MXPA97009693A - Novedosos nor-pregnanos, to induce hipotalami effects - Google Patents

Abstract

The present invention relates to a method for altering hypothalamic function in an individual. This method comprises nasally administering a human vomeropherin, for example a 19-nor-pregnane steroid, or a farnaceutical composition containing a vomeropherin, such that this vomeropherin binds to a specific neuroepithelial receptor. The esteride or the esterides are preferably administered in the form of a pharmaceutical composition containing one or more acceptable pharmaceutical carriers containing these steroids.

Description

NOVEDOSOS NOR-PREGNANOS. TO INDUCE HYPOTHALAMIC EFFECTS Reciprocal Reference to Related Requests This request relates to the US patent application, Serial No. 08 / 127,908, filed on September 28, 1993, which is a partial continuation of the US application, No. of Series 07 / 903,604, filed on June 24, 1992, which, in turn, is a partial continuation of the US application, Serial No. 07 / 708,936, filed on May 31, 1991, which, in in turn, it is a partial continuation of the US application, Serial No. 07 / 638,185, filed on January 7, 1991, now abandoned. The request also relates to the application for USA, Serial No. 08 / 127,980, filed September 28, 1993, which is another partial continuation of the US patent application, Serial No. 07 / 903,604, the patent application Serial No. 08 / 077,359, filed on June 15, 1993 and the commonly assigned US patent application, also pending, Serial No. 07 / 903,525, filed on June 24, 1992 (a partial continuation of the US application, No. of Series 07 / 707,862, filed on May 31, 1991, which, in turn, is a partial continuation of the US application, Serial No. 07 / 638,743, filed on January 7, 1991, now abandoned) entitled "Premiere Steroids, as Neurochemical Initiators of Change in Human Hypothalamic Function and Compositions and Related Pharmaceutical Methods", and the partial continuation, commonly assigned, also pending, of 07 / 903,525, the US patent application, No. 08 / 077,140. The aforementioned U.A. patent applications are incorporated herein by reference. Finally, this application may be related to the patent application of E. U. A., entitled "Fragrance Compositions Containing Human Pheromones", filed March 24, 1992, Serial No. E. U. A., 07 / 856,435. Technical Field This invention relates, generally, to pharmaceutical compositions and methods for effecting changes in human hypothalamic function, thus altering certain behavior and physiology mediated by the hypothalamus of individuals. More particularly, the invention relates to the use of 19-nor-pregnane steroids, as neurochemical performing agents of physiology and behavior. Description of the Related Art The present invention relates to certain compounds, ie the steroids of 19-norpregnane, particularly the steroids of 19-norpregnane and related compounds, as described herein, and to methods of using these compounds as human vomeropherins, with the purpose of altering the hypothalamic function, thus affecting certain behavior and consequent physiology, for example, the reduction of anxiety. The steroids of 19-nor-pregnane are characterized by a four-ring steroidal structure, methylation at position 13 and ethylation at position 17. The 19-nor-pregnanes are a subset that has at least one double bond. Ohloff, G et al (Helv. Chim. Acta (1983) 66: 192-217), which is incorporated herein by reference, has shown that several steroids (androstenes) have an odor, which varies with the different isomeric, diastereomeric forms and enantiomerics. Some members of this group have been reported to act as a pheromone in some mammalian species, for example, 5a-androst-16-en-3-one and 5a-androst-16-en-3a-ol in pigs (Melrose , DR et al., Br. Vet. J. (1971) 127: 497-502). These 16-androstenes produced by the parent pig induce mating behavior in estrus in sows (Claus, et al., Experimentia (1979) 35: 1674-1675). In some studies, it has been noted that, in some species, several characteristics of certain 16-androstenes (including 5a-androst-16-en-3a-ol and 5a-androst-16-en-3-one), such as the metabolism of concentration and location, they are sexually dimorphic (Brooksbank et al., J. Endocr. (1972) 52: 239-251; CLaus, et al. , J. Endocr. (1976) 68: 483-484; Rwan, et al. , Med. Sci. Res. (1987) 15: 1443-1444). For example, 5a-androst-16-en-3a-ol and 5a-androst-16-en-3-one, as well as androsta-4, 16-dien-3-one, have been found at different concentrations in the peripheral blood, saliva and axillary secretions of man and woman (K an, TX, et al., Med. Sci. Res. (1987) 15: 1443-1444), and their function as a human pheromone, in the extent of affecting selection and judgment have been suggested (Id., see also Gower, et al., "The Meaning of Odorous Steroids in Axillary Odor," in Per f umer and, pages 68-72, Van. Toller and Dodd, Eds., Chapman and Hall, 1988); Kirk-Smith, D.A., et al. , Res. Comm. Psychol, Psychiat. Behav. (1978) 3: 379). Androstenol (5a-androst-16-en-3a-ol) has been claimed to exhibit a pheromone-like activity in the commercial products of men's cologne and women's perfume (Andron for men and Andron for women by Jovan) . Japanese Patent Kokai No. 2295916, refers to perfume compositions containing androstenol and / or its analogs. 5a-androstadien-3ß-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 whether or not any putative pheromone currently plays any role in the sexual or reproductive behavior of mammals, particularly humans.See: Beauchamp, GX et al., "The Pheromone Concept in Chemical Communication of Mammals: A Critique", in Mammalian 01 f action, Reproductive Processes and Behavior, Doty RL, Ed., Academic Press, 1976). See also: Gower et al. , supra in 68-73. The properties of the pheromone of some premier steroids for some mammalian species has been described. Michael, R. P. et al. , Nature (1968) 218: 746 refers to estrogens (particularly estradiol) as a potential attraction of male Rhesus monkeys. Parrot, R. F., Hormones and Behavior (1976) 7: 207-21S, reports that the injection of estradiol benzoate induces mating behavior in ovariectomized rats; and the role of the blood level of estradiol in obtaining the sexual response (Phoenix, CH, Physiol. and Behavior (1976) 15: 305-310) and the sexual response of females (Phoenix, CH, Hormones and Behavior (1977) 8: 356-362) in Rhesus monkeys has been described. On the other hand, there is little agreement in the literature whether or not pheromones play a role in the reproductive behavior and interpersonal communication of mammals (Beuchamp, GK et al., "The Pheromone Concept in Chemical Mammal Communication: A Criticism ", in: Mammalian Olí action Reproductive Processes, and Behavior, Doty, RL, Ed., Academic Press, 1976).

One embodiment of the present invention relates to the nasal, non-systemic administration of certain steroids of 19-nor.pregnano and 19-nor-pregneno, to affect a specific behavior or physiological response in human subjects, for example a reduction of the effect negative, bad mood and character traits. In particular, nasal administration provides contact of neurochemical receptors of a neuroendocrine structure, hitherto poorly understood, commonly known as the vomeronasal organ ("VNO", also known as "Jacobson organ"), with one or more steroids or with compositions that contain steroids. This organ has access through the nostrils of most animals, from snakes to humans, and has been associated inter alia, with the reception of pheromones in certain species (see generally Muller-Schwarze &Silverstein, Chemical Signs , Plenum Press, New York (1980)). Neuroepithelial neuroanatomies of the vomeronasal organ, placed in the suprapalatal region, form the vomeronasal nerve and have a direct synaptic connection to the accessory olfactory bulb and indirect entry from there to the basal-medial amygdaloid basal-anterior brain and the hypothalamic nuclei of the brain. The distal neuraxes of terminal nerve neurons can also serve as neurochemical receptors in WNV. Stensaas, L. J., et al. , J. Steroid Biochem. and Molec. Biol. (1991) 39: 553. This nerve has a direct synaptic connection with the hypothalamus. Johnson, A. et al. , (J. Otolarynaoloav (1985) 14: 71-79) present evidence of the presence of the vomeronasal organ in the majority of adult humans, but concludes that the organ is probably not functional. Opposite results suggesting that WNV is a functional chi-sensitive receptor are presented by Stensaas, L., et al. , supra; and by Moran, D. T., et al. , García-Velasco, J. and M. Mondragon; MontiBloch, L. and B. Grosser, all in J. "Steroid Biochem, and Molec Biol. (1991) 39. It is evident that it would be desirable to identify and synthesize human vomeroferin and pheromones and develop pharmaceutical compositions and methods of use for the influence This invention relates to the unexpected discovery that, when administered to human beings nasally, certain neurochemical ligands, particularly the steroids 19-nor-pregnane, 19-nor-pregneno steroids and related compounds, or the compositions Pharmaceuticals containing the 19-nor-pregnanes, 19-nor-pregnenos and related compounds, bind specifically to the chemo-receptors of certain nasal neuroepithelial cells and this union generates a series of neurophysiological responses that result in an alteration of hypothalamic function of an individual, when properly administered, the effect of certain of these compounds on the hypothalamus affects function of the autonomic nervous system and a variety of behavioral or physiological phenomena that include, but are not limited to, the following: anxiety, premenstrual tension, fear, aggression, hunger, blood pressure and other behavioral and physiological functions normally regulated by the hypothalamus . See Otto Appenzeller, The Autonomic Nervous Systems. An Introduction of Basic an Clinical Concepts (1990); Rorner, PI Central nervous control of autonomic cardiovascular function and Levy NM and Martin, PJ Weural control of the heart, both in the manual Handbook of Physiology: Section 2: Cardiovascular System - the heart, Vol. I, Washington, DC, 1979, American Physiological Society: Fishman, AP et al., Editors, Handbook of Physiology: Section 3: Respiratory System. Vol. II, Control of Breathing, Bethesda MD. 1986, American Physiological Society. In some cases, a simple 19-nor-pregnane steroid, or a related compound, is administered, in other cases, combinations of 19-nor-pregnane steroids and / or related compounds are administered and in other cases one or plus 19-nor-pregnane steroids along with one or more estrano or premier steroids, androstane steroids or androstene or a related compound.

Background of the Invention Definitions An "affect" is a transient state of feeling. Typical negative affects are feelings of nervousness, tension, shame, anxiety, irritability, anger, anger and the like. The "bad mood" is a longer state of feeling, such as guilt, sadness, hopelessness, worthless remorse, misery, unhappiness, and the like. "Character traits" are more permanent aspects of an individual's personality. Typical negative traits are sensitivity, regret, guilt, stubbornness, resentment, bitterness, shyness, laziness, and the like. "Pregnane steroids" are aliphatic polycyclic hydrocarbons, characterized by a four-ring steroid structure with a methylation at positions 10 and 13 and an ethylation (including unsaturated groups) at position 17. The 19-nor compounds lack a methyl or another substituent that contains carbon in C-10, where C-19 will normally be found. A pregnen is a subset of pregnanes and is commonly understood to mean that the compound has at least one double bond. A "chemo-receptor" is a receptor molecule displayed on the surface of a "chemosensitive" neuroepithelial cell, which binds in a stereospecific manner to a particular ligand or ligands. This specific binding initiates signal transduction, which initiates an afferent nerve impulse. The chemo-receptors are found, inter alia, in the taste buds, olfactory epithelium and 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 position 13, ethylation (which includes unsaturated groups ) at position 17 and a group of oxo, hydroxyl or hydroxyl derivative, such as an alkoxy, ester, benzoate, cypionate, sulfate or glucuronide group at position 3. The 19-nor compounds lack a methyl group or other substituent containing carbon in C-10, where C-19 will normally be found. Derivatives containing these structural characteristics are also generically named as pregneno steroids. The following structure shows the four-ring steroidal structure, common to pregnane and pregnane steroids. When describing the location of the groups and substituents, the following number 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 the range of the amount and / or concentration that produces the desired physiological and / or psychological effect, when administered to an individual, who needs the drug. In the present case, an individual with this need is one with a physiological trait or behavior that is normally regulated by the hypothalamus and in which it is convenient to affect the function of the hypothalamus or the trait. The effective amount of a given drug can be very dependent 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 1 microgram / milliliter (μg / ml) up to 100 μg / ml, preferably 10 to 50 μg / ml and more preferably from 20 to 30 μg / ml. When the steroid is introduced directly into the WNV, an effective amount is about a picogram (pg) to 1 nanogram (ng), more preferably about 10 to 50 pg. When the steroid is administered to the nasal passage, ointment, cream or aerosol, or the like, an effective amount is from about 100 pg to about 100 pg, preferably about 1 ng to about 10 pg. It is concluded that some drugs can be effective when administered by the same routes, but not effective when 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 (sulcus) and includes the structures that form the floor of the ventricle, which includes the optic chiasm, cinero tubercle, infundibular body, and mammary bodies. . The hypothalamus regulates the autonomic nervous system and controls various physiological and behavioral functions, such as the so-called flight and flight responses, sexual motivation, water balance, metabolism of sugar and fats, hunger, regulation of body temperature, secretions endocrine and others. The hypothalamus is also the source of vasopressin, which regulates blood pressure, and oxytocin that induces labor and releases milk. All hypothalamic functions are potentially modulated by the vomeroferin therapy described here.

A "ligand", as used herein, is a molecule which acts 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 vomeronasal neuroepithelium or olfactory neuroepithelium, contains a multiplicity of neuro-receptor cells, each exhibiting at least one cell surface receptor. Many of the receptor molecules have an identical ligand specificity. Therefore, when the tissue is exposed to a ligand for which there is specificity (for example, an exposure of the VNO to a vomeropherin), a summed change in the cell surface receptor potential can be measured. As used herein, the term "lower alkyl" means a saturated, branched or unbranched hydrocarbon chain of 1 to 4 carbon atoms, such as, for example, methyl, ethyl, n-propyl, -butyl and the like . "Alkoxy", as used herein, in the conventional sense, means the group -OR, wherein R is the alkyl defined herein. A "pheromone" is a substance that provides chemical communication resources between members of the same species, through peripheral secretion and chemo-reception. In mammals, pheromones are usually detected by receptors in the vomeronasal organ of the nose. Pheromones commonly affect 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 includes 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 ng res equals 0.001 micrograms (μg). One μg equals 0.001 mg. The invention is directed to a group of certain 19-nor-pregnane steroids. A subset of 19-nor-pregnanes within the group is believed to be novel. The syntheses are described here for the following compounds, as designated in the letter: Letter 1 includes 19-norpregnanes to which the invention is directed, but does not limit its scope. The synthesis diagrams that follow illustrate the intermediate and substructure syntheses for the preparation of these 19-nor-pregnanes.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 and Figure 2 show the frequency of nerve discharge of EVG and vomeronasal, respectively, of steroid E2 / P4 and control, in female rats. Figures 3 to 24 show the data of EVG, EDA, RF, CF, EMG, BT and EEG (alpha-V, alpha-T, beta-V and beta-T) of the administration of the 19-nor-steroids designated in the vomeronasal organ VNO of women. Figures 25 to 46 show the EVG, EDA, RF, CF, EMG, BT and EEG data of the administration of designated 19-nor-steroid in the human VNO organ. SUMMARY OF THE INVENTION Therefore, it is an object of this invention to provide pharmaceutical compositions containing human vo eroferins or pheromones and which are suitable for nasal administration in an individual. It is also an object of this invention to provide methods for using these compositions to alter the hypothalamic function of an individual. It is a further object of this invention to provide methods of using these compositions to affect the physiological and behavioral functions of individuals, which are normally regulated by the hypothalamus. Finally, it is an object of this invention to provide methods of altering the hypothalamic function, which have the following advantages: 1) administration directly to the chemo-receptors in the nasal passage and the vomerónasal organ, without pills or needles, that is, not invasively 2) a mode of drug action through the Nervous System, and not through the Circulatory System - thus, brain function can be affected without considering the brain's blood barrier; 3) a direct resource to affect the hypothalamus - there is only a synaptic connection between the pheromone receptors and the hypothalamus; and 4) to provide a highly specific drug effect, thus greatly reducing the potential for unwanted side effects - this is because the sensory nerves are directed to a specific location in the brain. Objects, advantages and novel additional features of the invention will be set forth in part in the description that follows and in part will become apparent to those skilled in the art of the examination of the following invention or may be learned by practice of the invention. The objects of this invention are achieved by the provision of a pharmaceutical composition suitable for nasal administration to an individual. The composition contains a pharmaceutically acceptable carrier and a pregnane steroid of the formula: in which P ^ is oxo, a- or β-hydroxy, a- or β-acetoxy, a- or β-propionoxy, α- or β-lower alkoxy, α- or β-acyloxy or α- or β- benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m", and "n", are alternative sites for optional double links, and "k" may be absent or present, with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy with 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy with 1-6 carbon atoms, or halogen; P4 is methyl or ethyl; One class of preferred steroid compositions contains steroids where "d" is a double bond and "b" is optionally 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 a "c" present, with "f" optionally present. The novel class of 19-nor-pregnanes are those of the above formula, excluding the following compounds in cases where P3 and P6 are hydrogen; "f", "n", "h" and "g" are absent; P4 is methyl and R1 and R "are not halogen: i) where P ^ is oxo," c "is present and P2 and P5 are hydrogen, so either" j "or" i "can not be present alone," m "and" j "can not be present together or" i "and" j "or they can be present together or" m ", iijn and nj? ii ^ can not be present together and at least one of" i "," j "and" k "must be present, ii) when P ^ is OH," a "," d "and" e "are present and P5 is hydrogen, then either" j "," i "or" m " they can not be present alone, or "j" and "k" can not be present together, or "i" and "j" can not be present together, or "m", "j" and "k" can not be present together, and at least one of "i", "j", "k" and "m" must be present; (iii) when P ^ is beta-OH, "c" is present, and P2 and P3 are hydrogen, then "i" and "j" or can be present together, or "m", "j" and "k" they can not be present together; iv) when P- ^ is -OME and "d" and "b" are present, then any of "j" and "i" can not be present alone; v) when P ^ is oxo and "d" is present and P5 is hydrogen; then "i" can not be present alone or "j" and "k" can not be present together. The term lower alkyl, lower alkoxy, etc. , it is meant encompasses carbon chains with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Other objects of this invention are achieved by the provision of a method for altering the hypothalamic function and / or the autonomic function in an individual. A ligand for a chemo-receptor displayed on the surface of a neuroepithelial cell is provided, in which the cell is a part of a tissue different from the olfactory epithelium; and the ligand is administered within the nasal passage of the individual, so that this ligand binds specifically to the chemo-receptor, which results 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 revealed in these embodiments and to those modified steroids that demonstrate functional equivalence. In the following table, particularly preferred 19-nor-pregnanes are shown. 19-NORPREGNANOS Neither SYNTHESIS OF SÜBESTRÜCTÜRA: TYPE E ?? i Frank B. Cdton, Leonard N. Nysted, Byron Riegd, and Albert L Raymond, J. Amer. Chem. Soc., 1957, ISL, 1 1 23.

Also a commercially available substructure, for example 17a-ETINYL-19-NORTESTOSTERONE.

E2: OO This is a commercially available substructure, for example, ESTRONA, ETINILESTRADIOL Pierre Crabble, patent of E. U. A., No. 3,492,318, 1970, ?? i This is a commercially available substructure, for example 6-DEHYDROESTRONE.

IS: See Example.

£? (Acβtat * of E6) See Example See Example "J0O etf yes E2) XX (Eß)) 0. 1. Fedorova, O. S. Anisimova, and G. S. Grinenko, Khim. Phr. Soeán., 1976, 2. 180.

Frank B. Colton, Lenoard N. Nysted, Byron Riegd, and Albert L. Raymond, Amer. Chem. Soc., 1957, 13., 1123. _ This is a commercially available substructure, for example EQUILIN.

E? O: This is a commercially available substructure, for example EQUILENIN.

See Example E12: See Example Etf; XX) See Example SUBSTRUCTURAL SYNTHESIS: TYPE P He 0. 1. Fedorova, 0. S. Anisimova, and G. S. Grinenko, Khim. Ppr. Soeán 1976 2, 180. < A Hg / Pd-ßaSOj (P5) -.) ,.

Richard H. Peters, David F. Crowe, Mitchdl A. Av. Xery, X WesFley K. M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 22. 1642. Also see Example.

E2: ^ > Frank B. Colton, Leonard N. Nysted, Byron Riegd, and Albert L. Raymond, J. Amer. Chem. Soc., 1957, 79 1 123.

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

E3 H. Kaufmann, P. Widand, and J. Kalvoda, Heiv. CNm. Acta., 1972, 55 (2), 381.

E4? \5 O. I. Fedorova, O. S. Anisimova, and G. S. Grinenko, Khim. Prir. Soedin., 1976, 2, 180.

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

E5: Peter Kaspar and Herbert Witzd, J. Steroid Biochem., 1985, Vol. 23, No. 3, p. 259 Richard H. Peters, David R. Crowe, Mitchdl A. Avery, Wesley K. M. Chong, and Masato Tanabe, J. Med. Chem., 1989, 22. 1642.

Efi: Frank B. Colton, U.S. Patent 2,840,582, 1958.

E7 II Pierre Crabble and Esperanza Vdarde, U.S. Patent 3,681, 410, 1972.

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

Pfl; Rerre Crabble, U.S. Patent 3,492,318. 1970. M MßßOO Klaus Prezewowsky and Ruddf Wiechert, U.S. Patent 3,682,983, 1972.

METÍLNORPREGN? NOS The 19-nor-pregnanes in this series can be prepared with a methyl group at positions 6a, 7a, 18, 20 or 21.

The U.A. Patent No. 3,681,410 teaches the preparation of 6a-methyl analogs.

The U. A. patent, No. 3,682,983, teaches the preparation of 18-methyl analogues.

US Patent No. 3,492,318 teaches the preparation of 7a, 18 and 21-methyl analogs analogous 21-me ilo; THE. Van Dijck, B.J. Lankwerden, J.G.C.M. Vermeer, and A.J.H. Weber, Red. Trav. Chim. Pays-Bas Belg. , 1971, 90, 801.

Analogs of 7a, 18, 20 and 21-me i lo Richard H. Peters, David F. Crowe, Mftchell A. Averey, Wesley K. M. Chong. and aspato Tapabe. J. Med Chem. 1989. 32. 1642. In addition, certain methylated precursors are commercially available, for example: 70C-METILESTRONA NORGESTREL Of these, 7-methyl or 2.8-methyl analogues can be obtained from substances where estrone or 17a-ethynyl-19-nor-testosterone (nor-etindrona) are precursors, respectively "HALONORPREGNANOS The patent from the USA 2,840,582, teaches the preparation of: The patent of E.U.A. 3,681,410 teaches the preparation of: Richard H. Peters, David F. Crowe, ItchßíJ A. Avery, Wesley K. M. Chong, and Masato Tanabe. J. Med. Chem. 1989.98. 642, The alkoxy derivatives are prepared from their corresponding hydroxy steroids, by reaction with an alkylating agent, such as trimethyloxonium fluoroborate, triethyloxonium fluoroborate or methyl fluorosulfonate, in an inert chlorocarbon solvent, such as methylene chloride. Alternatively, alkylating agents, such as alkyl halides, alkyl tosylates, alkyl mesylates and dialkyl sulfates, 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, DMF, DMSO and hexamethylphosphoramide. General procedures for the synthetic reactions of steroids are well 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 intervals of each hour. These aliquots are analyzed by chromatography to inspect the disappearance of the starting material, at which point the manufacturing process is started. If the starting material is not consumed within twenty-four hours, the mixture is heated to reflux and aliquots are analyzed every hour, as before, until the starting material disappears. In this case, the mixture is allowed to cool before starting the manufacturing process. The purification of the products is achieved by means of chromatography and / or crystallization, as is known to those skilled in the art. PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE One embodiment of the present invention relates to a method for altering the hypothalamic function of an individual. Another modality is to alter an autonomic function of an individual. These autonomic functions include, but are not limited to, the heart rate, respiratory regimen, brain wave patterns (percentage of cortical alpha activity), body temperature. Other modalities include, but are not limited to, methods to diminish the negative affects, bad mood or negative character traits of an individual. Another modality is a method to treat premenstrual tension in women. All these modalities are achieved by the nasal, non-systemic administration of certain pregnane steroids, pregnane steroid combinations and combinations of one or more pregnane steroids and one or more androstane steroids and / or premiere. This particular mode of administration is distinguished from the alternative modes, such as ingestion or injection, in several important ways, these by virtue of direct contact with the WNV supplied by the nasal administration of the steroid ligand. In the methods of this invention, the appropriate ligand is administered directly to the chemo-receptors in the nasal passage and the vomeronasal organ, without pills or needles - that is, non-invasively. The action of the drug is mediated through the binding of the ligands, described here, to the specific receptors exhibited by the neuroepithelial cells in the nose, preferably in the WNV. Also, the mode of action of the drug is through the Nervous System and not through the Circulatory System - thus, the function of the brain can be affected regardless of the blood-brain barrier. These treatment methods provide a direct means of affecting the hypothalamus through the Nervous System, because there is only a synaptic connection between the pheromone and the hypothalamus receptors. By directing the sensory nerves to a specific location in the brain, this method has a highly specific drug effect, greatly reducing the potential for unwanted side effects. The contact of the VNO is important, because this VNO is associated with the qui-receptive / pheromonal function. The WNV consists of a pair of blind tubular diverticula located in the lower margin of the nasal septum. The WNV contains neuro-epithelial regions, whose neuroaxis have direct synapses to the tonsils and from there to the hypothalamus. The existence of WNV has been well documented in most terrestrial vertebrates, which include the human fetus; however, in human adults it is generally thought to be rudimentary (See Johnson, et al., supra). Antifertility Activity The steroid 19-norpregna-l, 3,5 (10) -trien-3-ol (compound E2 / P4 in the 19-norpregnane table) was tested in the WNV of female rats. The frequency of discharge of the EVG and the vomeronasal nerve (VNN) are shown in Figures 1 and 2, respectively. These data show the WNV stimulus. Steroid E2 / P4 is shown to have a postcoital antifertility activity when administered orally to female rats having low hormonal activity (as measured by the estrogen-receptor binding). (Peters et al., J. Med. Chem., 1989, 32, 1642-52.) The data in Figures 1 and 2 suggest that this antifertility activity is explainable because E2 / P4 is not a hormone, but It acts as a vomeropherin through the stimulus of WNV, which, in turn, affects the hypothalamus. Consistent with the rat model data, compound E2 / P4 also shows WNV stimulus in women (see Figure 22), and to a lesser extent, in men (see Figure 44), and thus it is expected that Vomeroferins have antifertility activity in humans.

The stimulation of the hypothalamus by means of WNV may allow one to suppress the release of LH and FSH. This can provide a clinical method for the treatment of prostate cancer, precocious puberty (in males and females), endometriosis, uterine leiomyoma, breast cancer, premenstrual syndrome and dysfunctional uterine bleeding. The ligand substances described herein, or their ciphered, benzoate, proprionised or sulfated glucuronase derivatives, can be administered directly, but are preferably administered as compositions. They are prepared in a liquid dosage form such as, for example, liquids, suspensions or the like, preferably in unit dosage forms suitable for the simple administration of the precise doses. The liquid doses can be administered as drops for the nose or as an aerosol. Alternatively, the active compound can be prepared as a cream or ointment composition and applied topically within the nasal cavity. In addition, a vomeropherin can be administered as vapor contained in a breath of air delivered into the nasal cavity. As another alternative, delivery may occur by the controlled release of these agents by encapsulation, in bulk or at a microscopic level using synthetic polymers, such as silicone, and natural polymers such as gelatin and cellulose. The release regime can be controlled by the appropriate selection of the polymer system used to control the diffusion regime (Langer, R. S. and Peppas, N. A., Bio aterials 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 include a conventional pharmaceutical carrier or excipient, one or more of the active 19-nor-pregnane compounds, and the composition may or may not additionally include one or more androstane steroids or premiere. In addition, the compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Probably the best communication resource of a semiochemical ligand is the inhalation of a pheromone, which occurs naturally, present in the skin of another. It is estimated that the maximum concentration, which occurs naturally of a pregnane steroid in human skin is 2 to 7 ng / cm2. During intimate contact, it is estimated that a human will be exposed to no more than 700 ng of a naturally occurring steroid. Since these compounds are relatively non-volatile, it is estimated that, even during intimate contact, a human subject will inhale no more than 0.7 pg of a naturally occurring steroid, from the skin of another. From the inhaled account, only about 1% will reach the receptors of the vomeronasal organ. Thus, the maximum natural exposure estimated to naturally produced pheromones will be 0.007 pg. The amount of vomeroferin administered, of course, will be dependent on the subject to be treated, the severity of the affliction, the manner of administration, the frequency of administration, and the judgment of the prescribing physician. However, a single dose of at least about 10 picograms, delivered directly into the lumen of the vomeronasal organ, is effective in producing a transient autonomic response. When administered to the nasal cavity, the dose is about 100 picograms to 10 micrograms, preferably about 1 nanogram to about 10 micrograms, more preferably about 10 nanograms to about 1 microgram. The frequency of administration is conveniently in the range of one dose per hour to one monthly dose, preferably 8 times / day to once every third day, more preferably 1 to 3 times per day. Ointments containing one or more active compounds and optional pharmaceutical adjuvants in a carrier, such as, for example, water, a saline solution, aqueous dextrose, glycerol, ethanol and the like, can be prepared using a base, such as, for example, petroleum jelly, lard or lanolin. Liquid compositions administrable pharmaceutically can, for example, be prepared by dissolving, dispersing, etc., an active compound, as defined above, and optional pharmaceutical adjuvants, in a carrier, such as, for example, water, a solution saline, aqueous dextrose, glycerol, ethanol and the like, to form a solution or suspension. If desired, the pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances, such as soaking agents or emulsifiers, pH regulating agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine acetate sodium, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 15th Ed., 1975. The composition or formulation to be administered, in any case, will contain one or more of the active compounds, in one embodiment. effective amount to relieve the symptoms of the subject to be treated. For aerosol administration, the active ingredient is preferably supplied in finely divided form, together with a surfactant and a propellant. Typical porcentages of active ingredients are from 0.001 to 2% by weight, preferably from 0.004 to 0.10%. The surfactants, of course, must be either toxic and preferably soluble in the propellant. Representative of such agents are partial esters or esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, olelestaric 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 (the sorbitan esters sold under the trademark of "Spans") and the derivatives thereof. polyoxyethylene and polyoxypropylene of these esters. Mixed esters, such as mixed or natural glycerides, may be employed. Preferred surfactants are oleates or sorbitan, for example, those sold under the trademark of "Arlacel C" (sorbitan sesquioleate), "Span 80" (sorbitan monooleate) and "Span 85" (sorbitan trioleate). . The surfactant may comprise from 0.1 to 20% by weight of the composition, preferably from 0.25 to 5%. The rest of the composition is ordinarily the propellant. Liquefied thrusters are gases typically at ambient conditions, and they condense under pressure. Among the suitable liquefied propellants are lower alkanes containing up to five carbons, such as butane and propane; Fluorinated or fluorinated alkanes, such as those sold under the trademark of "Freon". Mixtures of the above can also be used.

In producing 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. The ingredients are thus maintained at a high pressure until released by the action of the valve. Still another administration resource is the topical application of the volatile liquid composition to the skin, preferably the facial skin of an individual. The composition will usually contain an alcohol, such as ethanol or propanol. A pleasant fragrance can also be included in the composition. Measurement of Affection, Humor and Peculiarity of Character The states of feelings associated with affections, moodiness and character peculiarity are generally measured by the use of a questionnaire. For example, questionnaires that comprise a number of adjectives that refer to feelings states can be administered to an individual. The individual evaluates his state of feelings described by the adjective and the regimes and intensity of feelings on a numerical scale. The agglomeration of related adjectives and the statistical analysis of an evaluation of the subject of each adjective provides a basis for the measurement of various states of feeling.

Alternatively, feelings states can be measured by autonomic changes, such as those used in polygraph evaluations (galvanic skin response, pulse rate and the like). Cabanac M., Annual Review of Physiology (1975) 37: 415; Hardy, J. D. "Regulation of Body Temperature", Chapter 59, pages 1417. In: Medical Physiology, Vol. II, Ed.: VB Mountcastle (1980); Wolfram Bouscein. Electrodermal Activity (Plenum Press 1992). In addition, nonverbal indications, such as facial expression and body posture can be evaluated.

Examples The following examples are intended to illustrate, but not to limit the invention. The abbreviations used in the examples are the following: Ac. = aqueous; RT = room temperature; EP = petroleum ether (bp: 50-702C); DMF = N, N-dimethylformamide; DMSO = dimethyl-sulfoxide; THF = tetrahydrofuran.

Scheme 1. Synthesis of the 19-norpreqnanos O Xr No / NH3 Scheme 2. Synthesis of additional nor-presnanoa Scheme 3. Additional Synthesis of Norpresnanos 10 Scheme 4. 17-Ketone ethylenation HO? 14 Example l 19-norpreana-4,20-dien-3ß-ol, 1: A suspension of 19-norpregna-4, 20-dien-3-one (0.38 g, 13 mmol) and lithium tri-t-butoxyaluminohydride (1.36 g, 5.35 mmol) in 20 ml of anhydrous ether, was stirred by hours at room temperature, followed by the addition of Glauber's salt (6.74 g). The resulting mixture was stirred for 5 minutes and then filtered through a glass frit. The residue was washed with 5 portions of 20 ml of ether and the combined filtrates were concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (TLC) on silica gel GF, using 5% ethyl acetate / methylene chloride as eluent, to give a yellow resin (39.6 mg, 0.138 mmol, 11%) homogeneous to TLC (5% ethyl acetate / methylene chloride on silica gel, Rf = 0.29). Example 2 19-norprekna-l, 3.5 (10), 17, 20-pentaen-3-ol, 2; To a suspension of lithium aluminum hydride (LAH, 256.1 mg, 6.748 mmol) and aluminum chloride (296.8 mg, 2. 227 mmoles) in 20 ml of anhydrous ether under argon, the ethinylestradiol (1.0000 g, 3.3738 mmoles) in 20 ml of anhydrous ether was added. After refluxing for 20 hours, the reaction was quenched by the addition of the Glauber's salt (2.00 g) and stirred for a further 2 hours. The mixture was then filtered through diatomaceous earth and the residue was washed with 3 10 ml portions of ethyl acetate. Concentration of the combined filtrates, evaporative chromatography on silica gel with 15% ethyl acetate / hexanes, and recrystallization of aqueous ethanol twice gave slightly tanned colored needles (367.5 mg, 1.211 mmol, 39%), fusion (PF) of 132-1332C, homogeneous to TLC (20% ethyl acetate / hexanes on silica gel; Rf = 0.36; estra-l, 3.5 (10), 16-tetraen-3-ol, Rf = 9.36). Example 3 19-norprekna-l, 3,5 (l) trien-3-ol-2Qß-ino, 3: To a cooled solution (dry ice / acetone bath) of 19-norpregna-l, 3, 5 (10 ), 17, 20-pentaen-3-ol (2. 280.4 mg, 1,000 mmol) in 28 ml of anhydrous THF under argon, n-BuLi (2.5 M in hexane, 1.2 ml, 3.0 mmol) was added over 10 minutes . Stirring was continued for 18 hours, during which the reaction was allowed to warm gradually to room temperature. The reaction was quenched with 25 ml of IN HCl and then extracted with 3 portions of 10 ml of ether. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The resin was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography of the resulting yellow resin on silica gel with 20% ethyl acetate / hexanes, followed by recrystallization from aqueous ethanol gave fine white needles (150.5 mg, 0.5367 mmol, 54%), MP: 148-1492C, homogeneous to TLC (20% ethyl acetate / hexanes on silica gel, Rf = 0.34, starting material Rf = 0.37). Example 4 19-norprekna-l, 3.5 (10), l6,20-penta-3-ol, 4: 19-norpregna-l, 3, 5 (10), 16-tetraen-3-ol-20 -ino (200.0 g, 0.7184 mmol) in 9 ml of anhydrous THF was added to approximately 30 ml of anhydrous ammonia. Sodium (0.07 g, 3 atom-mg) was added in small pieces and the reaction was stirred for 1 hour, during which the color disappeared. Then absolute ethanol (3 ml) was added and the mixture allowed to warm to room temperature overnight. HCl (20 ml IN) was added and the mixture was extracted three times with 10 ml portions of methylene chloride. The combined organic extracts were washed with 10 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Preparative TLC (silica gel GF, with 20% ethyl acetate / hexanes) of the resulting amber resin, followed by recrystallization from benzene / hexanes provided an almost white powder, P.F .: 123-125SC. TLC (20% ethyl acetate / hexanes) showed a major product (Rf = 0.38) with a minor contaminant (Rf = 0.04). Example 5 l9-norprekane-5 (10), 20-dien-3-one, 5: The methyl ether of 19-norpregna-2,5 (10), 20-trien-3-yl (750.0 mg, 2.513 mmol ) was dissolved in 80 ml of acetone and oxalic acid (0.88 g, 7.0 mmol) in 12 ml of water was added. More acetone (20 ml) was added to bring most of the precipitate back into solution and the reaction was stirred for 6 hours. After cooling the reaction mixture with saturated sodium bicarbonate (30 ml), two 40 ml portions of ethyl acetate were added. The combined organic extracts were washed twice with 50 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (10% ethyl acetate / hexanes on silica gel) provided a colorless resin (0.54 g, 1.9 mmol, 76%). Example 6 19-norpre na-5 (l?), 20-dien-3-ol, 6; To an ethereal solution (8.4 ml) of 19-pregna-5 (10), 20-dien-3-one (0.42 g, 1.5 mmol) was added 69.7 mg (1.84 mmol) of LAH and the reaction was stirred for 30 minutes . Glauber's salt (2.79 g) was added and the suspension was stirred for a further 10 min. The mixture was then filtered through diatomaceous earth and the residue was extracted with 435 ml portions of ether. The combined filtrates were concentrated under reduced pressure and the resulting oil was subjected to evaporative chromatography (20% ethyl acetate / hexanes on silica gel) to give an almost white foam (0.38 g, 1.3 mmol, 88%). Example 7 19-norprekane-4,20-diene-10β-ol-3-one, 7; The 19-norpregna-5 (10), 20-dien-3-one (5, 0.45 g, 1.6 mmol) in DMF (5.7 ml) was cooled in an ice-acetone bath and the Jones reagent was added (2.67). M, 0.19 ml, 0.51 mmol). After stirring for 1 hour, an additional 0.19 ml of Jones's reagent was added. Stirring was continued for 45 minutes, after which 0.38 ml of Jones's reagent was added. The reaction was cooled after stirring for an additional 1 hour by the addition of 2-propanol (0.38 ml). Ethyl acetate (100 ml) was added and the mixture was washed with 3 portions of 50 ml of water + 50 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC in alumina with 50% ethyl acetate / hexanes provided a white crystalline film (89.2 mg, 0.297 mmol, 19%). TLC (50% ethyl acetate / hexanes on silica gel) showed mainly the product (Rf = 0.46), contaminated with little starting material (Rf = 0.73). Example 8 l9-norprecrine-4, 9 (10), 20-trien-3-one, 8t A solution of 19-norpregna-5 (10), 20-dien-3-one (0.34 g, 1.2 mmole) in pyridine Anhydrous (4.0 ml, 49 mmol) was cooled in an ice-salt bath to below -8BC and solid perbromide of pyridinium bromide (1.25 g, 3.94 mmol) was added at such a rate that the reaction temperature did not exceed - 22C. After stirring for 1 minute, 0.20 g of phenol was added, the cold bath was removed and the reaction was stirred at room temperature for 24 hours. Ethyl acetate or (50 ml) was added and the mixture was washed with 50 ml of IN HCl + 25 ml of saturated CuS04 + 25 ml of 5% sodium hydroxide + 25 ml of water + 25 ml of brine. The mixture was then dried over sodium sulfate for 4 hours and then filtered through a glass frit. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The dark syrup test (512.8 mg) was taken in 8 ml of absolute ethanol, and zinc powder (260.8 mg, 3,990 mg-atom) was added and the suspension was refluxed for an hour. The reaction mixture was filtered through cotton and the residue was washed with 10 ml of ethanol. Concentration of the combined filtrates and purification twice by preparative TLC, first on silica gel GF (1000 μ, 20% ethyl acetate / hexanes as eluent) then on GF alumina (1000 μ, 20% acetate ethyl acetate / hexanes) gave an almost colorless resin (152.8 mg, 0.5410 mmol, 45%), homogeneous to TLC (Rf-0.22, 10% ethyl acetate / hexanes on silica gel; pregna-4,20-dien -3-one, Rf = 0.25). Example 9 19-norprekna-l, 3.5 (10), 20-tetraen-3-ol, 9: Ethinyl estradiol acetate (2,0004 g, 5.2576 mmol) in 100 ml of anhydrous THF was added to approximately 140 ml of anhydrous NH3. and sodium (1.88 g, 81.8 mg-atom (in small strips in 5 minutes.) After stirring the dark blue solution for 1 hour, absolute ethanol was added and the reaction allowed to warm gradually to room temperature overnight. 100 ml of IN HCl were added and the layers were separated, and the aqueous layer was extracted twice with 50 ml portions of ether The combined organic phases were washed with 3 100 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth, the residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure, the residue was taken up in 25 ml of methylene chloride, dried over sodium sulfate and filtered at room temperature. through diatomaceous earth, the residue was washed twice On 10 ml portions of methylene chloride and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (15% ethyl acetate / hexanes on silica gel) provided a crystalline solid with yellow spots (0.86 g, 3.0 mmol, 58%). Example 10 Methyl ether of 19-norpresna-l, 3-5 (10). 20-tetraen-3-yl, 10: To 19-norpregna-l, 3.5 (19), 20-tetraen-3-ol (9, 0.86 g, 3.0 mmoles) in 75 ml of 90% ethanol, potassium carbonate (6.73 g) was added. , 55.2 mmoles) and the suspension was refluxed for% h. Dimethyl sulfate (0.75 ml) was added and the reaction was refluxed for an additional hour. Dimethyl sulfate was added in 3 aliquots of 1.8 ml (total = 6.15 ml, 65.0 mmol) over 1 hour and the reflux was continued for% hour. Ice water (65 ml) was added and the mixture was cooled in an ice bath and stirred for 2 hours. The suspension was centrifuged and then filtered through thick frit. The residue was washed with 50 ml of water + 50 ml of 5% sodium hydroxide + 3 50 ml portions of water. The residue was recrystallized from aqueous ethanol to give fine white needles, P.F .: 108.5-110ac (literature, P.F .: 108-1102C).

Example 11 Acetate dl9-norprekna-1.3.5 (10), 16-tetraen-6-on 20-in-3-yl, ll; Chromium trioxide (2.68 g, 2.68 mmol) was suspended in 40 ml of methylene chloride and the suspension was cooled in an ice-salt bath at -8dC. 3,5-Dimethylpyrazole (2.58 g, 26.8 mmol) was added and the suspension was stirred for 20 minutes. The acetate of 19-norpregna-l, 3,5 (10), 16-tetraen-20-in-3-ol (0.86 g, 2.7 mmol) was added in 5 minutes, so that the reaction temperature did not exceed -72C. After stirring for a further 2 hours, the reaction mixture was emptied through a 30 mm x 116 mm column of silica gel and the elution was continued under pressure with methylene chloride. The concentration of the appropriate fractions gave a brown film (0.16 g, 0.48 mmol, 18%). Example 12 19-norprekane-1, 3, 5 (10), 16-tetraen-3,6-diol-20-ino, 12: 19-norpregna-l, 3,5 (10), 16-tetraendetate 6-on-10-in-3-yl (11, 0.16 g, 048 mmol) was suspended in 20 ml of anhydrous ether, the LAH (36.7 mg, 0.967 mmol) was added and the mixture was refluxed to the exclusion of Water for 18 hours. After cooling, 1.22 g of the Glauber's salt were added and the suspension was stirred for an hour. The mixture was filtered through diatomaceous earth and the residue was washed with 4 portions of 10 ml of hot ethyl acetate. Concentration of the combined filtrates, followed by purification by preparative TLC (50% ethyl acetate / hexanes on silica gel GF, 1000 μ) gave a white solid (26.0 mg, 88.3 μmol, 18%) homogeneous to the TLC (50% ethyl acetate / hexanes on silica gel; Rf = 0.48). Example 13 19-norprekna-l, 3.5 (10), 17-tetraen-3-ol, 13: Ethyltriphenylphosphonium bromide (1.3947 g, 3.7572 moles) and potassium t-butoxide (422.5 mg, 3.765 mmol) it was suspended in anhydrous DMSO (4.1 ml) under argon and then placed in an oil bath (80-842C) and stirred for 1 hour. Equilin (200.2 mg, 0.7459 mmol) in 4.1 ml of anhydrous DMSO was added and the reaction was stirred for an additional hour. After cooling, 25 ml of ice-IN HCl was added and the mixture was extracted three times with 20 ml portions of ether. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (20% ethyl acetate / hexanes on silica gel), followed by preparative TLC (20% ethyl acetate / hexanes on silica gel GF, lOOO) gave a slightly yellow resin (182.9 mg, 0.6523). mmol, 87%), homogeneous to TLC (20% ethyl acetate / hexanes, Rf = 0.42). Example 14 19-norpreana-l, 3.5 (10), 6,17-pentaen-3-ol, 14: Ethyltriphenylphosphonium bromide (1.3945 g, 3. 7561 mmoles) and potassium t-butoxide (422.8 mg, 3.768 mmol), suspended in 4.0 ml of anhydrous DMSO under argon, was placed in a bath at 77-79dC and stirred for 1 hour. The 6-dehydroestrone (200.4 mg, 0.7466 mmol) in 4.1 ml of anhydrous DMSO was added and the reaction was stirred in 1 hour. The reaction mixture was allowed to cool and then emptied into 25 ml of ice-IN HCl. The mixture was extracted three times with 20 ml of ether and the combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (15% ethyl acetate / hexanes) and preparative TLC (15% ethyl acetate / hexanes on silica gel GF, 1000 μ) gave an almost white crystalline solid (212.9 mg,> 100%) homogeneous to TLC (15% ethyl acetate / hexanes on silica gel, Rf = 0.21).

Example 15 19-norprekna-l, 3.5 (10), 6.8, 17-hexa-en-3-ol, 15: Ethyltriphenylphosphonium bromide (1.3945 g, 3.7561 mmol) and potassium t-butoxide ( 422.3 mg, 3.763 mmole), suspended in 4.1 ml of anhydrous DMSO, under argon, was placed in an oil bath (74-832C) and the reaction was stirred for 1 hour. Equilenin (200.2 mg, 0.7518 mmol) in 4.1 ml of anhydrous DMSO was added and the reaction mixture was stirred for an additional hour. The mixture was poured into 25 ml of ice-IN HCl and extracted three times with 20 ml portions of ether. The combined organic extracts were washed with 25 ml of saturated sodium bicarbonate + 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure, evaporative chromatography (20% ethyl acetate / hexanes) and preparative TLC (20% ethyl acetate / hexanes on silica gel GF. , 1000 μ) gave a light yellow crystalline wax (180.6 mg, 0.6487 mmol, 86%), homogeneous to TLC.

Scheme 5 - Synthesis, catalysed with Pd (II), of the 19-norpregnenos Example 16 17-iodo-estra-l, 3,5 (10), 7,16-penta-en-3-ol, 16: A crude equilin-17-hydrazone (1.0058 g, < 3.5000 mmol) in 21 ml of anhydrous THF + 4.4 ml (32 mmol) of triethyleneamine under an Ar atmosphere and cooled in an ice bath, iodine (2.10 g) was added. , 16.5 mmol) in 21 ml of THF was anhydrous over 33 minutes, until the yellow color persisted and gas evolution ceased (solution of 12 remaining: 5 ml). Stirring was continued for 20 minutes, after which the reaction mixture was concentrated under reduced pressure and resuspended in 90 ml of ether. The suspension was washed with 35 ml of IN HCl + 35 g of 5% sodium wt. Pentahydrate (w / w) + 35 ml of saturated sodium bicarbonate + 35 ml of brine, dried over magnesium sulfate and filtered through of diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (20% ethyl acetate / hexanes on silica gel) of the residue provided a yellow foam (953.8 mg, 2.522 mmol, 72%). Example 17 19-norpre na-l, 3.5 (10) .7.16-penta-en-3-ol, 17: A mixture of 17-iodoestra-l, 3, 5 (10), 7, 16-penta-en- 3-ol (953.8 mg, 2.522 mmol), [1,1'-bis (diphenylphosphino) ferrocene] chloride [palladium (II), CH2C12 (51.5 mg, 63.1 μmol), 10 ml of THF, 2.8 ml (2.8 mmol) of 1.0 M triethylborane in THF, and 2.5 ml of 15% (w / w) of sodium hydroxide, was refluxed under an Ar atmosphere, for 24 hours. After cooling, 10 ml of IN HCl were added and the reaction mixture was extracted 3 times with 10 ml portions of methylene chloride. The combined organic extracts were washed with 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Preparative TLC (20% ethyl acetate / hexanes on silica gel GF, 1000 μ) of the residue provided an amber resin (54.4 mg, 0.194 mmole, 7.7%) homogeneous to TLC (20% ethyl acetate / hexanes on silica gel, product Rf = 0.39; 17-iodoestra-l, 3.5 (10), 16-tetra-en-3-ol, Rf = 0.37). Example 18 19-.norpre-na-2,5 (10), l6-trien-3-yl methyl ester, 18: The methyl-ether of 19-norpregna-l, 3-5 (10), 16-tetra -in-3-yl (1.00 g, 2.27 mmol) in 15 ml of anhydrous THF + 11.14 g of t-butanol was added to approximately 100 ml of anhydrous ammonia, followed by 0.41 g of lithium wire cut into small pieces. After stirring for 4 hours, the reaction was cooled with the addition of 3.8 ml of anhydrous methanol and the ammonia was allowed to boil and separate for 3 hours. 100 ml of water were added and the mixture was extracted twice with 100 ml portions of ether. The combined organic extracts were washed 3 times with 50 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Recrystallization of the resulting 95% ethanol syrup gave white crystals (586.7 mg, 1966 mmol, 58%), P.F .: 70-720C. Example 19 19-norpregna-4,16-dien-3-one, 19: To a solution of 19-norpregna-2,5 (10), 16-trien-3-yl raethyl ether (3,298.5 mg, 1,000 mmol) ) in 8 ml of acetone + 2.5 ml of methanol, 2.5 ml of IN HCl was added. After stirring for 1 hour, the hydrolysis was stopped by the careful addition of 3.00 g of sodium bicarbonate. Once the effervescence ceased, the mixture was extracted three times with 10 ml portions of methylene chloride. The combined organic extracts were washed with 10 ml of brine, dried over sodium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Preparative TLC (15% ethyl acetate / hexanes on silica gel GF, 1000 μ) twice from the resulting amber resin, provided a yellow solid (107.4 mg, 0.3776 mmol, 38%), homogeneous to TLC (15% ethyl acetate / hexanes on silica gel; product, Rf = 0.29; pregna-4, 16-dien-3-one, Rf = 0.32). Example 20 19-norpregna-5 (10), 16-dien-3-one, 20: To a solution of methyl-ether 19-norpregna-2,5 (10), 16-trien-3-yl (18, 1.38 g, 4.62 mmoles) in 65 ml of acetone, 1.60 g (12.7 mmoles) of oxalic acid dihydrate in 23 ml of water were added. Then 85 ml of acetone was added and the reaction mixture was stirred for 8 hours. The hydrolysis was stopped with the addition of 65 ml of saturated sodium bicarbonate and the mixture was extracted three times with 100 ml portions of ether. The combined organic extracts were washed twice with 100 ml portions of brine, dried over sodium sulfate overnight and filtered through a glass frit. Evaporative chromatography (10% ethyl acetate / hexanes on silica gel) of the resulting syrup, followed by recrystallization from hexanes, gave two crops of white crystals (775.8 mg, 2.727 mmol, 59%). For the first harvest: P.F .: 82.5-852C; TLC (5% ethyl acetate / hexanes on silica gel), Rf = 0.13; 19-norpregna-4, 16-dien-3-one, Rf = 0.03.

Example 21 19-norprekane-4,16-dien-lQß-ol-3-one, 21: To a solution of 19-norpregna-5 (10), 16-dien-3-one (20.341.3 mg, 1200 mmol ) in 8.2 ml of chloroform, cooled in an acetone / dry ice bath, was added 3-chloroperbenzoic acid (0.89 g, 5.2 mmol) in 9 ml of ether over 5.5 minutes. The reaction mixture was stirred for 2 hours and then left in the refrigerator for 16 hours. The reaction was then poured into 70 g of 5% (w / w) of sodium thiosulfate pentahydrate and the layers were separated. The aqueous layer was extracted 3 times in 15 ml portions of ethyl acetate. The combined organic phases were washed with 15 ml of saturated sodium bicarbonate + 15 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. To the resulting white solid 5% (w / w) potassium hydroxide in methanol was added and the mixture was refluxed with exclusion of moisture for 1 hour. The mixture was then poured into 140 ml of ice / brine and extracted 3 times with ether. The combined organic extracts were washed twice with 100 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Preparative TLC (silica gel GF, 1000 μ), once with 50% ethyl acetate / hexanes and once with 10% ethyl acetate / methylene chloride, gave a yellow resin (157.7 mg, 0.5249 mmoles, 44%, homogeneous to TLC (50% ethyl acetate / hexanes on silica gel, product, Rf = 0.32, pregnenolone, Rf = 0.40).

Scheme 6 - felt ie "i o.norpragnun? Q EXAMPLE 22 Methyl-ether of l9-norprekna-2,5 (l?) -dien-3-yl A solution of the methyl ether of 19-norpregna-l, 3,5 (10) -trien-3-yl (800.0 mg, 2,680 mmole) in 121 ml of anhydrous THF + 8.86 g of t-butanol was added to approximately 90 ml of anhydrous ammonia, followed by 0.33 g of lithium wire cut into small pieces. After stirring for 4 hours, 3.0 ml of methanol was added and the ammonia was allowed to boil and separate overnight. 80 ml of water were added and the mixture was extracted twice with 80 ml aliquots of ether. The combined organic extracts were washed 3 times with 40 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave a white solid (638.6 mg, 2125 mmol, 79%), P.F .: 84-88ac. TLC (5% ethyl acetate / hexanes on silica gel) showed a product (Rf = 0.56, starting material, Rf = 0.49) with traces of the less polar contaminant (Rf = 0.80). Example 23 19-norprekane-5 (10) -en-3-one, 23: To a solution of 19-norpregna-2,5 (10) -dien-3-yl methyl ether (2.2, 500.0 mg, 1664) mmoles) in 55 ml of acetone, oxalic acid dihydrate (0.58 g, 4.6 mmol) in 8.3 ml of water was added. After stirring for 7 hours, 25 ml of saturated sodium bicarbonate was added and the mixture was extracted 3 times with 35 ml portions of ether. The combined organic extracts were washed 3 times with 35 ml portions of brine, dried over sodium sulfate overnight, and filtered through a coarse frit. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (10% ethyl acetate / hexanes, on silica gel) gave a slightly yellow syrup (394.1 mg, 1376 mmol, 83%). Example 24 19-norprequin-4-en-10β-ol-3-one, 24: To a solution of 19-norpregn-5 (10) -en-3-one 23, 330. 3 mg, 1153 mmoles) in 7.9 ml of chloroform, cooled in an acetone / dry ice bath, 3-chloroper-benzoic acid (0.86 g, 5.0 mmol) in 8.6 ml of ether was added in 6 minutes. After stirring for 2 hours, the reaction was stored in the refrigerator for 24 hours. The mixture was then poured into 70 g of 5% sodium thiosulfate pentahydrate (w / w) and the layers were separated. The aqueous layer was extracted 3 times with 15 ml portions of ethyl acetate. The combined organic phases were washed with 15 ml of saturated sodium bicarbonate + 15 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. To the resulting colorless syrup 55 ml of 5% (w / w) potassium hydroxide in methanol was added and the mixture was refluxed for 1 hour, with exclusion of moisture. After cooling, the reaction mixture was poured into 140 ml of brine and extracted three times with 100 ml portions of ether. The combined organic extracts were washed twice with 100 ml portions of brine, dried over sodium sulfate overnight and filtered through coarse frit. The residue was washed with 25 ml of ether and the combined filtrates were concentrated under reduced pressure. Preparative TLC (10% ethyl acetate / methylene chloride on silica gel GF, 1000 μ) gave a yellow resin (105.6 mg, 0.3491 mmol, 30%). TLC (50% ethyl acetate / hexanes on silica gel) showed the product (Rf = 0.47.; pregnenolone, Rf = 0.42) with traces of contaminants (Rf = 9.39).

Scheme 7 - Additional synthesis of the 19-norpreknenes 26 27 Example 25 Methyl ether of 19-norprekna-l, 3,5 (10), 7,17,20-hexa-en-3-yl, 25: To lithium aluminum hydride (98.4 mg, 2.59 mmol) and aluminum chloride (115.2 mg, 0.8642 mmol) under A, 8.9 ml of anhydrous THF were carefully added, followed by a solution of methyl-ether of 19-norpregna-l, 3-5 (10), 7-tetra-in -17ß-ol-in-3-yl (400.0 mg, 1297 mmol) in 8.0 ml of anhydrous THF. The reaction mixture was refluxed for 24 hours, and then cooled with the addition of 0.77 g of Glauber's salt. After stirring for a further 2 hours, the mixture was filtered through diatomaceous earth and the residue was extracted three times with 5 ml portions of ethyl acetate. Concentration of the combined filtrates yielded a light yellow resin, which was purified by evaporative chromatography (5% ethyl acetate / hexanes on silica gel), preparative TLC (5% ethyl acetate / hexanes on gel of silica GF, 1000 μ) and recrystallization of 95% ethanol, to give very fine white needles (140.1 mg, 0.4791 mmol, 37%), PF: 79-962C, homogeneous to TLC (10% ethyl acetate hexanes on silica gel, product, Rf = 0.59, methyl ether of estra-1, 3, 5 (10), 16-tetra-en-3-yl, Rf = 0.62).

EXAMPLE 26 Methyl ether of 19-norprekane-1.3.5 (10), 7,16-penta-en-20-in-3-yl, 26: To a solution of methyl-ether of 19-norpregna-1,3 , 5 (10), 7-tetra-en-17β-ol-20-yn-3-yl (308.4 mg, 0.9999 mmol) in 2,4-lutidine (2.0 ml, 17 mmol) was added phosphorus oxychloride ( 0.31 g, 2.0 mmol). After stirring for 18 hours, the reaction mixture was emptied into 35 ml of 3.6N sulfuric acid and extracted 3 times with 10 ml portions of methylene chloride. The combined organic extracts were washed with 10 ml of 3.6N sulfuric acid + 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 5 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. The residual dark resin was purified by evaporative chromatography (5% ethyl acetate / hexanes on silica gel) and preparative TLC (5% ethyl acetate / hexanes), once on silica gel GF (1000 μ). and once over GF alumina (1000 μ), to yield a yellow solid (53.4 mg, 0.184 mmol, 18%).

Example 27 Acetate of 19-norprekane-1.3.5 (10), 7, 16-penta.en.20-in-3-yl, 27: To a solution of 19-norpregna-1,3,5 acetate (10 ), 7-tetra-en-17β-ol-20-yn-3-yl (672.9 mg, 2000 mmol) in 2.4-lutidine (4.0 ml, 35 mmol) was added phosphorus oxychloride (0.63 g, 4.1 mmol). After stirring for 16 hours, the reaction mixture was poured into 70 ml of 3.6N sulfuric acid, and extracted three times with 20 ml portions of ether. The combined organic extracts were washed with 40 ml of 3.6N sulfuric acid + 40 ml of saturated sodium bicarbonate + 40 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (10% ethyl acetate / hexanoe on silica gel) of the resulting foam, followed by crystallization from aqueous ethanol, gave slightly yellow needles (327.3 mg, 1.028 mmol, 51%), PF: 89-94SC . TLC (10% ethyl acetate / hexanes on silica gel) showed the product (Rf = 93.1; methyl-ether of 19-norpregna-1, 3.5 (10), 16-tetra-en-3-yl) , Rf = 0.64) with contaminants at Rf = 0.27, 0.14, 0.04 and 0.00.

Example 28 19-norpreqna-l.3.5 (10), 7, 6-penta-en-3-ol-20-ino. 28: To a solution of 19-norpregna-1,3,5 (10), 1, 16-penta-en-in-3-yl acetate (27, 328.4 mg, 1,000 mg) in 50 ml of hot methanol, 2.4 ml of 5% (w / w) of sodium hydroxide was added. After stirring per hour, 3 ml of IN HCl was added and the mixture was concentrated under reduced pressure. Preparative TLC (20% ethyl acetate / hexanes on GF alumina, 1000 μ), gave a light yellow resin (91.2 mg, 0.330 mmol, 33%), homogeneous to TLC (20% ethyl acetate / hexanes on silica gel, product Rf = 0.36, estra-l, 3.5 (10), 16-tetra-en-3-ol, Rf = 0.43).

Eachema 8 - Synthesis of the 19-norpreqnanos EXAMPLE 29 19-norprekane-5 (10), 17-dien-3-one, 29: To a solution of the methyl ether of 19-norpregna-2,5 (10), 17-trien-3-yl (422.2 mg , 1,425 mmoles) in 45 ml of acetone, oxalic acid dihydrate (0.49 g, 3.9 mmol) was added in 7 ml of water. After stirring for 7 hours, the hydrolysis was quenched by the addition of 20 ml of saturated sodium bicarbonate and the mixture was extracted 3 times with 30 ml portions of ether. The combined organic extracts were washed twice with 30 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (10% ethyl acetate / hexanes on silica gel) of the residual film gave a colorless syrup (0.35 g, 1.2 mmol, 87%). Example 30 19-norpregna-4, l7-dien-10ß-ol-3-one, 30: To a cooled solution (acetone / dry ice) of 19-norpregna-5 (10), 17-dien-3-one (29, 0.35 g, 1.2 mmol) was added 3-chloroperbenzoic acid (0.89 g, 5.2 mmol) in 9 ml of ether. After stirring for 2 hours, the reaction was placed in the refrigerator for 18 hours. The mixture was then poured into 70 g of 5% (w / w) of sodium thiosulfate pentahydrate and the layers were separated. The aqueous layer was extracted three times with 15 ml portions of ethyl acetate. The combined organic phases were washed with 15 ml of saturated sodium bicarbonate + 15 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. To the light yellow residual solid, 5% (weight / weight) of potassium hydroxide in methanol (55 ml) was added and the mixture was refluxed with the exclusion of moisture, for 1 hour. The reaction was then emptied into 140 ml of ice water and extracted with 140 ml of ether. The organic extract was washed twice with 140 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. The resulting yellow film was subjected to preparative TLC (50% ethyl acetate / hexanes on silica gel GF, 1000 μ) to give a light yellow foam (84.6 mg, 0.282 mmol, 23%), homogeneous to the TLC (50% ethyl acetate / hexanes on silica gel, product, Rf = 0.26, dihydroepiandrosterone, Rf = 0.36). %1 Scheme 9 - Synthesis of methyl-ether of 19-norpreqna- 1.3.5 (10), 16-tetra-en-3-yl 31 N2S04 / 2C03 Me234 / K2C03 32 Example 31 19-norprßqna-l-3-5 (10), 16-tetra-en-3-ol, 31: To a mixture of 17-iodoestra-l, 3,5 (10) -16-tetra-en- 3-ol (1.14 g, 3.00 mmol) and the monomethylene chloride complex of [1,11-bis (diphenylphosphino) -ferrocene] -palladium (II) chloride ("Pd (II) catalyst", 61.2 mg, 74.9 μmol) in tetrahydrofuran (THF, 12 ml) under argon, added triethylborane in THF (1.0 M, 3.3 ml, 3.3 mmol) followed by 15% (w / w) sodium hydroxide (3.0 ml) and the mixture of reaction was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure, IN HCl (12 ml) was added and the residual suspension was extracted three times with 10 ml aliquots of methylene chloride. The combined organic extracts were washed with 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 5 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (15% ethyl acetate / hexanes on silica gel) with subsequent recrystallization from aqueous methanol gave a white powder (606.2 mg, 2146 mmol, 72%), PF: 124-1252C, homogeneous to TLC (15 mL). % ethyl acetate / hexanes on silica gel, Rf = 0.31, starting material, Rf = 0.27).

EXAMPLE 32 Methyl ether of 19-norprekane-1.3.5 (10). 16-tetra-en-3-yl, 32, from 19-norprekna-l, 3.5 (10), 16-tetra-en-3 -ol Potassium carbonate (0.37 g, 2.7 mmol) was added to a solution of 19-norpregna-l, 3.5 (10), 16-tetraen-3-ol (31, 500.0 mg, 1770 mmol) in acetone (25 ml) and the suspension was heated to reflux, with the exclusion of moisture. Methyl sulfate (0.42 ml, 4.4 mmol) was added in one portion and the reaction mixture was refluxed with stirring, for 24 hours. After cooling, 35 ml of 5% (w / w) of sodium hydroxide was added and the mixture was extracted three times with 35 ml aliquots of ether. The combined organic extracts were washed with 35 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave white needles (476.3 mg, 1,607 mmol, 91%), PF: from 97-97.5BC TLC (1% ethyl acetate / hexanes on silica gel) showed the product (Rf = 0.1) with traces of a polar pollutant (Rf = 0.00). The P.F. and the TLC of the mixture showed that this product was identical to the product prepared below.

EXAMPLE 33 Methyl ether of 19-norpreqna-l.3.5 (l?), L6-tetra-en-3-yl. 33: from the methyl ether of 17-? Odo-19-norprßqna-l, 3,5 (10) .16- tetra-en-3-yl: Several different strategies for introducing an alkyl group at C-17 of the core premiere, they tried, before finding one successfully. As a first attempt, the ethyl bromide that traps the incipient 17-lithiostrene from the elimination of Shapiro (R. Chamberlin, EL Liotta and FT Bond, Org. Syn., 1982, 61: 141-146) of the estra-l , 3,5 (10) -trien-17-tosylhydrazone, simply gives compound 17H. Presumably, the steric hindrance in position 17 prevented the alkylation and allowed the hydrogen abstraction of ethyl bromide instead. The attempted displacement of iodine from 17-iodoestra-l, 3,5 (10), 16-tetra-en-3-ol with the alkyl cuprate (EJ Corey and GH Posner, J. Amer. Chem. Soc. , 1968. 90: 5615-5616) similarly gave the 17G product, apparently via the transmetallation followed by the protonolysis. The nickel (II) catalyzed displacement of the iodide, using the Grignar reagent of ethyl (M.Kumada, K, Tamao and K. Sumitani, Org. Syn., 1978, 58: 127-133) similarly failed. Surprisingly, the displacement of the iodide was effected using palladium (II) catalysis. Previous work (GA Potter, SE Barris, M. Jarman and MG Ro lands, J. Med. Chem., 1995, 38: 2463-2471) were able to show that aryl boronates can be used to displace triflate from the triflates of 17-enol. However, the transfer of the alkyl groups was considered not similar, given the propensity for the intermediate alkyl palladium to undergo β-elimination. Using the ethylborane as the alkyl transfer agent, the iodide was displaced from a variety of 17-iodoesnes to give the desired 17-aqlulesthrenes (see Schemes 9 and 10). To a mixture of the methyl-ether of 17-iodo-19-nor-pregna-l, 3.5 (10), 16-tetra-en-3-yl (394.3 mg, 1,000 mmol), the Pd catalyst (II) ) (20.4 mg, 25.0 mmol) 3.0 N sodium hydroxide (1.0 ml) and THF under argon, added triethylborane (1.0 M, 1.1 ml, 1.1 mmol). After refluxing for 24 hours and subsequent cooling, the reaction mixture was extracted with 10 ml of benzene. The organic extract was washed with 10 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 2 ml of benzene and the combined filtrates were concentrated under reduced pressure, recrystallization from 95% ethanol with carbon treatment gave tan needles (219.4 mg, 0.7401 mmolesP 74%), P.F .: 97SC. TLC (10% ethyl acetate / hexanes on silica gel) showed a polar contaminant trace (Rf-0.00) together with the product (Rf = 0.62, starting material, Rf = 0.55).

Scheme 10 - Sinteaia of 19-norpreqna- 1,3,5 (10), 7,16 pentenes. H2 33 3. 4 Example 34 Eatra-1.3.5 (10) .7-tetraen-17-hydrazone, 34: To equilin (939.4 mg, 3.500 mmol) suspended in 6.6 ml of absolute ethanol + 1.6 ml (11 mmol) of triethylamine, were added 3.1 ml (99 mmol) of hydrazine and the mixture was refluxed with exclusion of moisture for 1 hour. The reaction mixture was then added dropwise to 28 ml of water and the resulting suspension was placed in the refrigerator overnight. Filtration through a coarse frit and drying under reduced pressure on P2O5 gave fine white crystals (1.0213 g,> 100%), P.F .: 253-2552C. Example 35 17-? Odo-estra-l, 3.5 (10) .7.l6-pentaen-3-ol, 35: estra-l, 3,5 (10), 7-tetraen-17-hydrazone crude (1.0058 g, <3,500 mmol) suspended in 21 ml of anhydrous THF + 4.4 ml (32 mmol) of triethylamine under argon, cooled in a water bath and iodine (2.10 g, 16.5 mmol) in 21 ml of anhydrous THF , which was added in 33 minutes until the color no longer changed and the evolution of the gas stopped (the iodine solution remaining: 5.5 ml). After stirring for a further 20 minutes, the reaction mixture was concentrated under reduced pressure and the residue was suspended in 90 ml of ether. The suspension was washed with 35 ml of IN HCl + 35 g of 5% (w / w) of sodium thiosulfate pentahydrate + 35 ml of saturated sodium bicarbonate + 35 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Evaporative chromatography (20% ethyl acetate / hexanes on silica gel) with the recrystallization attempted, gave a yellow foam (953.8 mg, 2.522 mmol, 72%). Example 36 19-norprekna-l, 3,5 (10), 7,16-pentaen-3-ol, 36: To a mixture of 17-iodoestra-l, 3,5 (10), 7,16-pentaen- 3-ol (953.8 mg, 2.522 mmol) and the Pd (II) catalyst (51.5 mg, 63.1 μmol) suspended in 10 ml of THF under argon, 2.8 ml (2.8 mmol) of 1M triethylborane + 2.5 ml of methanol were added. % (weight / weight) of sodium hydroxide and the mixture was heated to reflux. After heating for 24 hours, during this time, the THF apparently separated by boiling, the cooled residue was suspended in 10 ml of IN HCl and extracted three times with 10 ml aliquots of methylene chloride. The combined organic extracts were added with 10 ml of saturated sodium bicarbonate + 10 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Preparative TLC (20% ethyl acetate / hexanes on silica gel GF, 1000 μ) gave an amber resin (54.4 mg, 0.194 mmol, 7.7%), homogeneous to TLC (20% ethyl acetate / hexanes, on silica gel, Rf = 0.39, 17-iodoestra-l, 3, 5 (19), 16-tetraen-3-ol, Rf = 0.37). Example 37 Electrophysiological Studies. The following electrophysiological studies were performed on clinically normal human volunteers, of both sexes, whose ages vary from 19 to 29 years. No anesthetic was used and the female subjects were excluded if they were pregnant. The stimulus and recording system consisted of a "multifunctional miniprobe" described elsewhere (Montí-Bloch, L. and Grosser, B. 1. (1991), "Effect of putative pheromones on the electrical activity of the human vomeronasal organ and the olfactory epithelium ", J. Steroid Biochem, Molec Biol. 39: 573582). The recording electrode is a 0.3 mm silver ball attached to a small silver wire (0.1 ip) insulated with Teflon®, the surface of this electrode is first treated to produce a silver chloride interface and then covered with gelatin . It was placed inside a small-bore Teflon® catheter (5 mm diameter) so that the tip of the electrode was projected by approximately 2 mm. The Teflon® catheter has a length of 10 cm and constitutes the terminal extension for a multi-channel delivery system, which delivers a continuous air stream that carries discrete pulses of chemosensitive stimuli. The air stream first passes into a small chamber and is bubbled through a solution containing either a vomeroferin or an olfactory substance in a diluent or the diluent alone. A solenoid was used to quickly redirect the air stream from the chamber to a route that deviates from the chamber. This creates a discrete pulse of stimulant in the air stream. A second Teflon® external tube with a diameter of 2 mm surrounds the electrode-catheter assembly and its central end is connected to a vacuum that supplies the continuous suction of 3 ml / sec. This concentric arrangement of the external suction tube allows the quiescent stimuli emitted to be located in a n area we call "minicamp" (approximately 1 mm in diameter), and prevents the diffusion of any substance to the area outside the stimulus site attempted or inside the respiratory system. The whole stimulus and recording can be placed either in the neurosensitive epithelium inside the WNV or on the surface of the olfactory or respiratory epithelium.

Electro-vomeronasoqrama (EVG) The recordings were carried out in a quiet room with the subject in the supine position; The multifunctional miniprobe was initially stabilized within the nasal cavity using a nasal retractor placed in the vestibule. The reference and ground electrodes consist of silver discs (8 mm), both of which are placed in the glabella. The entrance to the VNO, or vomeronasal fossa, is identified by first dilating the nasal opening and the vestibule. A binocular loupe with 6-fold amplification, with halogen illumination was then used to introduce the tip of the Teflon® catheter and the recording electrode assembly into the VNO opening, where it is set at a depth of approximately 1 mm inside the vomeronasal passage. Optimum placement of the recording electrode was noted after testing for adequate depolarization, in response to a test substance. The electrical signals from the recording electrode are fed to a DC amplifier, after which they are digitized, inspected and stored by the computer. The peak-to-peak amplitude of the signals is measured, and the area under the depolarization wave is integrated, while the signal is continuously inspected both on the computer screen and on the digital oscilloscope. Artifacts produced by respiratory movements are suppressed by training subjects to practice breathing through the mouth with the velopharyngeal closed. Samples of the vomeroferins at a concentration of 25 to 800 fmoles are delivered in the continuous air stream for durations of 300 milliseconds up to 1 second. Usually, intervals of 3 to 5 minutes each series of short test pulses are separated. All components of the lines that carry the test stimuli are made of Teflon®, glass or stainless steel and are carefully cleaned and sterilized before each use. The activity was recorded using standard electroencephalographic electrodes (EEG), placed in positions Cz-Al and Tz-Al, of the international system 10120, the ground electrode was placed in the masatoid process. The temperature of the skin (ST) was recorded by a small thermistor probe (1.0 mm), placed in the lobe of the right ear. The respiratory frequency (RF) was measured with an adjustable effort gauge, placed around the lower chest. All electrical signals were amplified by direct current and digitized (MP-100, Biopac Systems) and inspected continuously using a computer. Statistical Analysis: The EVG, changes from peak to peak and changes of frequency of other parameters were measured and analyzed statistically. The meaning of the results was determined by anyone using pairs of t tests or the analysis of variance (ANOVA). Effects of Reflexes of Vomeroferins: Studies were carried out to determine the reflex responses of the Central Nervous System to the VNO vomeropherin stimulus. The sexually dimorphic local responses induced by the vomeropherins are sometimes reflected in the autonomic response of the male and female subjects. The cortical activity of Cz and Tz was recorded in male and female subjects during the application to the VNO of air pulses (300 ms up to 1 sec) containing vomeroferin fmoles. There is also preliminary evidence that EVG is not associated with trigeminal nociceptor ends, since the application of a local anesthetic (2% 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 the olfactory epithelium", J. Steroid Biochem, Mole, Biol. 39: 573-581.) Similarly, the subjects failed in presenting sensations of pain, as a consequence of any stimulus procedure.

The following studies compare the effect of 23 vomeropherins with structure of 19-norpregnane and placebo (propylene glycol), in the autonomic activity and the EEG. Twelve healthy human subjects (6 women and 6 men) aged 19 to 29 years participated in this study. All substances were delivered through the air to the vomeronasal organ (VNO), blowing for at least 5 seconds. For this purpose, a miniprobe electrode was used, described elsewhere, which allows the local stimulation and the simultaneous recording of the electrovomerorgama (EVG of the organ.) The registered parameters were: electrodermal activity (EDA), respiratory frequency (RF) ), electrocardiogram (CF), electromyogram (EMG), body temperature (BT) and EEG from CzAl and T3A1 Autonomic activity, EEG and EVG, were recorded using surface electrodes.All techniques used were noninvasive. The procedure was carried out in two recording sessions, each lasting one hour.The electric recordings were amplified, digitized and monitored and stored in a computer.The process and analysis of the results are done offline.The data in the tests in The women are shown in Figures 3-24, and the data in the men are shown in Figures 25-46.

The results are summarized in the following tables, which show the general effect of each vomeropherin already subtracted from the control. An arbitrary rating of 0 to 5 was assigned to compare the activity of the compounds in relation to each other, but virtually all of the compounds tested had the same effect. These results show that the effect of some vomeropherins on autonomic activity and EEG is significantly different from placebo. It also shows that some substances do not have significant different effects in both genders (sexes).

SUMMARY OF EFFECTS OF THE VOMEROFERINAS OF THE 19-NOR-PREGNAN IN THE EEG AND THE AUTONOMOUS ACTIVITY IN WOMEN, n = 6 EVG QA R5 CF EMG BT a-CA PCA PERPORMANCE SCORE UTKH. MTtmcf-fífflS +100 4 -5 0 -15 -10 -35 EDA + tF-.CF- ^. 5 arn. +5 -K > -15 +10 +5 • 15 +5 45 CF +? + 3 £ f / rx + 2-5 -W 4 +5 4 0 +15 -15 EDA-JMO- 3 ST »+30 +70 4 • 5 0 0 -5 -2 ED? + RF-CF. 4 A e-mrs oF € t + so +130 0 0 0 + < 0 -15 EDA + .BT + aV 4 £ 3fí +20 +70 -15 • 15 0 +3 -10 • 30 EDA + 2 erorx +3 -10 0 +10 4 0 +10 +10 ED? -, CF + EMGMI + 5 ezp +25 +50 +5 • 5 0 +10 • 15 40 EDA + JT + 3 EZ / f * +25 +30 0 0 0 0 -10 -40 0 0 ezX +20 +50 0 • 5 0 0 -15 40 EDA + .CF- 3 airt +45 +110 +5 0 0 0 -5 -10 0 0 £ 2ñ +40 +95 +3 +5 0 0 0 -15 EDA +. RF + .CF + 4 n? Txn. £ V * ßt < ? £ * n +20 + SS -25 4 0 0 4 -20 EDA + .CF- 3 ea / rt +1 • 10 0 0 4 0 0 • 40 EDA-.EMG - ^ - 4 £ 0 / ñ +20 - 10 0 +5 -15 -1 0 -25 0 0 er / rt 0 -10 0 0 0 0 0 -40 0 0? C? MT = ot exr * +15 -10 • 15 +15 4 4 +10 -20 E 0-5T-, a + 5 eun +25 +110 0 0 0 +10 +7 -20 EDA + .BT +, a + ¿+ 5 ex / n. +20 +20 4 • 6 0 -2-5 +7 -25 CF- T -: * 5 e / +50 +110 +15 0 0 0 * 30 -10 EDA + .a * 4? r +35 +100 0 4 0 4 -10 -25 EDA + .CF-BT- 4 etf +35 +105 +15 0 0 • 1 -10 -40 0 0 SUMMARY AND EFFECTS OF THE VOMEROFERINES OF 19-NOR-PREGNANE IN THE EEG AND THE ACTIVIDAE > AUTONOMIC IN MEN. n = 6 EVG ES2A RF CF EMG BT a-CA ßCA PERPORMANCE SCORE "in"*. + W 0 4 -15 -15 +15 -10 EDA + .CF- 3 < +) GJ X +20 • 20 0 +15 • 15 -5 -7 -Mi BT- 2 Ef / n +15 O 0 +15 0 -15 .15 40 0 0 +18 +70 0 0 0 +7 • 15 40 EDA + .BT + &- 4 £ 7? 1 +40 + «0 0 0 * 15 -10 • 30 EDA + 2 £ 7 / +15 +50 0 • 15 0 4 .10 40 EDA *. BT-¿- 4 CUf / f? +20 -20 0 +15 4X5 -1 0 «40 0 0 í / rt +30 +120 0 +15 0 0 • 10 40 0 0 0 EDA + JBT + 4. 4 ez / r = +10 +90 0 0 0 +10 4 4 € Z / H +12 +100 0 0 0 • 15 0 -20 EDA * 2 yes / ñ +35 +120 4.5 0 0 +15 -15 40 EDA + 2 sx / n +30 +120 0 0 0 -7 • 10 .20 EDA + JT-.CEBL3 *) 4 Mcp ^ / t erwttefW + i5 +110 4 0 0 0 0 -20 EDA +? F- 3 8 ñ +20 4 0 0 • 15 0 4 -15 0 0 tx r + 1S 40 +15 0 0 -2J 4 .15 0 0 & h +10 40 0 '-15 -15 0 4 .10 0 0 ycaxrv ce etfn +15 40 0 -15 -15 -2-5 -5 -15 0 0 evn +30 +100 0 0 0 0 -10 • 20 0 0 / rz +15 + to 0 0 0 +15 4 45 0 0 ez rf +50 4 * 0 -15 0 0 4 • 10 40 EDA + -, (EB &t) 4 etz n +25 +120 0 0 0 +15 • 10 -25 EDA + 2 e # p +30 +130 0 0 0 + 2-5 4 -20 EDA * 2

Claims (58)

1. CLAIMS 1. A pharmaceutical composition, suitable for nasal administration in an individual, this composition comprises a 19-nor-pregnane steroid and a pharmaceutically acceptable carrier, wherein the steroid has the formula: in which P ^ is oxo, a- or β-hydroxy, a- or β-acetoxy, a- or β-propionoxy, α- or β-lower alkoxy, α- or β-acyloxy or α- or β- benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m", and "n", are alternative sites for optional double bonds, and "k" may be absent or present, with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy with 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy with 1-6 carbon atoms, or halogen; P4 is methyl or ethyl; P5 is hydrogen, methyl or halogen; Ps is hydrogen or methyl. R "and R" are independently hydrogen or halogen, or are absent.
2. 2. A composition, according to claim 1, wherein "a", "e" and "d" are double bonds.
3. 3. A composition, according to claim 2, wherein "h" is a double bond.
4. 4. A composition, according to claim 2, wherein "g" is a double bond.
5. 5. A composition, according to claim 4, wherein "n" is a double bond.
6. 6. A composition, according to claim 1, wherein "d" is a double bond.
7. 7. A composition, according to claim 6, wherein "b" is a double bond.
8. 8. A composition, according to claim 1, wherein "c" is a double bond.
9. 9. A composition, according to claim 8, wherein "f" is a double bond.
10. 10. A pharmaceutical composition according to any of claims 1 to 9, wherein the steroid is dissolved in the carrier.
11. 11. The pharmaceutical composition according to any of claims 1 to 9, wherein the composition is in the liquid form.
12. 12. The pharmaceutical composition according to any of claims 1 to 9, wherein the composition further contains a pharmaceutically acceptable ointment base.
13. 13. The pharmaceutical composition according to any of claims 1 to 9, which contains no more than one of the steroids.
14. 14. The pharmaceutical composition according to any of claims 1 to 9, which contains more than one of the steroids.
15. 15. A method to alter a hypothalamic function of an individual, this method includes: Supply a 19-nor-pregnane, of the formula: where ^ is oxo, a- or β-hydroxy, a- or β-acetoxy, α- or β-propionoxy, α- or β-lower alkoxy, α- or β-acyloxy or α- or β-benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m", and "n", are alternative sites for optional double links, and "k" may be absent or present, with "j" to form a triple bond; p2 is hydroxy, hydrogen, lower alkoxy with 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy with 1-6 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 on the surface of the neuroepithelial cells of an individual, in which the cell is a part of the tissue different from the olfactory epithelium, and to administer the derivative of 19-nor- Pregnane within a nasal passage of the individual, so that this derivative of 19-nor-pregnane binds specifically to the receptor and results in an alteration of the hypothalamic function of this individual.
16. 16. A method of altering an autonomic function of an individual, this method comprises: supplying a 19-nor-pregnane, of the formula: in which P! is oxo, a- or β-hydroxy, α- or β-acetoxy, α- or β-propionoxy, α- or β-lower alkoxy, α- or β-acyloxy or α- or β-benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m", and "n", are alternative sites for optional double links, and "k" may be absent or present, with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy with 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy with 1-6 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 on the surface of the neuroepithelial cells of an individual, in which the cell is a part of the tissue different from the olfactory epithelium, and to administer the derivative of 19-nor- Pregnane within a nasal passage of the individual, so that this derivative of 19-nor-pregnane binds specifically to the receptor and results in an alteration of the hypothalamic function of this individual.
17. 17. The method according to claim 16, wherein the neuroepithelial cell is located within a vomeronasal organ of this individual.
18. 18. The method according to claim 17, wherein "a", "e" and "d" are double bonds.
19. 19. The method according to claim 18, wherein "n" is a double bond.
20. 20. The method according to claim 18, wherein "g" is a double bond.
21. 21. The method, according to claim 20, wherein "n" is a double bond.
22. 22. The method according to claim 17, wherein "d" is a double bond.
23. 23. The method according to claim 22, wherein "b" is a double bond.
24. 24. The method according to claim 12, wherein "c" is a double bond.
25. 25. The method according to claim 24, wherein "f" is a double bond.
26. 26. The method of any of the claims 15 to 25, wherein the amount of the 19-nor-pregnane derivative that is administered is at least about 100 picograms, but not more than 100 micrograms.
27. The method of claim 15, wherein the amount of the 19-nor-pregnane derivative that is administered is at least about 1 nanogram, but no greater than about 10 microgram.
28. The method of claim 27, wherein the amount of the 19-nor-pregnane derivative that is administered is at least about 10 nanograms, but not more than about 1 microgram.
29. 29. The method of any of claims 15 to 25, further comprising preparing a pharmaceutical composition of the pregnane derivative, dissolved in a pharmaceutically acceptable carrier.
30. 30. The method of claim 29, wherein the pharmaceutical composition is an ointment.
31. 31. The method of claim 29, wherein the pharmaceutical composition is a liquid.
32. 32. The method of claim 29, wherein the administration is by aerosol.
33. 33. The method of claims 15 to 25, wherein more than one pregnane steroid is administered.
34. 34. A 19-nor-pregnano, of the formula: in which P ^ is oxo, a- or β-hydroxy, a- or β-acetoxy, a- or β-propionoxy, α- or β-lower alkoxy, α- or β-acyloxy or α- or β- benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m", and "n", are alternative sites for optional double bonds, and "k" may be absent or present, with "j" to form a triple bond; P2 is hydroxy, hydrogen, lower alkoxy with 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, lower alkoxy with 1-6 carbon atoms, or halogen; P4 is methyl or ethyl; P5 is hydrogen, methyl or halogen; P6 is hydrogen or methyl. R "and R" are independently hydrogen or halogen, or are absent with the conditions that, when P ^ and Pg are hydrogen, "f", "n", "h" and "g" are absent, when P4 is methyl and R1 and R "are not halogen, then: i) when P ^ is oxo," c "is present and P2 and P5 are hydrogen; then, either "j" or "i" can not be present alone, "m" and "j" can not be present together or "i" and "j" or can be present together or "", 11jn and »k ««, They can not be present together and at least one of "i", "j" and "k" must be present; ii) when P is OH, "a", "d" and "e" are present and P5 is hydrogen, then any of "j", "i" or "m" can not be present alone, or "j" and "k" can not be present together, or "i" and "j" can not be present together, or "m", "j" and "k" can not be present together, and at least one of "i", "j", "k" and "m" must be present; (iü) when P ^ is beta-OH, "c" is present, and ^ 2 And p3 are hydrogen, then "i" and "j" or can be present together, or "m", "j" and "k" can not be present together; iv) when P ^ is -OME and "d" and "b" are present, then any of "j" and "i" can not be present alone; v) when P ^ is oxo and "d" is present and P5 is hydrogen; then "i" can not be present alone or iijii and iij? ii can not be present together.
35. 35. A method for the alkylation of a steroid, having a D-ring of 17-halo-16-ene, comprising the step of contacting the steroid with the trialkyl-borane, in the presence of a catalytic amount of Pd (II ), to produce a 17-alkyl-16-ene steroid product.
36. 36. A method, according to claim 35, wherein the steroid comprises a D ring of 17-iodo-16-ene »
37. 37. A method, according to claim 35, wherein the alkyl group contains from 1 to 6 carbon atoms.
38. 38. A method, according to claim 35, wherein the alkyl group comprises the ethyl group.
39. 39. The compound, according to claim 34, which is 19-norpregna-4,20-dien-3ß-ol.
40. 40. The compound, according to the claims 34, which is 19-norpregna-l, 3, 5 (10), 16, 20-pentaen-3-ol.
41. 41. The compound, according to claim 34, which is 19-norpregna-5 (10), 20-dien-3-one.
42. 42. The compound, according to claim 34, which is 19-norpregna-5 (10), 20-dien-3-ol.
43. 43. The compound, according to claim 34, which is 19-norpregna, 4, 20-dien-10β-ol-3-one.
44. 44. The compound, according to the claims 34, which is 19-norpregna-4,9 (10), 20-trien-3-one.
45. 45. The compound, according to claim 34, which is 19-norpregna-l, 3,5 (10), 16-tetraen-6-one-20-in-3-yl acetate.
46. 46. The compound, according to the claims 34, which is 19-norpregna-l, 3.5 (10), 16-tetraen-3,6-diol-20-ino.
47. 47. The compound, according to claim 34, which is 19-1.3.5 (10), 17-tetraen-3-ol.
48. 48. The compound, according to the claims 34, which is 19-norpregna-l, 3.5 (10), 6,17-pentaen-3-ol.
49. 49. The compound, according to claim 34, which is 19-norpregna-l, 3.5 (10), 6.8, 17-hexaen-3-ol.
50. 50. The compound, according to claim 34, which is 19-norpregna-l, 3,5 (10), 7,16-pentaen-3-ol "
51. 51. The compound, according to claim 34, which is the methyl ether of 19-norpregna-2,5 (10), 16-trien-3-yl.
52. 52. The compound, according to claim 34, which is norpregna-4, 16-dien-3-one.
53. 53. The compound according to claim 34, which is 19-norpregna-5 (10), 16-dien-3-one.
54. 54. The compound, according to claim 34, which is 19-norpregna-4,16, dien-10β-ol-3-one.
55. 55. The compound, according to the claims 34, which is the methyl ether of 19-norpregna-2,5 * (10) -dien-3-yl.
56. 56. The compound, according to claim 34, which is 19-norpregna-5 (10) -en-3-one.
57. 57. The compound, according to the claims 34, which is 19-norpregna-4-en-10ß-ol-3-one.
58. 58. The compound, according to claim 34, which is 19-norpregna-4,17-dien-10β-ol-3-one.