, by their reaction with an alkylating agent, such as trimethylene oxonium fluoroborate, triethyl oxonium 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 dialkyl sulfate, may be used with a base such as NaH, KM or KOBut, silver oxide, or oxide of barium, in polar aprotic solvents, such as, for example, dimethyl formamide, dimethyl sulfoxide, and hexamethylphospho-ramide. General procedures for the synthetic reactions of steroids are known to those skilled in the art. Where the time and temperature of the reactions must be determined, they can be determined by a routine methodology. After the addition of the required reagents, the mixture is stirred under an inert atmosphere, and aliquots are removed at hourly intervals. The aliquots are analyzed by chromatography to monitor the disappearance of the starting material, at which point, the working procedure is started. If the starting material is not consumed within 24 hours, the mixture is heated to reflux, and aliquots are analyzed for hours, as before, until the starting material disappears. In this case, the mixture is allowed to cool before the work procedure is started. The purification of the products is carried out by means of chromatography and / or crystallization, as is known to those skilled in the art.

SYNTHESIS OF SUBSTRUCTURE Referring to the previous Table, the following are example syntheses for the intermediaries in a given row, (El a E2) or in a given column (NI a N4). Type E El: * 0 £ E2 methyl) (Et) E2: Substructure commercially available, for example, ESTRONA.

HO H (El) (E3) 77 (7), 724.

Substructure commercially available for example, -DESHIDROESTRONA. E5: .CO SAW. Mel'nikova and K.K. Pivnitskii, Zhurnal Organic-keskoi Khisnii, 1974, vol. 10, No. 5, pages 1014-1019.

CrO. AcO JCO AcO (Acetate E2) Acetate E) Hidetoshi Takagi, Ken-ichi Komatsu, and Itsuo Yoshisa-wa, Steroids, 1991, vol. 56, page 173.

Michel Mauney and Jean Rigaudy, Bull. Soo Chien, 1976, o. 11-12, 2021 ES:.

K. J. San, R. H. Blank, R. H. Evans, Jr. , L. Feldman, and C. E. Holmbund, J. Org. Chem., 1964, 29, 2351. E9.

Substructure commercially available, as in EQUILINA. E10: HO -CO Substructure commercially available, as in EQUILENINE. Eli: (EN) (E11) A. N. Cherkasov, A.M. Ponomarev, and K.K. Pivnitskii, Zhurnal Organiskeskoi Khimii, 1971, vol. 7, No. 5. pages 940-947. E12: (Methyl ether of E6) (Methyl ether of El 2) Hidetoshi Takagi, Ken-ichi Komatsu, and Itsuo Yoshisa-wa, Steroids, 1991, vol. 56, page 173. Type N HO '- HO LÓ®, 1. Robert H. Shapiro and Cari Djerassi, J. Am. Chem. Soc., 1964, 8_6, 2825. 2. Pilar Lupón, 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. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masako Tanabe, J. Med. Chem., 1989, 32, 1642. N4: Ó OTt? ' COLIDINE Ó (N4) 0T « Rosenkranz (1955) J. Am. Chem. Soc. 77: 4145. 2. William F. Johns, J. Org. Chem., 1961, 26, 4583.

Methylbrakes Horold 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.

Me O (RACEMICO) M.B. Green and F. J. Zeelen, Tetrahedron Letters, 1982, vol. 23, No. 35, pages 3611-3614. Accordingly, the synthesizable compounds include these, together with the derivatives thereof; that is, 17-methyl-Nl, 17/3-methyl-N2, or 14a-methyl-N4, in combination with El, E2, E3, E5, E6, E7, E8, Eli, or E12.

Halo releases TO . Boswell in Patent C.A 70: 58140g, following.

G. Michael Blackburn, Brian F. Taylor, and Andrew F. Worrall, Journal of Labelled Compounds and Radiopharmaceu i-cals, 1986, vol. XXIII, No. 2, page 197. Accordingly, the synthesizable compounds include these, together with those derived therefrom; that is, 17-fluoro-Nl in combination with El, E2, E3, E5, E6, E7, Eli, or E12. In addition, 17-iodo-Nl in combination with E2, E6, or E12. Br European Patent Application Number EP 208,497. Accordingly, the synthesizable compounds include these, together with the derivatives thereof; that is, (4-chloro, 4-bromo, 6o; -chloro, 6a-bromo, 6/3-chloro, 63-bromo, or 6-iodo) -Al, in combination with NI, N2, N3, or N . In addition, (17-fluoro, 17-chloro, 17-bromo, or 17-iodo) -Nl, in combination with Al, A2, A3, A4, A5, A6, A8, A9, AlO or All.

C. Synthetic Methods 1. Preparation of derivatives in positions 3, 5, 6, 18, and 19. The compounds used in the methods are androstane steroids substituted in positions 3, 5, 6, 18, and 19. Many of the 3- and 5-substituted steroids are known compounds that can be derived from 17-hydroxy- and 17-oxo-steroids (commercially available, for example, from Aldrich Chemical Co.), by elimination or reduction to the homologue ? 16 The syntheses of most of these compounds are described by Ohloff (supra). As shown in Figure 1, 17 ^ -hydroxy-5o; -Androstan-3-one (I) and methyl chloroformate (a) in pyridine, give methyl carbonate, 17jS-methoxycarbonyloxy-5o; -Androstan -3-one (II) which provides a starting material for 5a; -Androst-16-en- (3-one and 3-ol) (Ohloff, supra on page 200). The alkoxy derivatives are prepared from their corresponding hydroxysteroids, by their reaction with an alkylating agent such as trimethyl-1-oxonium fluoroborate, triethyl oxonium fluoroborate, or methyl fluorosulphonates, in an inert chlorocarbon 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 such as, for example, dimethyl formamide, dimethyl sulfoxide, and hexamethylphosphoramide. General procedures for the synthetic reactions of steroids are known to those skilled in the art. Where the time and temperature of the reactions must be determined, they can be determined by a routine methodology. After the addition of the required reagents, the mixture is stirred under an inert atmosphere, and aliquots are removed at hourly intervals. The aliquots are analyzed by chromatography to monitor the disappearance of the starting material, at which point, the working procedure is started. If the starting material is not consumed within 24 hours, the mixture is heated to reflux, and aliquots are analyzed for hours, as before, until the starting material disappears. In this case, the mixture is allowed to cool before the work procedure is started. The purification of the products is carried out by means of chromatography and / or crystallization, as is known to those skilled in the art. 2. Preparation of 19-OH derivatives. Synthesis of 19-OH-Androsta-4, 16-dien-3-one This compound has been reported as an intermediate in the synthesis of 19-oxo-3-aza-A-homo-5B-androstane (Habermehl, and collaborators, Z. Naturforsch. (1970) 25b: 191-195). A method for synthesizing this compound is provided.

DIAGRAM V. ANDROSTANOS ANDROSTANOS NOVEDOSOS 17-METILENANDROST-4-EN-3?! - OL (A4 / N3) 17-METHYLENEANDROST-4-EN-33-OL (A3 / N3) 6 / ß-HYDROXYANDROSTA-4,16-DIEN-3- ONA (A13 / N1) 6/3-HYDROXY-17-METHYL-18-NORANDROSTA-4,13 (17) -DIEN-3-ONA (A13 / N4) ANDROSTA-5,16-DIEN-3 / 3,19 -DIOL (DERIVED FROM 19-HIDROXI) DE A2 / N1) 17-METHYLENANDROST-4-IN-3,6-DIONA (A6 / N3) 17-METHYL-18-NORANDROSTA-4,13 (17) -DIEN-3a-OL (A4 / N4) 17-METHYL-18-NORANDROSTA-4,13 (17) -DIEN-3/3-OL (A3 / N4) 17/3-METHYLSTROST-4-EN-3, 6-DIONA (DERIVATIVE OF 11β-METHYL OF A6 / N2) 3 -METOXY-17 -METILENANDROSTA- 3, 5 -DIENO (8 / N3) 6/3-HYDROXY- 17-METILENANDROST-4-EN-3-ONA (A13 / N3) 17-METHYLENANDROSTA-1, 4-DIEN-3-ONA (A11 / N3) 6/3-HYDROXYANDROSTA-1, 4,16-TRIEN-3-ONA (DERIVATIVE OF 63-HIDROXI DE All / NI). 6jß-HYDROXY-17-METHYLENANDROSTA-1, 4-DIEN-3-ONA (DERIVA-DO OF 6/3-HYDROXY OF A11 / N3) 17 ^ -METILANDROST-4-EN-3o; -OL (DERIVATIVE OF 17 / 3-METHYL DE A4 / N2) 173-METHYLSTROST-4-IN-3, ß-OL (DERIVATIVE OF 17/3-METHYL DE A3 / N2) 3-METOXY-17-METHYL-18-NORANDROSTA-3, 5, 13 (17) -TRIENE (A8 / N4) Substructure Synthesis Referring to diagram V above, the following are example syntheses for the intermediaries in a given row (Al to All) or in a given column (Ni to N4). Type A Al: A2: This is a commercially available substructure, for example, DESHIDRO-EPI-ANDROSTERONA.

(Michio Matsui and Dav K. Fukus, J. Orcr. Chem. Vol.35, No. 3 pages 561-564). A4 Ohloff, G. and collaborators (Heyl, Chim. Acta (1983) - 217).

(Al) (A5) German Patent Number 2,631,915 J. Romer, H. Wagner, and W. Sihade, Steroids, 1988, 51 / 5-6, page 577-581. of A2) / Ay » (Habermehl, and collaborators, Z. Naturforsch. (1980! 256: 191-195 (Al) (AS) See Example 15. A9; O do Ohloff, G. and collaborators (Helv. Chim. Acta (1983! 66: 192-217).

Keskoi Khisnii, 1972, vol. 8, No. 1, page 68-74.

See Example 19.

Type N m. Chem.

Soc., 1964, 86., 2825. 2. Pilar Lupón, 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 Pcnold and Hans Schick, Be-richte, 1965.98, 604. 2. Richard H. Peters, David F. Crowe, Mitchell A. Avery, Wesley K.M. Chong, and Masako Tanabe, J. Med. Chem., 1989, 32, 1642. N Rosenkranz (1955) J. Am. Chem. Soc. 77: 4145. 2. William F. Johns, J. Org. Chem., 1961, 26., 4583.

Metilandrostenos German Patent Number 2,631,915 teaches the preparation of: with a methyl group in any of the following positions:;, 2a, 4, 6a, 6ß, la, and 16 6-METHYL THERAST-4,6-DIEN-3-ONA German Patent Number 2,428,679.

Daniel Bertin and Lucien Nedelac, Memoires Presents to the Societe Chimique, 1964, No. 345, page 2140. Accordingly, the synthesizable compounds include these, together with the derivatives thereof; that is to say, NI with methyl in the, 2QÍ, 4, 6a, 6ß, la, 16 or 17 combined with Al, A3, A4, A5, A8, A9, AlO, or All, as well as A2 or A6 with a 17-methyl.

Haloandrosteños Patent of the United States of America Number German Patent Number 2,631,915 D. Methods of Use The methods of the invention are carried out by means of the non-systemic nasal administration of certain steroids, and combinations of steroids. This particular mode of administration is distinguished from the alternative modes, such as ingestion or injection, in several important ways, by virtue of direct contact with the vomeronasal organ, by nasal administration of the steroid 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., in a non-invasive manner. The action of the drug is mediated through the binding of the ligands, described herein, to the specific receptors exhibited by the neuroepithelial cells of the nose, preferably in the vomeronasal organ. further, the mode of action of the drug is through the nervous system and not through the circulatory system - and consequently, the function of the brain can be affected without considering the blood-brain barrier. These methods of treatment provide a direct means to affect the hypothalamus through the nervous system, because there is only a synaptic junction between the pheromone receptors and the hypothalamus. Because the sensory nerves are directed to a specific location in the brain, this method has a highly specific drug effect, thereby greatly reducing the potential for undesirable side effects. The contact with the vomeronasal organ is important, because the vomeronasal organ is associated with the chemoreceptor / pheromonal function. The vomeronasal organ consists of a pair of blind tubular diverticula located in the lower margin of the nasal septum. The vomeronasal organ contains neuroepithelia, whose axons have direct synapses with the tonsils, and from there with the hypothalamus. The existence of the vomeronasal organ has been well documented in most terrestrial vertebrates, including the human fetus; however, in adult humans, it is generally thought to be rudimentary. (See Johnson, et al., Supra). The ligand substances described herein, or their sulfated, cipiones, benzonados, propionados, or glucuronados derivatives, can be administered directly, but preferably are administered as compositions. They are prepared in a liquid dosage form such as, for example, liquid suspensions, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The liquid dosages can be administered as drops for the nose or as an aerosol. Alternatively, the active compound can be prepared as a cream or an ointment composition, and can be applied locally inside the nasal cavity. In addition, a vomeropherin can be administered as vapor contained in an aspiration of air applied to the nasal cavity. As another alternative, the application can be presented by the 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 the appropriate choice of the polymer system used to control the rate of diffusion (Langer, R. S. and Peppas, N.A., Biomate-rials 2.201, 1981). Natural polymers, such as gelatin and cellulose, dissolve slowly in a matter of minutes to hours, while 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, and so on. The most possible means of communication of a semi-chemical ligand is the inhalation of a pheromone that occurs naturally, which is present on the skin of another. Since these compounds are relatively non-volatile, it is estimated that, even during intimate contact, a human subject will inhale amounts in picograms of a steroid that occurs naturally, from the skin of another. From the inhaled amount, it is estimated that only approximately 1 percent would reach the receptors of the vomeronasal organ. The amount of vomeroferin administered, of course, will depend on the subject being treated, the severity of the affliction, the mode of administration, the frequency of administration, and the judgment of the prescribing physician. However, a single dosage of approximately 10 picograms, applied directly to the lumen of the vomeronasal organ, is effective to elicit a transient autonomous response. When administered to the nasal cavity, the dosage is from about 100 picograms to about 100 micrograms, preferably from about 1 nanogram to about 10 micrograms, and more preferably from about 10 nanograms to about 1 microgram. The frequency of administration desirably ranges from a dose per hour to a monthly dose, preferably 8 times a day up to once every third day, more preferably 1 to 3 times a day. Ointments containing one or more active pharmaceutical adjuncts and auxiliary agents in a vehicle, such as, for example, water, serum, aqueous dextrose, glycerol, ethanol, and the like, can be prepared using a base, such as, for example, oil jelly, tallow, or lanolin. Liquid pharmaceutically administrable compositions, for example, can be prepared by dissolving, dispersing, etc., an active compound as defined above, and optional pharmaceutical adjuvants in a vehicle, such as, for example, water, serum, dextrose. aqueous, glycerol, ethanol, and the like, to thereby 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 or emulsifying agents, pH regulating agents, and the like, for example, sodium acetate, sorbitan monolaurate, sodium acetate of triethanolamine, triethanolamine oleate, and so on. The actual methods of preparation of these dosage forms are known, or will be apparent to those skilled in the art.; for example, see Remington's Pharmaceutical Sciences, Marck Publishing Co. , Easton, PA, 15th edition, 1975. The composition or formulation "to be administered, in any case, will contain an amount of one or more of the active compounds, in an amount etive to alleviate the symptoms of the subject" is being treated. For aerosol administration, the active ingredient is preferably supplied in a finely divided form, together with a surfactant and a propellant. Typical percentages of the active ingredients are from 0.001 to 2 weight percent, preferably from 0.004 to 0.10 percent.

The surfactants, of course, must be non-toxic, and preferably soluble in the propellant. Representative of these agents are esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, eleostearic, and oleic acids, with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, and hexitol anhydrides derived from sorbitol (sorbitan esters sold under the registered trademark "Spans"), and polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters may be employed, such as mixed or natural glycerides. Preferred surface active agents are orbital oleates, for example those sold under the registered trademarks "Arlacel C" (sorbitan sesquiolate), "Span 80" (sorbitan monoleate), and "Span 85" (sorbitan trioleate). ). The surfactant may constitute from 0.1 to 20 weight percent of the composition, preferably from 0.25 to 5 percent. The balance of the composition is ordinarily the propellant. The liquefied propellants are typically gases under ambient conditions, and they condense under pressure. Among the suitable liquefied propellants are lower alkanes containing up to 5 carbon atoms, such as butane and propane; Fluorinated or fluorochlorinated alkanes, such as those sold under the registered trademark "Freon". Mixtures of the above can also be used. In the production of the aerosol, a container equipped with a suitable valve is filled with the appropriate propellant, which contains the finely divided active ingredient and the surfactant. In this way, the ingredients are maintained at a high pressure until they are released by the action of the valve. Yet another means of administration is the local application of a volatile liquid composition to the skin, preferably to the facial skin, of an individual. The composition will usually contain an alcohol, such as ethanol or isopropanol. A pleasant odorant may also be included in the composition.

E. Activity Against Fertility The steroid 19-norpregna-l, 3, 5 (10) -trien-3-ol (compound E2 / P4 in the 19-norpregnane diagram (tested on the vomeronasal organ of female rats) The frequency of discharge of the EVG and the vomeronasal nerve (VNn) are shown in Figures 97 and 98, respectively. the vomeronasal organ stimulation, it was shown that the steroid E2 / P4 has an activity against post-coital fertility, when it is administered orally to female rats, while it has a low hormonal activity (through the estrogen-receptor binding. (Peters et al., J. Med, Chem., 1989 , 32, 1642-52) The data in Figures 97 and 98 suggest that this activity against fertility can be explained, because E2 / P4 is not a hormone, but acts as a vomeropherin through the stimulation of the vomeronasal organ, which in turn affects the hypothalamus Consistent with the data from the rat model, the compound E2 / P4 also shows the vomeronasal organ stimulus in women (see Figure 118), and to a lesser degree in men (See Figure 140), and therefore, it is expected that vomeropherins have an activity that controls fertility in humans.The stimulation of the hypothalamus by means of the vomeronasal organ, allows to suppress the release of luteinizing hormone and hormone. follicle stimulant. This may provide a clinical method for the treatment of prostate cancer, puberty 'recoz (in males and females), endometriosis, uterine leiomyoma, breast cancer, premenstrual syndrome, and dysfunctional uterine bleeding.

Fi. Measurement of Affection, Humor, and Traits of the Character The states of feeling associated with affections, moods, and character traits are usually measured by the use of a questionnaire. For example, questionnaires that include 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 califies the intensity of the feeling on a numerical scale. The grouping of related adjectives and the statistical analysis of the evaluation of a subject of each adjective provides a basis for the measurement of different states of feeling. In an alternative way, feeling states can be measured by autonomous changes, such as those used in polygraph evaluations (galvanic skin response, pulse rate, and the like). Cabanac, M.

Annual Review of Physiology (1975) 3_7: 415; 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, nonverbal cues can be evaluated, such as facial expression and body posture.

G. Change in Blood Levels of Luteinizing Hormone or Follicle Stimulating Hormone Vomeroferins, estra-1, 3, 5 (10), 16-tetraen-3-yl acetate (ETA), and pregna-4, 20 -dien-3, 6-dione (PDD), were applied as impulses in a stream of air directed either towards the lumen of the vomeronasal organ, or towards the respiratory epithelium of the nasal septum. Simple stimuli at a concentration of 10 ~ 10 M to 10 ~ 8 M to the vomeronasal organ produced dose-dependent changes of the electrovomer-gram. No significant effects were observed when the applicator delivered identical stimuli to the nasal respiratory epithelium or the olfactory epithelium. The administration of both vomeropherins to male subjects changed the pulsatility of gonadotropin. PDD (5 x 10 M) decreased the pulsatility of luteinizing hormone (LH), which resulted in a statistically significant reduction in plasma levels of luteinizing hormone (p <0.009) and the pulsatility of the follicle-stimulating hormone (p <0.021) in males, but not in female subjects. ETA (3 x 10 ~ 9M) had a less potent effect than PDD on the pulsatility of luteinizing hormone in male subjects, but did not modify the follicle-stimulating hormone release pattern. Prolactin (PRL) and thyroid stimulating hormone (TSH) were not affected significantly by these vomeropherins, either in male or female subjects. These data 'demonstrate the existence of a functional vomeronasal-hypothalamic-pituitary trajectory in adult humans. In addition to gonadotropin pulsatility during the vomeronasal organ stimulation by modulation with vomeropherin of the hypothalamic neurons that regulate luteinizing hormone (LHRH) release hormone levels, other concurrent reflex reflexes also occurred after stimulation of the vomeronasal organ with vomeropherins. These included decreased respiratory rate, higher body temperature, and changes related to electrodermal activity events. The tests were conducted as follows: A single-blind randomized protocol was used to study the effect of ETA and PDD on the vomeronasal organ in a total of 50 healthy volunteers, whose ages were from 20 to 45 years, «who participated in this project (Table 1) . The plasma levels of follicle-stimulating hormone, luteinizing hormone, and prolactin were measured. Group A consisted of male subjects in which 10 were exposed to ETA, and 10 to PDD in concentrations of 10"10 to 10" 8 M, followed by the stimulus with minison, and was registered with the application of the stimulus at intervals of 5 hours. minutes to the lumen of the vomeronasal organ or to the respiratory epithelium (1 cm from the orifice of the vomeronasal organ), as described (Monti-Bloch et al., J. Steroid Biochem. Molec. Biol., 39 (4): 573 -582 (1991), Psychoneuroendocrinology 19 (5-7): 673-686 (1994) Changes in heart rate (HR), respiratory rate (RF), body temperature (BT), the electrodermal activity (EDA) and in the electroencephalogram (EEG) see Group A, Table 1.

Group B consisted of 10 male subjects, where the effect of ETA on the plasma levels of prolactin (PRL), luteinizing hormone, follicle stimulating hormone, and thyroid stimulating hormone (TSH) was analyzed, following the exposure. to impulses of a second of a concentration of 5 x 10 ~ 9 M every 10 minutes during a period of 6 hours.

All subjects received ETA or placebo in a double-blind, randomized cross-over fashion. Group C received PDD (an air pulse of 5 x 10 ~ 9 M every 10 minutes for 6 hours) and placebo in its vomeronasal organ. An impulse of air of a second was applied that took the stimulus of test or control to the vomeronasal organ, using a crossed blind paradigm. In group B, ETA (3 x 10 ~ 9 M) was applied to the vomeronasal organ of 10 healthy male volunteers every 15 minutes for a period of 8 hours; in Group C PDD was applied in 5 x 10"9 M to the vomeronasal organ of 20 volunteers (10 males and 10 females) every 10 minutes for 6 hours (see Table I).

TABLE I. Experimental design In groups A and B, the vomeronasal organ was cannulated using a miniprobe. (Monti-Bloch et al., J. Ster. Biochem. Molec. Biol. 39 (4): 573-582 (1991) In group C, a special portable nasal applicator was used (patent pending). It was done in a simple-blind randomized design protocol, with placebo, and groups B and C were made in a double-blind, randomized, cross-over design protocol with placebo.

The ETA and PDD test substances were diluted in propylene glycol to concentrations of 10 ~ 10 M to 10 ~ 8 M, through which air was bubbled. The control substance was propylene glycol. Each was presented to the vomeronasal organ lumen as air pulses (duration = 1-3 seconds) containing a final concentration of 10"10M to 10" 8M in a stream of clean air (flow = 30 milliliters / minute). The impulses were applied either at intervals of 5 or 10 minutes.

Registries (Autonomic Reflexes) Group A The registers were carried out in a quiet room and with the supine subject (Monti-Bloch et al., Supra, 1991, 1994). The multifunctional miniprobe was placed inside the right vomeronasal organ, using amplifying optics and halogen lighting. It remained in place with a nasal retractor located in the nasal vestibule. Conventional electro conductors were used to record the EDA of the palmar surface of the middle and annular fingers. A tight caliber placed around the lower thorax was used to record the respiratory rate. The body temperature was measured with the help of a miniature thermistor probe placed in the inner ear canal, and the electroencephalogram was monitored from cza1 and t- ^ a1 (see reference). All the signals were electrically amplified, digitized (Biopac Sistems), and continuously monitored using a computer (Macintosh Ilvx). The amplitude and / or frequency of the electrical signals were measured, and the statistical significance of the results was obtained using the student's t-test and the variation analysis (ANOVA).

Methods for Measuring Hormones A peripheral vein was cannulated in all subjects of groups B and C and 4 milliliters of blood were taken every 10 minutes for the duration of the session (6 hours), and the following plasma hormones were measured: Luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone, prolactin, and testosterone. These hormones were analyzed by immunoassay or radioimmunoassay methods (Sufi et al, WHO Special Program of Research, Development and Research Training in Human Reproduction, Method Manual, 10th edition (1986), WHO, Geneva, Veldhuis et al. Am. J. Physiol, 250 (1986): 486-494). The pulsatile characteristics of gonadotropin secretion were analyzed by cluster analysis (Press). The gonadotropin pulsatility analysis can best be described by the following measurements: 1. Peaks - Numbers of events defined by the pulse analysis program. 2. Average peaks - Average interval between peaks (minutes). 3. Peak width - in minutes. 4. Peak height - in milliliters of U / milliliter. 5. Average area - average area below the peak (concentration / time). 6. I.A. Baseline - higher average value as it increased above the baseline. By analyzing and comparing each of these measurements for the treated subjects and the untreated controls it is possible to determine the changes in plasma gonadotropin values after the vomerofe-rabies treatment. The statistical significance of the results was obtained using tests and ANOVA. Inspection of all subjects revealed normal nasal cavities where the bilateral vomeronasal organs had an average orifice diameter of 1.05 millimeters, standard deviation +0.7 millimeters.

Electrovomerogram (EVG). Figure 201A shows overlapping traces of electrovomerograms recorded from a male subject of 25 years of age. The ETA stimulus produced an electrovomerogram significantly different from the control. The average amplitude of the electrovomerogra as produced in all the subjects studied was M = 1.95 mV. standard deviation = +0.8 mv, (n = 10). An impulse of air carrying the same amount of PDD induced a larger electrovomerogram. The average amplitude for the same dose of PDD, in all the subjects registered was M = 3.6 V, standard deviation = 0.7 mV, (n = 10). The results of the action of the vomeropherins on the electrogram of the nasal respiratory mucosa are shown in Figure 201B. Studies show that the respiratory mucosa did not respond to ETA or PDD (p> 0.1, n = 10). The same vomeropherins when tested in the olfactory epithelium (unpublished observation), also showed no response from the electrogram. Figure 202 illustrates the dose effect curves of ETA and PDD obtained in male subjects. Note that for both vomeropherins, the amplitude of the electrovomerogram is increased as a function of the concentration, and the dose - effect relationship for the intervals between stimuli of 5 minutes, is sigmoidal. The slope for ETA is not significantly different from that for PDD (p> 0.02, n = 20).

Autonomous Reflexes Produced by Vomeroferins Studies of the central nervous system (CNS) reflex response to the vomeronasal organ stimulus with air pulses containing ETA (5 x 10-9M), and PDD (5 x 10-9M) are shown in Figure 203, discussed later.

Electro-thermal activity (EDA). Both vomeropherins induced an increase in the conductance of the skin, compared to the control (p <001). The effect of a single impulse of air containing vomeropherin, either ETA or PDD, consisted of a transient monophasic wave, with a latency of XLat = 520 milliseconds, standard deviation = 110 milliseconds .. The average peak amplitude of the effect for PDD was XPDD = 21.1 S, standard deviation = 19 μS, and for ETA it was XETA = 22.01 μS, standard deviation = 13.S μS. The average duration of the wave was 32 seconds. Vomeroferins ETA and PDD also changed the frequency of spontaneously occurring electrodermal activity events. After the application of ETA or PDD, the frequency of the waves decreased from 4.1 to 0.9.

Body temperature (BT). A single pulse of air containing ETA produced a small but significant temperature increase (XLTA = 0.24 ° C, standard deviation = 0.1 ° C, p <0.02), which lasted approximately 2 minutes, and then returned to the baseline. However, PDD did not induce a significant change in body temperature in these subjects.

Heart rate (CF). The heart rate was measured from the R intervals of the EKG. The effect induced by both vomeropherins is significantly different in male subjects (p < 0.01), (see Figure 204). Compared with the control values, the ETA decreased the heart rate by XETA = -3.3 beats / minute, standard deviation = 1 beats / minute, while the PDD increased the heart rate by XpDD = 3.8 beats / minute, standard deviation = 1.5 beats / minute. These changes developed approximately 10 seconds after the stimulation of the vomeronasal organ with vomeropherins, and after approximately 2 minutes, the heart rate returned to the control values.

Respiratory frequency (RF). PDD induces a small but significant decrease in the respiratory rate (XRF = -2 cycles / minute, standard deviation = 1 cycle / minute, n = 10), which appeared approximately 5 seconds after the vomeronasal organ stimulus, and lasted 1 minute . There is a suggestion that ETA may decrease the respiratory rate slightly, but the data are not statistically significant.

Electroencephalogram (EEG). Electroencephalograms were recorded from the vertex (CzA-j, and the temporal region and the temporal region (T3A1), and 4-minute off-line times were analyzed using the Fast Fourier Transformation. of brain wave activity alpha to beta (alpha / beta) at one time, occurring before, and another after the administration of a vomeropherin to the vomeronasal organ.The PDD changed the alpha / beta ratio of control subjects 0.11 to treated subjects 1.85, while ETA changed the proportion of control subjects 0.14 to treated subjects 1.71 These effects were significantly different from the control values (p <0.02) Autonomic reflex measurements as described , demonstrates that the stimulation of the human vomeronasal organ with vomeropherins, triggers reflex activity in the central nervous system.

Plasma levels of Pituitary and Testosterone Hormones. The effect of vomeronasal organ stimulation with vomeropherins on plasma levels of pituitary hormones is shown in Tables II and III. Table II shows the characteristics of the pulsatile release of thyroid stimulating hormone, prolactin, follicle stimulating hormone, and luteinizing hormone in 10 subjects of group B, before and during treatment with ETA. In 10 normal male volunteers treated with ETA, no significant differences could be detected for thyroid stimulating hormone, prolactin, and follicle-stimulating hormone, 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 subjects 79 against treated subjects 92, and control subjects 45 against treated subjects 54, respectively (p <0.05). The number of luteinizing hormone peaks for In 10 male subjects and 10 female subjects (Group C), PDD was administered at a concentration of 5 x 10 ~ 9 M, every 10 minutes, for 6 hours. Pulsatility analysis was applied to serum concentrations of luteinizing hormone and follicle stimulating hormone obtained at each sampling time. As shown in Table III, the average area of low peaks (concentration / time), and the increase above the basal were significantly reduced during treatment with PDD for both gonadotropins, but only in males without changes apparent in the female subpopulation. In the males treated with PDD, the follicle stimulating hormone values decreased significantly for both the mid-area measurements and the arribal increment of the basal: Treaties 12.7 versus Control 17.6, and Treaties 0.63 versus Control 0.89, respectively. In the same way, for the same group, the values of luteinizing hormone decreased significantly for the measurements of the Average Area as well as the increase above the baseline: Treaties 44 against Control 77, and Treaties 1.4 against Control 2.0, respectively. For all the measurements described, no statistically significant changes could be detected in the female subjects treated with PDD. (Table III). The main change was observed in the reduction of the increments above the baseline values, particularly for luteinizing hormone (2.0 versus 1.4 p <0.009). In a manner similar to the findings during the administration of ETA, another analyzed pituitary hormone (prolactin and thyroid stimulating hormone) did not show statistically significant changes, either in their absolute concentrations or in the pulsatility characteristics. The vomeropherins ETA and PDD appear to be gender specific in their effect on the vomeronasal organ, and on hypothalamic responses. Gonadotropin pulsatility is significantly reduced in males, but not in female subjects (see Table III). This specific effect of the genus on the vomeronasal organ (electrovomerogram) has been previously reported using naturally occurring vomeropherins (pheromones) of human skin: Estra-1, 3, 5- (10), 16-tetraen-3-ol specifically stimulates the human vomeronasal organ in males, but not in females. However, Androsta-4, 16-dien-3-one specifically stimulates the human vomer nasal organ in females, but not in males. The data provides support for a functional connection between the vomeronasal organ and the basal forebrain. In addition, the stimulation of the human vomeronasal organ in males with ETA (3 x 10 ~ 9M) significantly changes the pulsatility of luteinizing hormone, but not of follicle-stimulating hormone. PDD (5 x 10"9M) significantly changes the pulsatility of luteinizing hormone and follicle-stimulating hormone in males only, these discoveries open an opportunity to use a specific vomeropherin (chemically synthesized and not found in nature). ) that could be used in the treatment of certain diseases that are specific to the genus The release of luteinizing hormone-releasing hormone, and of gonadotropins through exposure to semi-chemicals of conspecifics 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 was also demonstrated in laboratory animals that vomeronasal organ receptors are essential for trigger this neuroendocrine reflex (Johns 1978, Wysocki 2979, Meredith 1994) The present results show here this refl Neuroendocrine is functional in humans, and can be modulated through vomerone-salt organ receptor sites that are sensitive to vomeropherins. See Tables II and III, in which there is a decrease in the peak height of luteinizing hormone and follicle-stimulating hormone, and in the frequency and increase in the peak interval. Therefore, ETA and PDD must affect the vomeronasal afferent signals that modulate the group of hypothalamic luteinizing hormone-releasing hormone neurons. Experimental studies in several animal species have shown a close correlation between the "pulsatility of luteinizing hormone and the episodic release of GnRH in the hypothalamic-pituitary-portal blood (Veldhuis et al., J. Clin. Endocr. Metab., 64 (1987): 1275-1282). The pulsatile release of luteinizing hormone in normal men, in post-menopausal women, and in young women studied throughout the menstrual cycle, reflects the action of the endogenous gonadotropic releasing hormone (GnRH) episodic. Although variations in pulse amplitude of bioactive luteinizing hormone can result from changes in the amplitude of the endogenous GnRH impulse signal and / or changes in the responsiveness of gonado-tropic pituitary cells, alterations can be taken In the frequency of impulse of luteinizing hormone, to reflect the corresponding modulation of the hypothalamic GnRH impulse (Knobil, E. 1980, Recent Prog Horm Res 36:53).

The changes observed in the amount and pattern of gonadotropin release in male subjects during the administration of femtomolar amounts of vomeropherins to the vomeronasal organ result in a neuropharmaco logical effect at the hypothalamic / pituitary level. The pulsatile release of luteinizing hormone-releasing hormone from the preoptic hypothalamus boosts the release of both gonadotropins (luteinizing hormone and ** follicle-stimulating hormone) from the pituitary (Yenand Jaffe, Textbook of Reproductive Endocrinology). Data from several patients are shown for the blood testosterone level (subjects 1, 2, 4, and 8, respectively, shown in Figures 204, 205, 206, and 207). Visit "A" shows the levels after administration of pregna-4, 20-dien-3, 6-dione to the vomeronasal organ. Visit "B" shows testosterone levels after the administration of a placebo. The inclinations of the curves for the levels after the treatment with pregnadiendione are statistically different from the inclinations of the control curves. Also, in most cases, testosterone levels are lower after treatment with pregnadiendione, compared to the control. This shows the ability to affect the level of testosterone in the blood by administering a vomeroferin to the vomeronasal organ.

III. The invention The following examples are intended to illustrate, but not limit, the invention. The abbreviations used in the examples are as follows: aq. = aqueous; RT = room temperature, PE = petroleum ether (boiling point of SO70 ° C); DMF = N, N-dimethyl formamide; DMSO = dimethyl sulfoxide; THF = tetrahydrofuran.

SCHEME 1 Ol SCHEME 2 Jones Pregna-5.20-dien-3g-ol SCHEME 3 17-a-etinilandrostenodiol lfi 12 11 SCHEME 4 fifteen SCHEME 5. Oxidation of pregnanes ESQtfEMA 6. Synthesis of 21-methylene-20 (R) -methyl pregnanes 23 SCHEME 8. Synthesis of a colatriene fifteen SCHEME 9. Synthesis of Colanos 27 28 EXAMPLES Example 1 - Prßqna-4, 20-dien-3o; - (ß) -ol To a 1M solution of trisiamlyl lithium borohydride (5.0 milliliters, 5.0 mmol) at -78 ° C under argon, a solution of pregna-4, 20-dien-3-one (1.10 grams, 3.70 mmol) in dry tetrahydrofuran (14 milliliters), 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 in sequence: water (2 milliliters), ethanol (6 milliliters), 12 percent aqueous KOH solution (10 milliliters), and 3 percent hydrogen peroxide (50 milliliters). The mixture was allowed to warm to room temperature with stirring. After 2 hours, ethyl acetate (200 milliliters) was added, and stirring was continued. The organic layer was separated, and washed with a saturated solution of NaHCO 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 grams of the crude material. This was purified by chromatography by evaporation on 210 grams of silica gel (230-400 mesh), eluting with EtOAc / CH2C12 (5:95 -> 7:93), to give three fractions. Fraction 1 (0.8 grams) contained alcohol 3o; impure. Fraction 2 (0.1 grams) was a mixture of the 3o alcohols; and 33. Fraction 3 (0.25 grams) was pure 3ß alcohol (23 percent). The fraction was re-purified by chromatography by evaporation on 80 grams of silica gel (230-400 mesh), eluting with EtOAc / hexane (10:90 -> 15:85) to give 0.15 grams of 3o alcohol.; pure (14 percent).

Example 2 - Pregna-3, 5, 20-trien-3-ylmethyl 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 grams, 3.35 mmol) in 2,2-dimethoxypropane (5.0 ml, 41 mmol), dimethyl formamide (5.0 ml), and methanol 0.2 ml), was refluxed with monohydrate of catalytic p-toluenesulfonic acid (26.9 milligrams, 0.141 millimoles) for 2 hours. After cooling, sodium bicarbonate (153.6 milligrams, 1828 millimoles) was added, and the reaction mixture was divided between 75 milliliters of hexanes and 50 milliliters of ice water. The organic phase was washed twice with portions of 50 milliliters of water, and once with 50 milliliters of brine, after which, it was filtered through a column of 17 milliliters high by 30 millimeters diagonally, of gel silica 60. The product was further eluted with 100 milliliters of hexanes. Concentration of the combined eluates, and recrystallization from acetone / methanol, gave very light yellow glossy platelets (828.7 milligrams, 2.652 millimoles, 79 percent), m.p. 111-114 ° C.

Example 3 - Pregna-1, 4, 20-trien-3 -one The pregna-4, 20-dien-3-one (1, 1.19 grams, 3.99 mmol) was refluxed for 24 hours with 2,3-dichlor -5,6-dicyan-l, 4-benzoquinone (DDQ, 2.72 grams, 12.1 mmol) in 40 milliliters of benzene under argon. The cooled suspension was diluted with ether and washed with two portions of 100 milliliters of 5 weight percent sodium hydroxide (w / w) two 100 milliliter portions of water, and once with 100 milliliters of brine. Ether (100 milliliters) was added to the resulting emulsion, which was dried over sodium sulfate, and then filtered through a column of sodium sulfate (20 grams). After washing the residue twice with 50 milliliter portions of ether, the combined filtrates were concentrated under reduced pressure, and then chromatographed by evaporation (25 percent ethyl acetate / hexanes on silica gel), to give a slightly yellow crystalline solid (0.26 grams, 0.88 millimoles, 22 percent).

Example 4 - Pregna-1,4, 20-trien-3-ol, 4. Pregna 1, 4, 20-trien-3 -one (3_, 0.26 grams, 0.88 millimoles) in 25 milliliters of anhydrous ether was reduced under an argon atmosphere, with lithium aluminum hydride (250.5 milligrams, 6.601 millimoles) for 2 hours, and then quenched with 2.50 grams of Glauber's salt. The resulting suspension was stirred for 70 minutes, filtered, and washed twice with 50 milliliter portions of ether. After concentrating the combined filtrates under reduced pressure, the residue was purified using preparative thin layer chromatography (35 percent ethyl acetate / hexanes) on alumina to give white needles (26.1 milligrams, 87.4 micromoles, 10%). cent), pf 98-128 ° C.

Example 5 - Pregna-4,20-dien-6i8-ol-3-one, 5. M-chloroperbenzoic acid (MCPBA, 77.4 percent, 763. 4 milligrams, 3.42 millimoles), suspended in 30 milliliters of 1,2-dimethoxyethane (DME), 6 milliliters of water, and 2.4 milliliters of 5 percent (w / w) sodium hydroxide, was added to an ether solution pregna-3, 5, 20-trien-3-ylmethyl (2, 400.3 milligrams, 1281 millimoles) in 20 milliliters of 1,2-dimethoxyethane + 2 milliliters of water for 85 minutes with stirring. The reaction was continued for 5 hours, and then poured into 50 milliliters of saturated sodium bicarbonate. The mixture was extracted three times with 50 milliliters of ether, and the combined organic extracts were washed-with 50 grams of 5 percent (w / w) sodium thiosulfate pentahydrate + three 50-milliliter portions of brine, dried over magnesium sulfate, and filtered through Celite. After washing the residue with 10 milliliters of ether, the combined filtrates were concentrated in vacuo. Evaporation chromatography (35 percent ethyl acetate / hexanes, on silica gel), and thin layer chromatography (35 percent ethyl acetate / hexanes on silica gel) gave a mixture hardly separable as white crystals (95.5 milligrams, 0.304 millimoles, 24 percent).

Example 6-20, 21-dimethylpregna-5, 20-dien-33-ol, 6. Referring to Scheme 2, compounds 6, 1_, 8, and 9 were prepared as follows. Ethyl triphenyl phosphonium bromide (25.99 grams, 70. 00 millimoles), and tertiary potassium butoxide (7.86 grams, 70.0 mmol) with 80 milliliters of anhydrous dimethyl sulfoxide, were stirred under argon in an oil bath at about 80 ° C for 1 hour, after which, it was added pregn-5-en-3S-ol-20-one (4.43 grams, 14.0 mmol) in 80 milliliters of hot anhydrous dimethyl sulfoxide. The red suspension was stirred for 1 hour, removed from the heat, and poured into 200 milliliters of ice-cold brine. It was then extracted three times with 100 milliliters of ether, and the combined organic extracts were washed with 100 milliliters of brine, dried over sodium sulfate, and filtered through Celite. After washing the residue with 50 milliliters of ether, the combined filtrates were concentrated under reduced pressure. The yellow residue was recovered in 95 percent ethanol with heating, briefly boiled with 1 gram of carbon, and filtered through Celite. After cooling and filtration, the residue was recrystallized twice more from ethane, to give white crystals (1746 grams, 5.314 mmol, 38 percent), m.p. 140-145 ° C.

Example 7-20, 21-dimethylpregna-4, 20-dien-3, β-dione, 7. Jones reagent (2.67 M, 1.0 milliliter, 5.3 mmol) was added to a solution of 20, 21-dimethylpregna-5, 20-dien-3jS-ol (6., 460.1 milligrams, 1400 millimoles) in 50 milliliters of acetone, and the reaction was stirred for 45 minutes. After quenching with 2-propanol (1.0 milliliters) the mixture was poured into 100 milliliters of water, and extracted three times with 50 milliliters of ethyl acetate. The combined organic extracts were washed with 50 milliliters of saturated sodium bicarbonate + 50 milliliters of brine, dried over magnesium sulfate, and filtered through Celite. The residue was washed with 25 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (24 percent ethyl acetate / hexa-nos on silica gel), and recrystallization of the residue from 95 percent ethanol, gave yellow needles (138.2 milligrams, 0.4059 millimoles, 29 percent) , pf 172-178 ° C. Example 8-20, 21-dimethylpregna-4, 20-dien-3-one, 8. The 20,21-dimethylpregna-5,20-diene-3/3-ol (6, 400.3 milligrams, 1218 millimoles) in 5 milliliters of methylene chloride was oxidized with pyridinium chlorochromate (525.4 milligrams, 2437 millimoles) for 42 hours. Ether was added (3.5 milliliters), and the suspension was filtered through a column of 5 millimeters in diameter by 60 millimeters high in silica gel. The column was further eluted with 3.5 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Chromatography by evaporation of the resin, followed by recrystallization from aqueous ethanol, gave yellow crystals (43.6 milligrams, 0.134 millimoles, 11 percent), m.p. 157-165 ° C.

Example 9 - Pregna-4, 20-dien-3,6-dione 9. A solution of pregna-5, 20-dien-3/3-ol (300.5 milligrams, 1,000 millimoles) in 35 milliliters of acetone was cooled in a bath of ice water, and Jones 2.67 M reagent (0.71 milliliters, 1.9 millimoles) was added. After stirring for 1 1/2 hours, another 0.71 milliliters of Jones reagent was added, and the reaction was continued for 45 minutes, 2-propanol (1.0 milliliters) was added, and the mixture was poured into 100 milliliters of water. Then the mixture was extracted twice with 50 milliliters of ethyl acetate, and the combined extracts were washed with 50 milliliters of saturated sodium bicarbonate + 50 milliliters of water + 50 milliliters of brine, and filtered through a column of 21 millimeters in diameter by 22 millimeters in height of silica gel 60. The column was further eluted with 25 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residue from 95 percent ethanol gave a light yellow powder (104.6 milligrams, 0.3348 millimoles, 33 percent), m.p. 114-120 ° C.

Example 10 - Pregna-5, 17, 20-trien-3? 8-ol, 10. A solution of 17a; -etinilandrostenediol (439.4 milligrams, 1397 millimoles) in 10 milliliters of dry tetrahydrofuran, was added to a suspension of hydride lithium and aluminum (106.5 milligrams, 2 millimoles), and aluminum chloride (122.9 milligrams, 0.9220 millimoles) in 10 milliliters of dry tetrahydrofuran under argon. After refluxing for 17 hours, the reaction mixture was quenched by stirring for 2 hours with sodium sulfate decahydrate (1.00 grams, 3.10 mmol). The reaction was filtered, and the residue was washed with three 10 milliliter portions of tetrahydrofuran. The concentration of the combined filtrates under reduced pressure gave 0.44 grams of a white solid, which was purified by evaporation chromatography (30 percent ethyl acetate / hexanes on silica gel), and twice recrystallization from ethanol aqueous, giving lustrous white crystals (92.0 milligrams, 0.303 millimoles, 22 percent) pf 144-149 ° C.

Example 11-5o; -chloro-6? S, 19-epoxipregn-17-en-3g-ol, 11. With reference to Scheme 3, compounds 11, 12, 13., and 14. 'were made, as follow. Phosphonium ethyltriphenyl bromide (3.05 grams, 8.22 mmol), and potassium tertiary butoxide (0.92 grams, 8.2 mmol) were reacted under argon in anhydrous dimethyl sulfoxide (9.2 milliliters) for 1 hour in a bath at 76-86. ° C, followed by 5o; -chloro-6 / 3-19-epoxyandrostan-3/3-ol-17-one (555.9 milligrams, 1640 millimoles) in 9.2 milliliters of hot anhydrous dimethyl sulfoxide; and the mixture was stirred for an additional hour. Then the reaction was poured into 25 milliliters of ice brine, and extracted three times with 10 milliliter 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 milliliters of ether, and the combined filtrates were dried in vacuo. The residual yellow oil was purified by evaporation chromatography (60 percent ethyl acetate / hexanes on silica gel), to give a solid in the form of white syrup (0.34 grams, 0.97 millimoles, 59 percent).

Example 12 - 5of-chloro-6/3, 19-epoxipregn-17-en-3-one, 12. A solution of 5o; -chloro-6jd, 19-epoxipregn-17-en-33-ol (11, 0.34 grams, 0.97 millimoles) in 35 milliliters of acetone, cooled in an ice-cold acetone bath, and 0.47 milliliters of Jones 2.67M reagent were added. After stirring for 40 minutes, the reaction was quenched with the addition of 0.5 milliliters of 2 -propanol. Water (15 milliliters) was added, the volatile components were removed under reduced pressure and the mixture was extracted three times with 15 milliliter portions of methylene chloride. The combined organic extracts were washed with 15 milliliters of saturated sodium bicarbonate + 15 milliliters of brine, dried over magnesium sulfate, and filtered through Celite. After washing the residue twice with 5 milliliters of methylene chloride, the combined filtrates were dried in vacuo. The residue was passed through chromatography by evaporation on silica gel, using 30 percent ethyl acetate / hexanes as eluent, to give a white crystalline solid (0.34 grams, 0.97 mmol, quantitative).

Example 13 - 6β, 19-ßpoxipregn-4, 17-dien-3-one, 13. The 5o; -chloro-6/3, 19-epoxipregn-17-en-3-one (12., 0.34 grams, 0.97 millimoles) was dissolved with heating in 10 milliliters of anhydrous methanol, potassium acetate was added (0.60 grams, 6.1 millimoles), and 6.5 milliliters of the solvent were distilled at ambient pressure. The residue was concentrated under reduced pressure, taken up in 25 milliliters of water, and extracted three times with 10 milliliter portions of methylene chloride. The combined organic extracts were dried over magnesium sulfate, and filtered through Celite. The residue was washed with 10 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure to give a white crystalline solid (290.0 milligrams, 0.9281 millimole, 96 percent) homogeneous for thin layer chromatography (60 percent strength). ethyl acetate / hexanes on silica gel; Rf 0.61).

Example 14 - Pregna-4, 17-dien-19-ol-3-one, 14. To a solution of 63, 19-epoxypregna-4, 17-dien-3-one (290.0 milligrams, 0.9281 millimoles) in 10 milliliters of glacial acetic acid, zinc powder (1.12 grams, 17.1 milligrams-atom) activated was added by stirring for 2 minutes with 10 percent hydrochloric acid, followed by washing with water and acetone. The suspension was vigorously stirred for 10 minutes at 99-102 ° C, and then filtered through Celite. The residue was washed four times with 10 milliliters of acetic acid, and the combined filtrates were concentrated in vacuo. The residue was taken up in 50 milliliters of ethyl acetate, washed with 50 milliliters of water + 50 milliliters of saturated sodium bicarbonate + 50 milliliters of brine, dried over magnesium sulfate, and filtered through Celite. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were dried in vacuo. The residue was recrystallized from ethyl acetate, to give white crystals (46.4 milligrams, 0.148 millimoles, 16 percent), m.p. 192-195 ° C.

Example 15 - Pregn-4-en-3, g-ol-20-ino, 15. Pregn-4-en-3g-ol-20-ino, 15; The pregna-4-in-3-on-20-ino (200.1 milligrams, 0.6750 millimoles), and tri (tertiary butoxy) lithium aluminum hydride (343.8 milligrams, 1352 millimoles), were suspended in 3.6 milliliters of anhydrous ether. After reacting for 4 hours, another 343.5 milligrams (1351 millimoles) of hydride was added, and the reaction was allowed to continue for 16 hours. See Scheme 4. After quenching with sodium sulfate decahydrate (3.41 grams), the reaction mixture was stirred for 15 minutes, and then filtered through diatomaceous earth. The residue was extracted five times with 10 milliliter portions of ether, and the combined filtrates were concentrated under reduced pressure. Chromatography by evaporation of the residue (25 percent ethyl acetate / hexanes on silica gel), followed by recrystallization from aqueous ethanol, yielded a white powder (85.0 milligrams, 0.285 millimole, 42 percent), m.p. 120.5 - 123.5 ° C. ' Example 16-20, 21-dimethylpregna-4, 20E-dien-3,6-dione, 16. Jones reagent (2.67 M, 1.75 milliliters, 4.67 mmol) was added to a solution of 20, 21-dimethylpregna-5, 20E-dien-3/3-ol (400.0 milligrams, 1281 millimoles) in 45 milliliters of acetone, and the reaction was stirred for 30 minutes. The mixture was then poured into 85 milliliters of water, and extracted three times with 40 milliliter portions of ethyl acetate. The combined organic extracts were washed with 40 milliliters of saturated sodium bicarbonate + 40 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (20 percent ethyl acetate / hexanes on silica gel) of the residue, followed by recrystallization from aqueous ethanol, gave light yellow needles (119.1 milligrams, 0.3497 millimoles, 29 percent), m.p. 171-173 ° C. Thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel) showed a higher component in Rf 0.17, with a minor contaminant in Rf 0.24.

Example 17-20-methylpregna-4, 20-dien-3, β-dione, 17. Jones reagent (2.67 M, 1.83 milliliters, 4. 89 mmol) was added to a solution of 20-methylpregna-5, 20-dien-3/3-ol (400.0 milligrams, 1,272 millimoles) in 45 milliliters of acetone, and the reaction was stirred for 20 minutes. After quenching with 2-propanol (0.91 milliliters), the mixture was poured into 85 milliliters of water, and extracted three times with 40 milliliter portions of ethyl acetate. The combined organic extracts were washed with 40 milliliters of saturated sodium bicarbonate + 40 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters 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 milligrams, 0.7298 millimoles, 57 percent), m.p. 148-150 ° C. • Thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel) showed a higher product in Rf 0.24, with a lower impurity in the origin.

Example 18 - Pregna-4, 16-dien-3,6-dione, 18. Jones reagent (2.67 M, 0.23 milliliters, 0.61 mmol) was added to a solution of pregna-5, 16-dien-3 / 3- ol (45.5 milligrams, 0.151 millimoles) in 5 milliliters of acetone, and the mixture was stirred for 20 minutes. After quenching with 2-propanol (0.11 milliliters), 10 milliliters of water were added, and the mixture was extracted three times with 5 milliliter portions of ethyl acetate. The combined organic extracts were washed with 5 milliliters of saturated sodium + 5 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 5 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) of the residue gave a light yellow solid (10.6 milligrams, 33.9 micromoles, 22 percent) homogeneous for thin layer chromatography (Rf 0.41, 25 percent 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 milliliters, 2.75 millimoles) was added to pregna-5, 17, 20-trien-3/3 -ol (214.5 milligrams, 0.7187 millimoles) in 25 milliliters of acetone, and the mixture was stirred for 20 minutes. After quenching with 2-propanol (0.52 milliliters), the mixture was poured into 50 milliliters of water, and extracted three times with 25 milliliter portions of ethyl acetate. The combined extracts were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Recrystallization with concomitant treatment with charcoal in aqueous ethanol gave light yellow needles (67.7 milligrams, 0.218 millimoles, 30 percent), m.p. 140-143. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) shows the product at Rf 0.43, with minor contaminants at Rf 0.86, 0.14, 0.08, and 0.00 (pregna-5, 17-dien-3 / 3-ol Rf 0.32).

Example 20-21-methylene-20 (R) -methylpregn-4-en-3-one, 20. Aluminum isopropoxide (0.39 grams, 1.9 mmol) in 3.6 milliliters of hot toluene, was added to a solution of 21- methylene-20 (R) -methylpregn-5-en-3/3-ol (208.2 milligrams, 0.6337 millimoles) in cyclohexanone (3.6 milliliters, 35 millimoles) and 18 milliliters of toluene, and the mixture was refluxed to the exclusion of humidity for 2 hours. After cooling on ice, 0.92 milliliters of water and 2.2 milliliters of 3.6 N sulfuric acid were added, and the mixture was stirred for 1 minute. More water (4.6 milliliters) was added, the mixture was stirred for 5 minutes, and the aqueous phase was discarded. The volatile components were removed by azeotropic distillation / steam, and the resulting aqueous suspension was extracted three times with 5 milliliter 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 of which was contained in a Pasteur pipette. The residue was washed with 5 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residue film gave white needles (152.7 milligrams, 0.4677 millimoles, 74 percent), m.p. 138-139 ° C. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) showed a higher product in Rf 0.54, with a trace contaminant in Rf 0.71 (starting material Rf 0.36).

Example 21-21-methylene-20 (R) -methylpregn-4-en-3? 8-ol, 21. A suspension of 21-methylene-20 (R) -methylpregn-4-en-3 -one (5. , 100.0 milligrams, 0.3063 millimoles), and tertiary tributoxy aluminum hydride (319.4 milligrams, 1,256 millimoles) in 5 milliliters of anhydrous tetrahydrofuran, was stirred under argon for 6 hours, after which water (48 microliters), 15 percent (w / w) sodium hydroxide (48 microliters), and water were added. (143 microliters). The mixture was filtered through diatomaceous earth, the residue was extracted four times with aliquots of 5 milliliters of tetrahydrofuran. Concentration of the combined filtrates under reduced pressure, and double recrystallization from aqueous ethanol, gave white platelets (42.6 milligrams, 0.114 millimoles, 42 percent), m.p. 121-123 ° C. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) shows the highest product in Rf 0.38, and a minor 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 M, 0.68 milliliters, 1.8 mmol) was added to 21-methylene-20 (R) -methylpregn-5-en-3/3-ol (149.8 milligrams, 0.4560 millimoles) in 15 milliliters of acetone. , and the reaction was stirred for 20 minutes. After quenching with 2-propanol (0.34 milliliters), the mixture was poured into 30 milliliters of water, and extracted three times with 15 milliliter portions of ethyl acetate. The combined organic extracts were washed with 15 milliliters of saturated sodium bicarbonate + 15 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography of the residue preparation (25 percent ethyl acetate / hexanes on silica gel, GF, 1000 μ) gave a homogeneous crystalline yellow solid (49.7 milligrams, 0.146 millimoles, 32 percent) for the chromatography of thin layer (25 percent ethyl acetate / hexanes, Rf 0.47, starting material, Rf 0.35). Example 23 - Pregn-4-en-3ff-ol-20-ino, 23. Aluminum hydride of tertiary lithium tributoxy (343.8 milligrams, 1,352 millimoles) was added to pregn-4-en-3-on-20-ino (200.1 milligrams, 0.6750 millimoles) suspended in 3.6 milliliters of anhydrous ether, and the mixture was stirred for 4 hours. Additional hydride (343.5 milligrams, 1351 millimoles) was added, and the reaction was stirred for another 16 hours. Glauber's salt (3.41 grams) was added, and the suspension was stirred for 15 minutes. The mixture was filtered through diatomaceous earth, and the residue was extracted five times with 10 milliliter portions of ether. The concentration of the combined filtrates under reduced pressure, followed by evaporation chromatography (25 percent ethyl acetate / hexanes on silica gel), and recrystallization from aqueous ethanol, gave a white powder (85.0 milligrams, 0.285). millimoles, 42 percent), pf 120.5-123.5 ° C. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) showed the product (Rf 0.23) contaminated with traces of what appeared to be the starting material (Rf 0.29).

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

Example 25 - Cola-5, 16, 20 (22) -trien-33-ol, 25. A suspension of phosphonium propyltriphenyl bromide (12.13 grams, 31.48 millimoles) and tertiary potassium butoxide (3.54 grams, 31.5 millimoles) in sulfoxide of anhydrous dimethyl (35 milliliters) under an argon atmosphere was placed in an oil bath (72-87 ° C), and then stirred for 1 hour. Pregna-5, 16, dien-3/3-ol-20-one (1.9807 grams, 6.298 mmol) was added in 35 milliliters of hot dimethyl-anhydrous sulfoxide, and the reaction was stirred for 90 minutes. The mixture was then poured into 90 milliliters of ice-cold brine and extracted with three 45-milliliter portions of ether. The combined organic extracts were washed with 45 milliliters of brine, dried over sodium sulfate, and filtered. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (20 percent ethyl acetate / hexanes on silica gel) of the resulting oil gave an amber resin (103.6 milligrams, 0.3042 millimoles, 4.8 percent).

Example 26 - Cola -4, 20 (22) E-dien-4,6-dione, 26. Jones reagent (2.67 M, 1.26 milliliters, 3.36 millimoles) was added to glue 5, 20 (22) E-diene 3/3-ol (300.0 milligrams, 0.8758 millimoles) in 30 milliliters of acetone, and the reaction was stirred for 20 minutes. After quenching with 2-propanol (0.63 milliliters), the mixture was poured into 60 milliliters of water, and extracted three times with portions of 30 milliliters d-; ethyl acetate. The combined organic extracts were washed with 30 milliliters of saturated sodium bicarbonate + 30 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave a yellow solid (139.3 milligrams, 0.3929 millimoles, 45 percent), p.f. 109- 116 ° C. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) shows a higher product (Rf 0.45) with contaminants in Rf 0.24, 0.1, and 0. 08 (cola-4,20 (22) E-dien-3-one Rf 0.49).

Example 27 - Cola-4, 20 (22) E-dien-3-one, 27. Aluminum isopropoxide (2.82 grams, 13.8 millimoles) in 26 milliliters of hot toluene was added to cola 5.20 (22) E -dien-3/3-ol (1.5777 grams, 4.605 millimoles) in cyclohexanone (26 milliliters, 0.25 moles) + 130 milliliters of toluene, and the reaction was refluxed for 4 hours with the exclusion of moisture. After cooling, water (6.7 milliliters) and 3.6 N sulfuric acid (16 milliliters) were added, and the mixture was stirred for 1 minute. More water (32 milliliters) was added, the mixture was stirred for 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 milliliter portions of methylene chloride. The combined organic extracts were dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol with the concomitant treatment with carbon gave clear yellow crystals (1.3317 grams, 3.9104 mmol, 85 percent), m.p. 133-135 ° C. Thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel) showed that the product was homogeneous (Rf 0.49, starting material, Rf 0.31).

Example 28 - Tail-4, 20 (22) E-dien-3g-ol, 28. A suspension of tail-4, 20 (22) E-dien-3 -one (3., 400.0 milligrams, 1175 mmol), and lithium tertiary tributary-lithium aluminum hydride (1.2250 grams, 4.8158 millimoles) in 15 milliliters of anhydrous ether, was stirred under argon for 8 hours. Glauber's salt (6.07 grams) was added, the mixture was stirred for 5 minutes, and then filtered through diatomaceous earth. The residue was extracted 5 times with 15 milliliter portions of ether, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography (5 percent ethyl acetate / methylene chloride on silica gel, 1000 μ) of the residue gave a light yellow solid (49.9 milligrams, 0.146 millimole, 12 percent) homogeneous for chromatography thin layer (5 percent ethyl acetate / methylene chloride on silica gel, Rf 0.34, pregna-5, 20-dien-3/3-ol rf 0.26).

Example 29 - Tail ether-3, 5, 20 (22) E-trien-3-ylmethyl, 29. A mixture of tail-4, 20 (22) E-dien-3-one (808.6 milligrams, 2374 millimoles), 2, 2-dimethoxypropane (3.1 milliliters, 25 mmol), dimethyl formamide (3.1 milliliters), methanol (0.13 milliliters), and p-toluenesulphonic acid monohydrate (28.0 milligrams, 0.147 millimoles), was refluxed for 4 hours with the exclusion of smoked. After cooling, sodium bicarbonate (0.17 grams) was added, and the mixture was divided between 30 milliliters of water and 50 milliliters of ether. The organic layer was washed with 30 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The xecrystallization of the resulting solid from acetone gave a pale yellow solid (453.8 milligrams, 1280 millimoles, 54 percent), m.p. 94-96 ° C. Thin layer chromatography (10 percent ethyl acetate / hexanes on silica gel) showed the product in Rf 0.62, with a trace of starting material (Rf 0.14).

Example 30 - Cola-4, 20 (22) E-dien-6g-ol-3-one, 30. 3-Chloroperbenzoic acid - (183.0 milligrams, 1060 millimoles) in 5.9 milliliters of 1,2-dimethoxyethane + 2.3 was added. milliliters of water, to ether-3, 5, 20 (22) E-trien-3-ylmethyl in 5.9 milliliters of 1,2-dimethoxyethane for 2 1/2 minutes. After stirring the reaction for another 1/2 hour, it was poured into 30 milliliters of saturated sodium bicarbonate, and extracted three times with 30 milliliter portions of ethyl acetate. The combined organic extracts were washed with 30 grams of sodium thiosulfate pentahydrate at 5 percent (w / w) + 3 'portions of 30 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (60 percent ethyl acetate / hexanes on silica gel) of the resulting solid, and thin layer chromatography of subsequent preparation (50 percent ethyl acetate / hexanes on silica gel) of the resulting solid , and thin layer chromatography of subsequent preparation (50 percent ethyl acetate / hexanes on silica gel, 1000 μ) gave a white crystalline solid (114.3 milligrams, 0.3206 millimoles, 33 percent), consisting of two components by thin-layer chromatography (50 percent ethyl acetate / hexanes 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 Autonomic Responses to the Vomeronasal Organ Stimulus Different autonomous parameters were monitored, as it was administered: A1-P3 Pregna-4, 16-dien-3-one, A2-P3 Pregna-5,16-dien -3 / 3-ol, A8-P1 3-methoxy-pregna-3, 5, 20 -triene, A6-P1 Pregna-4,20-dien-3,6-dione, 20,21-dimethylpregna-5,20 -dien-3/3-ol, 20, 21-dimethylpregna-5, 20-dien-3-one, A14-P2 Gß, 19-epoxypregne-4, 17-dien-3-one, A7-P2 19-hydroxy-pregna-4, 17 (20) -dien-3-one, A13-P1 Pregna-4, 20- dien-6/3-ol-3-one, All-Pl Pregna-l, 4,20-trien-3-one, Al-Pl Pregna-4, 20-dien-3-one, A2-P1 Pregna-5 , 20-dien-3/3-ol, A4-P1 Pregna-4, 20-3QI-O1, A3-P1 Pregna-4,20-3 / 3-ol, A1-P4 Pregn-4-en-3 ona, A2-P4 Pregn-5-en-3/3-ol, to 24 female subjects and 24 male subjects, using the procedure described in Example 32. Propylene glycol was also administered as a control. When compared with a propylene glycol control, the test compounds induced a significant change in the potential of the integrated receptor in the vomeronasal organ, in the response of the galvanic skin (GSR), in the temperature of the skin (ST), in the percentage of cortical alpha wave activity, measured by encephalogram (EEG), electrocardiogram (EKG), and respiratory rate (RF). The results are shown in Figures 2 to 58. Additional tests were performed on other pregnane derivatives, the results of which are shown in Figures 59-84. The results of the tests on the colane derivatives are shown in Figures 85-96.

SCHEME 10 Synthesis of 19-norpregnans SCHEME 11. Synthesis of other Norpregnanes S 2 SCHEME 12 Other syntheses of Norpregnans 12 eleven ÜAIH4 SCHEME 13. 17-ethylenation of ketones 12 H Example 32 - 19-norpre na-4, 20-dien-3? 8-ol. A suspension of 19-norpregna-4, 20-dien-3-one (0.38 grams, 13 mmol), and lithium tributyl lithium aluminum hydride (1.36 grams, 5.35 millimoles) in 20 milliliters of anhydrous ether was added. stirred for 5 hours at room temperature, and Glauber's salt (6.74 grams) was added. The resulting mixture was stirred for 5 minutes, and then filtered through a glass frit. The residue was washed with five 20 milliliter portions of ether, and the combined filtrates were concentrated under reduced pressure. The crude product was purified by thin layer chromatography of preparation on silica gel GF, using 5 percent ethyl acetate / methylene chloride as eluent, to give a yellow resin (39.6 milligrams, 0.138 millimole, 11 percent) homogeneous for thin layer chromatography (5 percent ethyl acetate / methylene chloride on silica gel, Rf 0.29).

Example 33 - 19-norpregna-l, 3, 5 (10), 17.20-pentaen-3-ol To a suspension of lithium aluminum hydride (LAH, 256. 1 milligrams, 6.748 millimoles), and aluminum chloride (296.8 milligrams, 2.227 millimoles) in 20 milliliters of anhydrous ether under argon, ethinylestradiol (1.0000 grams) was added in 20 milliliters of anhydrous ether. After refluxing for 20 hours the reaction was quenched with the addition of Glauber's salt (2.00 grams), and stirred for another two hours. Then the mixture was filtered through diatomaceous earth, and the residue was washed with 3 portions of 10 milliliters of ethyl acetate. Concentration of the combined filtrates, chromatography by evaporation on silica gel with 15 percent ethyl acetate / hexanes, and double recrystallization from aqueous ethanol, gave slightly tanned needles (367.5 milligrams, 1.311 millimoles, 39%). cent), pf 132-133 ° C, homogeneous for thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel, Rf 0.36, estra-l, 3, S (10), 16-tetraen-3-ol, Rf 0.36).

Example 34-19-norpregna-l, 3, 5 (1) -trien-3-ol-20? -ino. To a cooled solution (dry ice / acetone bath) of 19-norpregna-1, 3, 5 (10), 17, 20-pentaen-3-ol (2, 280.4 milligrams, 1,000 millimoles) in 28 milliliters of anhydrous tetrahydrofuran under argon, normal butyl lithium (2.5 M in hexane, 1.2 milliliters, 3.0 mmol) was added for 10 minutes. Stirring was continued for 18 hours, during which time, the reaction was allowed to gradually warm to room temperature. The reaction quenched with 25 milliliters of 1 N HCl, and then extracted with 3 portions of 10 milliliters of ether. The combined organic extracts were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Chromatography by evaporation of the resulting yellow resin on silica gel with 20 percent ethyl acetate / hexanes, followed by recrystallization from aqueous ethanol, gave fine white needles (150.5 milligrams, 0.5367 millimoles, 54 percent), pf 148-149 ° C, homogeneous for thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel, Rf 0.34, starting material, Rf 0.37).

Example 35-19-norpregna-l, 3, 5 (10), 16,20-pentaen-3-ol. 19-Norpregna-1, 3, 5 (10), 16-tetraen-3-ol-20-ino (200.0 milligrams, 0.7184 millimoles) in 9 milliliters of anhydrous tetrahydrofuran was added to approximately 30 milliliters of anhydrous ammonia. added sodium (0.07 grams, 3 milligrams-atom) in small pieces, and the reaction was stirred for 1 hour, during which the color disappeared. Absolute ethanol (3 milliliters) was added, and the mixture was allowed to warm to room temperature overnight. HCl (IN, 20 milliliters) was added, and the mixture was extracted three times with 10 milliliter portions of methylene chloride. The combined organic extracts were washed with 10 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. Preparation thin layer chromatography (silica gel GF, with 20 percent ethyl acetate / hexanes) of the resulting amber resin, followed by recrystallization from benzene / hexanes, gave a white powder, m.p. 123-125 ° C. Thin layer chromatography (20 percent 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-ylmethyl ether (750.0 milligrams, 2,513 millimoles) was dissolved in 80 milliliters of acetone, and oxalic acid (0.88 grams) was added, 7.0 millimoles) in 12 milliliters of water. More acetone (20 milliliters) was added, to bring most of the precipitate back into solution, and the reaction was stirred for 6 hours. After quenching with saturated sodium bicarbonate (30 milliliters), the reaction mixture was washed twice with 40 milliliter portions of ethyl acetate. The combined organic extracts were washed twice with 50 milliliter portions of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Chromatography by evaporation (10 percent ethyl acetate / hexanes on silica gel 15) gave a colorless resin (0.54 grams, 1.9 mmol, 76 percent).

Example 37-19-norpregna-5 (10), 20-dien-3-ol. To an ethereal solution (8.4 milliliters) of 19-norpreg-na-5 (10), 20-dien-3-one (0.42 grams, 1.5 millimoles), 69.7 milligrams (1.84 millimoles) of LAH were added, and the reaction was stirred for 30 minutes. Glauber's salt (2.79 grams) was added, and the suspension was stirred for an additional 10 minutes. The mixture was then filtered through diatomaceous earth, and the residue was extracted with 435 milliliter portions of ether. The combined filtrates were concentrated under reduced pressure, and the resulting oil was passed by evaporation chromatography (20 percent ethyl acetate / hexanes on silica gel), to give a white foam (0.38 grams, 1.3 mmol, 88 percent). ).

Example 38-19-norpregna-4, 20-dien-10? S-ol-3-one. The 19-norpregna-5 (10), 20-dien-3-one (5, 0.45 grams, 1.6 mmol) in dimethyl formamide (5.7 milliliters) was cooled in an ice-cold acetone bath, and Jones reagent was added, (2.67 M. 0.19 milliliter, 0.51 millimoles). After stirring for 1-1 / 2 hours, another 0.19 milliliters of Jones reagent was added. The situation was continued for 45 minutes, after which 0.38 milliliters of Jones reagent was added. The reaction was quenched after stirring for an additional 1 hour by the addition of 2-propanol (0.38 milliliters). Ethyl acetate (100 milliliters) was added, and the mixture was washed with 3 portions of 50 milliliters of water + 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography of the preparation on alumina with 50 percent ethyl acetate / hexanes gave a white crystalline filler (89.2 milligrams, 0.2-97 millimoles, 19 percent). Thin layer chromatography (50 percent ethyl acetate / hexanes on silica gel) showed mostly the product (Rf 0.46), contaminated with a 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 grams, 1.2 mmol) in anhydrous pyridine (4.0 milliliters, 49 mmol) was cooled in an ice-salt bath until less from -80 ° C, and solid pyridinium bromide perbromide (1.26 grams, 3.94 millimoles) was added at a rate such that the reaction temperature did not exceed -2 ° C. After stirring for 1 minute 0.20 grams of phenol were added, the cold bath was removed, and the reaction was stirred at room temperature for 24 hours. Ethyl acetate (50 milliliter) was added, and the mixture was washed with 50 milliliters of 1 N HCl + 25 milliliters of saturated CuC04 + 25 milliliters of 5 percent sodium hydroxide + 25 milliliters of water + 25 milliliters 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 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. The resulting dark syrup (512.8 milligrams) was recovered in 8 milliliters of absolute ethanol, zinc powder (260.8 milligrams, 3,990 milligrams-atom) was added, and the suspension was refluxed for half an hour. The reaction mixture was filtered through cotton, and the residue was washed with 10 milliliters of ethanol. The concentration of the combined filtrates, and the double purification by thin layer chromatography of preparation, first on silica gel GF (1000 [mu], 20 percent ethyl acetate / hexanes as eluent), and then over GF alumina (1000 [mu], 20 percent ethyl acetate / hexanes), gave an almost colorless resin (152.8 milligrams, 0.5410 millimoles, 45 percent), homogeneous for thin layer chromatography (Rf 0.22, 10 percent ethyl acetate / hexanes on silica gel, pregna-, 20-dien-3 -one Rf 0.25).

Example 40-19-norpregna-l, 3, 5 (10), 20-tetraen-3-ol. Ethinylestradiol diacetate (2,0004 grams, 5.2576 mmol) in 100 milliliters of anhydrous tetrahydrofuran was added to approximately 140 milliliters of anhydrous NH3, and sodium (1.88 grams, 81.8 milligrams-atom) was added in small pieces 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 milliliters of 1 N HCl were added, the layers were separated, and the aqueous layer was extracted twice with 50 milliliter portions of ether. The combined organic phases were washed with 3 portions of 100 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 25 milliliters of methylene chloride, dried over sodium sulfate, and filtered through diatomaceous earth. The residue was washed twice with 10 milliliter portions of methylene chloride, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (15 percent ethyl acetate / hexanes on silica gel) gave a white crystalline solid with yellow spots (0.86 grams, 3.0 mmol, 58 percent).

Example 41 - Ether 19-norpregna-l, 3, 5 (10), 16-tetraen-3-ylmethyl-L-19-norpregna-l, 3, 5 (10), 20-tetraen-3-ol crude (9 , 0.86 grams, 3.0 millimoles) in 75 milliliters of 90 percent ethanol, potassium carbonate (6.73 grams, 55.2 millimoles) was added, and the suspension was refluxed for 1/2 hour. Dimethyl sulfate (0.75 milliliters) was added, and the reaction was refluxed for another 1/2 hour. Dimethyl sulfate was added in 3 aliquots of 1.8 milliliters (total = 6.15 milliliters, 65.0 millimoles) for 1 hour, and reflux was continued for 1/2 hour. Ice water (65 milliliters) was added, 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 milliliters of water + 50 milliliters of 5 percent sodium hydroxide + 3 portions of 50 milliliters of water. The residue was recrystallized from aqueous ethanol, to give fine white needles, m.p. 108.5-110 ° C (p.f. lit. 108-110 ° C).

Example 42 - 19-Norpregna-l, 3, 5 (10), 16-tetraen-6-on-20-yn-3-yl acetate Chromium trioxide (2.68 grams, 2.68 mmol) was suspended in 40 milliliters of chloride of methylene, and the suspension was cooled in an ice-salt bath at -8 ° C. 3, 5-Dimethylpyrazole (2.58 grams, 26.8 mmol) was added, and the suspension was stirred for 20 minutes. 19-Norpregna-1,3,5 (10), 16-tetraen-20-yn-3-yl acetate (0.86 grams, 2.7 mmol) was added for 5 minutes, such that the reaction temperature did not exceed -7 ° C. After stirring for an additional 2 hours, the reaction mixture was poured through a column of 30 millimeters by 116 millimeters of silica gel, and elution was continued under pressure with methylene chloride. The concentration of the appropriate fractions gave a brown film (0.16 grams, 0.48 millimoles, 18 percent).

Example 43-19-norpregna-l, 3, 5 (10), 16-tetraen-3, 6,3-diol-20-ino. Acetate of crude 19-norpregna-l, 3, 5 (10), 16-tetraen-6-on-20-yn-3-yl (11., 0.16 grams, 0.48 millimoles) in anhydrous ether 20 was suspended, LAH (36.7 milligrams, 0.967 mmol) was added, and the mixture was refluxed to the exclusion of water for 18 hours. After cooling, 1.22 grams of Glauber's salt was added, and the suspension was stirred for 1/2 hour. The mixture was filtered through diatomaceous earth, and the residue was washed with 4 portions of 10 milliliters of a hot concentration of the combined filtrates, ethyl acetate, followed by purification by thin layer chromatography of preparation (50 percent acetate). ethyl acetate / hexanes on silica gel GF, 1000 μ), and this gave a white solid (26.0 milligrams, 88.3 mmol, 18 percent), homogeneous for thin layer chromatography (50 percent ethyl acetate / hexanes on silica gel; Rf 0.48).

Example 44-19-norpregna-l, 3, 5 (10), 17-tetraen-3-ol. Ethyltriphenyl Phosphonium Bromide was placed (1.3947 grams, 3.7572 millimoles) and tertiary potassium butoxide (422.5 milligrams, 3.765 millimoles) suspended in anhydrous dimethyl sulfoxide (4.1 milliliters) under argon, in an oil bath (80-84 ° C), and stirred for 1 hour. hour. Equilin (200.2 milligrams, 0.7459 millimoles) was added in 4.1 milliliters of anhydrous dimethyl sulfoxide, and the reaction was stirred for an additional 1 hour. After cooling, 25 milliliters of ice cold 1 N HCl was added, and the mixture was extracted three times with 20 milliliter portions of ether. The combined organic extracts were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (20 percent ethyl acetate / hexanes on silica gel), followed by thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel GF, 1000 μ), gave a resin slightly yellow (182.9 milligrams, 0.6523 millimoles, 87 percent) homogeneous for 19.4 thin layer chromatography (20 percent ethyl acetate / hexanes, Rf 0.42).

Example 45 - 19-norpregna-l, 3, 5 (10), 6, 17-pentaen-3-ol. Ethyltriphenyl Phosphonium Bromide was placed (1.3945 grams, 3.7561 millimoles) and tertiary potassium butoxide (422.8 milligrams, 3.768 millimoles) suspended in 4.1 milliliters of anhydrous dimethyl sulfoxide under argon, in a bath at 77-79 ° C, and stirred for 1 hour. 6-dehydrostrone (200.4 milligrams, 0.7466 mmol) was added in 4.1 milliliters of anhydrous dimethyl sulfoxide, and the reaction was stirred for 1 hour. The reaction mixture was allowed to cool, and then poured into 25 milliliters of ice cold 1 N HCl. The mixture was extracted three times with 20 milliliters of ether, and the combined organic extracts were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. . The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (15 percent ethyl acetate / hexanes) and thin layer chromatography (15 percent ethyl acetate / hexanes on silica gel GF, 1000 μ) gave a white crystalline solid (212.9 milligrams,> 100 percent) homogeneous for thin-layer chromatography (15 percent ethyl acetate / hexanes on silica gel, Rf 0.21).

Example 46-19-norpregna-l, 3, 5 (10), 6.8.17-hexaen-3-ol. Phosphonium ethyltriphenyl bromide (1.3945 grams, 3.7561 millimoles) and tertiary potassium butoxide (422.3 milligrams, 3.763 millimoles) suspended in 4.1 milliliters of anhydrous dimethyl sulfoxide under argon, in an oil bath (74-83 ° C) were placed, and the reaction was stirred for 1 hour. Equilenin (200.2 milligrams, 0.7518 millimoles) was added in 4.1 milliliters of anhydrous dimethyl sulfoxide, and the reaction mixture was stirred for an additional 1 hour. The mixture was poured into 25 milliliters of ice cold 1 N HCl, and extracted three times with 20 milliliter portions of ether. The combined organic extracts were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (20 percent ethyl acetate / hexanes), and thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel GF, 1000μ.), Gave a clear yellow crystalline wax (180.6 milligrams, 0.6487 millimoles, 86 percent) homogeneous for thin layer chromatography.

Example 47. The following study compares the effect of 23 vomeropherins with the structure of 19-norpregnane, and placebo (propylene glycol), on autonomic activity and the electroencephalogram. Twelve healthy human subjects (6 women and 6 men), ages 19 to 29, participated in this study. All the substances were applied in air to the vomeronasal organ (VISTO), the aspiration lasting 5 seconds. For this purpose, we used a miniprobe electrode described elsewhere, which allowed us to do the local stimulation and the simultaneous recording of the organ electrovomerogram (EVG). The parameters recorded were: electrodermal activity (EDA), respiratory frequency (RF), electrocardiogram (CF), electro-myogram (EMG), body temperature (BT), and electroencephalogram, CzAl and T3A1. The autonomous activity, the electroencephalogram and the electrovomerogram, were recorded using surface electrodes. All the techniques used were non-invasive. The procedure was done in two registration sessions, each lasting 1 hour. The electrical records were amplified, digitized, and monitored and stored on a computer. The processing and analysis of the results were done offline. The data from the tests on women are shown in Figures 99-120, and the data on men are shown in Figures 121-142.

The results were summarized in the following tables, which show the overall effect of each vomeropherin already subtracted from the control. An arbitrary score of 0 to 5 was assigned to compare the activity of the compounds relative to each other, but virtually all of the compounds tested had some effect. These results show that the effect of some vomeropherins on autonomic activity and electroencephalogram is significantly different from placebo. It also shows that some substances do not have significantly different effects in both genders.

Example 48 - Synthesis of Estra-1, 3, 5 (10), 16-etraen-3-ol. The following synthesis method is illustrated in Figure 1: Estrone-p-toluenesulfonylhydrazone. Estrone (270 grams, 1.00 moles) and p-toluenesulfonylhydrazide (232.8 grams, 1.25 moles) in dry methanol (2.5 liters) 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 (300 milliliters). Additional cultures of the product were obtained by sequential evaporation of the filtrate to 2000 milliliters, 800 milliliters, and 400 milliliters, and allowing to crystallize each time. The total yield was 433.5 grams (99 percent). 1,3,5 (10), 16-estratetraen-3 -ol. Estrone-p-toluenesulfonylhydrazone (219.9 grams, 500 millimoles) in dry tetrahydrofuran (8.0 liters) was cooled in a sodium chloride / ice bath. The mixture was stirred mechanically, while adding normal butyl lithium (800 milliliters of a 2.5M solution in hexane, 2.00 moles) by means of a double ended needle. The mixture was stirred at room temperature for 3 days. Ice (250 grams) was added, followed by a saturated solution of ammonium chloride (500 milliliters). 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 milliliters). The two organic phases were washed in sequence with the same batch of saturated sodium bicarbonate solution (500 milliliters), followed by saturated sodium chloride solution (500 milliliters). The organic layers were dried (MgSO4), and evaporated in vacuo to give the crude product. This was subjected to filtration by evaporation on 500 grams 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 milliliters) / water (75 milliliters), washing with methanol (80 milliliters) / water (20 milliliters). Further recrystallization from ethyl acetate / hexane (12.5: 87.5) gave the pure product (88.9 grams, 70 percent).

Example 49 - Synthesis of acyl derivatives of 1,3, 5 (10), 16-estratetraen-3-ol. To 1.3, 5 (10), 16-estratetraen-3-ol (254 milligrams, 1.00 millimoles) in ether (10 milliliters), acetic anhydride (0.25 milliliters) (or propionic anhydride for propionate) is added, followed by pyridine (0.25 milliliters), and the mixture is stirred at room temperature for 16 hours. The mixture is poured into ice water, and extracted with ether (2 x 20 milliliters). The organic extracts are waswith water, a saturated solution of copper sulphate, water, and a saturated solution of sodium chloride, dried (MgSO4), and evaporated in vacuo, to give the pure product (192 milligrams, 65%). hundred) .

Example 50 - Synthesis of Estra-4, 16-dien-3-one. Ether estra-1, 3, 5 (10), 16-tetraen-3-methyl (551.1 milligrams, 2.055 millimoles) in 8.6 milliliters of anhydrous tetrahydrofuran, approximately 30 milliliters of anhydrous ammonia, and 6.76 grams of tertiary butyl alcohol, He added lithium wire (0.24 grams, 35 milligrams-atom) cut into small pieces. The reaction mixture was refluxed for 4-1 / 2 hours under argon, after which methanol (2.3 milliliters) was added, and the ammonia was allowed to boil overnight. The residue was dissolved in 25 milliliters of methanol, and acidified to about 1 pH of 1 with 5 N HCl. After heating in an oil bath between 55 ° C and 70 ° C for 15 minutes, the cooled hydrolysis mixture divided between 25 milliliters of water and 50 milliliters of ethyl acetate, and the aqueous phase was extracted with 25 milliliters of ethyl acetate. The combined organic extracts were waswith 25 milliliters of saturated sodium bicarbonate, and 25 milliliters of brine, dried over magnesium sulfate, and filtered. Removal of the solvent under reduced pressure yielded 0.57 grams of an oily residue, which was purified by chromatography by evaporation on silica gel (eluent: 15 percent ethyl acetate / hexane), followed by recrystallization from pentane, give crystals (206.1 milligrams, 39 percent) homogeneous for thin layer chromatography, mp 67-71 ° C.

Example 51 - Synthesis of ether estra-2, 5 (10), 16-trien-3-methyli-co. Ether estra-1, 3, 5 (10), 16-tetraen-3-methyl (1.22 grams, 4.54 millimoles) in 19 milliliters of anhydrous tetrahydrofuran, 14.99 grams of tertiary butyl alcohol, and approximately 70 milliliters of anhydrous ammonia , lithium wire (0.53 grams, 76 milligrams-atom) cut into small pieces was added. After refluxing under argon for 6 hours, the reaction was paid with 5 milliliters of methanol, and the ammonia was allowed to boil overnight. A suspension of the residue in 100 milliliters of water was extracted twice with 100 milliliter portions of ethyl acetate, and the combined organic extracts were waswith brine, and dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was passed through chromatography by evaporation on silica gel, using 1 percent ethyl acetate / hexane as eluent, and then recrystallized from absolute ethanol, to give crystals. fluffy whites (884.1 milligrams, 3.269 millimoles, 72 percent), mp 72-73 ° C homogeneous for thin layer chromatography.

Example 52 - Synthesis of estra-5 (10), 16-dien-3 -one. The estra-2, 5 (10), 16-trien-3-methyl (2) ether (646.3 milligrams, 2,390 millimoles), dissolved in 50 milliliters of acetone, was hydrolyzed for 6 hours at room temperature, using acid dihydrate oxalic (0.84 grams, 6.7 millimoles). The reaction mixture was quencwith 25 milliliters of saturated sodium bicarbonate, and then extracted twice with 25 milliliter portions of ethyl acetate. The combined organic extracts were wastwice with 25 milliliters of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane, to give the product. (462.5 milligrams, 1,804 millimoles, 75 percent), p.f. 112-116 ° C.

Example 53 - Synthesis of estra-5 (10), 16-dien-3-ol. (4) Estra-5 (10), 16-dien-3-on (3) (301.1 milligrams, 1174 mmol), in 6 milliliters of anhydrous ether, was reduced for 1 hour at room temperature, using lithium hydride and aluminum (50.0 milligrams, 1.32 millimoles). After switching off with decahydrate (2.00 grams) for 10 minutes. The suspension was filtered through Celite, and the residue was washed with 4 portions of 25 milliliters of ether. The combined filtrates were concentrated under reduced pressure, and purified by evaporation chromatography (silica gel, 5 percent ethyl acetate / hexanes as eluents) with thin layer chromatography of subsequent preparation of mixed fractions. The more polar product can be recrystallized with a considerable loss of aqueous ethanol, to give 4.8 milligrams of a solid. The less polar product was recrystallized from aqueous methanol, to give white crystals (59.5 milligrams), m.p. 98-100 ° C. The total yield was 64.3 milligrams (0.249 millimoles, 21 percent).

Example 54 - Synthesis of Estra-4, 9, 16-trien-3-one. Estra-5, 10, 16-dien-3-one (3) (0.38 grams, 1.5 millimoles), in pyridine (5.0 milliliters, 62 millimoles), was cooled in an ice-salt bath at -13 ° C, and pyridinium perbromide (1.58 grams, 4.94 millimoles) was added in small portions, such that T < -4 ° C. After swirling for 1 minute, phenol (0.25 grams, 2.7 mmol) was added, and the reaction was continued for 24 hours at room temperature. Ethyl acetate (50 milliliters) was added, and the reaction mixture was washed with 25 milliliters of IN HCl, 2 portions of 25 milliliters of saturated copper sulfate, 25 milliliters of 5% sodium hydroxide, and 25 milliliters. of brine After drying the magnesium sulfate, filtering, and concentrating under reduced pressure, the residue was recovered in 10 milliliters of absolute ethanol, granular zinc (0.33 grams, 5.0 milligrams-atom) was added, and the mixture was placed at reflux for half an hour. The supernatant was removed, the residue was washed with 10 milliliters of absolute ethanol, and the combined supernatants were concentrated under reduced pressure. The resulting resin was passed through chromatography by evaporation on silica gel, using 15 percent ethyl acetate / hexane as eluent. The appropriate fractions were pooled, concentrated, and then recrystallized from hexane, to give the solid product (117.5 milligrams, 0.4619 millimoles, 31 percent), m.p. 87-92 ° C.

Example 55 - Synthesis of 3-acetate of Estra-1, 3, 5 (10), 16-tetraen-6-one. Chromium trioxide (13.40 grams, 0.1340 moles) was suspended in 200 milliliters of methylene chloride, and then cooled to -10 ° C in an ice-salt bath. 3,5-Dimethyl-pyrazole (12.90 grams, 0.1342 moles) was added and the mixture was stirred for 20 minutes. Estra-1, 3, 5 (10), 16-tetraen-3-yl acetate (4.00 grams, 13.5 mmol) was added in an ice-cold solution of 20 milliliters of methylene chloride, and the reaction was stirred for 2 hours, during which time T < -8 ° C. Then the mixture was filtered through 200 grams of silica gel, and the product was eluted with additional methylene chloride. After combining and concentrating the appropriate fractions, the crude product was passed through chromatography by evaporation on silica gel, using 15 percent ethyl acetate / hexane as eluent. Grouping the appropriate fractions and concentrating under reduced pressure yielded a white solid (0.92 grams, 3.0 mmol, 22 percent), m.p. 87-103 ° C.

Example 56 - Synthesis of estra-1, 3, 5 (10), 16-tetraen-3-ol-6-one. The 3-acetate estra-1, 3, 5 (10), lß-tetraen-6-one (203.1 milligrams, 0.6543 millimoles) in 30 milliliters of methanol was saponified with 1.5 milliliters of sodium hydroxide at 5 percent (w / w) for 40 minutes. The reaction mixture was concentrated under reduced pressure, it was recovered in 50 milliliters of water, neutralized with 1 N HCl, and extracted three times with 25 milliliter portions of methylene chloride. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, filtered, and concentrated to give a white solid, which was purified by recrystallization from benzene / hexane, and layer chromatography. thin preparation, to give a white crystalline solid (52.8 milligrams, 0.197 millimoles, 30 percent), mp 188-191 ° C.

Example 57 - Synthesis of Estra-1, 3, 5 (10), 16-tetraen-6a.-ol-3-yl acetate. Estra-1, 3, 5 (10), 16-tetraen-6-one-3-yl acetate (421.4 milligrams, 1,358 millimoles), suspended in 35 milliliters of 95 percent ethanol, was reduced with borohydride of sodium (98.8 milligrams, 2.61 millimoles) for 100 minutes at room temperature. After concentrating under reduced pressure, the residue was suspended in 25 milliliters of water, neutralized with 1 N HCl, and extracted three times with 25 milliliter portions of methylene chloride. The combined extracts were washed with 25 milliliters of brine, dried over magnesium sulfate, filtered, and concentrated. The resulting white foam was passed through chromatography by evaporation on silica gel, using 25 percent ethyl acetate / hexane as eluent. The combination of the fractions and the concentration gave a white solid (0.12 grams, 0.38 millimoles, 28 percent), m.p. 209-212 ° C.

Example 58 - Synthesis of Estra-1, 3, 5 (10), 16-tetraen-3,6-diol To a suspension of lithium aluminum hydride (LAH, 95 percent, 46.9 milligrams, 1.17 millimoles) in 5 milliliters of anhydrous tetrahydrofuran, estra-1,3,5 (10), 16-tetraen-6-one-3-yl acetate (6) (422.9 milligrams) was added. , 1,360 millimoles) in 5 milliliters of anhydrous tetrahydrofuran by dripping, with stirring. The reaction was stirred for 50 minutes, after which additional LAH (46.5 milligrams, 1.16 millimoles) was added, and the reaction was stirred for 22 hours. After refluxing for 4 h, thin layer chromatography still showed starting material. The reaction was quenched with 0.5 milliliters of water + 0.5 milliliters of 20 percent (w / w) sulfuric acid, and concentrated under reduced pressure. The residue was extracted 4 times with 10 milliliter portions of hot ethyl acetate, and filtered through Celite. The combined filtrates were concentrated and purified twice by evaporation chromatography, to give the solid product (0.05 grams, 0.2 mmol, 10 percent), m.p. 150-157 ° C.

Example 59 - Synthesis of estra-1, 3, 5 (10), 7-tetraen-3-ol To a suspension of equilin (100.2 milligrams, 0.3733 millimoles) in 2 milliliters of diethylene glycol, hydrazine (59 microliters) was added. , 1.9 millimoles), and potassium hydroxide (0.04 grams, 0.7 millimoles). The mixture was stirred in an oil bath at 200-214 ° C for 2 hours, after which the cooled reaction was diluted with 10 milliliters of water, neutralized with IN HCl, and extracted three times with 25 milliliters of ether. . The combined organic extracts were washed with 10 milliliters of brine, dried over magnesium sulfate, filtered, concentrated and purified by thin layer chromatography (silica gel, 15 percent 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 tanned crystals (13.2 milligrams, 51.9 μM, 14 percent), m.p. 130-134 ° C.

Example 60 - Synthesis of 20-homoestra-l, 3, 5 (10), 6, 8, 17-hexaen-3-ol. A suspension of triphenylmetichilic phosphonium bromide (671.0 milligrams, 1878 millimoles) and tertiary potassium butoxide (212.1 milligrams, 1890 millimoles) in 2.1 milliliters of anhydrous dimethyl sulfoxide was heated in a bath at 76-86 ° C under argon. for 1 hour, after which equilenin (100.1 milligrams, 0.3579 mmol) was added in 2.1 milliliters of anhydrous dimethyl sulfoxide, and the green solution was stirred for 1 hour. After cooling, 10 milliliters of ice cold HCl was added, and the mixture was extracted with 3 portions of 10 milliliters of ether. The combined organic extracts were washed with 10 milliliters of saturated sodium bicarbonate + 10 milliliters of brine, dried over magnesium sulfate, filtered through Cel_te, and concentrated under reduced pressure. The residual orange oil was purified by preparative thin layer chromatography (silica gel, 25 percent ethyl acetate / hexane), to give the product (75.5 milligrams, 0.286 millimole, 76 percent), homogeneous for the chromatography of thin layer, mp 113-121 ° C.

Example 61 - Synthesis of 20-homoestra-l, 3, 5 (10), 6, 8, 17-hexaen-3-ol. Estra-1, 3, 5 (10), 6-tetraen-3-ol-17-one (91.1 milligrams, 0.339 millimoles), hydrazine (54 microliters, 1.7 millimoles), and potassium hydroxide (0.06 grams) in 1.8 milliliters of diethylene glycol were heated in a bath at 200 ° C under argon for 2 hours. After cooling to room temperature, 10 milliliters of water were added, and the solution was acidified to a pH of about 2 with 1 N HCl. The resulting suspension was extracted three times with 10 milliliters of ether, and the combined organic extracts were washed with 10 milliliters of brine, dried over magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The crude solid was purified by thin layer chromatography (25 percent ethyl acetate / hexane on silica gel), to give the homogeneous product for thin layer chromatography (5.9 milligrams, 23 millimoles, 7 percent) .

Example 62 - Synthesis of estra-4, 16-dien-3-ol. To the estra, 4, 16-dien-3-one, (1) (87.2 milligrams, 0. 340 millimoles) in 1.7 milliliters of anhydrous ether, lithium aluminum hydride (15.0 milligrams, 0.395 millimoles) was added, and the suspension was stirred for 17 minutes. Then the reaction was stirred for 10 minutes with 0.50 grams of sodium sulfate decahydrate, and filtered through Celite. The residue was washed with 3 portions of 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography (5 percent ethyl acetate / dichloromethane on silica gel) gave the crude product (50.0 milligrams) as a yellow resin. This could be passed through chromatography until it was sufficiently pure.

Example 63 - Estra-4, 16-dien-3-one. This synthesis is illustrated in Figure 153. The 19-nor-testosterone (XIX) is commercially available, for example, from Chemical Dynamics Corp. It provides the starting material for the 19-nor-16-androstene derivatives. The 19-nor-testosterone (XIX) was converted into acetate (Hartman, J.A. and collaborators, J. Am. Chem. Soc. (1956) 78: 5662) with acetic anhydride and pyridine. (a) A solution of this acetate (4.8 grams, 15.17 mmol) in toluene (10 milliliters) was pyrolyzed (b) at 540 ° C (200 Torr, low N2 stream) in a glass tube packed with pieces of quartz. Chromatography of the crude pyrolyzate (3.1 grams) on silica gel (150 grams) with CH2C12 gave 1.1 grams (28 percent) of the homogeneous oily ketone 9; + 57.9 ° (C 1) ((27): mp 71-73 ° C). - IR: (CHC13): 1660s, 1615m, 1585w, ^ H-NMR. (90 MHz): 0.84 (s, 3H); 5.82 (m, 2H); 5.87 (br. S, ÍH).

Example 64 - Estr-16-en-3-one This synthesis is illustrated 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. and collaborators (J. Am. Chem. Soc. (1960) 82: - 5693). Androsta-5a, 17-diol-3 -one (XX) was converted to acetate (Hartman, J.A. et al., J. Am. Chem. Soc. (1956) 78: 5662) with acetic anhydride and pyridine (a). A solution of 17B-acetoxy-5a-estran-3 -one (8.0 grams, 25.1 mmol) in octane / acetone 10: 1 (22 milliliters) was pyrolyzed (b) at 550 ° C (200 Torr, low N2 current) . Chromatography of the crude product (5.4 grams) on silica gel (600 grams) with CH2C12, and recrystallization of the homogeneous fractions from PE gave 3.13 grams (48.3 percent) of the pure ketone 10. P.f. 51-54 °, [a] - + 72.8 ° (C 1.0). -GO. (CHC13): 1705S, 1585w, - ^ -H-NMR. (90 MHz): 0.79 (s, 3H); 5.71 (m, ÍH); 5.87 (m, ÍH).

Example 65 - Estra-16-en-3a-ol. This synthesis is illustrated in Figure 153. L-Selectride (d, tri (secondary butyl) lithium hydruroborate, 4 milliliters of a 1M solution in tetrahydrofuran, 4 mmol) was added dropwise, at 0 ° C to a ketone solution 10 (800 milligrams, 3.10 millimoles) in dry ether (5 milliliters). After stirring for 1 hour at 0 ° C, water (10 milliliters) was added. The boranes were oxidized by the addition of an aqueous solution of 10 percent NaOH (5 milliliters), followed by an aqueous solution of 30 percent H202 (3 milliliters), and stirring for 3 hours at room temperature. After work (ether), the crude product (790 milligrams, a mixture of about 9: 1 of 11 and 12) was chromatographed on silica gel with CH2C12, to give 700 milligrams (87 percent) of pure alcohol. pf 119-120 ° C-123 ° C-124 ° C (from PE), [a] D + 40.6 ° (C = 1.0). -GO. (CHCl3): 3640m, 3500 br., 1585w. - ^? - RMN. (90 MHz): 0.78 (s, 3H); 4.09 (m, wl / 2 ~ 8, ÍH); 5.71 (m, ÍH) 5.87 (m, ÍH).

Example 66 - Estra-16-en-3B-ol. This synthesis is illustrated in Figure 153. A solution of the ketone 10 (800 milligrams, 3.10 mmol) in dry ether (5 milliliters) was added dropwise at room temperature to a slurry of LiAlH4 (38 milligram, 1 millimole). in ether (3 milliliters) (e). After 1 hour, the mixture was hydrolyzed with 10 percent aqueous H2SO4. After work (ether), the crude product (802 milligrams, 9: 1 mixture of 12 and 11) was chromatographed on silica gel with CH2C12. First a small fraction of 11 (70 milligrams) was eluted, followed by the main fraction- of 12 (705 milligrams, 87 percent), m.p. 113-115 ° C, [a] + 36.3 ° (C = 1.0). -GO. (CHC13): 3640m, 3500 br. , 1585w. - ^? - RMN. (90 MHz): 0.78 (s, 3H); 3.60 (m, wl / 2 ~ (m, 20, ÍH); 5.71 (m, ÍH) 5.87 (, ÍH).

Example 67 - Alternative synthesis of estra-4, 16-dien-3-one It is ra-4, 16-dien-3-one; Ether estra-1, 3,5 (10), 16-tetraen-3-methyl (551.5 milligrams, 2,055 millimoles) in 8.6 milliliters of anhydrous tetrahydrofuran, approximately 30 milliliters of anhydrous ammonia, and 6.76 grams of tertiary butyl alcohol, He added lithium wire (0.24 grams, 35 milligrams-atom) cut into small pieces. The reaction mixture was refluxed for 4-1 / 2 hours under argon, after which methanol (2.3 milliliters) was added, and the ammonia was allowed to boil overnight. The residue was dissolved in 25 milliliters of methanol, and acidified to approximately pH 1 with 5N HCl. After heating in an oil bath between 55 ° C and 70 ° C for 15 minutes, the cooled hydrolysis mixture was divided between 25 milliliters of water and 50 milliliters of ethyl acetate, and the aqueous phase was extracted with 25 milliliters of water. ethyl acetate. The combined organic extracts were washed with 25 milliliters of saturated sodium bicarbonate and 25 milliliters of brine, dried over magnesium sulfate, and filtered. Removal of the solvent under reduced pressure yielded 0.57 grams of an oily residue, which was purified by chromatography by evaporation on silica gel (eluent: 15 percent ethyl acetate / hexane), followed by recrystallization from pentane, give crystals (206.1 milligrams), 39 percent homogeneous for thin layer chromatography, mp 67-71 ° C.

Example 68 - Estra-2, 5 (10), 16-trien-3-methyl ether, 2 Al estra-1, 3, 5 (10), 16-tetraen-3-methyl ether ('1.22 grams, 4.54 mmol) in 19 milliliters of anhydrous tetrahydrofuran, 14.99 grams of tertiary butyl alcohol, and approximately 70 milliliters of anhydrous ammonia, they were added to the hunger for lithium (0.53 grams, 76 milligrams-atom) cut into small pieces. See Figure 12. After refluxing under argon for 6 hours, the reaction was quenched with 5 milliliters of methanol, and the ammonia was allowed to boil overnight. A suspension of the residue in 100 milliliters of water was extracted twice with 100 milliliter portions of ethyl acetate, and the combined organic extracts were washed with brine, and dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was chromatographed on silica gel using 1 percent ethyl acetate / hexane as eluent, and then recrystallized from absolute ethanol to give white crystals. fluffy (884.1 milligrams, 3.269 millimoles, 72 percent), mp 72-73 ° C, homogeneous for thin layer chromatography.

Examples 69 - Estra-5 (10), 16-dien-3-one, 3 The ether estra-2, 5 (10), 16-trien-3-methyl 2 (646.3 milligrams, 2390 millimoles), dissolved in 50 milliliters of acetone, hydrolyzed for 6 hours at room temperature, using oxalic acid dihydrate (0.84 grams, 6.7 mmol). See Figure 12. The reaction mixture was quenched with 25 milliliters of saturated sodium bicarbonate, and then extracted twice with 25 milliliter portions of ethyl acetate. The combined organic extracts were washed twice with 25 milliliters of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane to give the product (462.5 milligrams, 1,804 millimoles, 75 percent), m.p. 112-116 ° C.

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

Example 71 - Estra-4, 9, 16-trien-3-one. The extra-5 (10), 16-dien-3-one, 3 (0.38 grams, 1.5 millimoles) in pyridine (5.0 milliliters, 62 millimoles) was cooled in an ice-salt bath at -13 ° C, and added pyridinium bromide perbromide (1.58 grams, 4.94 millimoles) in small portions, such that T < -4 ° C. After swirling for 1 minute, phenol (0.25 grams, 2.7 mmol) was added, and the reaction was continued for 24 hours at room temperature. See Figure 12. Ethyl acetate (50 milliliters) was added, and the reaction mixture was washed with 25 milliliters of IN HCl, 2 portions of 25 milliliters of saturated copper sulfate, 25 milliliters of 5 percent sodium hydroxide. , and 25 milliliters of brine. After drying over magnesium sulfate, filtering, and concentrating under reduced pressure, the residue was taken up in 10 milliliters of absolute ethanol, granular zinc (0.33 grams, 5.0 milligrams-atom) was added, and the mixture was refluxed. for 1/2 hour. The supernatant was removed, the residue was washed with 10 milliliters of absolute ethanol, and the combined supernatants were concentrated under reduced pressure. The resulting resin was passed through chromatography by evaporation on silica gel, using 15 percent ethyl acetate / hexane as eluent. The appropriate fractions were pooled, concentrated, and then recrystallized from hexane, to give a solid product (117.5 milligrams, 0.4619 millimole, 31 percent), m.p. 87-92 ° C.

Example 72 - Acetate of Estra-1, 3, 5 (10), 16-tetraen-6-one Chromium trioxide (13.40 grams, 0.1340 moles) was suspended in 200 milliliters of methylene chloride, and then cooled to -10 ° C in an ice-salt bath. 3,5-Dimethyl-pyrazole (12.90 grams, 0.1342 moles) was added, and the mixture was stirred for 20 minutes. See Figure 13. Acetate of estra-1, 3, 5 (10), 16-tetraen-3-yl (4.00 grams, 13.5 mmol) was added in an ice solution of 20 milliliters of methylene chloride, and the reaction was stirred for 2 hours, during which time T- > -8 ° C. Then the mixture was filtered through 200 grams of silica gel, and the product was eluted with more methylene chloride. After combining and concentrating the appropriate fractions, the crude product was passed by chromatography by evaporation on silica gel, using 15 percent ethyl acetate / hexane as eluent. Grouping the appropriate fractions and concentrating under reduced pressure gave a white solid (0.92 grams, 3.0 millimoles, 22 percent), m.p. 87-103 ° C.

Example 73 - Estra-1, 3, 5 (10), 16-tetraen-3-ol-6-one Estra-1, 3, 5 (10), 16-tetraen-6-one 3-acetate (203.1 milligrams, 0.6543 millimoles) in 30 milliliters of methanol, was saponified with 1.5 milliliters of sodium hydroxide at 5 percent (w / w) for 40 minutes. See Figure 156. The reaction mixture was concentrated under reduced pressure, it was recovered in 50 milliliters of water, neutralized with IN HCl, and extracted three times with 25 milliliter portions of methylene chloride. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, filtered, and concentrated, to give a white solid, which was purified by recrystallization from benzene / hexane, and thin layer chromatography. of preparation, to give a white crystalline solid (52.8 milligrams, 0.197 millimoles, 30 percent), mp 188-191 ° C.

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

Example 75 - Estra-1, 3, 5 (10), 16-tetraen-3,6-diol. To a suspension of lithium aluminum hydride (L7? H, 95 percent, 46.9 milligrams, 1.17 millimoles) in 5 milliliters of anhydrous tetrahydrofuran, estra-1,3, 5 (10), 16-tetraen acetate was added. -6-one-3-yl, 6 (422.9 milligrams, 1360 millimoles) in 5 milliliters of anhydrous tetrahydrofuran by dripping, with stirring. See Figure 156. The reaction was stirred for 50 minutes, after which more LAH (46.5 milligrams, 1.16 millimoles) was added, and the reaction was stirred for 22 hours. After refluxing for 4 hours, thin layer chromatography still showed starting material. The reaction was quenched with 0.5 milliliters of water + 0.5 milliliters of 20% sulfuric acid (w / w), and concentrated under reduced pressure. The residue was extracted four times with 10 milliliter portions of hot ethyl acetate, and filtered through Celite. The combined filtrates were concentrated and purified twice by evaporation chromatography, to give a solid product (0.05 grams, 0.2 mmol, 10 percent), m.p. 150-157 ° C.

Example 76 - Estra-1, 3, 5 (10), 7-tetraen-3-ol To a suspension of equilin (100.2 milligrams, 0.3733 millimoles) in 2 milliliters of diethylene glycol, hydrazine (59 microliters, 1.9) was added. millimoles) and potassium hydroxide (0.04 grams, 0.7 millimoles). See Figure 157. The mixture was stirred in an oil bath at 200-214 ° C for 2 hours, after which, the cooled reaction was diluted with 10 milliliters of water, neutralized with IN HCl, and extracted. times with 25 milliliters of ether. The combined organic extracts were washed with 10 milliliters of brine, dried over magnesium sulfate, filtered, concentrated and purified by preparative thin layer chromatography (silica gel, 15 percent ethyl acetate / hexane. as the eluent) * to give a yellow resin. The product was further purified by decolorization with carbon and recrystallization from aqueous ethanol, to give tanned crystals (13.2 milligrams, 51.9 μM, 14 percent), m.p. 130-134 ° C.

Example 77 - 20-homoestra-l, 3, 5 (10), 6, 8, 17-hexaen-3-ol. A suspension of triphenylmetichilic phosphonium bromide (671.0 milligrams, 1878 millimoles) and tertiary potassium butoxide (212.1 milligrams, 1890 millimoles) in 2.1 milliliters of anhydrous dimethyl sulfoxide was heated in a bath at 76-86 ° C. under argon for 1 hour, after which equilenin (100.1 milligrams, 0.3579 millimoles) was added in 2.1 milliliters of anhydrous dimethyl sulfoxide. See Figure 157, and the green solution was stirred for 1 hour. After cooling, 10 milliliters of ice cold HCl were added, and the mixture was extracted with three portions of 10 milliliters of ether. The combined organic extracts were washed with 10 milliliters of saturated sodium bicarbonate + 10 milliliters of brine, dried over magnesium sulfate, filtered through Celite, concentrated and purified.

Example 78 - Estra-1, 3, 5 (10), 6-tetraen-3-ol-17- (p-toluensulfo-nyl) hydrazone. A suspension of 6-dehydroestrone (538.0 milligrams, 2,004 millimoles) and p-toluenesulfonyl hydrazide (pTsNHNH2, 466.6 milligrams, 2,506 millimoles) in anhydrous methanol (5.4 milliliters) was refluxed for 25 hours with exclusion of moisture. See Figure 15. After concentrating under reduced pressure, the residue of the reaction was passed by evaporation chromatography (50 percent ethyl acetate / hexanes on silica gel) to give a white foam. (942.5 milligram), which represented a yield of > 100 percent.

Example 79 - Estra-1, 3, 5 (10), 6-tetraen-3-ol-17- (p-toluensulfo-nyl) hydrazone. To a cooled solution (ice water bath) of estral, 3, 5 (10), 6-tetraen-3-ol-17- (p-toluenesulfonyl) hydrazone crude (1,942.5 milligrams, < 2,004 millimoles) in tetrahydrofuran (THF) under argon, normal butyl lithium (2.5 M in hexane, 3.2 milliliters, 8.0 mmol) was added by dripping with stirring, over a period of 7 minutes. See Figure 158. Stirring was continued for 48 hours, during which time, the reaction was allowed to gradually warm to room temperature. 50 milliliters of 1 N hydrochloric acid was added, and the reaction mixture was extracted with 3 portions of 25 milliliters of ether. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The crude product was purified by evaporation chromatography (20 percent ethyl acetate / hexanes on silica gel) and thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel GF, thickness 1000). microns) to give a white crystalline film (134.5 milligrams, 0.5331 millimole, 27 percent) homogeneous for thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel, Rf 0.39).

Example 80 - Estra-1, 3, 5 (10), 6,16-pentaen-3-yl acetate. A solution of estra-1, 3, 5 (10), 16-pentaen-3-ol (2.97.9 milligrams, 0.388 mmol) in anhydrous pyridine (1.3 milliliters, 16 mmol) and acetic anhydride. (0.18 milliliters, 1.9 mmol), was stirred for 24 hours, after which ethyl acetate (15 milliliters) was added, and the mixture was washed with 3 aliquots of 5 milliliters of 1N hydrochloric acid + 5 milliliters of sodium bicarbonate. saturated sodium + 5 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Figure 15. The residue was washed with 5 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography (10 percent ethyl acetate / hexanes on silica gel GF, thickness 1000 microns) of the residue gave a slightly yellow crystalline solid (74.9 milligrams, 0.254 millimole, 66 percent) homogeneous for thin layer chromatography (10 percent ethyl acetate / hexanes on silica gel, Rf, 0.40).

Example 81 - Estra, 1, 3, 5 (10), 7-tetraen-3-ol-17- (p-toluensulfo-nil) idrazone. Equilin (500.1 milligrams, 1863 millimoles) and p-TsNHNH2 (433.7 milligrams, 2.329 millimoles) suspended in anhydrous methanol (5.0 milliliters) were refluxed for 24 hours with the exclusion of moisture. See Figure 15. After concentrating under reduced pressure, the residual reaction mixture was passed by evaporation chromatography (35 percent ethyl acetate / hexanes on silica gel), to give a white foam (899.9 milligrams) which represented a performance of > 100 percent.

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), crude 7-tetraen-3-ol-17- (p-toluenesulfonyl) hydrazone (4.899.9 milligrams, <1,863 mmol) in anhydrous tetrahydrofuran (20 milliliters) under argon, was added normal butyl lithium (2.5 M in hexane, 3.0 milliliters, 7.5 mmol) by dripping with stirring over a period of 3 minutes. See Figure 15. Stirring was continued for 48, during which time the reaction was allowed to warm gradually to room temperature. The reaction was poured into 50 milliliters of IN hydrochloric acid and the mixture was extracted with 3 portions of 25 milliliters of ether. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The product was passed through chromatography by evaporation (20 percent ethyl acetate / hexanes on silica gel), and decolorized with charcoal, to give a yellow crystalline solid (274.8 milligrams, 1.089 millimoles, 58 percent).

Example 83 - Acetate of estra-1, 3, 5 (10), 7,16-pentaen-3-yl. A solution of estra-1, 3, 5 (10), 7, 16-pentaen-3-ol (5, 192. 1 milligrams, 0.7612 millimoles) in anhydrous pyridine (2.6 milliliters, 32 millimoles) and acetic anhydride (0.36 milliliters, 3.8 millimoles), was stirred for 6 hours, after which 30 milliliters of ethyl acetate was added. The mixture was washed with 3 portions of 10 milliliters of IN hydrochloric acid + 10 milliliters of saturated sodium bicarbonate + 10 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography of preparation (5 percent ethyl acetate / hexanes on silica gel GF, thickness 1000 microns), and recrystallization from aqueous ethanol, gave fine white needles (78.6 milligrams, 0.267 millimoles, 35 percent), pf 77-80 ° C. Thin layer chromatography (4 percent ethyl acetate / hexanes on silica gel (showed two spots at Rf 0.21 and 0.24.

Example 84 - Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol-17- (p-toluensu-fonyl) hydrazone. Equilenin (0.6559 milligrams, 2.463 millimoles) and p-TsNHNH2 (573.6 milligrams, 3080 millimoles), suspended in anhydrous methanol (8.2 milliliters), were refluxed for 24 hours with the exclusion of moisture. See Figure 16. After cooling and concentrating under reduced pressure, the reaction mixture was passed by evaporation chromatography (35 to 40 percent ethyl acetate / hexanes, 57 percent), m.p. 95-96 ° C. Thin layer chromatography (2 percent ethyl acetate / hexanes on silica gel) showed that the product (Rf 0.1) contained a trace contaminant at the origin.

Example 85 - Estra-1, 3, 5 (10), 6, 8, 16-hexaen-3-ol To a cooled solution (ice water bath) of estra-1, 3, 5 (10) 6, 8- crude pentaen-3-ol-17- (p-toluenesulfonyl) hydrazone (7, 1.0887 grams, <2463 mmol) in anhydrous tetrahydrofuran (25 milliliters) under argon, was added normal butyl lithium (2.5 M in hexane, 3.9 milliliters) , 9.8 millimoles) by dripping with stirring for 2 minutes. See Figure 159. Stirring was continued for 3 days, during which time the reaction was allowed to gradually warm to room temperature. 50 milliliters of ice cold hydrochloric acid was added, and the mixture was extracted three times with 25 milliliter portions of ether. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (20 percent ethyl acetate / hexanes on silica gel) and recrystallization from aqueous ethanol with carbon decolorization gave tanned platelets (245.8 milligrams, 0.9819 millimoles, 40 percent), m.p. 162-163 ° C.

Example 86 - Estra-1, 3, 5 (10), 6, 8,16-hexaen-3-yl acetate. A solution of estra-1, 3, 5 (10), 6, 8, 16-hexaen-3-ol, (8.888.8 milligrams, 0.5944 millimoles) in anhydrous pyridine (2.0 milliliters, 25 millimoles) and acetic anhydride ( 0.28 milliliters, 3.0 mmol) was stirred for 6 hours, after which ethyl acetate (20 milliliters) was added. See Figure 159. The mixture was washed with 3 portions of 10 milliliters of IN hydrochloric acid + 10 milliliters of saturated sodium bicarbonate + 10 milliliters of brine, dried over sodium sulfate, and filtered. The residue was washed with 5 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Recrystallization from 95 percent ethanol gave glossy white platelets (99.4 milligrams, 0.340 millimoles, 55 percent), m.p. 95-96 ° C. Thin-layer chromatography (2 percent ethyl acetate / hexanes on silica gel) showed that the product (Rf 0.1) contained a trace contaminant at the source.

Example 87-17-methylenenestra-l, 3, 5 (10) -trien-3-ol. A suspension of phosphonium methyltrifenium bromide (100.03 grams, 0.28001 moles) and tertiary potassium butoxide (31.42 grams, 0.2800 moles) in anhydrous dimethyl sulfoxide (DMSO, 320 milliliters) under argon, was stirred in a water bath. oil (68-81 ° C) for 1 hour, after which estrone (15.14 grams, 55.99 mmol) in anhydrous dimethyl sulfoxide (320 milliliters) was added via syringe. See Figure 160. Stirring was continued for 1 hour, and the reaction was allowed to cool. The mixture was poured into 800 milliliters of ice cold hydrochloric acid, and then extracted three times with aliquots of 400 milliliters of ether. The combined organic extracts were washed with 350 milliliters of saturated sodium bicarbonate + 400 milliliters of brine, dried over sodium sulfate, and filtered by evaporation through a 58 millimeter high by 84 millimeter diameter gel column. silica (200-400 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 grams, 42.73 millimoles, 76 percent), m.p. 134-136 ° C, homogeneous for thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel, 0.45).

Example 88 - 17-methylenenestra-l, 3, 5 (10) -rien-3-yl acetate. A solution of 17-methylenenestra-l, 3, 5 (10) -trien-3-ol (10, 5.84 grams, 21.8 mmol) in anhydrous pyridine (32 milliliters, 0.40 moles) and acetic anhydride (9.7 milliliters, 0.10 moles) was stirred for 24 hours, after which ethyl acetate (250 milliliters) was added. See Figure 160. The mixture was washed with 3 portions of 100 milliliters of 1N hydrochloric acid + 100 milliliters of saturated sodium bicarbonate + 100 milliliters of saturated copper sulfate + 100 milliliters of brine, dried over magnesium sulfate, and it leaked through diatomaceous earth. The residue was washed with 25 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave glossy white platelets (5.84 grams, 18.8 millimoles), m.p. 77-79 ° C.

Example 89 - 17-methylene-tetra-1,3,5 (10) -trien-6-on-3-yl acetate. To a suspension of chromium trioxide (6.19 grams, 61.9 mmol) cooled to -8 ° C (ice-salt bath) in methylene chloride (100 milliliters), 2-dimethylpyrazole (5.95 grams, 61.9 mmol) was added. . See Figure 17. After stirring for 20 minutes, a solution of 17-methylene-tetra-1,3,5 (10) -trien-3-yl acetate (11.20001 grams, 6.4428 mmol) in 10 milliliters of ethyl acetate was added. ice-cold methylene chloride, for a period of 2 minutes, such that the temperature does not reach -6 ° C. Stirring was continued for 2 hours, and then the mixture was passed through a column of 100 grams of silica gel (200-400 mesh). The product was further eluted with additional methylene chloride. Pooling and concentration of the appropriate fractions under reduced pressure gave the crude product, which was further purified by double recrystallization from aqueous ethanol, to give lustrous white crystals (334.0 milligrams, 1030 millimoles, 16 percent), m.p. 91-94 ° C. Thin layer chromatography (25 percent 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-l, 3, 5 (10) -trien-3,6B-diol. To a suspension of lithium aluminum hydride (53.6 milligrams, 1.41 millimoles) in anhydrous tetrahydrofuran (3.0 milliliters) under argon, cooled in a dry ice / acetone bath, was added 17, 35-methylene-lethra acetate. , 3, 5 (10) -trien-6-on-3-yl (12, 251.7 milligrams, 0.7758 mmol) in anhydrous tetrahydrofuran (3.0 milliliters) per drop with stirring for 8 minutes. See Figure 160. After shaking for 2 hours, the bath was removed, and the stirring was continued for an additional 1 hour. The reaction was quenched by stirring for 1/2 hour with Glauber's salt (1.78 grams). The resulting mixture was applied to a short cushion of diatomaceous earth, and extracted four times with 10 milliliter portions of ethyl acetate. The continuous extraction with 5 portions of 10 milliliters of hot ethyl acetate, and the concentration of. All the extracts under reduced pressure gave a colorless film. Thin layer chromatography (40 percent ethyl acetate / hexanes on silica gel GF, thickness 1000 microns) gave a white foam (15.3 milligrams, 53.8 millimoles, 7 percent). Thin layer chromatography (40 percent ethyl acetate / hexanes on silica gel) showed higher (Rf 0.29) and lower (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 grams, 20.0 mmol) and potassium carbonate (50.82 grams, 0.3678 mol) at reflux in 90 percent ethanol, (500 milliliters), dimethyl sulfate (5.0 milliliters, 53 millimoles) was added. After 1/2 hour of reflux, additional dimethyl sulfate (36 milliliters, 0.38 moles, in 3 aliquots of 12 milliliters) was added over the period of 1 hour. See Figure 160. The reaction was refluxed for an additional 1 hour, after which 360 milliliters of water were added, and the mixture was placed in the refrigerator overnight. The resulting suspension was filtered and washed with 80 milliliters of 60 percent methanol + 3 portions of 80 milliliters of 5 percent (w / w) sodium hydroxide + 3 portions of 80 milliliters of water. The residue was recrystallized from aqueous methanol to give white crystals (3.88 grams, 13.7 mmol, 69 percent), m.p. 59-62 ° C. Thin layer chromatography (20 percent 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-ylmethyl ether. Approximately 70 milliliters of anhydrous ammonia were distilled through a KOH tower, in a 250 milliliter fire-dried three-necked flask, adapted with an inlet adapter, magnetic stir bar, dry ice / acetone condenser, and a ground glass stopper V. See Figure 160. A solution of 17-methylenestra-1,3,5 (10) -trien-3-ylmethyl ether (14, 11297 grams, 40001 millimoles) and tertiary butyl alcohol (13.21) was added. grams, 0.1782 moles) in dry tetrahydrofuran (17 milliliters), followed by lithium wire (0.47 grams, 68 milligrams-atom) cut into small pieces. After refluxing under argon for 6 hours, anhydrous methanol (6.0 milliliters) was added, and the suspension was stirred overnight while ammonia was allowed to boil. Water (100 milliliters) was added, and the suspension was extracted three times with 50 milliliter portions of methylene chloride. The combined organic extracts were washed with 100 milliliters of brine, dried over sodium sulfate, and filtered. The residue was washed with 25 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. The resulting light yellow oil was crystallized from aqueous ethanol, to give lustrous white crystals (815.0 milligrams, 2865 millimoles, 72 percent), m.p. 77-78 ° C, homogeneous for thin layer chromatography (Rf 0.60, 10 percent ethyl acetate / hexanes on silica gel).

Example 93-17-Methylene-4-en-3 -one Concentrated hydrochloric acid (6.0 milliliters) and water (6.0 milliliters) were added to a solution of 17-methylene-2-ether (2) -dien-3 ether. -amethyl (15, 702.8 milligrams, 2471 millimoles) in methanol (6 milliliters) and acetone (20 milliliters). See Example 160. After stirring for 1 hour, sodium bicarbonate (7.50 grams) was added cautiously. The mixture was concentrated under reduced pressure once the effervescence ceased, and water (50 milliliters) was added. The mixture was extracted three times with 25 milliliter portions of methylene chloride. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. The product was purified by charcoal decolorization, chromatography by evaporation (20 percent ethyl acetate / -hexanes on silica gel), and recrystallization from aqueous ethanol, to give a white powder (302.8 milligrams, 1120 millimoles, 45 percent), pf 83-89 ° C.

Example 94-17-methylene-4-en-3 < goal . Lithium tributary tributarium aluminum hydride (766.6 milligrams, 3015 millimoles) was added to a solution of 17-methylene-4-en-3-one (16, 203.7 milligrams, 0.7533 millimoles) in 10 milliliters of anhydrous ether, and the The reaction is stirred for 420 hours. See Figure 161. Glauber's salt (3.80 grams) was added, and the suspension was stirred for an additional 1/2 hour. The mixture was filtered through diatomaceous earth, and the residue was washed 5 times with 10 milliliter portions of ether. The combined filtrates were concentrated under reduced pressure, and then subjected to thin layer chromatography (5 percent ethyl acetate / methylene chloride on silica gel GF, thickness 1000 microns), to give white needles (60.2 milligrams, 0.221 millimole, 29 percent) homogeneous for thin layer chromatography (Rf 0.37, 5 percent ethyl acetate / methylene chloride on silica gel).

Example 95-17-methylenenestra-l, 3, 5 (10), 7-tetraen-3-ol. Phosphonium methyltriphenyl bromide (1.9967 grams, 5.5892 millimoles) and tertiary potassium butoxide (627.2 milligrams, 5.589 millimoles) suspended in 6.1 milliliters of anhydrous dimethyl sulfoxide under argon were stirred for 1 hour in an oil bath (71-83). ° C), after which equilin (300.0 milligrams, 1118 millimoles) was added in 6.1 milliliters of anhydrous dimethyl sulfoxide, by means of a syringe. See Figure 161. After stirring for an additional 70 minutes, the reaction mixture was poured into 40 milliliters of ice water, and extracted three times with 25 milliliter portions of ether. The combined organic extracts were washed with 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (15 percent ethyl acetate / hexanes on silica gel), followed by thin layer chromatography (20 percent ethyl acetate / hexanes on silica gel GF, thickness 1000 microns) an opaque white film (162.3 milligrams, 0.6093 millimoles, 54 percent).

Example 96 - 17-methylenenestra-l, 3, 5 (10), 7-tetraen-3-yl acetate. Phosphonium methyltriphenyl bromide (3.33 grams, 9.32 mmol) and tertiary potassium butoxide (1.05 grams, 9.36 mmol) suspended in 10 milliliters of anhydrous dimethyl sulfoxide under argon were stirred for 1 hour in an oil bath (77-79). ° C), followed by equilin (500.0 milligrams, 1863 millimoles) in 10 milliliters of anhydrous dimethyl sulfoxide, by means of a syringe. See Figure 161. After stirring for an additional 1 hour, the cooled reaction mixture was poured into 50 milliliters of ice cold 1N hydrochloric acid, and extracted three times with 25 milliliter portions of ether. The combined organic extracts were washed with 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The resulting light yellow syrup was recovered in anhydrous pyridine (6.3 milliliters, 78 mmol), acetic anhydride (0.88 milliliters, 9.3 mmol) was added, and the reaction mixture was stirred for 16 hours. The mixture was then poured into 100 milliliters of 1N hydrochloric acid, and extracted three times with 50 milliliter portions of ether. The combined organic extracts were washed with 100 milliliters of saturated sodium bicarbonate + 100 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The crude acetate was passed by evaporation chromatography (5 percent ethyl acetate / hexanes on silica gel) to give a yellow resin (494.7 milligrams, 1604 millimoles, 86 percent).

Example 97 - Estra-4, 16-dien-10j8-ol-3-one. To a frozen suspension (dry ice / acetone) of estra-5 (10), 16-dien-3-one (1, 115.7 milligrams, 0.4513 millimoles) in chloroform (3 milliliters), m-chloroperbenzoic acid (MCPBA) was added. , 77.4 percent, 420.8 milligrams, 1.89 milliequivalents of peracid) suspended in ether (4.3 milliliters), and the mixture was stirred for 2 hours. See Figure 162. The reaction was then stored in a refrigerator for 18 hours, after which sodium thiosulfate pentahydrate [5 percent (w / w), 25 grams] was added. After stirring for 5 minutes, the mixture was extracted three times with 10 milliliter portions of ether. The combined organic extracts were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography suggested that the intermediate of 5B, lOB-epoxide had undergone partial elimination. The removal was terminated by refluxing the white crystalline residue for 1 hour in 20 grams of 5 percent (w / w) potassium hydroxide in anhydrous methanol. The reaction mixture was poured into 50 milliliters of ice water, and extracted with 50 milliliters of ether. The organic extract was washed twice with 50 milliliter portions of water, dried over sodium sulfate, and filtered through diatomaceous earth. The residue was washed with 20 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The residue was subjected to thin layer chromatography (50 percent ethyl acetate / hexanes on silica gel GF, thickness 1000 microns), to give a colorless resin (19.7 milligrams, 72.3 micromoles, 16 percent).

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 grams, 0.90 millimoles) in anhydrous methanol (2.3 milliliters), added sodium borohydride (0.23 grams, 6.1 mmol), and the reaction was stirred for 2 hours. See Figure 162. The solvent was removed under reduced pressure, and 10 milliliters of water was added to the residue. The mixture was then extracted three times with 10 milliliter portions of methylene chloride. The combined organic extracts were washed with 10 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed twice with 5 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. The resulting light yellow solid was purified by thin layer chromatography (5 percent ethyl acetate / methylene chloride on silica gel GF, thickness 1000 microns), to give a yellow solid (53.6 milligrams, 0.207 millimoles, 23 percent) homogeneous for thin layer chromatography (5 percent 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 known for the conversion of testosterone to androsta-, 16-dien-3-one (Brooksbank et al., Biochem .

J. (1950) AZ: 36). Alternatively, thermolysis (460 ° C) of methyl carbonate 15 of testosterone gives androsta-4, 16-dien-3-one in a 90 percent yield. 17B-methoxycarbonyloxy-androst-4-en-3-one (IV) was prepared from testosterone (III, Fluka) with methyl chloroformate / pyridine (a) in a yield of 76 percent (after recrystallization from of MeOH). p.f. 140-141 ° C. [a] D = + 95.4 ° (c = 1.10) - IR. (CDC13): 1740s, 1665s, 1450S, 1280S, - ^? - NMR. (360 MHz): 0.87 (s, 3H); 1.20 (s, 3H); 3.77 (s, 3H); 4.53 (br.t, J 8, ÍH); 5.75 (s, ÍH). A solution of the methyl carbonate IV in toluene was pyrolyzed (b) as described for I. Recrystallization of the crude product from acetone at room temperature gave the pure ketone 4 in a yield of 90 percent m.p. 127-129 ° C. (a) D = + 118.9 ° (c = 1.32) - ([3]: p.f. 131.5-133.5 ° C (hexane) [a] D16 = + 123 + 3.5 ° (C = 1.03)) - IR. (CDCl 3): 3050w, 1660s, 1615m, - ^ -H-NMR. (360 MHz): 0.82 (s, 3H); 1.22 (s, 3H); 5.70 (m, ÍH); 5.73 (s, ÍH); 5.84 (m, ÍH).

Example 100 - Androsta-4, 16-dien-3o; -ol (5) v -3? 8-ol. These syntheses are illustrated in Figure 178. Androsta-4, 16-dien-3 -one (4) was reduced to -55 ° C with 5 tris (1, 2-dimethylpropyl) hydride of lithium in tetrahydrofuran (c) as described for the preparation of 2 (Figure 1). Chromatography on silica gel with CH2Cl2 / ethyl acetate, 9: 1, gave pure axial alcohol 5 (48 percent yield), and pure equatorial alcohol 6 (48 percent yield). The analytical samples were further purified by recrystallization (from PE at -30 ° C for 5, and from cyclohexane at room temperature for 6). Data of 5. P.f. 77-79 ° C, [a] D + 120.6 ° (C = 1.26) -IR (CDC13): 3620m, 3440m br. , 1660m, 1595w. ^ -RMN. (360 MHz): 0.79 (S, 3H); 1.02 (s, 3H); 4.07 (m, w1 / 2 ~ 10, ÍH); 5.48 (d x d, J5 and 2, ÍH); 5.71 (m, ÍH); 5.85 (m, ÍH). Data of 6. P.f. 116-1190 ° C [a] D + 53.9 ° (C = 1.28) ([47]: mp 116-1180, [8] D + 59.3 ° (C = 0.4) - IR (CDC13).: 3610m, 3420mb, 3050m, 1660m, 1590w - ^ -RMN (360 MHz): 078 ( s, 3H); 1. 08 (s, 3H); 4.15 (m, w- ^ ~ 20, ÍH); 5.30 (m, w1 / 2 ~ 5, ÍH); . 71 (m, ÍH), - 5.85 (m, ÍH). Example 101 - Androsta-5, 16-dien-3o; -ol. This synthesis is illustrated in Figure 179. To a solution of the alcohol 8 (545 milligrams, 2.0 millimoles) in acetone (100 milliliters) at 0 ° C under N2, Jones reagent (i, 1.5 milliliters, approx. millimoles). After 5 minutes the mixture was poured into a dilute phosphate buffer (pH 7.2, 1200 milliliters), and extracted with ether. The extracts were washed with a saturated aqueous solution of NaCl, dried (Na 2 SO 4), and evaporated, to give mainly androsta-5,16-dien-3-one as an oil (567 milligrams). The crude product was dissolved in tetrahydrofuran (7 milliliters), and reduced with lithium (1) tr, is (1, 2-dimethylpropyl) borate hydride at 55 ° C as described for the preparation of 2. The crude product (530 milligrams) was passed through chromatography on silica gel (100 grams) with * CH2Cl2 / ethyl acetate, 4: 1, to give 280 milligrams (51 percent) of the pure a-alcohol 7 (eluted first), and 13 milligrams of 5, starting alcohol 8. A small sample of 7 was recrystallized from acetone / water at room temperature. P.f. 1380 ° C [8] D-77.5 ° (C = 1.2) - IR (CDC13) .: 3580m, 3430m, 1665w 1590w - ^ -H-NMR (360 MHz): 0.80 (s, 3H); 1.06 (s, 3H); 4.02 (m, 1/28, ÍH); 5.44 (m, ÍH); 5.72 (m, ÍH); 5.86 (m, ÍH).

Example 102 - Androsta-5, 16-dien-3B-ol. This compound was prepared in a 73 percent yield, by a known method (Marx, A.F. et al, German Patent No. 2,631,915; Chem. Abst. 87: 23614p (1977)) from commercial 3B-hydroxy-androsta-5-en-17-one (VII) (Fluka). P.f. 137 ° C [a] D -71.9 ° (C = 1.5) ([48]: p.f. 140-141 ° C, [a] D 68 ° - IR (CDC13).: 3600m, 3420m br., 1670w, 1590w - ^ -RMN (360 MHz): 0.80 (s, 3H); 1.05 (s, 3H); 3.53 (m W1 / 2 ~ 22, 1H); 5.38 (m, lh); 5.72 (m, ÍH); 5.86 (ÍH).

This synthesis is illustrated in Figure 4.

Example 103 - Alternative synthesis of androsta-4, 16-dien-3-one. The following synthesis method is illustrated in Figure 180: P-Toluenesulfonylhydrazone dehydroepiandrosterone. Dehydroepiandrosterone (VII) (14.4 grams, 50.0 mmol) and p-toluenesulfonyl hydrazide (12.75 grams, 68.5 mmol) in dry methanol (300 milliliters) 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 milliliters). Other cultures of the product were obtained by sequential evaporation of the filtrate to 75 milliliters and 20 milliliters, and crystallization was allowed each time. The total yield was 21.6 grams (95 percent).

Androsta-5, 16-dien-3/3-ol. The p-toluenesulfonylhydrazone dehydroepiandroste-roña (22.8 grams, 50.0 mmol) in dry tetrahydrofuran (1.0 liters) was cooled in a dry ice / isopropanol bath. The mixture was stirred while adding normal butyl lithium (125 milliliters of a 1.6M solution in hexane, 200 millimoles). The mixture was allowed to warm to ambient temperature, and was stirred for 24 hours. Water (50 milliliters) was added with cooling on ice. The mixture was poured into a saturated solution of ammonium chloride / ice (500 milliliters), and extracted with ether (2 times). The organic layers were washed with a saturated solution of sodium bicarbonate (500 milliliters), and a saturated solution of sodium chloride (500 milliliters), dried (MgSO 4), and evaporated in vacuo to give the crude product. This was purified by flash chromatography on 190 grams of silica gel 60, 230-400 mesh, eluting with ethyl acetate / hexane (20: 80- >).; 59: 59), to give a crystalline material. The product was recrystallized from methanol (45 milliliters) / 3 percent hydrogen peroxide - (8 milliliters) 25, washing with methanol (30 milliliters) / water (8 milliliters), to give the pure product (6.75 grams, 50 percent) .

Androsta-4, 16-dien-3-one A solution of 10 grams of androsta-5, 16-dien-3/3-ol in 475 cubic centimeters of toluene and 75 cubic centimeters of cyclohexanone 30, (approximately 50 centimeters were collected of distillate) for removing moisture; 5 grams of Al (OPr1) 3 in 50 cubic centimeters of toluene was added, and the solution was refluxed for 1 hour. Then water was added, the volatile components were removed by steam distillation, and the residue was extracted with chloroform. Evaporation of the dry extract, followed by crystallization of the residue from chloroform-hexane, yielded 7.53 grams of androsta-4, 16-dien-3 -one (25). Another 0.97 grams (total, 8.5 grams, 86 percent) was obtained by chromatography of the mother liquor on neutral alumina.

Example 104 - Synthesis of androsta-3,5,16-trien-3-ylmethyl ether. To a partial solution of androsta-4, 16-dien-3-one (1.00 grams, 3.70 millimoles) in 2,2-dimethoxypropane (5.0 milliliters, 41 millimoles) and 5 milliliters of dimethyl formamide, methanol (0.2 milliliters) was added. ) and p-toluenesulfonic acid monohydrate (26.4 milligrams, 0.139 millimoles). The mixture was refluxed for 5 hours, after which it was cooled, and sodium bicarbonate (152.5 milligrams) was added. The suspension was divided between 50 milliliters of ice water and 50 milliliters of ethyl acetate. The organic layer was washed with 2 portions of 50 milliliters of water + 50 milliliters of brine, dried magnesium sulfate, filtered, and concentrated under reduced pressure. The residual oil was recovered in 50 milliliters of hot hexane, and filtered through a column of silica gel 60 of 12 millimeters by 30 millimeters, using 150 milliliters of hot hexane. The combined filtrates were concentrated under reduced pressure, and recrystallized from acetone-methanol, to give white crystals (468.0 milligrams, 1645 millimoles, 44 percent), m.p. 83-92 ° C.

Example 105 - Synthesis of 17-methylene-androst-4-en-oles. To the 20-homoandrosta-4, 17-dien-3-one (119.0 milligrams, 0.4184 millimoles) in 5 milliliters of methanol, sodium borohydride (6.0 milligrams, 0.16 millimoles) and 77 microliters of water were added. After stirring for 2 hours, additional sodium borohydride (32.0 milligrams, 0.846 mmol) was added, and the mixture was stirred overnight. After concentrating under reduced pressure, chromatography (5 percent ethyl acetate / hexane on silica gel) gave a more molar product (59.8 milligrams) and a less molar product (1.7 milligrams).

Example 106 - Synthesis of 17-methylene-6-oxo-androsta-4-en-3-one. To a cooled solution of homoandrosta-5, 17-dien-3-ol. (399.4 milligrams, 1,394 millimoles) in 50 milliliters of acetone, Jones 2.67M reagent (2.0 milliliters, 5.3 millimoles) was added. After stirring for 1 hour, the reaction was quenched with isopropanol (1.0 milliliter, 13 mmol), and poured into 100 milliliters of water. The mixture was extracted three times with 50 milliliter portions of ethyl acetate, and the combined organic extracts were washed with 50 milliliters of saturated sodium bicarbonate + 50 milliliters of brine. The organic phase was then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from 95 percent ethanol, to give an almost white powder (177.8 milligrams, 0.5958 millimoles, 43 percent), m.p. 113-115 ° C.

Example 107 - Synthesis of 6? S-OH-Androsta-4,16-dien-3-one. To a solution of androsta-3, 5, 16-trien-3-ylmethyl ether (12) (200.5 milligrams, 0.7049 mmol), in 5 milliliters of 1,2-dimethoxyethane (DME), and 1 milliliter of water, it was added m-chloroperbenzoic acid (MCPBA, 77.4 percent, 173.2 milligrams, 0.776 millimoles) suspended in 5 milliliters of 1,2-dimethoxyethane + 1 milliliter of water + 0.40 grams of 5 percent NaOH (w / w) by drip, with agitation, during a period of 90 minutes. After stirring for 18 hours, additional m-chloroperbenzoic acid was added dropwise (247.0 milligrams, 1.11 millimoles) suspended in 10 milliliters of 1,2-dimethoxyethane + 2 milliliters of water + 0.8 grams of % (w / w) NaOH, with stirring, for 1-1 / 2 hours. The reaction mixture was stirred for 1/2 hour, and then poured into 25 milliliters of saturated sodium bicarbonate. The aqueous mixture was extracted three times with 25 milliliters of ether, and the combined organic extracts were washed with 50 grams of sodium thiosulfate at 5 percent (w / w) + 3 portions of 50 milliliters of brine, dried over sodium sulfate. magnesium, filtered through Celite, and concentrated under reduced pressure. The resulting crystalline residue was purified by preparative thin layer chromatography (35 percent ethyl acetate / hexane on silica gel), followed by double recrystallization from aqueous ethanol, to give glossy white platelets (102.3 milligrams, 0.3571 millimoles, 51 percent), m.p. 165-166 ° C.

Example 108-18-nor-17-methylandrosta-4, 13 (17) -dien-3-ol. Refer to Figure 189. To a solution of 18-nor-17-metilandrosta-4, 13 (17) -dien-3-one (1, 378.2 milligrams, 1399 millimoles) in 7.5 milliliters of anhydrous ether was added 59.7 milligrams (1.57 millimoles) of lithium aluminum hydride (LAH). After stirring the resulting suspension for 30 minutes, 2.00 grams of Glauber's salt was added, and the mixture was stirred for another 30 minutes. Then the mixture was filtered and extracted with 4 portions of 25 milliliters of ether. The combined filtrates were concentrated under reduced pressure, and then subjected to thin layer chromatography (silica gel GF, 1000 microns, 5 percent ethyl acetate / methylene chloride as eluent), to give a less polar fraction (Rf 0.63, 34.5 milligrams, 0.127 millimoles, 9 percent), and a more polar fraction (Rf 0.45, 273.8 milligrams, 1,005 millimoles, 72 percent).

Example 109 - 18-nor-17-metilandrosta-3, 5, 13 (17) -trien-3-ylmethyl Refer to Figure 189. A solution of l8-nor-l7-methilandrosta-4, 13 (17) - dien-3-one (1, 0.86 grams, 3. 2 mmol) in 2,2-dimethoxypropane (4.3 milliliters, 35 mmol) and dimethyl formamide (DMF, 4.3 milliliters) containing anhydrous methanol (0.17 milliliters) and p-toluenesulfonic acid monohydrate (21.3 milligrams), was refluxed for 4 hours. hours, and then left to cool. Sodium bicarbonate (0.13 grams) was added, and the mixture was divided between 65 milliliters of hexanes and 40 milliliters of ice water. The organic phase was washed with 2 portions of 40 milliliters of water + 40 milliliters of brine, and then it was filtered by evaporation through a column of silica gel of 17 millimeters high by 30 millimeters in diameter (200-400 mesh) . Concentration of the combined filtrates, followed by recrystallization from 95% acetone / ethanol, gave bright yellow crystals (489.6 milligrams, 1721 millimoles, 54 percent), m.p. 95-101 ° C. Thin layer chromatography (10 percent ethyl acetate / hexanes on silica gel) showed a higher product in Rf 0.69, with a trace contaminant at the origin.

Example 110-18-nor-17-metilandrosta-4, 13 (17) -dien-6? 8-ol-3-one Refer to Figure 189. The reaction was performed in a manner similar to the D.N. Kirk and J. M. Wiles, J. Chem. Soc., Chem. Commun. 1974, 927. To a stirred solution of 18-nor-17-methilandrosta-3,5,17 (17) -trien-3-ylmethyl ether (477.0 milligrams, 1677 millimoles) in 1,2-dimethoxyethane (DME, 20- 26 milliliters), was added 77 percent m-chloroperbenzoic acid (MCPBA, 999.7 milligrams, 4.48 milliequivalents) suspended in 1,2-dimethoxyethane (39 milliliters), water (8 milliliters) and 5 percent sodium hydroxide ( weight / weight) (7.1 milliliters), for a period of 88 minutes. After stirring for 20 hours, the reaction mixture was poured into saturated sodium bicarbonate (50 milliliters), and extracted with 3 portions of 50 milliliters of ether. The combined organic extracts were washed with 50 grams of 5 percent (w / w) sodium thiosulfate pentahydrate + 3 50-milliliter portions of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters of ether, and the combined filtrates were concentrated under reduced pressure to give a yellow syrup. Purification by preparative thin layer chromatography (silica gel GF, 1000 microns, 35 percent ethyl acetate / hexanes as eluent) gave a white crystalline film (132.1 milligrams, 0.4612 millimole, 28 percent), and chromatography thin layer (35 percent ethyl acetate / hexanes on silica gel) showed that it contained a major component (Rf 0.23) and a minor component (Rf 0.18).

Example 111 - 173-metilandrost-4-en-3,6-dione. Refer to Figure 189. Jones reagent (2.67 M, 0.88 milliliters, 2.3 mmol) was added to a solution of 17/3-metilandrost-5-en-3/3-ol (5_, 135.5 milligrams, 0.4697 millimoles) (JB Jones and KD Gordon, Can J. Chem. 1972, 50, 2812-2718) in acetone (15 milliliters), and the mixture was stirred for 45 minutes. The reaction was quenched with the addition of 2-propanol (0.44 milliliters). After stirring for an additional 10 minutes, the reaction mixture was poured into 30 milliliters of water, and extracted with 3 portions of 15 milliliters of ethyl acetate. The combined extracts were washed with 15 milliliters of saturated sodium bicarbonate + 15 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Thin layer chromatography (silica gel GF, 1000 microns, 25 percent ethyl acetate / hexane, as eluyen-te), and recrystallization from aqueous ethanol, gave lustrous white crystals (37.5 milligrams, 0.125). millimoles, 27 percent), pf 94-95 ° C, homogeneous for thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel, Rf 0.39).

Example 112-17? S-metilandrost-4-en-3-ol. Refer to Figure 189. LAH (21.3 milligrams, 0.561 millimoles) was added to a solution of 17/3-metilandrost-4-en-3-one (2, 143.2 milligrams, 0.4999 millimoles) (JB Jones and KD Gordon, Can. Chem. 1972, 50, 2712-2718) in 2.8 milliliters of anhydrous ether. After stirring the suspension for 30 minutes, Glauber's salt (0.76 grams) was added, and the mixture was stirred for another 1/2 hour. Ether (10 milliliters) was added, and the suspension was filtered through diatomaceous earth. The residue was washed with 3 portions of 10 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. The crude product was separated by preparative thin layer chromatography (silica gel GF, 1000 microns, 5 percent ethyl acetate / methylene chloride as eluent), in a more polar component (Rf 0.30, 77.9 milligrams, 0.270 mmol , 54 percent), and a less polar component (Rf 10 0.43, 10.3 milligrams, 0.0357 millimoles, 7 percent).

Example 113 - 17-Methylenandrosta-3,5-dien-3-methylmethyl ether. Refer to Figure 190. To 17-methylene-nandrost-4-en-3-one (9., 2.0000 grams, 7.0314 millimoles) in 2,2-dimethoxypropane (9.4 milliliters, 76 millimoles) and dimethyl formamide (9.4 milliliters), were added 0.37 milliliters of anhydrous methanol and 47.0 milligrams of p-toluenesulfonic acid. After refluxing for 4 hours, the reaction mixture was allowed to cool, and then divided into 340 milliliters of hexanes and 90 milliliters of water. The organic phase was washed with 2 portions of 90 milliliters of water + 90 milliliters of brine, dried over magnesium sulfate, and filtered by evaporation through a column of silica gel 30 millimeters in diameter by 37 millimeters high. (200-400 mesh). The product was further eluted with 200 milliliters of hexanes. Concentration of the combined filtrates under reduced pressure, and recrystallization of the residue from acetone / methanol, gave very slightly yellow platelets (1.5291 grams 5.1231 mmol, 73 percent), m.p. 97-99 ° C, homogeneous for thin layer chromatography (25 percent ethyl acetate / hexanes on silica gel, Rf 0.72).

Example 114-17-methylenandrost-4-en-6-g-ol-3-one. Refer to Figure 190. To a stirred solution of 17-methylenandrosta-3,5-dien-3-ylmethyl ether (10, 500.1 milligrams, 1676 millimoles) in 1,2-dimethoxyethane (10 milliliters), acid was added. m-chloroperbenzoic acid (318.6 milligrams, 1,846 millimoles) in 1,2-dimethoxyethane (10 milliliters) and water (4 milliliters) over a period of 15 minutes. After stirring for 30 minutes, the mixture was poured into 50 milliliters of saturated sodium bicarbonate, and extracted with 3 portions of 50 milliliters of ether. The combined organic extracts were washed with 50 grams of 5 percent (w / w) sodium thiosulfate pentahydrate + 3 50-milliliter portions of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters of ether, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (45 percent ethyl acetate / hexanes on silica gel) followed by recrystallization from aqueous ethanol gave slightly yellow crystals (187.1 milligrams, 0.6228 millimoles, 37 percent), m.p. 192-194 ° C, and thin-layer chromatography (35 percent ethyl acetate / hexanes on silica gel) showed that it consisted of major (Rf 0.17) and minor (Rf 0.13) components.

Example 115-17-methylenandrost-1,4-dien-3-one. Refer to Figure 190. A solution of 17-methylenandrost-4-en-3-one (9., 1,0001 grams, 3.5160 millimoles), and 2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ, 2.43 grams, 10.7 millimoles) in dioxane (60 milliliters, freshly distilled after being refluxed overnight over sodium), refluxed for 6 hours, and then quenched in tap water. Tertiary methyl butyl ether (MTBE, 50 milliliters) was added, and the suspension was filtered through diatomaceous earth. The residue was washed with 2 portions of 50 milliliters of methyl tertiary butyl ether, and the combined filtrates were concentrated under reduced pressure. Chromatography by evaporation of the residue (20 percent ethyl acetate / hexanes on silica gel), followed by recrystallization from 95 percent ethanol, gave white crystals (498.9 milligrams, 1767 millimoles, 50 percent), m.p. 155-157 ° C.

Example 116 - 17-Methylenandrosta-l, 3,5-trien-3-yl benzoate, Reference is made to Figure 190. The reaction was carried out in a procedure adapted from R.W. Draper and collaborators, Arzneim. -Forsch. 1982, 32, 317-322, as follows: 17-methylenandrosta-l, 4-dien-3-one (12., 389.0 milligrams, 1378 millimoles), anhydrous pyridine (4.7 milliliters, 58 mmol), and benzoyl chloride (1.2 milliliters, 10 mmol) under argon, were stirred for 18 hours in an oil bath (69-73 ° C). After cooling on ice, the reaction mixture was poured into 40 milliliters of ice cold IN HCl, and extracted with 3 portions of 20 milliliters of methylene chloride. The combined organic extracts were washed with 40 milliliters of cold IN HCl, + 40 milliliters of saturated sodium bicarbonate + 40 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (4 percent ethyl acetate / hexanes on silica gel) gave a yellow solid (0.43 grams, 1.1 mmol, 81 percent).

Example 117-17-methylenandrosta-l, 4-dien-6j8-ol-3 -one. Refer to Figure 190. The reaction was performed in a procedure adapted from R.W. Draper and collaborators, Arznoim. -Forsch. 1982, 32, 317-322, as follows: M-chloroperbenzoic acid (211.4 milligrams, 1225 millimoles) in 1,2-dimethoxyethane (6.6 milliliters) and 30 water (2.7 milliliters) were added to benzoate of 17-methylenandrosta-l, 3, 5-trien-3-yl (13, 0.43 grams, 1.1 mmol) in 6.6 milliliters of 1,2-dimethoxyethane, over a period of 20 minutes with stirring. Stirring was continued for 30 minutes, and the reaction mixture was then poured into 35 milliliters of saturated sodium bicarbonate. The mixture was extracted with 3 portions of 35 milliliters of ethyl acetate. The combined organic extracts were washed with 35 grams of sodium thiosulfate pentahydrate + 3 portions of 35 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. Preparation thin layer chromatography (silica gel GF 1000 micras, 50 percent ethyl acetate / hexanes as eluent) gave a yellow crystalline solid (83.7 milligrams, 0.280 millimoles, 25 percent) homogeneous for the chromatography of thin layer (50 percent ethyl acetate / hexanes on silica gel, Rf 0.50).

Example 118 - Androsta-1, 4, 16-trien-6? 8-ol-3-one. Refer to Figure 190. Androsta 1,4, 16-trien-3-one (15, 500.0 milligrams, 1863 millimoles), anhydrous pyridine (6.4 milliliters, 79 millimoles), and benzoyl chloride (1.6 milliliters, 14 millimoles ) under argon, placed in an oil bath (70-73 ° C), and stirred for 18 hours. After cooling on ice, the mixture was poured into 50 milliliters of ice cold HCl, and extracted with 3 portions of 25 milliliters of methylene chloride. The combined organic extracts were washed with 50 milliliters of cold IN HCl + 50 milliliters of saturated sodium bicarbonate + 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of methylene chloride, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (2 percent ethyl acetate / hexanes on silica gel) gave yellow crystals (0.47 grams, 1.3 mmol, 68 percent) of the benzoate intermediate. This was recovered in chloroform (30 milliliters) with m-chloroperbenzoic acid (240.0 milligrams, 1391 millimoles). After stirring for 1 hour, additional m-chloroperbenzoic acid (239.5 milliliters, 1388 millimoles) was added, and the reaction was stirred for another hour. The mixture was then washed with 30 grams of 5 percent sodium thiosulfate pentahydrate (w / w) plus 30 milliliters of saturated sodium bicarbonate + 30 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of chloroform, and the combined filtrates were concentrated under reduced pressure. Evaporation chromatography (40-45 percent ethyl acetate / hexanes on silica gel) gave a yellow resin (106.1 milligrams, 0.3731 millimoles, 29 percent), and thin layer chromatography (40 percent acetate). ethyl / hexanes on silica gel) showed that it contained major component (Rf 0.34) and minor (Rf 0.40).

Example 119 - Androsta-4, 16-dien-68-ol-3-one To a solution of androsta-3,5,16-trien-3-ylmethyl ether, 12 (200.5 milligrams, 0.7049 mmol), in 5 milliliters of 1, 2-dimethoxyethane (DME) and 1 milliliter of water, was added m-chloroperbenzoic acid (MCPBA 77.4 percent, 173.2 milligrams, 0.776 millimoles) suspended in 5 milliliters of 1,2-dimethoxyethane, + 1 milliliter of water, + 0.40 grams of 5 percent (w / w) NaOH per drip, with stirring, for a period of 90 minutes. After stirring for 18 hours, additional m-chloroperbenzoic acid (247.0 milligrams, 1.11 millimoles) suspended in 10 milliliters of 1,2-dimethoxyethane + 2 milliliters of water + 0.8 grams of 5 percent sNaOH (weight / weight), with shaking, for 1-1 / 2 hours. The reaction mixture was stirred for 1/2 hour and then poured into 25 milliliters of saturated sodium bicarbonate. The aqueous mixture was extracted three times with 25 milliliters of ether, and the combined organic extracts were washed with 50 grams of sodium thiosulfate at 5 percent (w / w) + 3 portions of 50 milliliters of brine, dried over sodium sulfate. magnesium, filtered through Celite, and concentrated under reduced pressure. The resulting crystalline residue was purified by thin layer chromatography (35 percent ethyl acetate / hexane on silica gel), followed by double recrystallization from aqueous ethanol, to give white glossy platelets (102.3 milligrams, 0.3571 millimoles , 51 percent), pf 165-166 ° C.

Example 120-20-homoandrosta-4, 17-dien-3 -one. Refer to Figure 191. To a partial solution of 20 homoandrosta 5, 17-dien-3-ol (1,0001 grams, 3. 4911 millimoles) in 100 milliliters of toluene and 20 milliliters (0.19 moles) of cyclohexanone, aluminum isopropoxide (2.00 grams, 9.79 millimoles) in 20 milliliters of hot toluene was added. After refluxing for 4 hours, the cooled reaction mixture was stirred for 1 minute with 5 milliliters of water and 12.5 milliliters of 3.6 N sulfuric acid. The organic layer was washed with 50 milliliters of brine, dried over magnesium sulfate , filtered through Celite, and concentrated under reduced pressure. Following steam distillation to remove the cyclohexanone, the non-volatile residue was taken up in 2 aliquots of 10 milliliters of dichloromethane, dried over magnesium sulfate, filtered, and concentrated. The oily residue was purified by evaporation chromatography (15 percent ethyl acetate / hexane on silica gel), and recrystallization from aqueous acetone, to give colorless needles (238.8 milligrams, 0.8400 millimoles, 24 percent), m.p. 130-134 ° C [lit. (B.S. Macdonald and collaborators, Steroids 1971, 18, 753-766) p.f. 129-131 ° C].

Example 121 - 20-homoandrosta-4, 17-dien-3-ols. Refer to Figure 191. At 20-homoan-drosta-4, 17-dien-3-one (119.0 milligrams, 0.4184 mmol), in 5 milliliters of methanol, sodium borohydride was added. (6.0 milligrams, 0.16 millimoles) and 77 milliliters of water.

After stirring for 2 hours, additional sodium borohydride (32.0 milligrams, 0.846 mmol) was added, and the mixture was stirred overnight. After concentrating under reduced pressure, the residue was purified by preparative thin layer chromatography (5 percent ethyl acetate / hexane on silica gel), to give a more polar product (59.8 milligrams), and a less polar product. (1.7 milligrams).

Example 122 - 20-homoandrosta-4, 17-dien-3,6-dione. Refer to Figure 191. To a cooled solution of 20-homoandrosta-5, 17-dien-3-ol (399.4 milligrams, 1394 millimoles) in 50 milliliters of acetone was added Jones Reagent 2.67 M (2.0 milliliters, 5.3 millimoles). After stirring for 1 hour, the reaction mixture was quenched with isopropanol (1.0 milliliter, 13 mmol), and poured into 100 milliliters of water. The mixture was extracted three times with 50 milliliter portions of ethyl acetate and the combined organic extracts were washed with 50 milliliters of saturated sodium bicarbonate + 50 milliliters of brine. The organic phase was then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from 95 percent ethanol to give an almost white powder (177.8 milligrams, 0.5958 millimoles, 43 percent), m.p. 113-115 ° C.

Example 123 - Cetal 6β, 19-epoxy-17-iodoandrosta-4,16-diene-3-ethylene. Refer to Figure 192. A mixture of crude 6 / 3-19-epoxy-5/3-chloro-17-iodoandrost-16-ene (17, 1.38 grams, 3.09 millimoles) (G. Habermehl and A. Haaf, Z. Naturforsch, 1970, 25b, 191-195), ethylene glycol (0.97 grams, 16 mmol), toluene (50 milliliters), and p-toluenesulfonic acid monohydrate (20.3 milligrams, 0.107 mmol), was reflux for 19 hours with azeotropic water removal (Dean-Stark). After cooling, ethyl acetate (100 milliliters) was added, and the reaction mixture was washed with 100 milliliters of saturated sodium bicarbonate + 100 milliliters of brine. The organic phase was dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure, to give a tan crystalline solid (1.47 grams). This residue was suspended in anhydrous methanol (40 milliliters), potassium acetate (2.44 grams, 24.9 mmol) was added, and approximately 25 milliliters of methanol were distilled. The remainder was concentrated under reduced pressure, water (50 milliliters) was added, and the mixture was extracted three times with aliquots of 25 milliliters of methylene chloride. The dried extracts (sodium sulfate) were filtered through diatomaceous earth, and the residue was washed with 10 milliliters of methylene chloride. Concentration of the combined filtrates under reduced pressure gave a yellow solid, which was further purified by chromatography by evaporation (5-7.5-10 percent ethyl acetate / methylene chloride on silica gel), and recrystallization from from methanol, to give light yellow needles (914.6 milligrams, 2.013 millimoles, 65 percent), mp 187-189 ° C. ^ -H-NMR 6.13 d, ÍH, dd, 16-H; 5.82 d, ÍH, s, 4-H; 4.71 3, ÍH, d, 6a-H; 4.22 d and 3.53 d, 2H, AB, 19-H's; 4.10-3.28 d, 4M, 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 Figure 192. Anhydrous ammonia (approximately 75 milliliters) was styled through a KOH tower, in a 150 milliliter fire-dried 3-necked flask, adapted with an inlet adapter, a magnetic stir bar, a dry ice / acetone condenser, 35, and a stopper. A solution of ketal 6/3, 19-epoxy-17-iodoandrosta, 4,16-di-3-ethylene (18.880.4 milliliters, 1938 millimoles) in dry tetrahydrofuran (THF, 45 milliliters) was added, followed by sodium metallic (0.20 grams, 8.7 milligrams-atom) cut into small pieces. After stirring under argon under pressure for 30 minutes, the reaction was quenched with the addition of absolute ethanol (1.0 milliliter). The ammonia was boiled overnight, 50 milliliters of water was added, and the mixture was extracted with 3 portions of 25 milliliters of methylene chloride. The combined organic extracts were washed with 50 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth.

After washing the residue with 10 milliliters of methylene chloride, the combined filtrates were concentrated under reduced pressure. The ketal intermediary proved remarkably unreactive, but was finally hydrolysed by refluxing for 18 hours in 5 milliliters of chloroform and 2.5 milliliters of 4N hydrochloric acid. To the cooled hydrolysis mixture was added ethyl acetate (50 milliliters), and the layers were separated. The organic phase was washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. The resulting brown foam was purified by evaporation chromatography (50 percent ethyl acetate / hexanes on silica gel), followed by thin layer chromatography (50 percent ethyl acetate / hexanes on silica gel GF, thickness of 1000 microns), to give a partially crystalline film (66.7 milliliters, 0.233 millimoles, 12 percent). ^? - NMR 5.92 d, ÍH, s, 4-H; 5.87-5.64 3, 2H, mult., 16.17-H's; 4.10 3 and 3.94 3, 2H, AB, 19-H's; 0.79 3, 3H, s, 18-Me.

Example 125 - Androst-5-en-3β, 19-diol-17- (p-toluenesulfonyl) hydrazone. Refer to Figure 193. A suspension of androst-5-en-3/3, 19-diol-17-one (1, commercially available in Research Plus, 512.5 milligrams, 51,684 millimoles), and p-toluenesulfonylhydrazide (p- TsNHNH2, 392.1 milligrams, 2.105 millimoles) in 2-propanol (6.0 milliliters), was refluxed for 24 hours. To the cooled reaction mixture, 20 milliliters of ether was added, and the solvent was removed under reduced pressure. The residue was recovered in 10 milliliters of ether, and the solution was filtered through diatomaceous earth. 10 milliliters of hexanes were added to the filtrate, and the suspension was concentrated under reduced pressure. The residue was taken up in 10 milliliters of hot benzene, and the cooled solution was filtered. The filtrate was concentrated under reduced pressure, and then chromatographed by evaporation (40 percent ethyl acetate / hexanes on silica gel), to give an opaque resin (0.69 grams, 1.5 mmol, 87 percent).

Example 126 - Androsta-5, 16-dien-3? S, 19-diol. Refer to Figure 193. A solution of androst-5-en-3/3, 19-diol-17- (p-toluenesulfonyl) hydrazone (2, 0.69 grams, 1.5 mmol) in anhydrous tetrahydrofuran (THF, 35 milliliters) , cooled in an ice / acetone bath under argon, and normal butyl lithium (2.5 M in hexanes, 3.7 milliliters, 9.3 mmol) was added by dripping, with stirring, over a period of 1 minute. The reaction mixture was stirred for 4 days, during which time it was allowed to gradually warm to room temperature. Then the reaction was poured into 50 milliliters of ice cold saturated ammonium chloride, and the layers were separated. The aqueous layer was extracted twice with a 25 milliliter portion of ethyl acetate. The combined organic phases were washed with 25 milliliters of saturated sodium bicarbonate + 25 milliliters of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 milliliters of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. The residual yellow resin was passed by evaporation chromatography (50-55-60 percent ethyl acetate / hexanes on silica gel), and crystallized from methyl tertiary butyl ether / benzene, to give white fluffy crystals ( 92.5 milligrams, 0.361 millimoles, 24 percent), pf 169-171 ° C.

Example 127 - Electrophysiology of the Androstane Stimulus of the Human Vomeronasal Organ and the Olfactory Epithelium. A non-invasive method has been used to record local electrical potentials from the human vomeronasal organ (VNO) and from the olfactory epithelium (OE). The localized gaseous stimulus was applied to both nasal structures in different instances, using a specially designed catheter / electrodes, connected to a multi-channel drug delivery system. This electrode and application system have been described by Monti and Grosser (J. Steroid Biochem. And Molec. Biol. (1991) 39: 573) and in the pending United States Patent Application, in common property with number USSN 07 / 771,414 series, incorporated herein by reference. The local response of the vomeronasal organ and the olfactory epithelium showed a correlation with the concentration of the stimulus with the ligand. The study was conducted in 10 clinically normal volunteers (selected) -2 men and 8 women, aged 18 to 85 years. The studies were conducted without general or local anesthesia. The catheter / electrodes were designed to apply a localized stimulus, and to simultaneously record the response. In the case of the registry of the vomeronasal organ, the subject's right nasal fossa was explored using a nasosco-pio (nasal specula), and the vomeronasal opening was located near the intersection of the anterior edge of the vomer and the nasal floor. The catheter / electrode was gently pushed through the opening of the vomeronasal organ, and the tip of the electrode was placed in the organ lumen 1-3 mm from the opening. Then the nasoscope was removed. In the case of the olfactory epithelium, the recording procedure was similar, with the exception that the placement of the catheter / electrode was placed gently deep in the lateral part of the nasal duct, reaching the olfactory mucosa.

The localized gaseous stimulus was made through the catheter / electrode. A constant stream of clean, odorless, humidified air was passed continuously at room temperature through a channel of the stimulus system. The stimulating ligand substances were diluted in propylene glycol, mixed with the humidified air, and aspirated for 1 to 2 seconds through the catheter / electrode. It is 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 is measured in millivolts-seconds (mV x s). Androsta-4, 16-dien-3-one causes a significantly stronger response of the vomeronasal organ in women, than the other compounds tested (Figure 18OA). In addition, the response of the vomeronasal organ to androsta-4, 16-dien-3-one is sexually dimorphic - twice as strong in women as in men (Figure 180B). In contrast, the response of the olfactory epithelium in both men and women is low, compared to a strong odorant such as nail (Figure 180C).

Example 128 - Measurement of the Change in the Receptor Potential of the Vomeronasal Organ Neuroepithelium in Response to Different Steroids. The change in receptor potential was measured in the response to 5 different ligands in 40 women (Figure 18IA) and 40 men (Figure 181B). Each subject was administered 60 picograms of each of seven substances, as indicated in the Figure. The substances were administered separately for 1 second. The change in neuroepithelial potential of the vomeronasal organ was recorded over time, and the integral of the change in potential for each of the 40 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 129 - Measurement of Autonomic Responses to the Stimulus with 16-Andros ene of the Vomeronasal Organ. Different autonomous parameters were monitored as androsta-, 16-dien-3-one was administered to 40 women, using the procedure described in Example 10. Propylene glycol was also administered as a control. The ligand was administered as a 1 second pulse. First the change in the autonomous function was scored within 2 seconds, and lasted up to 45 seconds. As shown in Figure 182, when compared to a propylene glycol control, androstane induced a significant change in the potential receptor integrated in the vomeronasal organ (182A), in the galvanic skin response (182B), in the temperature of the skin (182C), and in the percentage of cortical alpha wave activity, measured by electroencephalogram (182D), in the peripheral arterial pulse (182E), and in the respiratory frequency (182F).

EXAMPLE 130 - Comparison of the Change in Receptor Potential Induced by Two Androstane Steroids 60 picograms of each steroid ligand, and one control of propylene glycol, were administered to 5 women.

As shown in Figure 183, androsta-4, 16-dien-3/3-ol induced a greater change in the receptor potential than andros-ta-4, 16-dien-3-one.

Example 131 - Psychophysiological Effect of the Stimulus with Androstane of the Vomeronasal Organ. The psychophysiological effect of the Androstane stimulation of the vomeronasal organ was measured by means of the coordinated administration of pheromone and evaluation with subject questionnaire, before and after the administration. The questionnaire included a panel of adjectives used as part of the standard evaluation of the Sexual Inventory of Derogatis. The subjects were 40 women between the ages of 20 and 45 years, all in good health. 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 women were given a 70-point questionnaire, which assessed the states of feeling immediately before and 30 minutes after the administration of the placebo or the experimental substance. The 70 adjectives of the questionnaire were administered randomly, and subsequently grouped for evaluation, based on their relevance to each mood, feeling, or character trait. The results were as follows: changes in feelings of social warmth, personal well-being, awakening / excitement, and aggression, from before administration until 30 minutes after administration, were not significant in people exposed to 16-androstene, comparing with the changes resulting from the administration of control. However, the decrease in negative affect (nerves, tension, embarrassment, anxiety, irritability, anger, anger - test T: p <; 0.0001, Anova: p < 0.04), negative mood, and character (sensitive, sorry, guilty, remorse, sadness, hopelessness, resentment, contempt, misery, unhappiness, bitterness, shyness - proof T: p <0.0004, Anova: p <0.06), and overall negativity (the combination of affect and character - T test: p <0.0003, Anova: p <0.05), were highly significant after the administration of 16-androstene, compared to the administration of the control. Above all, these results suggest a sedative and / or anti-anxiety, and / or anti-depressant effect of androsta-4, 16-dien-3-one when administered intranasally.

Example 132 - Treatment of Women for Premenstrual Tension Women who experienced the symptoms of premenstrual tension (PMS) were given a pharmaceutical preparation of an androstane steroid (preferably androsta-4, 16-dien-3-one, or androsta-4, 16-dien-3o).; (ß) -ol), suitable for nasal administration. The steroid is provided as an ointment at a concentration of approximately 1 microgram / milliliter, and applied to approximately 0.1 milliliter, the ointment is applied just inside each nostril, three times a day. A similar method for premenstrual tension treatment uses an aerosol preparation of the same steroid. The spray is sprayed into each pit three times a day.

Example 133 - Electrophysiological Studies. The following electrophysiological studies were performed on 60 clinically normal human volunteers of both sexes (30 men and 30 women) whose ages were from 20 to 45 years. No anesthetics were used, and women were excluded if they were pregnant. The stimulus and registration system consists of a "multifunctional miniprobe" described elsewhere (Monti-Bloch, L. and Grosner, B. 1. (1991), "Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory 35 epithelium "J. Steroid Biochem. Molec.

Biol. 3.9: 573-582). The registration electrode is a 0.3 mm silver ball attached to a small silver wire (0.1 mm) isolated with Teflon0; The surface of the electrode is first treated to produce a silver chloride interface, and then covered with gelatin. It is placed inside a small Teflonc-gauge catheter (diameter = 5 milliliters), such that the tip of the electrode protrudes approximately 2 millimeters. The Teflon0 catheter is 10 centimeters long, and constitutes the terminal extension for a multi-channel application system, which applies a continuous air stream that carries separate pulses of chemosensory stimuli. The air stream passes first into a small chamber, and is bubbled through a solution containing a vomeropherin, or an olfactant in a diluent, or the diluent alone. A solenoid is used to quickly redirect the air stream from the chamber to a path that is derived from the chamber. This creates a separate impulse of stimulant in the air stream. A second external tube of Teflon0 with a diameter of 2 milliliters surrounds the catheter-electrode assembly, and its central end is connected with a vacuum that provides a continuous suction of 3 milliliters / second. This concentric configuration of the external suction tube allows the chemosensory stimuli emitted to be located in an area that we call a "minicamp" (approximate diameter = 1 milliliter), and prevents the diffusion of substances either to the area outside the site of intended stimulus, or into the respiratory system. The entire stimulus and registration assembly can be placed either on the neurosensory-epithelium inside the vomeronasal organ, or on the surface of the olfactory or respiratory epithelium.

Electrovomeronasogram (EVG); The records are made in a quiet room, with the supine subject; The multifunctional miniprobe is initially stabilized inside the nasal cavity, using a nasal retractor placed in the vestibule. The reference and ground electrodes consist of silver discs (8 milliliters), both of which are placed on the glabelos. The entrance to the vomeronasal organ, or vomeronasal orifice, is identified by first dilating the nasal opening and the vestibule. Then a 6x magnification binocular loupe with halogen illumination is used to introduce the tip of the Teflon catheter, and the electrode assembly is recorded inside the opening of the vomeronasal organ, where it is stabilized at a depth of approximately 1 milliliter inside the vomeronasal passage. The optimal placement of the recording electrode is indicated after the test, for an adequate depolarization in response to a test substance. The electrical signals from the recording electrode are fed to a direct current amplifier, after which they are digitized, monitored by computer, and stored. The peak-to-peak amplitude of the signals is measured, and the area under the depolarization wave is integrated, while the signal is monitored continuously, both on the computer screen and on the digital oscilloscope. The artifacts produced by respiratory movements are suppressed by training subjects to practice breathing through the mouth with velopharyngeal closure.

Guimiosensory stimulants; The substances of the olfactory test are cineol, and 1-carvone; the vomeropherins are A, B, C, D, E, and F in Figures 180-184. Vomeroferin samples are applied in a concentration of 25 to 800 fmoles in the continuous air stream, for durations from 300 milliseconds to 1 second. Normally, intervals of 3 to 5 minutes separate each series of short test pulses. All the components of the lines that carry the test stimuli are made of Teflon0 glass or stainless steel, and are cleaned and sterilized carefully before each use.

Electro-olfatorama (EOG); The olfactory registers used the same multifunctional stimulus and registration minison that was used for the vomeronasal organ. The tip was introduced slowly, until the recording electrode touched the olfactory mucosa. Proper placement was signaled by a depolarization in response to an impulse of the odorant test substance. Induced cortical activity was induced by stimulation of the vomeronasal organ with vomeropherins, and olfactory stimulation with odorants applied in 300 millisecond air impulses. It was recorded using conventional electroencephalographic electrodes (EEG) placed in the Cz-Al and Tz-Al positions of the 10120 international system; the ground electrode was placed in the mastoid process. Electrodermal activity (EDA) was recorded using conventional 8-millimeter silver electrodes in contact with the palmar skin of the middle and annular fingers, respectively, through a conductive gel interface. The temperature of the skin (ST) was recorded by means of a small thermistor probe (1.0 mm) placed in the lobe of the right ear. Peripheral arterial impulse (PAP) is monitored with a plethysmograph connected to the tip of the index finger. The respiratory frequency (RF) was measured with an adjustable tension meter placed around the lower chest. All electrical signals were amplified in direct current, digitized (MP-100, Biopac Systems), and continuously monitored using a computer.

Statistic analysis; The EVGs or EOGs, the peak-to-peak changes, and the frequency changes of other parameters were measured and analyzed statistically. The meaning of the results was determined using t-tests in pairs, or variation analysis (ANOVA).

Effect of Vomerofßrinas on the EVG; We discovered that each of the vomeropherins produces a sexually dimorphic potential receptor (Figures 184A and 184B). The EVG records were made in 30 men and 20 women (ages 20 to 45 years). The vomeropherins were diluted and applied in pulses of 1 second to the vomeronasal organ, with intervals of 1 minute between the impulses; when questioned the subjects could not "smell" or consciously detect in any other way any of the vomeropherins. This finding is in agreement with the previously reported results (Monti-Bloch, L. and Grosser, B. 1. (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 stimulation of the olfactory test nor vomeropherin applied to the vomeronasal organ produces a perceptible sensation in the applied concentration. Figure 184A shows the average response of men (ages 20 to 38) to the diluent, and to equimolar amounts (100 fmoles) of five vomeropherins (A, B, C, D, and F), and of E, a stereoisomer of F. The response profile for each of the substances was similar in all subjects, regardless of age, and no significant differences were revealed through the to-tests by 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 M84 = 15.1 mV, SD = 4.9 mV, p <0.01), that were consistent in all individual cases. Other vomeropherins depolarized vomeronasal organ receptors to a much lesser degree, but with average response amplitudes consistent from individual to individual. Active vomeropherins in men produced greater responses than diluent (p <; 0.001). B, F, and similar concentrations of olfactants induced significantly reduced responses in the male vomeronasal organ (Figure 184A and Figure 185). A similar experimental protocol was followed with the 10 women (ages 20 to 45 years). Among the vomeropherins, F (100 fmol) produced the most significant differences within the group (Figure 184B). Here, A induced a small effect that was significantly different from F (p <0.01).

In both populations of subjects, the active vomeropherins induced receptor responses that had large standard deviations (Figure 184). When we studied the frequency distribution of the effects of A and F in men and women, respectively, we discovered a bimodal distribution. The meaning of this observation is being studied at this point. E, a stereoisomer of F, does not stimulate the vomeronasal organ in women, whereas F does (Figure 184B). This is a demonstration of the specificity of the vomeronasal organ recognition of vomeropherins. In this regard, it is interesting to note that, although F is a superior vomeropherin, E generates a stronger olfactory effect than F (Figure 184B and Figure 185).

Effects of Vomeroferins on the EOG; The receptor potential summed from the olfactory epithelium (EO) was recorded in 20 subjects: 10 men and 10 women. In contrast to the sensitivity of the vomeronasal organ to vomeropherins, the olfactory epithelium is less sensitive to these substances. This is true for both men and women (Figure 185A). The amplitude of the average receiver potential was 2.3 mV up to 0.78 mV. In this study, B was the only vomeropherin that had a significant effect on the olfactory epithelium (p <0.02). Of the subjects questioned about odorant sensations following each stimulus presentation, 16 reported no olfactory sensation, while 3 men and 1 woman described B as an unpleasant odor. This discovery reveals that, in the concentrations used in our study, most vomeropherins are not effective stimulants of olfactory receptors, but they do have a clear effect on vomeronasal receptors.

Effects of the Olfatantes On the EVG and the EOG; The contrast with the vomeropherins, the olfatantes 1-carvone and cineol, produce only a minor local response in the vomeronasal organ (Figure 185B). This was true for both men and women. As expected, these olfactants produced a strong response in both men and women (p <0.01) when applied locally to the olfactory epithelium (Figure 185A). The diluent depolarized the olfactory receptors to a lesser degree than cineol or 1-carvone (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 vomitoroferin stimulation of the vomeronasal organ. The sexually dimorphic local responses induced by the vomeropherins (Figure 184A and Figure 184B) were a mirror in the autonomous response of male and female subjects. In men (Figure 184C), A and C decreased skin resistance (electrodermal activity = EDA) (p <0.01, n = 30). In women (Figure 184B), F and B produced a greater decrease in electrodermal activity than A or C (p <0.01, n = 30). Vomeroferins A and C induced a significant increase in skin temperature (ST) (Figure 184G) in 30 men (p <0.01); however, D induced a significant temperature decrease (p <0.01). In 30 women (Figure 184H), B and F caused a significant increase in skin temperature (ST) (p <0.01) compared to A and C. In women, vomeropherins produced changes in the electrodermal activity and in the temperature of the skin with a higher standard deviation than in men. Cortical activity was recorded from Cz and Tz in men and women during the application to the vomeronasal organ of air impulses (300 milliseconds to 1 second) containing 200 fmol of vomeropherin (Figures 184G and 184H). In men (Figure 184E), A, C, and D significantly increased cortical alpha activity with a latency of 270 to 380 milliseconds. The D and A caused a stronger effect (p <0.01). The synchronization of the electroencephalogram was sustained for 1.5 to 2.7 minutes after the application of a single pulse of active substance. In women (Figure 184F), a single impulse (200 fmoles) of B or F applied to the vomeronasal organ increased cortical alpha activity, independently of the response of the olfactory receptors. We discovered characteristic specificities in the response of the human vomeronasal organ and the olfactory-epithelium, suggesting that they are independent functional systems with separate connections to the central nervous system (Brooko-ver, 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 noniceptive terminals, since the application of a local anesthetic (2 percent lidocaine) to the respiratory epithelium of the nasal septum, does not block or diminish the EVG (Monti-Bloch, L.

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), and the subjects also reported no pain sensations as a consequence of any of the stimulus procedures. We conducted additional tests using androsta-5, 16-dien-33, 19-diol and four other androstanes, identified by their positions in the diagram. The results are shown in Figures 193 to 200. The response of EEG, RF, and EKG to androsta-5, 16-dien-3/3, 19-diol is stronger in women, compared to men, while " that the response of ST, GSR and EVG is stronger in men. Some women who were given the compound reported feelings of happiness, which is unusual, because these reports are usually accompanied by much higher RF and GSR data than those shown in Figures 194B and 194C. Vomeronasal organ receptors are clearly more sensitive to vomeropherins than any of the olfactants tested; The opposite is true for olfactory receptors. Although the olfactory epithelium may have receptor sites for some vomeropherins, the specificity of response of the vomeronasal organ is clearly different. Sex differences were observed in the specificities and effects of 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 the components of the autonomic nervous system in the adult human being by stimulation with vomeroferin of the vomeronasal organ. In addition, the results suggest that the stimulation of the vomeronasal organ with vomeropherins produces the synchronization of the electroencephalogram (Figure 184G and 185H). Therefore, the evidence hereby indicates that the vomeronasal system responds to a variety of chemosensory stimuli, and that some may induce reflex autonomous activity.

Example 134 - Electrophysiological Studies Electrophysiological studies were performed as described in Example 133, in clinically normal human volunteers of both sexes, whose ages were from 20 to 45 years. No anesthetics were used, and women were excluded if they were pregnant. Electrovomeronasogram (EVG); The integrated electrovomeronaso-grama is shown in Figures 1 and 2 for the compounds Al-Pl, A2-P1, A4-P1, A3-P1, A1-P4, A2-P4 (referring to the diagram). The artifacts produced by respiratory movements are suppressed by training subjects to practice breathing through the mouth with velofa-ringeo closure. Vomeroferin samples were applied in concentrations of 25 to 800 fmoles in the continuous air stream for durations of 300 milliseconds to 1 second.

SUMMARY OF THE EFFECTS OF 19-NORPREGNAN VOMEROFERINES ON THE ELECTROENCEPHALOGRAM AND ON THE ACTIVITY AUTONOMY IN WOMEN n = 6 EVG EDA RF CF EMG BT a-CA ßCA PERFORMANCE POINTS etol ether +25 + 100 .5 .5 0 -2.5 -10 -35 EDA +, RJ-.CF-, ß- 5 of E2 / P8 E9P2 -t-5 - 10 -25 + 10 +5 -2.5 +5 -35 CF-.a + .ß- 3 E4 / F2 --2.5 -10 .1 -5 -5 0 +25 +2.5 EDA-.E G- 3 E7 / P1 +30 +70 -5 -5 0 0 -5 .2 EDA-RF-CF- 4 Acetate of -50 + 130 0 0 0 +6 0 -15 EDA +, BI +, ß- 4 E2 / P8 E3 / P! +20 -70 '-25 -2.5 0 -3 -10 -30 EDA- -) E10P2. -3 -10 0 + 10 -5 0 + 10 + 10 EDA-.CF-EMG- 5 a- E2 / P "* -25 +50 -5 -5 0 -10 -15 -30 EDA-.BT- 3 E2. 5 +25 +30 0 0 0 0 -10 -40 0 0 E2 / P6 -20 +50 0 5 0 0 -15 -30 EDA-.CF- 3 The / Pl +45 -110 -5 0 0 0 -5 -10 0 0 E2 P1 -40 -95 -3 -5 0 0 0 -15 EDA + .RF-.CF- 4 Metol ether -20 -85 -25 .5 0 0 -6 -20 EDA-.CF- 3 of E2P1 E13T! -1 -10 0 0 -5 0 0 -40 EDA-.EMG-.3- 4 Ell / Pl +20 -10 0 -5 _2 -1 0 -25 0 0 E5T1 0 -10 0 0 0 0 0 -40 0 0 Acetate -2.5 -10 -2.5 +2.5 -5 -3 + 10 -20 EMG-.BT-.a-.ß- 5 E2 / T8 -25 -110 0 0 0 + 10 +7 -20 EDA + .BT + .a + .6 + 5 E2 / P -20 +20 -2.5 5 0 -2.5 +7 -25 CF-.BI-.a + .ß- 5 E2 / T4 +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 THE EFFECTS OF THE VOMEROFERINES OF 19-NORPREGNAN IN THE ELECTROENCEFALOGRAM AND IN THE ACTIVITY AUTONOMOUS: IN MEN n = 6 EVG EDA RF CF EMG BT a-CA ßCA PERFORMANCE I > UNTOS Metol ether + 12 +95 0 -5 -2.5 -2.5 +2.5 -10 EDA +, CF-3 (-) E2 / P8 E9P2 +20 -20 0 +2.5 -2.5 -5 -7 +40 BT- E4 / P2 + 15 -20 0 +2.5 0 -2.5 -2.5 -20 0 0 E7 / PI + 18 +70 0 0 0 +7 -2.5 -30 EDA +. BT + ß- 4 Acetate +40 +80 0 0 0 +2.5 -10 -20 EDA-E2 / P8 E3 p 1 -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- - > EI P1 -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 Metol ether + 15 + 110 -5 0 0 0 0 -20 EDA +. RF- 3 of E2PI E13 / P1 -20 -20 0 0 -2.5 0 -5 -15 0 0 Ell / Pl + 18 -20 +2.5 0 0 -2.5 -5 -15 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 E6 / 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- E8 / P1 +30 + 130 0 0 0 +2.5 -5 -20 EDA- -)

Claims (73)

1. A method for altering the blood level of luteinizing hormone in an individual, comprising this method: providing a steroid that binds to the receptors on the surface of the nasal neuroepithelial cells of this individual, where the cells are part of a different tissue of the olfactory epithelium; administering the steroid within a nasal passage of the individual, such that the steroid specifically binds to these receptors, and results in an alteration of the blood level of luteinizing hormone of this individual.

2. A method for altering the blood level of follicle-stimulating hormone of an individual, comprising this method: providing a steroid that binds to the receptors on the surface of the nasal neuroepithelial cells of this individual, wherein the cells are part of a different tissue of the olfactory epithelium; administering the steroid within a nasal passage of the individual, such that the steroid specifically binds to these receptors, and results in an alteration of the blood level of follicle-stimulating hormone of this individual.

3. The method for altering the blood level of testosterone in an individual, comprising this method.- providing a steroid that binds to the receptors on the surface of the nasal neuroepithelial cells of this individual, where the cells are part of a tissue different from the olfactory epithelium; administering the steroid within an individual's nasal passage, such that the steroid specifically binds to these receptors, and results in an alteration of the blood level of testosterone in this individual.

4. The method of claim 1, 2, or 3, wherein the neuroepithelial cell is located within a vomeronasal organ of this individual.

5. The method of claim 4, wherein the steroid comprises a pregnane of the formula: wherein P1 is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, 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, halogen, hydroxy, alkoxy, and acyloxy; P4 to P12 can each be, independently, hydrogen, halogen, methyl, or halo-, dihalo-, or perhalo-methyl, - P13 is hydrogen, methyl, methylene, methyl substituted by halogen, methylene substituted by halogen, ethyl, ethylene -lo, acetylenyl, methyl-methylenyl, methyl-methynyl, - and "a", "b", "c", "d", "e", "h", "i", "j" and "k" , they are alternative sites for optional double links, and "j" or "k" can also be triple links; and wherein P2 is methyl, and P3 is / 3-hydroxy, P2 and P3 can be joined to form a cyclic ether.

6. A method according to claim 5, wherein "b" is a double bond.

7. A method according to claim 6, wherein "c" or "d" is a double bond.

8. A method according to claim 5, wherein "a" and "c" are double bonds.

9. A method according to claim 5, wherein "h" is an optional double bond, and "i" and "j" are absent.

10. A method according to claim 5, wherein "j" is a double bond.

11. A method according to claim 5, wherein "j" is a triple bond.

The method of claim 5, wherein the amount of the pregnane that is administered is at least about 100 picograms, but not greater than about 100 micrograms.

The method of claim 12, wherein the amount of the pregnane that is administered is at least about 1 nanogram, but not more than about 10 microgram.

14. The method of claim 13, wherein the amount of the pregnane derivative that is administered is at least about 10 nanograms, but not more than about 1 microgram.

The method of claim 1, 2, or 3, which further comprises a step of preparing a pharmaceutical composition of the steroid dissolved in a pharmaceutically acceptable carrier.

16. The method of claim 15, wherein the pharmaceutical composition is an ointment.

17. The method of claim 15, wherein the pharmaceutical composition is a liquid.

18. The method of claim 15, wherein the administration is by aerosol.

19. The method of claim 1, 2, or 3, wherein more than one steroid is administered.

The method of claim 3, wherein said steroid comprises a 19-nor-pregnane of the formula: wherein P1 is oxo, a- or / 3-hydroxy, a- or / 3-acetoxy, a- or / 3-propionoxy, a- or / 3-acetoxy lower, a- or / 3-acyloxy, or a- or ß-benzyloxy;: "a", "b", "c" II f 11"g" "i", "i", "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; Pg is hydrogen or methyl.

R 'and R "are independently hydrogen or halogen, or are absent 21.

The method of claim 20, wherein the neuroepithelial cell is located within a vomeronasal organ of this individual 22.

A method according to claim 21 wherein "a", "e", and "d" are double bonds 23.

A method according to claim 22, wherein "h" is a double bond 24.

A method according to claim 22 , where "g" is a double bond 25.

A method according to claim 24, wherein "n" is a double bond 26.

A method according to claim 21, wherein "d" is a double bond 27.

A method according to claim 26, wherein "b" is a double bond 28.

A method according to claim 26, wherein "c" is a double bond. according to claim 28, wherein "f" is a double bond 30.

The method of claim 7, wherein the amount of 19-nor-pr egnan that is administered is at least about 100 picograms, but not more than about 100 micrograms.

The method of claim 30, wherein the amount of the 19-nor-pregnane derivative that is administered is at least about 1 nanogram, but not more than about 10 microgram.

32. The method of claim 31, wherein the amount of the 19-nor-pregnane derivative that is administered is at least about 10 nanograms, but not more than about 1 micrograms.

33. The method of claim 4, wherein the steroid is a premiere having the formula: wherein R- | _ is selected from the group consisting essentially of 1 or 2 hydrogen atoms, methyl, methylene, and one or two halogen atoms; R 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, and halogen; R5 is absent, or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, and lower acyloxy; Rg is hydrogen or halogen; and "a" represents optional aromatic unsaturation of ring A of this steroid, or "b", "c", and "d" are each optional double bonds; and "e", "f", "g", "h", "i" and "j" are each optional double bonds.

34. A method according to claim 33, wherein "a" is present, and "g", "h", or "i" are optional double bonds.

35. A method according to claim 34, wherein "h" and "i" are both double bonds.

36. A method according to claim 33, wherein "b" is a double bond.

37. A method according to claim 33, wherein "j" is a double bond.

38. A method according to claim 33, wherein "c" is a double bond.

39. A method according to claim 33, wherein "c" and "d" are double bonds.

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

41. A method according to claim 33, 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-3o-ol; estra-4, 9 (10), 16-trien-3 -one; estra-1, 3, 5 (10), 16-tetraen-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-3,6-diol.

42. A method according to claim 33, wherein R5 is methyl.

43. A method according to claim 42, 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.

44. A method according to claim 33, wherein R. * _ Is methylene.

45. A method according to claim 44, wherein the steroid is 17-methylene-estra-l, 3, 5 (10), 6, 8 (9) he-xaen-3-ol.

46. A method according to claim 33, wherein R-_ is methylene or a simple hydrogen, and R2 is methyl.

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

48. The method of claim 47, 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-3-yl, and propionate of 1, 3, 5 (10), 16-estratetraen-3-yl.

49. The method of claim 48, wherein the premier steroid is 1, 3, 5 (10), 16-estratetraen-3-ol.

50. The method of claim 33, wherein the premiere amount that is administered is at least about 100 picograms.

51. The method of claim 50, wherein the premiere amount that is administered is at least about 1 nanogram, but not more than about 10 microgram.

52. The method of claim 51, wherein the premiere amount that is administered is at least about 10 nanograms, but not more than about 1 microgram.

53. The method of claim 4, wherein the steroid is an androstane of the formula: wherein PL is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, a; - (ß-) methoxy, a - (ß-) lower acyloxy, ex- (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 1 or 2 substituents, wherein P5 comprises 1 or 2 hydrogen atoms, methyl, methylene, or 1 or 2 halogen atoms; P6 is hydrogen or halogen; and "a", "c", "d", "e", "f", and "h" are alternative sites for optional double bonds.

54. A method according to claim 53, wherein "b" is a double bond.

55. A method according to claim 54, wherein "c" or "d" is a one double bond.

56. A method according to claim 53, wherein "a" and "c" are double bonds.

57. A method according to claim 53, wherein P3 is methyl, "h" is an optional double bond, and P5 is methylene or 1 or 2 hydrogen atoms.

58. A method according to claim 53, wherein P3 is methyl, and "h" is a double bond.

59. A method according to claim 58, wherein the 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.

60. A method according to claim 53, wherein P3 is methyl.

61. A method according to claim 60, wherein the steroid is androst-4-en-3-one.

62. A method according to claim 53, wherein P5 is methylene.

63. A method according to claim 62, wherein the steroid is selected from the group consisting of 20-homo-androsta-4, 17-dien-3-ol; 20-homo-androsta-4, 17-dien-33-ol; and 20-homo-androsta-4, 17-dien-3,6-dione.

64. A method according to claim 53, wherein P5 is methyl, and "f" is a double bond.

65. The method of claim 53, wherein "a" or "b" is a double bond.

66. The method of claim 53, 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-3/3-ol.

67. The method of claim 66, wherein the steroid is androsta-4, 16-dien-3 -one.

68. The method of claim 53, wherein the amount of androstane that is administered is at least about 100 picograms, but not more than about 100 micrograms.

69. The method of claim 68, wherein the amount of the ligand that is administered is at least about 1 nanogram, but not more than about 10 microgram.

70. The method of claim 69, wherein the amount of the ligand that is administered is at least about 10 nanograms, microgram.

71. A pharmaceutical composition for altering the blood level of luteinizing hormone in an individual, which comprises an effective amount of a compound in a pharmaceutically acceptable carrier, for stimulating the receptors in the vomeronasal organ of this individual, selecting said compound from the group consisting of a pregnane of the formula: wherein P is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, 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, halogen, hydroxy, alkoxy, and acyloxy; P4 to P12 can each be, independently, hydrogen, halogen, methyl, or halo-, dihalo-, or perhalo-methyl; P13 is hydrogen, methyl, methylene, methyl substituted by halogen, methylene substituted by halogen, ethyl, ethylene, acetylenyl, methyl-methylenyl, methyl-methinyl; and "a", "b", "c", "d", "e", "h", "i", "j" and "k", are alternative sites for optional double links, and "j" or "k" can also be triple links; and wherein P2 is methyl, and P3 is / 3-hydroxy, P2 and P3 can be joined to form a cyclic ether; a 19-nor-pregnane of the formula: R " wherein V1 is oxo, a- or / 3-hydroxy, a- 6/3-acetoxy, or; - or /? - propionoxy, a- or / 3-acetoxy lower, a- or / 3-acyloxy, or - 6-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; P4 is methyl or ethyl; P5 is hydrogen, methyl, or halogen; Pe is hydrogen or methyl. -R 'and R "are independently hydrogen or halogen, or are absent, a premiere of the formula: wherein R2 is selected from the group consisting essentially of 1 or 2 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, and halogen; R5 is absent, or is selected from the group _ which consists essentially of hydrogen, hydroxy, lower alkoxy, and lower acyloxy; R6 is hydrogen or halogen; and "a" represents optional aromatic unsaturation of ring A of this steroid, or "b", "c", and "d" are each optional double bonds; and "e", "f", "g", "h", "i" and "j" are each optional double bonds. an androstane of the formula: wherein Px is selected from the group consisting of oxo, a- (ß-) hydroxy, or; - (ß-) acetoxy, a- (ß-) propio-noxy, 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 1 or 2 substituents, wherein P5 comprises 1 or 2 hydrogen atoms, methyl, methylene, or 1 or 2 halogen atoms; P6 is hydrogen or halogen; and "a", "c", "d", "e", "f", and "h" are alternative sites for optional double bonds.

72. A pharmaceutical composition for altering the blood level of the follicle-stimulating hormone of an individual, which comprises an effective amount of a compound in a pharmaceutically acceptable carrier, for stimulating the receptors in the vomeronasal organ of this individual, said composed from the group consisting of a pregnane of the formula: where P? is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, a- (ß-) methoxy, a- (ß-) ) lower acyloxy, or; - (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, halogen, hydroxy, alkoxy, and acyloxy; P4 to P12 can each be, independently, hydrogen, halogen, methyl, or halo-, dihalo-, or perhalo-methyl, - P13 is hydrogen, methyl, methylene, methyl substituted by halogen, methylene substituted by halogen, ethyl, ethylene -lo, acetylenyl, methyl-methylenyl, methyl-methynyl; and "a", "b", "c", "d", "e", "h", "i", "j" and "k", are alternative sites for optional double links, and "j" or "k" can also be triple links; and wherein P2 is methyl, and P3 is / 3-hydroxy, P2 and P3 can join to form a cyclic ether. a 19-nor-pregnane of the formula: wherein '1 is oxo, a- or /? -hydroxy, a- or β-acetoxy, a- or 3-propionoxy, a- or 3-acetoxy, a- or 3-acyloxy, or - ó / 3-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; P4 is methyl or ethyl; P5 is hydrogen, methyl, or halogen; P is hydrogen or methyl. R 'and R "are independently hydrogen or halogen, or are absent, a premiere having the formula: where R? is selected from the group consisting essentially of 1 or 2 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, and halogen; R5 is absent, or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, and lower acyloxy; R6 is hydrogen or halogen; and "a" represents optional aromatic unsaturation of ring A of this steroid, or "b", "c", and "d" are each optional double bonds; and "e", "f", "g", "h", "i" and "j" are each optional double bonds; and an androstane of the formula: wherein PL is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, a- (ß-) methoxy, a- (β-) lower acyloxy, - (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 1 or 2 substituents, wherein P5 comprises 1 or 2 hydrogen atoms, methyl, methylene, or 1 or 2 halogen atoms; P6 is hydrogen or halogen; and "a", "c", "d", "e", "f", and "h" are alternative sites for optional double bonds.

73. A pharmaceutical composition for altering the blood level of testosterone in an individual, which comprises an effective amount of a compound in a pharmaceutically acceptable carrier, for stimulating the receptors in the vomeronasal organ of this individual, said compound being selected from of the group consisting of a pregnane of the formula: P- where P? is selected from the group consisting of oxo, a- (ß-) hydroxy, a- (ß-) acetoxy, a- (ß-) propio-noxy, a- (ß-) methoxy, a- (ß-) ) lower acyloxy, a- (β-) lower alkyloxy, and a-. { β-) enzoyloxy; 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, halogen, hydroxy, alkoxy, and acyloxy; P4 to P12 can each be, independently, hydrogen, halogen, methyl, or halo-, dihalo-, or perhalo-methyl; P13 is hydrogen, methyl, methylene, methyl substituted by halogen, methylene substituted by halogen, ethyl, ethylene, acetylenyl, methyl-methylenyl, methyl-methinyl; and "a", "b", "c", "d", "e", "h", "i", "j" and "k", are alternative sites for optional double links, and "j" or "k" can also be triple links; and wherein P2 is methyl, and P3 is / 3-hydroxy, P2 and P3 can be joined to form a cyclic ether. a 19-nor-pregnane of the formula: wherein P1 is oxo, a- or /? -hydroxy, or; - or / 3-acetoxy, a- or / 3-propionoxy, a- or lower / 3-acetoxy, a- or / 3-acyloxy, or - ó / 3-benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "" and "n" are alternative sites for double optional links, 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; Pg is hydrogen or methyl. R 'and R "are independently hydrogen or halogen, or are absent, a premiere having the formula: wherein R-L is selected from the group consisting essentially of 1 or 2 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, and halogen; R5 is absent, or is selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, and lower acyloxy; R6 is hydrogen or halogen; and "a" represents optional aromatic unsaturation of ring A of this steroid, or "b", "c", and "d" are each optional double bonds; and "e", "f", "g", "h", "i" and "j" are each optional double bonds; and an androstane of the formula: wherein P ± is selected from the group consisting of oxo, α- (β-) hydroxy, OÍ- (β-) acetoxy, α- (β-) propio-noxy, α- (βß) methoxy, - (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 1 or 2 substituents, wherein P5 comprises 1 or 2 hydrogen atoms, methyl, methylene, or 1 or 2 halogen atoms; P5 is hydrogen or halogen; and "a", "c", "d", "e", "f", and "h" are alternative sites for optional double bonds.