Steroid compound

 

(57) Abstract:

The invention relates to extrenely steroids that are associated with neuroepithelial cells in the vomeronasal organ of the human body. These steroids is preferably introduced in the form of pharmaceutical compositions containing one or more pharmaceutically acceptable excipients, and are used as biochemical effectors of physiology and behavior. Describes the steroid compound of formula I, where R1selected from the group consisting of one or two hydrogen atoms, methyl or methylene; R2selected from the group comprising hydrogen or methyl; R3selected from the group consisting of oxo, hydroxy, lower alkoxy, lower acyloxy, benzoyl, leonil, glukoronid and sulfonyl; R4selected from the group comprising essentially hydrogen, hydroxy, lower alkoxy, lower acyloxy, oxo and halogen; R5absent or selected from the group comprising essentially hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6is a hydrogen or halogen atom; a represents optional aromatic unsaturation of ring And specified steroid, or b and d each indicates an optional double bond, e, f, g, h, i and j each mean neo is.p. f-crystals, 34 ill., 1 PL.

Background of the invention

References to related applications

This application is a partial continuation of application N 08/127980, filed September 28, 1993, which is a partial continuation of application for U.S. patent N 07/903525 filed June 24, 1991, which, in turn, is a partial continuation of application for U.S. patent N 07/707862, filed may 31, 1991, which, in turn, is a partial continuation of application for U.S. patent N 07/638743, filed January 7, 1991, and is now cancelled.

This application is related also to the partial continuation of another application for a U.S. patent N 07/903525, application for U.S. patent N 08/077140 filed June 15, 1993, and at the same time a pending application for U.S. patent N 07/903604 filed June 24, 1991 (partial continuation of application for U.S. patent N 07/708936, filed may 31, 1991, which, in turn, is a partial continuation of application N 07/638185, filed January 7, 1991 (now repealed), which was entitled "Androstenone steroids as neurochemical initiators of change in the function of the hypothalamus human, pharmaceutical compositions and methods of use"; and at the same time rassmatrivayutsya patent application U.S. included in this description of the invention as references.

Finally, this application may include simultaneously pending application for U.S. patent entitled "Aromatic compositions containing human pheromones", which was filed on March 24, 1992, N 07/856435.

The technical field

This invention relates primarily to new compounds and methods for making changes in the function of the hypothalamus, and thus change a particular behavior and physiology mediated by the hypothalamus of the individual. More specifically, the present invention relates to the use of some astramovich steroids as neurochemical effectors of physiology and behavior.

Description of the prior art

The present invention relates to certain compounds, namely astronomy steroids and related compounds, as described here, and to methods of using these compounds as synthetic funds with the aim of changing the function of the hypothalamus person and thus affecting a specific sequence of behavior and physiology, for example, the reduction of fear. A typical example astramovich steroids it is 17-estradiol (1,3,5(10)- estratrien-3,17-diol), and they are characterized by nicogenin. Were described properties of pheromones such astramovich steroids for some mammalian species. Michael R. P. et al. , Nature (1968) 218:746 refer to astrogeny (particularly estradiol) as attractant pheromone of male macaques of resursov. Parrot R. F., Hormones and Behavior (1976) 2:207-215, reports that the introduction of estradiol benzoate in rats with removed ovaries caused them mating behavior has been described the role of estradiol in the blood in the formation of sexual response (Phoenix S. N. , Physiol. and Behavior (1976) 16:305-310) and sexual response in females (Phoenix S. N. , Hormones and Behavior (1977) 8:356-362) in macaques of resursov. On the other hand, in the scientific literature there is lack of consensus regarding the role of pheromones in the reproductive behaviour and the establishment of relations between individuals mammals (Beauchamp, G. K., et al., "The Pheromone Concept in Mammalian Chemical Communication: A Critique", the Mammalian Olfaction, Reproductive Processes and Behavior, Doty, R. L., Ed., Academic Press, 1976).

The embodiment of the present invention is a non-systemic nasal introduction of some astramovich steroids for the purpose of impact on a specific behavioral or physiological response in humans, for example, to alleviate negative emotional States, improved mood, and character traits. In particular, the nasal route of administration provides a basal body ("VNO", and as jacobsonís organ") with one or more steroids or with compositions containing the steroid(s). Access to this organ can be obtained through the nostrils of most higher animals, from snakes to humans, the effect is due inter alia to the sensitivity of the receptors for pheromones in some species (see, mainly, Muller-Schwarze & Silverstein, Chemical Signals, Plenum Press, New York (1980)). Axons of vomeronasal neuroepithelium of the body, localized in the sky, form the vomeronasal nerve and have a direct synaptic connection with the accessory olfactory bulb, and there is indirect access to corticomedullary almond-shaped anterior brain and nuclei of the hypothalamus of the brain. The distal axons of neurons in the nerve endings can also serve as a neurochemical receptors in the vomeronasal organ. 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. Otolaryngology (1985) 14:71-79) reported the presence of the vomeronasal organ in most adults, but comes to the conclusion that this body, apparently, does not perform any function. Controversial results, which suggest that the vomeronasal organ J. and M. Mondragon; Monti-Bloch, L. and B. Grosser - all publications in the journal J. Steroid Biochem. and Molec. Biol. (1991) 39.

It is obvious that it is highly desirable to identify and synthesize synthetic products and pheromones humans and to develop pharmaceutical compositions and methods of their use in order to impact on the function of the hypothalamus. This invention relates to the unexpected discovery that when natalina introduction man some neurochemical ligands, in particular some astronomie steroids and related compounds or pharmaceutical compositions, containing some Estrany and related compounds, specifically associated with chemoreceptors nasal neuroepithelial cells, resulting in a number of neurophysiological reactions, leading to changes in the hypothalamus of the individual. During correct introduction of some of these compounds on the hypothalamus causes a change in the functions of the autonomic nervous system and various behavioral or physiological reactions that include, but are not limited to, the following States: fear, premenstrual stress, phobia, aggression, hunger, blood pressure and other behavioral and linical concepts (1990); Korner, P. I. Central nervous control of autonomic cardiovascular function, and Levy N. M. and Martin H. J. Neural control of the heart, both articles published in the Handbook of discrimination; Section 2: the Cardiovascular System - the heart, Vol I, Washington DC, 1979, American Physiological Society; Fishman, A. P., et al. editors, Handbook of discrimination. Section 3: The Respiratory System. Vol II. Control of breathing. Bethesda MD. 1986. American Physiological Society.

In some cases, introducing only astronomy steroid or related connection, some combination astramovich steroids and/or related compounds.

A brief statement of the substance of the invention

Thus, the aim of the present invention is the creation of new steroids, which are synthetic products or pheromones humans and suitable for nasal administration the individual.

Other objectives, advantages and new features of the invention will partially become apparent from the description and partly as a result of studying the submitted materials, or implement it in practice.

The purpose of the present invention are achieved by steroids of the formula:

< / BR>
where R1selected from the group consisting essentially of one or two hydrogen atoms, methyl, methylene, and one or two halogen atom; R2absent or selected from the group consisting essentially of hydrogen soil, leonil, glucuronide and sulfonyl; R4selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy, lower acyloxy, oxo and halogen; R5absent or selected from the group consisting essentially of hydrogen, hydroxy, lower alkoxy and lower acyloxy; R6represents hydrogen or halogen; a represents optional aromatic unsaturation of ring And specified steroid, or b, c and d each indicate an optional double bond, and e, f, g, h, i and j each indicate an optional double bond. In accordance with this embodiment of the present invention, the steroid is preferably introduced in the form of pharmaceutical compositions containing one or more pharmaceutically acceptable carriers; provided that:

(1) when a is present, R3is hydroxy and j, i, g, and h are absent, then (a) R4cannot be hydrogen; or (b) R4cannot be oxo, if no e and f;

(II) when a is present, R3is hydroxy and j, i and g are absent, h is present, then R1cannot be methylene;

(III) when a, h and i are present, then (a) at least one of e or f is present, (b) R1is methylene or (c) R1no one is born, then (a) R1there can be one or two hydrogen atoms, if f is missing, or (b) if f is present, R1may not be the stands;

(V) when b and j are present and R3is oxo, then you must attend at least one of e or f or R1must be methylene;

(VI) when c is present, d is absent and R3is hydroxy, then (a) must attend at least one of e or f, or (b) R1must be methylene;

(VII) when c and d are present, and R3is methoxy; then (a) must attend at least one of the elements of e or f, or (b) R1must be methylene;

(VIII) when b is present, R3is hydroxy and R5is a hydrogen atom, then (a) must attend at least one of e or f, or (b) R1must be methylene.

A preferred class of compounds is one in which a is present and g, h or i to indicate an optional double bond. Another preferred class includes b, C or j in the form of double bonds. Another class of compounds includes C and d in the form of double bonds. The following class includes R2as noted, in the form of a double bond.

The term "Nissi the volume of carbon. Halogens are I, Br, F and Cl.

The steroids of the present invention alter the function of the hypothalamus and vitutation nervous system of the individual. Proposed ligand for chemoreceptor located on the surface of the nasal neuroepithelial cells, where the cell is part of any tissue except the olfactory epithelium; and the ligand is injected into the bow of the individual in such a way that the ligand specifically binds to chemoreceptors, leading to changes in the hypothalamus of the individual.

All embodiments of the present invention include and refer to the described functional equivalents of steroid structures and modified steroids, which are specified functional equivalence, regardless of whether given or not a complete description of modified steroids.

Brief description of drawings

In Fig. 1 shows the synthesis of 1,3,5(10),16-estracecream-3-ol.

Fig. 2A, 2B and 2C are graphical images electrophysiological effects on potential receptors at the local introduction of certain steroids in the vomeronasal organ of the male (Fig. 2A) and olfactory epithelium (Fig. 2C). Fig. 2B is a graphical sravnivaetsa graphical representation of the electrophysiological effects of local administration of certain steroids in the vomeronasal organ of men (3A) and women (3V).

Fig. 4 is an image of the various reactions of the autonomic nervous system men 1,3,5(10),16-estracecream-3-yl-acetate. A = potential receptors in the vomeronasal neuroepithelium of the body; In = change / her galvanic skin response (K-Ohm), C = change of skin temperature (oC).

Fig. 5 is a comparative image changes the potential of the vomeronasal organ after exposure to methyl ether and acetate 1,3,5(10), 16-estracecream-3-ol.

Fig. 6 is a depiction of sexual dimorphism in the form of local reactions and reactions of the autonomic nervous system irritation vomeronasal organ through vomeropherins. Various vomeropherins (200 fmoles) and control the solvent was administered in accordance with the above description 30 men and 30 women (aged 20 to 45 years). Histograms show the average response of subjects.

Fig. 6A and b: measurement of reactions electrophoretogram (EVG) in men (a) and women (B) in accordance with the above description.

Fig. 6C and D: the measurement of electrical skin resistance in accordance with the above description. Change of the reaction (measured in Ohms) due to the introduction of vomeropherins in the vomeronasal organ to test the conformity with the above description. Changes in the response due to the introduction of vomeropherins in the vomeronasal organ of men (E) and females (F).

Fig. 6G and H: measurement of skin temperature (ST) in accordance with the above description. Changes in the response due to the introduction of vomeropherins in the vomeronasal organ is shown for men (G) and women (H).

A = 1,3,5,(10),16-estracecream-Z-yl-acetate

In = Androsta-4,16-Dien-3-one

C = 1,3,5(10),16-estracecream-3-ol

D = 3-Methoxy-östra-1,3,5(10),16 - tetraen

E = Androsta-4,16-Dien-3-ol

F = Androsta-4,16-Dien-3-ol

Fig. 7 is an image electroretinogram obtained in men and women as a result of stimulation of the olfactory epithelium by olfactorily and vomeropherins: 400 fmoles such olfaction as 1 - carvon and cineole, 200 fmole vomeropherins a, b, C, D and a and stereoisomer E was introduced separately in the form of pulses with a duration of one second in the olfactory epithelium of 20 subjects (men and women), with each reaction EOG were recorded in accordance with the above description. Olfactory, and substances (E) and caused a significant (p<0,01) local reaction. In: 400 fmoles such olfaction as 1-carvon and cineole, did not cause a significant reaction EVG when introduced into the vomeronasal organ muic is rinow on vomeronasal organ 20 women:

G = Androst-4 - EN-3-one

H = Androsta-4,16-Dien-3,6-dione

J = 10,17-Dimethylene-4,13(17)-Dien-3-one

K = 1,3,5(10),16-Estracecream-3-ol methyl ether

L = 1,3,5(10),16-Estracecream-3-yl-propionate

EVG = Electrophoretogram

GSR = galvanic Skin reaction

EDA = Electrical resistance of the skin

ST = skin Temperature

Fig. 9 is an image of the electrophysiological effects vomeropherins on vomeronasal organ 20 men.

M = 1,3,5(10)-Estratrien-3-ol

In Fig. 10 shows the synthesis of östra-1,3,5(10),6-tetraen-3-ol and östra-4,16-Dien-3-ol.

In Fig. 11 shows the synthesis of compounds described in examples 16 to 19.

In Fig. 12 illustrates the stages of synthesis described in examples 20 to 24.

In Fig. 13 illustrates the stages of synthesis described in examples 25 through 28.

In Fig. 14 illustrates the stages of synthesis described in examples 29 and 30.

In Fig. 15 illustrates the stages of synthesis described in examples 31 to 36.

In Fig. 16 illustrates the stages of synthesis described in examples 37 to 39.

In Fig. 17 illustrates the stages of synthesis described in examples 40 to 46.

In Fig. 18 illustrates the stages of synthesis described in the note is 20A, 20B and 20C are illustrated data electrophoretogram, galvanic skin response and skin temperature in women in relation to 13 estrano, are shown in table 1.

Fig. 21 A, 21B and 21C is an illustration of data electrophoretogram, galvanic skin response and skin temperature in men for 13 estrano, are shown in table 1.

Fig. with 22A and 34A and b are an illustration of the data electroencephalogram (EEG) in men (a) and women (b) for 13 estreno indicated in Fig. 20.

Detailed description of the invention

1. Definition

"Emotional reaction" is a temporary state of feeling. Typical negative emotional reactions are feelings of nervousness, tension, embarrassment, anxiety, irritation, anger, rage and others. "Mood" is a more prolonged state of feelings, such as guilt, sadness, hopelessness, uselessness, sorrow, suffering, unhappiness, and the like. "Traits" are more permanent aspects of human personality. Typical negative character traits are resentment, remorse, guilt, stubbornness, sadness, shyness, linearity, having chetyrehkolkoy steroid structure, methylated at the 10 - and 13-positions. Androstenone steroids are a subset of androstenol, characterized by the presence of at least one double bond. If the described connection is not gonan, it is quite clear that such a connection has a carbon group at the 18-position. However, 18-norandrosterone here considered as androstenone steroids. In addition, all derivative having the above-described structural characteristics also apply to androstenone steroids.

The following structure shows chetyrehkolkoy steroid structure common to androstenone and astramovich steroids. To describe the location of groups and substituents use the following numbering system:

< / BR>
"Sexual dimorphism" means the difference in the impact of pharmaceuticals or in response to male and female individuals of the same species. "Effective amount" of a drug refers to the amount and/or concentration that provides the desired physiological and/or psychological impact of its introduction to the needy person. In this case, that subject is che the physiological or behavioral model, which is usually determined by the hypothalamus. An effective amount of this drug may vary depending on route of administration. For example, when applying the steroid in the form of a solution on the skin of the patient an effective concentration is from about 1 to about 100 μg/ml, preferably from about 10 to about 50 μg/ml and preferably from about 20 to about 30 μg/ml If the steroid is injected directly into the vomeronasal organ, an effective amount ranges from about 1 PG to about 1 ng, preferably from about 10 to about 50 PG. If the steroid is injected into the nasal passage in the form of ointment, cream, spray and similar substances, the effective amount is from about 100 PG to about 100 μg, preferably from about 1 ng to about 10 μg. This implies that some medicines may be effective in the introduction some ways and inefficient with the introduction of other ways.

"The hypothalamus is a part of the intermediate brain, representing the ventral wall of the third ventricle below the hypothalamic sulcus and comprising structure forming the base of the ventricle, including patterns that form the optic chiasm, the gray matter of goals is istemi and manages some of the physiological and behavioral functions, in particular aggressiveness and panic fear, sexual motivation, balance water, glucose and fat metabolism, hunger, body temperature, internal secretion and others. The hypothalamus is also the source of vasopressin, which regulates blood pressure, and oxytocin, which causes childbirth and milk production. All functions of the hypothalamus can be adjusted with the help of therapy semisynthetic drugs described here.

"Ligand" used herein is a molecule that acts as a chemical signal through specific binding to a receptor molecule located on the cell surface receptor, thus initiating the transmission of the signal through the cell surface. Ligand binding with the dynamics of the receptor can be measured. Dynamics of tissue, such as the vomeronasal neuroepithelium or olfactory neuroepithelium contains many neuroreceptors cells, each of which has at least one receptor. Many receptor molecules have identical ligand specificity. Therefore, when the tissue affected by the ligand, in respect of which it has specificity is the change of the surface potential of the receptor cell.

"Lower alkyl" means a branched or unbranched saturated hydrocarbon chain containing from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isobutyl, and others. "Alkoxy" has the usual meaning and represents the group-OR where R is alkyl.

"Pheromone" is a substance, which is a chemical means of communication between members of the same species due to secretion and perceptual abilities. In mammals, pheromones are usually recognized by receptors in the vomeronasal organ of the nose. Usually, pheromones affect development, reproduction and behavior associated with these functions. "Semi-synthetic product" is the more General term, which includes pheromones and describes the substance from any source, which acts as the dynamics of the messenger binds to a specific neuroepithelial receptor and causes physiological or behavioral effect. "Vomeropherins is semiochemical substance, physiological effect of which is mediated by the vomeronasal organ.

Picograms (PG) corresponds to 0.001 nanogram (ng). Nanogram is set to 0.001 micrograms (mcg). Micrograms is set to 0.001 milligram.

II. Spoleczno applies to some astronomy steroidal, are structurally related to estradiol (which is also known as 1,3,5(10)-estratrien-3,17 - diol). Steroids are included in this group are characterized by the presence of aromatic 1,3,5(10)-And-rings and hydroxyl derivatives of hydroxyl in 3-position.

Estrany, especially suitable for use in the present invention include compounds in which, independently, R1= oxo, hydroxy, hydrogen; R2= methyl, hydrogen (as shown in the formula 1).

Most of these steroids and their derivatives in the form of a glucuronidase, sulfates, cypionate and benzoato known in this field and commercially available; for example, from Sigma Chemical Co., Aldrich Chemical Co. etc. Alkoxybenzenes and receive them well known and discussed in U.S. patent N 2984677, which is incorporated herein by reference.

Table 1 presents Estrany included in the present invention but without limiting its scope. The following synthesis schemes shown the synthesis of intermediate compounds and substructures with the aim of obtaining these estreno (attached at the end of the description).

NEW ESTRANY

Östra-1,3,5(10),6,16-pentaen-3-yl-acetate (acetate of compound E4/N1).

Östra-1,3,5(10),7-tetraen-3-ol (E9/N2).

6/N1).

17-Methyltetra - 1,3,5,7,9-pentaen-3-ol (E10/N3).

Östra-1,3,5(10),16-tetraen-3,6 - diene (E12/B1).

6 - Hydroxyestra-1,3,5(10), 16-tetraen-3-yl-acetate (acetate of compound E12/N1).

Östra-4,16-Dien-3 - ol (E3/N1).

17-Methylene-6-exestr-1,3,5(10)-triene-3 - yl-acetate (acetate of compound E6/N3).

Östra-4,9,16-triene-3-one (E5/N1).

Östra 1,3,5,7,9,16-hexaen-3-ol (E10/N1).

Östra-1,3,5(10),6-tetraen-3-ol (E4/N2).

3-Petoksista-2,5(10),16-triene (E8/N1).

10-Hydroxyestra-4,16-Dien-3-one (E7/N1).

17-Methyltetra-1,3,5(10),7-tetraen-3-ol (E9/N3).

Östra 5(10),16-Dien-3 - ol ( 3 - epimer of compound E11/N1).

Östra 5(10),16-Dien-3 - ol (E11/N1).

17-Methyltetra-4-EN-3-one (E1/N3).

Östra 1,3,5,7,9,16-hexaen-3-yl-acetate (acetate connection E10/N1).

17-Methylgene-4,13(17)-Dien-3 - ol (E3/N4).

Östra-1,3,5,(10),7,16-pentaen-3-ol (E9/N1).

3-Methoxy-17-methyltetra-2,5(10)-diene (E8/N3).

17-Methyltetra-4-EN-3 - ol (E3/N3).

17-Methyltetra-1,3,5(10)-triene-3,6 - diol (E12/N3).

Östra-1,3,5(10),7,16-pentaen-3-yl-acetate (acetate connection E9/N1).

Östra-1,3,5(10),6,16-pentaen-3-ol (E4/N1).

17-Methyltetra-1,3,5(10),7-tetraen-3-ylacetic (acetate connection E9/N3) (Synthesis of substructures, see the end of optiroam compounds include these substructures together with their derivatives; 17-fluoro-N1 in conjunction with E1, E2, E3, E5, E6, E7, E11 or E12. And 17-iodine-N1 in combination with E2, E6 or E12.

C. Methods of synthesis of

General methods of synthesis of steroids are well known to specialists in this field (see, for example, Fieser, L. F. and M. Fieser, Steroids, Reinhold, N. Y., 1959). The time and temperature of the reactions in those cases when it is necessary, you can define in the usual way. After adding the reagents, the mixture is stirred in an inert atmosphere and selected aliquots at intervals of one hour. Aliquots subjected to analysis by thin-layer chromatography to determine the expenditure of the original product, and then start processing. If the original product is not consumed within twenty-four hours, the mixture is heated under reflux and every hour analyze aliquots, as above, up until the original product will not remain. In this case, before you start treatment, the reaction mixture is cooled.

Alkoxybenzenes of estrenos obtained from the relevant hydroxysteroids by interacting with alkylating agent such as fluoroborate trimethylhexane, fluoroborate trityloxy or methylpredisolone, in an inert chloropercha dissolve contraty and diallylsulfide, can be used with such a Foundation, as silver oxide or barium oxide, in polar aprotic solvents, such as, for example, DMF, DMSO and hexamethylphosphoramide. Alternatively, a base such as K2CO3can be used in solvents, such as ethanol or acetone.

Cleaning products is carried out using chromatography and/or crystallization, as is well known to specialists in this field.

C. Pharmaceutical compositions and methods of use

The implementation object of the invention is a method of changing the function of the hypothalamus person. Another implementation is to modify the functions of the autonomic nervous system of the individual. These functions of the autonomic nervous system include, but are not limited to, heart rate, respiratory rate, electroencephalogram (percentage of alpha-rhythm of the cerebral cortex), body temperature and other. Other implementation of the present invention include, but are not limited to, ways to alleviate negative emotional impact of a bad mood or negative traits of a person. Another implementation is a method for the treatment of premenstrual stress in women. Prov. combinations.

This method of introduction is different from alternative methods, such as ingestion or injection, that such use is achieved directly contacting with the vomeronasal organ. In accordance with the methods of the present invention corresponding ligand apply directly to the chemoreceptors in the forward course and vomeronasal organ without the use of pills or needles, that is a non-invasive way. The impact of the drug is achieved by linking the above-described ligands with specific receptors neuroepithelial cells in the nose, preferably in the vomeronasal organ. In this way of introducing the influence of drugs occurs through the nervous system, and not through the cardiovascular system, resulting in brain function can be adjusted without the necessity of overcoming the blood-brain barrier. These treatments involve a direct effect on the hypothalamus through the nervous system, since there is only one synaptic junction between pheromone receptors and the hypothalamus. Because sensory nerves associated with a specific place in the brain, this method has a high specific impact of the different side effects.

Contact vomeronasal organ is important because it is associated with chemoreceptor/pheromone function. Vomeronasal organ consists of two blind tubular diverticula, which are located at the lower border of the nasal septum. Vomeronasal organ contains the neuroepithelium, the axons of which are in contact with the almond-shaped body, and then with the hypothalamus. The existence of the vomeronasal organ documented in most terrestrial vertebrates, including the human fetus; however, it was considered that in adults this body remained rudimentary (See. above Johnson, et al.).

Described here, the active compounds or their sulfates, cypionate, benzoate, propionate, halogenate or glucuronate you can enter as such, but it is preferable to use them in the form of compositions. Get them in a liquid dosage form, such as liquids, suspensions and similar forms, preferably intended for single introduction of an accurate dose. Liquid dosage forms can be entered into the nose drops or spray.

Alternatively, the active compound can be obtained in the form of a cream or ointment and enter locally in the nasal cavity. is prepared from silicone and natural polymers, such as gelatin and cellulose. The rate of release can be controlled by the appropriate selection of the polymer system at a certain rate of diffusion (R. S. Langer and Peppas N. A. , Biomaterials 2201, 1981). Natural polymers such as gelatin and cellulose, dissolve slowly in the content within a few minutes to several hours, while the silicone remains untouched for months. The compositions contain an acceptable pharmaceutical carrier or excipient and one or more active compounds estrena formula I. in Addition, the compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvant, etc.

The most likely way of getting pheromone in humans is inhalation of natural pheromone present on the skin of another person. Some 16-androstene steroids, including 5 - androst-16-ene 3 - ol and 5 - androst-16-EN-3-one, 4,16-androsta-Dien-3-one, 5 - androstadien-3 - ol and possibly 5 - androstadien-3 - ol, produced by the human body and may be present on the skin. It is established that naturally the maximum concentration of 16-androstenol steroid in human skin ranges from 2 to 7 ng/cm2. It is established that at blinkleuchte relatively nonvolatile, it is established that the person breathes no more than 0.7 PG of natural steroid with the skin of another person. This inhaled number only 1% reaches the receptors, vomeronasal organ. Thus, the prescribed maximum affecting natural pheromones is 0,007 PG.

The number of input active compounds, of course, will depend on being treated of the subject, the severity of the disease, the route and frequency of administration and determined by the treating physician. However, single dose, equal to at least about 10 picograms entered directly into the cavity of the vomeronasal organ, is effective to call a temporary reaction of the autonomic nervous system. Upon introduction into the nasal cavity dose of from about 100 picograms to about 100 micrograms, preferably from about 1 nanogram to about 10 micrograms, more preferably from 10 nanograms to 1 microgram. The frequency of injection, preferably, varies from once per hour to once per month, preferably from 8 times per day to once every other day, more preferably from 1 to 3 times a day. Ointments containing one or more active compounds and optional pharmaceutical adjuvants in the nose the like, you can get on such basis as, for example, vaseline jelly, lard or lanolin.

Liquid pharmaceutical compositions can be obtained by dissolving, dispersing, etc. to the above active compound and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, resulting in a solution or suspension. If desired, enter the pharmaceutical composition may also contain a minimum number of non-toxic auxiliary substances such as wetting or emulsifying means, pH buferiruemoi agents and the like, for example sodium acetate, monolaurate sorbitan, triethanolaminato sodium, triethylamine etc., Modern methods for such dosage forms are well known or will be clear to experts in the field; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 15th Ed., 1975. Composition or a composition intended for insertion must, in any case, contain one or more active compounds in sufficient quantity to oslableniya symptoms of the subject being treated.

When used in widesystem and propellant. The percentage of active ingredients is from 0.001 to 2% by weight, preferably from 0.004 to 0.10%.

Surfactants must, of course, be non-toxic and preferably soluble in the propellant. Typical examples of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as esters of Caproic, octanoic, lauric, palmitic, stearic, linoleic, holesterinovmi and oleic acids with an aliphatic polyhydric alcohols or their cyclic anhydrides, such as, for example, ethylene glycol, glycerin, erythritol, arabitol, mannitol, sorbitol and anhydrides hexitol derived from sorbitol (complex sorbitane esters sold under the trademark "Spans"); and polyoxyethylene and polyoxypropylene derivatives of these esters. You can use mixed esters, such as mixed or natural glycerides. The preferred surfactants are the oleates sorbitan, for example, sold under the trademarks "Arlacel C" (servicesecurity), "Span 80" (servicemanual) and Span 85 (sarbatorile). Surfactant may costallat. Liquefied propellants are normally gaseous under normal conditions of matter, condensed at high pressure. Suitable liquefied propellants are the lower alkanes containing up to five carbon atoms, such as butane and propane; fluorinated or ferroresonance alkanes, such as sold under the trademark "Freon". In addition, you can use a mixture of the above funds.

In the manufacture of the aerosol container, accompanied by an appropriate valve, fill in the appropriate propellant containing finely ground active ingredient and a surfactant. Thus, the ingredients are at high pressure to release the contents of a container by pressing on the valve.

Another method of introduction is the local application of a volatile liquid composition onto the skin, preferably facial skin of the individual. Such a composition typically contains alcohol, such as ethanol or isopropanol. The composition may also contain a pleasant flavor.

D. Assessment of emotional States, moods, and traits

Emotional States associated with action, humor and character traits, usually prewoski emotional state. The individual evaluates his or her emotional state described definitions, and digital scale determines the degree of intensity of the condition. The close grouping of definitions and statistical analysis of the subjective assessment of each determination is the basis for the measurement of different emotional States.

Alternatively, the emotional state can be measured by changes in the autonomic nervous system, such as used in the detector estimates (galvanic skin response, pulse rate and the like). Cabanac, M., Annual Review of discrimination (1975) 37:415; Hardy, J. D. , "Body Temperature Regulation, Chapter 59, pp. 1417. In the publication of Medical discrimination, Vol. II Ed.: VB Mountcastle (1980); Wolfram Bouscein. Electrodermal Activity (Plenum Press, 1992).

In addition, you can assess nonverbal manifestations such as facial expression and body posture.

III. Examples

The following examples only illustrate the present invention but do not restrict it.

In these examples, the following abbreviations are used: PE = petroleum ether (boiling temperature of 50-70oC); DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; THF = tetrahydrofuran.

Example 1

Synthesis östra-1,3,5(10),16-tetraen-3-ol (28)

The following, ,00 mol) and p-toluensulfonate (232,8 g, 1.25 mol) in dry methanol is heated under reflux for 20 hours. The reaction mixture was transferred into a conical flask and allow it to cool. The crystalline product is filtered with suction and washed with methanol (300 ml). Additional portions of this product are obtained by sequential evaporation of the filtrate to 2000 ml, 800 ml and 400 ml, leaving each time crystallizability. Total output is 433,5 g (99%).

1.3.5(10),16-Estracecream-3-ol (28)

Estrone-p-toluensulfonate (27) (219,0 g, 500 mmol) in dry tetrahydrofuran (8.0 liters) is cooled in a bath with a sodium chloride/ice. This mixture is stirred mechanically with the simultaneous addition of n-utility (800 ml of 2.5 M solution in hexane, 2.00 mol) using a two-sided needles. The reaction mixture was stirred at room temperature for 3 days. Add ice (250 g), and then a saturated solution of ammonium chloride (500 ml). Phase mix and leave to rasstavatjsja. The aqueous phase is removed by suction through a Teflon tube and extracted with ether (500 ml). The two organic phases are successively washed with one portion of saturated sodium bicarbonate solution (500 ml), and then Nasser product. This product is subjected to flash filter on 500 g of silica gel 60, 230-400 mesh cell mesh, elwira a mixture of ethyl acetate and hexane (25: 75, 2.5 liters). The filtrate is evaporated in vacuum to obtain a crystalline product. The product is recrystallized from a mixture of methanol (300 ml) and water (75 ml) and washed with a mixture of methanol (80 ml) and water (20 ml). Subsequent recrystallization from a mixture of ethyl acetate and hexane (12,5:87,5) gives the pure product (88.9 g, 70%).

Example 2

Synthesis of acyl derivatives of 1,3,5(10),16-estracecream-3-ol

To 1,3,5(10), 16-estracecream-3-Olu (254 mg, 1.00 mmol) in ether (10 ml) is added acetic anhydride (0.25 ml) (or propionic anhydride to obtain propionate), then pyridine (0.25 ml) and the mixture is stirred at room temperature for 16 hours. The mixture is then poured into ice water and extracted with ether (2 x 20 ml). The organic extracts washed with water, saturated copper sulfate solution, water and saturated sodium chloride solution, dried (MgSO4) and evaporated in vacuo to obtain the crude product. The product was then purified by flash chromatography 17.5 g of silica gel 60 (230-400 mesh mesh), elwira a mixture of 10%-12% ethyl acetate and hexane, resulting in a pure product (192 mg, 65%).

Example 3

Synthesis östra 4,16-underwater ammonia and 6.76 g of tert-butyl alcohol add finely cut lithium wire (0.24 g, 35 mg-atom). The reaction mixture is heated under reflux for 4 1/2 hours in an argon atmosphere, and then add methanol (2.3 ml) and allow to evaporate the ammonia during the night. The residue is dissolved in 25 ml of methanol and acidified to approximately pH 1 with 5 n HCl solution. After heating in an oil bath at a temperature of from 55 to 70oC for 15 minutes, cooled and gidralizovanny the mixture was partitioned between 25 ml of water and 50 ml of ethyl acetate and the aqueous phase is extracted with 25 ml ethyl acetate. The combined organic extracts are washed with 25 ml saturated sodium bicarbonate solution and 25 ml of saturated salt solution, dried over magnesium sulfate and filtered. After removal of the solvent under reduced pressure gain of 0.57 g of oily residue, which was purified by flash chromatography on silica gel (eluent: a mixture of 15% ethyl acetate and hexane) and then recrystallized from pentane, resulting in a gain crystals (206,1 mg, 39%), homogeneous according to TLC, etc., 67-71oC.

Example 4

Synthesis östra-2,5(10),16-triene-3-methyl ether (2)

To östra-1,3,5(10), 16-tetraen-3-methyl ether (1.22 g, of 4.54 mmol) in 19 ml of anhydrous THF, 14,99 g of tert-butyl alcohol and about 70 ml of anhydrous AMM is m in argon atmosphere for 6 hours, the reaction mixture was quenched with 5 ml of methanol and allow to evaporate the ammonia during the night. A suspension of the residue in 100 ml of water twice extracted with 100 ml portions of ethyl acetate, the combined organic extracts washed with saturated salt solution and dried over magnesium sulfate. After removal of the solvent under reduced pressure the residue is purified using flash chromatography on silica gel, elwira a mixture of 1% ethyl acetate and hexane, and then recrystallized from abs. ethanol with the formation of loose white crystals (884,1 mg, 3,269 mmol, 72%), etc., 72-73oC, homogeneous by TLC.

Example 5

Synthesis östra 5(10),16-Dien-3-one

Östra-2,5(10),16-triene-3-methyl ether (2) (646,3 mg, 2,390 mmol), dissolved in 50 ml of acetone, hydrolyzing within 6 hours at room temperature, using the dihydrate of oxalic acid (0.84 g, 6.7 mmol). The reaction mixture was quenched with 25 ml saturated sodium bicarbonate solution and then twice extracted with 25 ml portions of ethyl acetate. The combined organic extracts washed twice with 25 ml of saturated salt solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from hexane to obtain the product (462,5 mg, 1,804 mmol, 75%), etc., wing 112-116oC.

Example 6

Synthesis östra 5(10),16-Dien-3-ol (4)

Östra 5(10), 16-Dien is using alumalite lithium (50.0 mg, of 1.32 mmol). After blanking decahydrate sodium sulfate (2.00 g) for 10 minutes, the resulting suspension is filtered through celite, and the residue is washed with four 25 ml portions of ether. The combined filtrates are concentrated under reduced pressure and purified flash chromatography (silica gel, mixture of 5% ethyl acetate and hexane as eluent) followed TJC mixed fractions. The more polar product can be recrystallized from significant losses from aqueous ethanol to obtain 4,8 mg of solid product. The less polar product is recrystallized from aqueous methanol to obtain white crystals (59,5 mg), etc., 98-100oC. the Total yield at 64.3 mg (0,249 mmol, 21%).

Example 7

Synthesis östra-4,9,16-triene-3-one (5)

Östra 5(10), 16-Dien-3-one (3) (0,38 g, 1.5 mmol) in pyridine (5.0 ml, 62 mmol) is cooled to -13oC in a bath containing a mixture of ice, salt and add perbromide pyridinium bromide (1,58 g, 4,94 mmol) in small portions so that the temperature was < -4oC. After vigorous stirring for 1 minute add the phenol (0.25 g, 2.7 mmol) and continue the reaction for 24 hours at room temperature. Add ethyl acetate (50 ml) and washed reaction mixture of 25 ml of 1 n HCl solution, DV the ears over magnesium sulfate, filtration and concentration under reduced pressure, the obtained residue is dissolved in 10 ml of absolute ethanol, add granules of zinc (0.33 g, 5.0 mg-atom) and heat the mixture under reflux for 1/2 hour. The supernatant is removed, the residue was washed with 10 ml of absolute ethanol, and the combined supernatant concentrated under reduced pressure. The obtained resin was purified flash chromatography on silica gel, using as eluent a mixture of 15% ethyl acetate and hexane. The appropriate fractions are combined concentrated and recrystallized from hexane with the formation of the solid product (117,5 mg, 0,4619 mmol, 31%), etc., 87-92oC.

Example 8

Synthesis östra-1,3,5(10),16-tetraen-6-one-3-acetate (6)

The chromium trioxide (13,40 g, 0,1340 mol) are suspended in 200 ml of methylene chloride and then cooled to -10oC in a bath containing a mixture of ice and salt. Add 3,5-dimethylpyrazol (12,90 g, 0,1342 mol) and stir the resulting mixture for 20 minutes. After that, the mixture is injected östra-1,3,5(10),16-tetraen-3-yl-acetate (of 4.00 g, 13.5 mmol) in a chilled solution of 20 ml of methylene chloride, and continue to stir the reaction mixture for 2 hours so that the temperature was < -8oC. This mixture was then filtered through 200 g of silica gel and aliraki the crude product was purified flash chromatography on silica gel, using as eluent a mixture of 15% ethyl acetate and hexane. By combining the appropriate fractions and concentrate them under reduced pressure to obtain white solid (0,92 g, 3.0 mmol, 22%), etc., 87-103oC.

Example 9

Synthesis östra-1,3,5(1),16-tetraen-3-ol-6-she (7)

Östra-1,3,5(10), 16-tetraen-6-one-3-acetate (203,1 mg, 0,6543 mmol) in 30 ml of methanol for 40 minutes omelet 1.5 ml of 5% (in weight ratio) of sodium hydroxide. The reaction mixture was concentrated under reduced pressure, dissolved in 50 ml of water, neutralize 1 N. HCl solution and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts washed with 50 ml of saturated salt solution, dried over magnesium sulfate, filtered and concentrated to obtain a white solid, which is purified by recrystallization from a mixture of benzene and hexane and preparative TLC, resulting in a get a white crystalline solid (52,8 mg, 0,197 mmol, 30%), etc., 188-191oC.

Example 10

Synthesis östra-1,3,5(10),16-tetraen-6 - ol-3-yl-acetate (8)

Östra-1,3,5(10), 16-tetraen-6-one-3-yl-acetate (6) (421,4 mg, 1,358 mmol) in 35 ml of 95% ethanol restore with sodium borohydride (98,8 mg, 2,61 mmol) for 100 minutes at room temperature the thief HCl and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts are washed with 25 ml of saturated salt solution, dried over magnesium sulfate, filtered and concentrated. The obtained white foam purified flash chromatography on silica gel, using as eluent a mixture of 25% ethyl acetate and hexane. By combining and concentrating fractions receive a white solid (0.12 g, 0.38 mmol, 28%), etc., 209-212oC.

Example 11

Synthesis östra-1,3,5(10),16-tetraen-3,6-diol (9)

To a suspension of lithium aluminum hydride (95%, 46,9 mg, 1,17 mmol) in 5 ml of anhydrous tetrahydrofuran with stirring, added dropwise östra-1,3,5(10), 16-tetraen-6-it-S-yl-acetate (6) (422,9 mg, 1,360 mmol) in 5 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 50 minutes, then add another portion of lithium aluminum hydride (46,5 mg of 1.16 mmol) and stirred for 22 hours. After heating under reflux for 4 hours the reaction mixture is still starting material according to the results of thin-layer chromatography. The reaction mixture was quenched with 0.5 ml of water + 0.5 ml of 20% (in weight ratio) of sulfuric acid and concentrated under reduced pressure. The residue is extracted four times with 10 ml portions of hot ethyl acetate and filtered through celite. Ob, 0.2 mmol, 10%), etc., 150-157oC.

Example 12

Synthesis östra-1,3,5(10),7-tetraen-3-ol (10)

To a suspension Aquilina (100,2 mg, 0,3733 mmol) in 2 ml of diethylene glycol added hydrazine (59 μl, 1.9 mmol) and potassium hydroxide (0.04 g, 0.7 mmol). This mixture is stirred on an oil bath at a temperature of 200-214oC for 2 hours, after which the cooled reaction mixture is diluted with 10 ml of water, neutralize 1 N. HCl solution and extracted three times with 25 ml of ether. The combined organic extracts are washed with 10 ml of saturated salt solution, dried over magnesium sulfate, filtered, concentrated and purified preparative TLC (silica gel, mixture of 15% ethyl acetate and hexane as eluent) to give a yellow resin. The resulting product is subjected to further purification by bleaching with charcoal and recrystallization from aqueous ethanol, which allows to obtain a yellowish-brown crystals (13.2 mg, with 51.9 mmol, 14%), etc., 130-134oC.

Example 13

Synthesis of 20-gamestro-1,3,5(10),6,8,17-hexaen-3-ol (11)

A suspension of methyl triphenylethylene (671,0 mg, 1,878 mg) and tert-butoxide potassium (212,1 mg, 1,890 mmol) in 2.1 ml of anhydrous dimethyl sulfoxide for 1 hour and heated at a bath temperature 76-86oC tseleng color is stirred for 1 hour. After cooling, add 10 ml of a mixture of 1 n HCl solution with ice and shaken out this mixture three 10 ml portions of ether. The combined organic extracts are washed with 10 ml saturated sodium bicarbonate solution +10 ml of saturated salt solution, dried over magnesium sulfate, filtered through celite and concentrated under reduced pressure. The remainder in the form of an orange oil purified preparative thin-layer chromatography (silica gel, mixture of 25% ethyl acetate and hexane), resulting in a product (and 75.5 mg, 0,286 mmol, 76%), homogeneous according to TLC, etc., 113-121oC.

Example 14

Synthesis östra-1,3,5(10),6-tetraen-3-ol (17)

Östra-1,3,5(10), 6-tetraen-3-ol-17-one (for 91.1 mg, 0,339 mmol), hydrazine (54 μl, 1.7 mmol) and potassium hydroxide (0.06 g) in 1.8 ml of diethylene glycol for 2 hours, heated at a bath temperature of 200oC in argon atmosphere. After cooling the reaction mixture to room temperature, add 10 ml of water and acidified with 1 N. a solution of HCl to pH2. The resulting suspension is shaken out three times with 10 ml of ether, the combined organic extracts are washed with 10 ml of saturated salt solution, dried over magnesium sulfate, filtered through celite and concentrated under reduced pressure. The crude solid is purified of prep is popular according to TLC (5.9 mg, 23 μmol, 7%).

Example 15

Synthesis östra-4,16-Dien-3-ol (18)

To östra-4,16-Dien-3-ONU (1) (87,2 mg, 0,340 mmol) in 1.7 ml of anhydrous ether is added alumoweld lithium (15,0 mg, 0,395 mmol) and the resulting suspension is stirred for 17 minutes. The reaction mixture is then stirred for another 10 minutes with 0.50 g of decahydrate sodium sulfate and filtered through celite. The residue was washed with three 10 ml portions of ether and the combined filtrates concentrated under reduced pressure. As a result of performing preparative thin-layer chromatography (mixture of 5% ethyl acetate and dichloromethane on silica gel) to obtain the crude product (50.0 mg) as a yellow resin. This product again chromatographic to achieve a sufficiently pure state.

Example 16

Östra-4,16-Dien-3-one (9)

This synthesis is depicted in Fig. 11. 19-Nortestosterone (XIX) is produced on an industrial basis, for example, Chemical Dynamics Corp. He is the starting material for obtaining derivatives of 19-nor-16-androstene. 19-Nortestosterone (XIX) is converted into the acetate (Hartman J. A. et al., J. Am. Chem. Soc. (1956) 78:5662) with acetanhydride and pyridine. (a) a Solution of the acetate (4.8 g, 15,17 mmol) in toluene (10 ml) is subjected to pyrolysis (b) at a temperature of 540oC (200 mm RT. Art. , slowly the and silica gel (150 g) using CH2Cl2that gives 1.1 g (28%) homogeneous oily ketone 9; +57,9o(1) ((27): so p. 71 - 73oC).

Infrared spectrum (CHCl3): 1660s, 1615m, 1585w.

Range1H-NMR (90 MHz): 0,84 (s, 3H), of 5.82 (m, 2H), by 5.87 (broad singlet, 1H).

Example 17

Östra-16-EN-3-one (10)

This synthesis is depicted in Fig. 11. 19-Nortestosterone restore to 19-nor-5A-androstane-17-ol-3-one (XX) with lithium and ammonia (C) in accordance with the method presented Villotti R. et al. (J. Am. Chem. Soc. (1960) 82:5693). Androsta-5A,17-diol-3-one (XX) is converted into the acetate (Hartman, J. A. et al., J. Am. Chem. Soc. (1956) 78:5662) with acetanhydride and pyridine (a). A solution of 17B-acetoxy-5A-estran-3-one (8.0 g, a 25.1 mmol) in a mixture of octane and acetone with the ratio of 10:1 (22 ml) is subjected to pyrolysis (b) at a temperature of 550oC (200 mm RT. century, in a slow stream of N2). The chromatography was carried out crude product (5.4 g) on silica gel (600 g) using CH2Cl2and recrystallization homogeneous fractions from petroleum ether to give 3.13 g (48,3%) of pure ketone 10. T. p. 51-54oC, [a] - +72,8 (1,0)

Infrared spectrum (CHCl3): 1705s, 1585w.

Range1H-NMR (90 MHz): 0,79 (s, 3H), 5,71 (m, 1H), by 5.87 (m, 1H).

Example 18

Östra-16-ene 3 - ol (11)

This synthesis is depicted in Fig. 11. L-SUP>C added dropwise to a solution of ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml). After stirring for 1 hour at 0oC add water (10 ml). Borates is acidified by adding 10% aqueous NaOH solution (5 ml), and then 30% aqueous solution of H2O2(3 ml) and stirred for 3 hours at room temperature. After treatment with ether, the crude product (790 mg, mixture of compounds 11 and 12 with the ratio 9:1) purify by chromatography on silica gel using CH2CL2that gives 700 mg (87%) of pure alcohol 11. T. p. 119-120oC --->23-124oC (PE), [and]D+40,6oC (=1,0).

Infrared spectrum (CHCl3): 3640m, 3500 br., 1585w.

Range1H-NMR (90 MHz): 0,78 (s, 3H), 4.09 to (m, w1/28, 1H), 5,71 (m, 1H), by 5.87 (m, 1H).

Example 19

Östra-16-EN-3 - ol (12)

This synthesis is depicted in Fig. 11. A solution of ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml) at room temperature is added dropwise to a suspension of LiAlH4(38 mg, 1 mmol) in ether (3 ml) (e). After 1 hour the mixture hydrolyzing a 10% aqueous solution of H2SO4. After treatment with ether, the crude product (802 mg, mixture of compounds 12 and 11 with the ratio 9:1) purify by chromatography on silica gel using CH2Cl2. First elute small is C (=1,0).

Infrared spectrum (CHCl3): 3640m, 3500 br., 1585w.

Range1H-NMR (90 MHz): 0,78 (s, 3H), 3,60 (m, w1/2(m, 20, 1H), 5,71 (m, 1H), by 5.87 (m, 1H).

Example 20

Alternative synthesis of östra-4,16-Dien-3-one, 1

To östra-1,3,5(10),16-tetraen-3-methyl ether (551,5 mg, 2,055 mmol) in 8.6 ml of anhydrous tetrahydrofuran (THF, 30 ml anhydrous ammonia and 6.76 g of tert-butyl alcohol add finely cut lithium wire (0.24 g, 35 mg-atom). The reaction mixture is heated under reflux in an argon atmosphere for 4 1/2 hours, then add methanol (2.3 ml) and allow to evaporate the ammonia during the night. The residue is dissolved in 25 ml of methanol and acidified to approximately pH 1 5 N. HCl solution. After heating for 15 minutes at an oil bath at a temperature of from 55 to 70oC gidralizovanny the cooled mixture was partitioned between 25 ml of water and 50 ml of ethyl acetate. The aqueous phase is extracted with 25 ml ethyl acetate. The combined organic extracts are washed with 25 ml saturated sodium bicarbonate solution and 25 ml of saturated salt solution, dried over magnesium sulfate and filtered. After removal of the solvent under reduced pressure gain of 0.57 g of oily residue, which was purified flash chromatography on silicagel is in (206,1 mg, 39%), homogeneous according to TLC, 67-71oC. (NA-1993A-38,42 D)

Example 21

Östra-2,5(10),16-triene-3-methyl ether, 2

To östra-1,3,5(10), 16-tetraen-3-methyl ether (1.22 g, of 4.54 mmol) in 19 ml of anhydrous tetrahydrofuran, 14,99 g of tert - butyl alcohol and 70 ml of anhydrous ammonia add finely cut lithium wire (of 0.53 g, 76 mg-atom). Cm. Fig. 12. After heating for 6 hours under reflux in an argon atmosphere, the reaction mixture was quenched with 5 ml of methanol and allow to evaporate the ammonia during the night. A suspension of the residue in 100 ml of water twice extracted with 100 ml portions of ethyl acetate, the combined organic extracts washed with saturated salt solution and dried over magnesium sulfate. After removal of the solvent under reduced pressure the residue is purified flash chromatography on silica gel, using as eluent a mixture of 1% ethyl acetate and hexane, and then recrystallized from absolute ethanol to obtain a friable white crystals (884,1 mg, 3,269 mmol, 72%), etc., 72 - 73oC, homogeneous according to TLC. (NA-1993A-74,77)

Example 22

Östra 5(10),16-Dien-3-one, 3

Östra-2,5(10), 16-triene-3-methyl ether, 2 (646,3 mg, 2,390 mmol), dissolved in 50 ml of acetone, hydrolyzing within 6 hours at room temperature, using on the Nata sodium, and then twice extracted with 25 ml portions of ethyl acetate. The combined organic extracts washed twice with 25 ml of saturated salt solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from hexane to obtain the product (462,5 mg, 1,804 mmol, 75%), etc., wing 112-116oC. (NA-1993A-78A)

Example 23

Östra 5(10),16-Dien-3-ol, 4

Östra 5(10), 16-Dien-3-one, 3 (301,1 mg, 1,174 mmol) in 6 ml of anhydrous ether recover for 1 hour at room temperature, using alumalite lithium (50.0 mg, of 1.32 mmol). Cm. Fig. 12. After blanking decahydrate of sodium sulfate (2.00 g) for 10 minutes, the resulting suspension is filtered through celite, and the residue is washed with four 25 ml portions of ether. The combined filtrates are concentrated under reduced pressure and purified flash chromatography (silica gel, as eluent a mixture of 5% ethyl acetate and hexane) and subsequent preparative TLC mixed fractions. The more polar product is recrystallized with significant losses from aqueous ethanol, giving 4,8 mg solids. The less polar product is recrystallized from aqueous methanol to obtain white crystals (59,5 mg), etc., 98-100oC. Total yield equal 64,3 mg is l) in pyridine (5.0 ml, 62 mmol) is cooled to -13oC in a bath containing a mixture of ice, salt and add perbromide pyridinium bromide (1,58 g, 4,94 mmol) in small portions so that the temperature was < -4oC. After vigorous stirring for 1 minute add the phenol (0.25 g, 2.7 mmol) and continue the reaction for another 24 hours at room temperature. Cm. Fig. 12. In the reaction mixture is injected ethyl acetate (50 ml) and washed with 25 ml of 1 n HCl solution, two 25 ml portions of saturated copper sulfate solution, 25 ml of 5% sodium hydroxide and 25 ml of saturated salt solution. After drying over magnesium sulfate, filtration and concentration under reduced pressure the residue is dissolved in 10 ml of absolute ethanol, add granules of zinc (0.33 g, 5.0 mg-atom) and heat the mixture under reflux for 1/2 hour. The supernatant is removed, the residue was washed with 10 ml of absolute ethanol, after which the United supernatant concentrated under reduced pressure. The resulting residue is purified flash chromatography on silica gel, using as eluent a mixture of 15% ethyl acetate and hexane. The appropriate fractions are combined concentrated and recrystallized from hexane to obtain a solid product (117,5 mg, 0,4619 mmol, 31%), etc., 87-92oC. (NA-1993A-62,65)

PR is inflorida and cooled to -10oC in a bath containing a mixture of ice and salt. Add 3,5-dimethylpyrazol (12,90 g, 0,1342 mol) and stirred the mixture for 20 minutes. Cm. Fig. 13. In the reaction mixture is injected östra-1,3,5(10),16-tetraen-3-yl-acetate (of 4.00 g, 13.5 mmol) in a chilled solution of 20 ml of methylene chloride and stirred for 2 hours so that the temperature was < -8oC. the mixture is Then filtered through 200 g of silica gel and elute the product with another portion of methylene chloride. After pooling and concentration of appropriate fractions of the crude product is purified by chromatography on silica gel, using as eluent a mixture of 15% ethyl acetate and hexane. Pooling and concentration of appropriate fractions under reduced pressure gives a white solid (0,92 g, 3.0 mmol, 22%), etc., 87-103oC. (NA-1993B-39B)

Example 26

Östra-1,3,5(10),16-tetraen-3-ol-6-he

Östra-1,3,5(10),16-he-3-acetate (203,1 mg, 0,6543 mmol) in 30 ml of methanol for 40 minutes omelet 1.5 ml of 5% (in weight ratio) solution of sodium hydroxide. Cm. Fig. 13. The reaction mixture was concentrated under reduced pressure, dissolved in 50 ml of water, neutralize 1 N. HCl solution and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts washed with 50 ml of saturated salt solution, sercretariate from a mixture of benzene and hexane and preparative TLC, that gives a white crystalline solid (52,8 mg, 0,197 mmol, 30%), etc., 188-191oC. (NA-1993B-24,27)

Example 27

Östra-1,3,5(10),16-tetraen-6 - ol-3-yl-acetate, 8

Östra-1,3,5(10), 16-tetraen-6-one-3-yl-acetate, 6 (421,4 mg, 1,358 mmol), suspended in 35 ml of 95% ethanol, restore with sodium borohydride (98,8 mg, 2,61 mmol) in 100 minutes at room temperature. Cm. Fig. 13. After concentration under reduced pressure the residue is suspended in 25 ml of water, neutralize 1 N. HCl solution and extracted three times with 25 ml portions of methylene chloride. The combined organic extracts are washed with 25 ml of saturated salt solution, dried over magnesium sulfate, filtered and concentrated. The obtained white foam purified flash chromatography on silica gel, using as eluent a mixture of 25% ethyl acetate and hexane. Pooling and concentration of the fractions gives a white solid (0.12 g, 0.38 mmol, 28%), etc., 209-212oC. (NA - 1993B-42D)

Example 28

Östra-1,3,5(10),16-tetraen-3,6-diol, 9

To a suspension of lithium aluminum hydride (95%, 46,9 mg, 1,17 mmol) in 5 ml of anhydrous tetrahydrofuran with stirring, added dropwise östra-1,3,5(10),16-tetraen-6-one-3-yl-acetate, 6 (422,9 mg, 1,360 mmol) in 5 ml of anhydrous tetrahydrofuran. Cm. Fig. 13. The reaction mixture persival 22 hours. After heating under reflux for 4 hours the reaction mixture is still starting material according to thin-layer chromatography. The reaction mixture was quenched with 0.5 ml of water + 0.5 ml of 20% (in weight ratio) of sulfuric acid and concentrated under reduced pressure. The residue is extracted four times with 20 ml portions of hot ethyl acetate and filtered through celite. The combined filtrates are concentrated and twice purified flash chromatography to obtain a solid product (0.05 g, 0.2 mmol, 10%), etc., 150-157oC. (NA - 1993B-29, 32V)

Example 29

Östra-1,3,5(10),7-tetraen-3-ol, 10

To a suspension Aquilina (100,2 mg, 0,3733 mmol) in 2 ml of dietilen-glycol added hydrazine (59 μl, 1.9 mmol) and potassium hydroxide (0.04 g, 0.7 mmol). Cm. Fig. 14. This mixture is stirred on an oil bath at a temperature of 200-214oC for 2 hours, after which the cooled reaction mixture is diluted with 10 ml of water, neutralize 1 N. HCl solution and extracted three times with 25 ml of ether. The combined organic extracts are washed with 10 ml of saturated salt solution, dried over magnesium sulfate, filtered, concentrated and purified preparative TLC (silica gel, as eluent a mixture of 15% ethyl acetate and hexane) to give a yellow resin. The resulting product delato - brown crystals (13.2 mg, 51,9 μmol, 14%), etc., 130-134oC. (NA-1993B-25C)

Example 30

20-Gamestro-1,3,5(10),6,8,17-hexaen-3-ol, 11

A suspension of the bromide triphenylphosphine (671,0 mg, 1,878 mg) and tert-butoxide potassium (212,1 mg, 1,890 mmol) in 2.1 ml of anhydrous dimethyl sulfoxide for 1 hour and heated at a bath temperature 76-86oC under a layer of argon, and then add equilenin (100,1 mg, 0,3579 mmol) in 2.1 ml of anhydrous dimethyl sulfoxide and the resulting green solution is stirred for 1 hour. Cm. Fig. 14. After cooling, add 10 ml of a mixture of 1 n HCl solution with ice and extracted with three 10 ml portions of ether. The combined organic extracts are washed with 10 ml saturated sodium bicarbonate solution +10 ml of saturated salt solution, dried over magnesium sulfate, filtered through celite, concentrate and purify.

Example 31

Östra-1,3,5(10),6-tetraen-3-ol-17-(p - toluensulfonyl)-hydrazone, 1

A suspension of 6-dehydration (538,0 mg, at 2,004 mmol) and p-toluene-sulfonylhydrazide (n-TsNHNH2, 466,6 mg, 2,506 mmol) in anhydrous methanol (5.4 ml) is heated under reflux for 25 hours to remove moisture. Cm. Fig. 15. After concentration under reduced pressure, the reaction residue is purified flash chromatography (mixture of 50% stroke is >100%. (NA-1994A-295A)

Example 32

Östra-1,3,5(10),6,16-pentaen-3-ol, 2

To a cooled (bath with a mixture of ice / water) solution of crude östra-1,3,5(10), 6-tetraen-3-ol-17-(p-toluensulfonyl)-hydrazone (1, 942,5 mg, at 2,004 mmol) in tetrahydrofuran under a layer of argon for 7 minutes with stirring, added dropwise n-utility (2.5 M solution in hexane, to 3.2 mol, 8.0 mmol). Cm. Fig. 15. Stirring is continued for 48 hours, allowing the reaction mixture to gradually warm to room temperature. Add 50 ml of 1 n hydrochloric acid and the reaction mixture is extracted with three 25 ml portions of ether. The combined organic extracts washed with 50 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates concentrated under reduced pressure. The crude product was purified flash chromatography (mixture of 20% ethyl acetate and hexane on silica gel) and preparative TLC (mixture of 20% ethyl acetate and hexane on silica gel GF thickness of 1000 microns) to obtain a white crystal film (134,5 mg, 0,5331 mmol, 27%), homogeneous according to TLC (mixture of 20% ethyl acetate and hexane on silica gel, Rf0,39). (NA-1994A-307A)

Example 33

Östra-1,3,5(10),6,16-pentaen-3-and what susne anhydride (of 0.18 ml, 1.9 mmol) is stirred for 24 hours, then add ethyl acetate (15 ml) and washed with a mixture of three 5-ml aliquot of 1 N. hydrochloric acid + 5 ml saturated sodium bicarbonate solution + 5 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. Cm. Fig. 15. The residue was washed with 5 ml of ethyl acetate and the combined filtrates concentrated under reduced pressure. Preparative thin layer chromatography of the residue (a mixture of 10% ethyl acetate and hexane on silica gel GF thickness of 1000 MK) gives a light yellow crystalline solid (74,9 mg, 0,254 mmol, 66%), homogeneous according to TLC (mixture of 10% ethyl acetate and hexane on silica gel, Rf0,40). (NA-1884B-21B)

Example 34

Östra-1,3,5(10),7-tetraen-3-ol-17-(p-toluensulfonyl)-hydrazone, 4

Equilin (500,1 mg, 1,863 mmol) and n-TsNHNH2(433,7 mg, 2,329 mmol) suspended in anhydrous methanol (5.0 ml), heated under reflux for 24 hours to remove moisture. Cm. Fig. 15. After concentration under reduced pressure the residue of the reaction mixture is purified flash chromatography (mixture of 35% ethyl acetate and hexane on silica gel) to give a white foam (899,9 mg), the output of which is > 100%. (NA-1994A-246B)

Example 35(10), 7-tetraen-3-ol-17-(p-toluensulfonyl)-hydrazone (4, 899,9 mg, 1,863 mmol) in anhydrous tetrahydrofuran (20 ml) in an argon atmosphere for 3 minutes with stirring, added dropwise n-utility (2.5 M solution in hexane, 3.0 ml, 7.5 mmol). Cm. Fig. 15. Stirring is continued for 48 hours, allowing the reaction mixture to gradually warm to room temperature. The reaction mixture is poured into 50 ml of 1 n hydrochloric acid and extracted with three 25 ml portions of ether. The combined organic extracts washed with 50 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 20 ml of ether and the combined filtrates concentrated under reduced pressure. The resulting product was then purified flash chromatography (mixture of 20% ethyl acetate and hexane on silica gel) and discolor coal with a yellow crystalline solid (274,8 mg, 1,089 mmol, 58%). (NA-1994A-278A)

Example 36

Östra-1,3,5(10),7,16-pentaen-3-yl-acetate, 6

The solution östra-1,3,5(10),7,16-pentaen-3-ol (5, USD 192.1 mg, 0,7612 mmol) in anhydrous pyridine (2.6 ml, 32 mmol) and acetic anhydride (0,36 ml, 3.8 mmol) is stirred for 6 hours, then add 30 ml of ethyl acetate. This mixture was washed with three 10-day salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. Cm. example 15. The residue was washed with 10 ml of ethyl acetate and the combined filtrates concentrated under reduced pressure. Preparative thin layer chromatography (mixture of 5% ethyl acetate and hexane on silica gel GF thickness of 1000 MK) and recrystallization from aqueous ethanol to give fine white needles (78,6 mg, 0,267 mmol, 35%), etc., 77-80oC. Thin layer chromatography (mixture of 4% ethyl acetate and hexane on silica gel) shows the presence of two spots in the Rfof 0.21 and 0.24. (NA - 1994A-286A)

Example 37

Östra-1,3,5(10),6,8-pentaen-3-ol-17-(p-toluensulfonyl)-hydrazone, 7

Equilenin (0,6559 mg, 2,463 mmol) and n-TsNHNH2(573,6 mg, 3,080 mmol) suspended in anhydrous methanol (8.2 ml), heated under reflux for 24 hours to remove moisture. Cm. Fig. 16. After cooling and concentration under reduced pressure, the reaction mixture was purified flash chromatography (mixture of 35-40% ethyl acetate and 57% hexane), etc., 95-96oC. Thin layer chromatography (mixture of 2% ethyl acetate and hexane on silica gel) shows that the obtained product (Rf0,1) contains negligible amounts of contaminants in the beginning of the spectral bands. (NA-1994A-273B)

Example 38
0), 6,8-pentaen-3-ol-(p-toluensulfonyl)-hydrazine (7, 1,0887 g 2,463 mmol) in anhydrous tetrahydrofuran (25 ml) under a layer of argon for 2 minutes added dropwise n-utility (2.5 M solution in hexane, 3.9 ml, 9.8 mmol). Cm. Fig. 16. Stirring is continued for 3 days, allowing the reaction mixture to gradually warm to room temperature. Add 50 ml of a mixture of 1 n hydrochloric acid with ice and extracted three times this mixture 25 ml portions of ether. The combined organic extracts washed with 50 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates concentrated under reduced pressure. Flash chromatography (mixture of 20% ethyl acetate and hexane on silica gel), recrystallization from aqueous ethanol and discoloration charcoal give a yellowish-brown plate (245,8 mg, 0,9819 mmol, 40%), etc. 162-263oC. (NA-1994A-269A)

Example 39

Östra-1,3,5(10),6,8,16-hexaen-3-yl-acetate, 9

The solution östra-1,3,5(10),6,8,16-hexaen-3-ol Q8 (mg 148, 8 persons, 0,5944 mmol) in anhydrous pyridine (2.0 ml, 25 mmol) and acetic anhydride (of 0.28 ml, 3.0 mmol) is stirred for 6 hours, then add ethyl acetate (20 ml). Cm. Fig. 16. This mixture propria +10 ml of saturated salt solution, dried over sodium sulfate and filtered. The residue was washed with 5 ml of ethyl acetate and the combined filtrates concentrated under reduced pressure. Recrystallization from 95% ethanol gives shiny white plates (99,4 mg, 0,340 mmol, 55%, etc., 95-96oC). Thin layer chromatography (mixture of 2% ethyl acetate and hexane on silica gel) shows that the product (Rf0,1) contains negligible amounts of impurities in the beginning of the spectral bands.

Example 40

17-Methyltetra-1,3,5(10)-triene-3-ol, 10

A suspension of the bromide methyltriphenylphosphonium (100,03 g, 0,28001 mol) and tert-butoxide potassium (31,42 g, 0,2800 mol) in anhydrous dimethyl sulfoxide (320 ml) is stirred at an oil bath (68-81oC) under a layer of nitrogen for 1 hour, then using a syringe add estrone (15,14 g, 55,99 mmol) in anhydrous DMSO (320 ml). Cm. Fig. 17. The stirring is continued for a further 1 hour, after which the reaction mixture is left to cool. This mixture is then poured into 800 ml of a mixture of 1 n hydrochloric acid with ice, and then extracted three times with 400 ml aliquot of the ether. The combined organic extracts washed with 350 ml of saturated sodium bicarbonate solution and 400 ml of saturated salt solution, dried over sodium sulfate and filtered L additional amount of ether. Concentration of the appropriate fractions under reduced pressure, and the three-fold recrystallization from aqueous ethanol to give a very fine white needles (11,47 g, 42,73 mmol, 76%), etc., 134-136oC, homogeneous according to TLC (mixture of 20% ethyl acetate and hexane on silica gel, Rf0,45). (NA - 1994A-242B)

Example 41

17-Methyltetra-1,3,5(10)-triene-3-yl-acetate, 11

A solution of 17-methyltetra-1,3,5(10)-triene-3-ol (10, of 5.84 g, and 21.8 mmol) in anhydrous pyridine (32 ml, 0.40 mol) and acetic anhydride (9.7 ml, 0.10 mol) is stirred for 24 hours, then add ethyl acetate (250 ml). Cm. Fig. 17. This mixture was washed with three 100 ml portions of 1 n hydrochloric acid solution +100 ml saturated sodium bicarbonate solution +100 ml of a saturated solution of copper sulphate +100 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates concentrated under reduced pressure. Recrystallization from aqueous ethanol gives shiny white plates (of 5.84 g of 18.8 mmol), etc., 77-79oC. (NA-1994A-248B)

Example 42

17-Methyltetra-1,3,5(10)-triene-6-one-3-yl-acetate, 12

To a suspension of chromium trioxide (to 6.19 g of 61.9 mmol), cooled to - 8oC (bath with a mixture of ice, salt), in the chickpeas to the reaction mixture for 2 minutes, add a solution of 17-methyltetra-1,3,5(10)-triene - 3-yl-acetate (11, 2,0001 g, 6,4428 mmol) in 10 ml of cold methylene chloride so that the temperature was below -6oC. Stirring is continued for another 2 hours, after which the reaction mixture was passed through a column Packed with 100 g of silica gel (200-400 mesh). Product elute another portion of methylene chloride. Pooling and concentration of appropriate fractions under reduced pressure gives the crude product which is further purified by double recrystallization from aqueous ethanol to obtain brilliant crystals of white color with a yellowish tinge (334,0 mg, 1,030 mmol, 16%), etc., 91-94oC. Thin layer chromatography (mixture of 25% ethyl acetate and hexane on silica gel) shows that the obtained product (Rf0,47) contains two minor impurities in the Rf0.30 to 0.39. (NA-1994A-272A)

Example 43

17-Methyltetra-1,3,5(10)-triene-3,6 - diol, 13

To a suspension of lithium aluminum hydride (53,6 mg of 1.41 mmol) in anhydrous tetrahydrofuran (3.0 ml) under a layer of nitrogen, cooled in a bath with a mixture of dry ice with acetone for 8 minutes with stirring, added dropwise 17-methyltetra-1,3,5(10)-triene-6-one-3-yl-acetate (12, 251,7 mg, 0,7758 mmol) in anhydrous tetrahydrofuran (3.0 ml). Cm. Fig. 17. After stirring for 2 hours bath is removed and prodromoi salt (1.78 g). The resulting mixture is applied to the layer of diatomaceous earth and extracted four times with 10 ml portions of ethyl acetate. Subsequent extraction with five 10 ml portions of hot ethyl acetate and concentration of all extracts under reduced pressure to give a colorless film. Preparative thin layer chromatography (mixture of 40% ethyl acetate and hexane on silica gel GF thickness1000IL) gives a white foam (15.3 mg, 53,8 IL mol, 7%). TLC (mixture of 40% ethyl acetate and hexane on silica gel) shows the presence of primary (Rf0,29) and byproducts (Rf0,37). (NA-1994A-283B)

Example 44

17-Methyltetra-1,3,5(10)-triene-3-yl methyl ether, 14

To a stirred suspension of 17-methyltetra-1,3,5(10)-triene-3-ol (lower than the 5.37 g, 20.0 mmol) and potassium carbonate (50,82 g, 0,3678 mol) at reflux in 90% ethanol (500 ml) add dimethylsulfate (5.0 ml, 53 mmol). After heating under reflux for 1/2 hour to introduce an additional amount of dimethylsulfate (36 ml, 0.38 mol, in the form of three 12 ml aliquot) for 1 hour. Cm. Fig. 17. The reaction mixture is heated under reflux for one hour, after which it was added 360 ml of water and placed overnight in a refrigerator. The resulting suspension is filtered and washed with 80 ml of 60% methanol + three 80 ml GIP methanol to obtain white crystals (3.88 g, 13.7 mmol, 69%), etc., 59-62oC. TLC (mixture of 20% ethyl acetate and hexane on silica gel) shows that the obtained product (Rf0,63) contains minor amounts of contaminants in the Rf0,37 and early spectral bands. (NA-1994A0247)

Example 45

17-Methyltetra-2,5(10)-Dien-3-yl-methyl ester, 15

About 70 ml anhydrous ammonia is distilled through a column of KOH in 250 ml of warmed over a flame three-neck flask equipped with an input coupling device, a magnetic stirrer, a condenser with a mixture of dry ice with acetone and ground glass stopper. Cm. Fig. 17. To the reaction mixture add a solution of 17-methylene - östra-1,3,5(10)-triene-3-yl-methyl ester (14, 1,1297 g, 4,0001 mmol) and tert-butyl alcohol (13,21 g, 0,1782 mol) in dry tetrahydrofuran (17 ml), and then finely cut lithium wire (0,47 n, 68 mg-atom). After heating under reflux under a layer of argon for 6 hours add anhydrous methanol (6.6 ml) and stirred suspension during the night, giving to evaporate the ammonia. Add water (100 ml) and the suspension is shaken out three times with 50 ml portions of methylene chloride. The combined organic extracts are washed with 100 ml of saturated salt solution, dried over sodium sulfate no. Crystallization of the obtained pale-yellow oil from aqueous ethanol gives shiny white crystals (815,0 mg, 2,865 mmol, 72%), etc., 77-78oC, homogeneous according to TLC (Rf0,60, a mixture of 10% ethyl acetate and hexane on silica gel). (NA-1994A-257)

Example 46

17-Methyltetra-4-EN-3-one, 16

To a solution of 17-methyltetra-2,5(10)-Dien-3-yl-methyl ester (15, 702,8 mg, 2,471 mmol) in methanol (6 ml) and acetone (20 ml) is added concentrated hydrochloric acid (6.0 ml) and water (6.0 ml). Cm. example 17. After stirring for 1 hour, carefully add sodium bicarbonate (7.50 g). This mixture is concentrated under reduced pressure to complete the termination of allocation of gas bubbles and add water (50 ml). The reaction mixture was thrice extracted with 25 ml portions of methylene chloride. The combined organic extracts washed with 50 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of methylene chloride and the combined filtrates concentrated under reduced pressure. The product was then purified by discoloration charcoal, flash chromatography (mixture of 20% ethyl acetate and hexane on silica gel) and recrystallization from aqueous ethanol to obtain a white powder (302,8 mg, 1,120 mmol who EN-3-one (16, 203,7 mg, 0,7533 mmol) in 10 ml of anhydrous ether type three-tert-butoxylated lithium (766,6 mg, 3,015 mmol) and stirred for 4 hours. Cm. Fig. 18. Add Glauber's salt (3.80 g) and stir the suspension for another 1/2 hour. The mixture is filtered through diatomaceous earth and washed five times the residue with 10 ml portions of ether. The combined filtrates are concentrated under reduced pressure, and then purified preparative thin-layer chromatography (mixture of 5% ethyl acetate and methylene chloride on silica gel GF thickness of 1000 MK) to give white needles (60,2 mg, 0,221 mmol, 29%), homogeneous according to TLC (Rf0,37, a mixture of 5% ethyl acetate and methylene chloride on silica gel). (NA-1994A-282)

Example 48

17-Methyltetra-1,3,5(10),7-tetraen-3-ol, 18

Bromide methyltriphenylphosphonium (1,9967 g, 5,5892 mmol) and tert - piperonyl potassium (627,2 mg, 5,589 mmol), suspended 6.1 ml of anhydrous DMSO under a layer of argon, stirred for 1 hour on an oil bath (71-83oC), after which the syringe is injected equilin (300,0 mg, 1,118 mmol) 6.1 ml of anhydrous dimethyl sulfoxide. Cm. Fig. 18. After stirring for a further 70 minutes, the reaction mixture was poured into 40 ml of a mixture of ice water and extracted three times with 25 ml portions of ether. The combined organic extracts washed out 10 ml of ether and the combined filtrates concentrated under reduced pressure. Flash chromatography (mixture of 15% ethyl acetate and hexane on silica gel) and preparative thin layer chromatography (mixture of 20% ethyl acetate and hexane on silica gel GF thickness of 1000 MK) give Matt white film (162,3 mg, 0,6093 mmol, 54%). (NA)-1994A-258)

Example 49

17-Methyltetra-1,3,5(10),7-tetraen-3-yl-acetate, 19

Bromide methyltriphenylphosphonium (3.33 g, to 9.32 mmol) and tert - piperonyl potassium (1,05 g, 9,36 mmol), suspended in 10 ml of anhydrous DMSO under a layer of argon, stirred for 1 hour in an oil bath (77-79oC), after which the syringe is injected equilin (500.0 mg, 1,863 mmol) in 10 ml of anhydrous dimethyl sulfoxide. Cm. Fig. 18. After stirring for a further one hour, the cooled reaction mixture is poured into 50 ml of a mixture of 1 n hydrochloric acid with ice and extracted three times with 25 ml portions of ether. The combined organic extracts are washed with 25 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ether and the combined filtrates concentrated under reduced pressure. The obtained light yellow syrup was dissolved in anhydrous pyridine (6.3 ml, 78 mmol), add acetic anhydride (0,88 ml, 9.3 mmol) and stirred the reaction mixture for what rceme ether. The combined organic extracts are washed with 100 ml saturated sodium bicarbonate solution +100 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of ether and the combined filtrates concentrated under reduced pressure. The crude acetate purified flash chromatography (mixture of 5% ethyl acetate and hexane on silica gel) to give a yellow resin (494,7 mg, 1604 mmol. 86%). (NA-1994A-305)

Example 50

Östra-4,16-Dien-10 - ol-3-one, 2

To a frozen mixture of acetone with dry ice) suspension östra 5(10), 16-Dien-3-one (1, by 115.7 mg, 0,4513 mmol) in chloroform (3 ml) is added a suspension of metallocarboranes acid (77,4%, 420,8 mg, 1.89 milliequivalent percolate) in ether (4.3 ml) and stirred the mixture for 2 hours. Cm. Fig. 19. Then the reaction mixture is placed in a refrigerator for 18 hours, then add the pentahydrate of sodium thiosulfate solution [5% (in weight ratio), 25 g] . After stirring for 5 minutes the mixture is shaken out three times with 10 ml portions of ether. The combined organic extracts are washed with 25 ml saturated sodium bicarbonate solution + 25 ml of saturated salt solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml apidologie, intermediate compound 5B, 10-epoxide is removed only partially. This substance is completely removed by heating the white crystalline residue under reflux for 1 hour in 20 g of 5% (in weight ratio) of potassium hydroxide in anhydrous methanol. The reaction mixture is poured into 50 ml of a mixture of ice water and extracted with 50 ml of ether. The organic extract is washed twice with 50 ml portions of water, dried over sodium sulfate and filtered through diatomaceous earth. The residue was washed with 20 ml of ether and the combined filtrates concentrated under reduced pressure. The residue is purified preparative TLC (mixture of 50% ethyl acetate and hexane on silica gel GF thickness of 1000 microns) to obtain a colorless resin (19.7 mg, 72,3 mmol, 16%). (NA-1993B-80)

Example 51

18-nor-17-methylestra-4,13(17)-Dien-3-ol, 4

To a cooled (bath with a mixture of ice / water) solution of 18-nor-17 - methylestra-4,13(17)-Dien-3-one (3, to 0.23 g, 0.90 mmol) in anhydrous methanol (2.3 ml) add borohydride sodium (0,23 g, 6.1 mmol) and stirred the reaction mixture for 2 hours. Cm. Fig. 19. The solvent is removed under reduced pressure and add to the residue 10 ml of water. This mixture is then extracted three times with 10 ml portions of methylene chloride. The combined organic extracts are washed with 10 ml of myauth 5 ml of methylene chloride and the combined filtrates concentrated under reduced pressure. The obtained light yellow solid is purified by preparative thin-layer chromatography (mixture of 5% ethyl acetate and methylene chloride on silica gel GF thickness of 1000 microns) to obtain yellow solid (53,6 mg, 0,207 mmol, 23%), homogeneous according to TLC (mixture of 5% ethyl acetate and methylene chloride on silica gel; Rf0,32). (NA-1993B-120)

Example 52

Electrophysiology irritation astronom vomeronasal organ and olfactory epithelium man

To register local electrical potentials in the vomeronasal organ (VNO) and olfactory epithelium (OE) used non-invasive method. Local irritation of the gas produced in the case of both nasal structures, using specially created the design of the catheter with electrodes connected to a multichannel system the introduction of drugs. Local reaction vomeronasal organ and olfactory epithelium indicated the dependence on the concentration of ligand, which is an irritant.

The research was conducted with the participation of ten healthy (strictly chosen) volunteers - 2 men and 8 women aged 18 to 85 years. These studies were performed without General or local anesthesia.

Local irritation of the gas produced using a catheter electrode. A constant flow of clean, odorless, humidified air at room temperature was continuously sent through the channel system irritation. Annoying ligands were dissolved in the propylene glycol was mixed with humidified air and blew out within 1-2 seconds through a catheter with an electrode. It was found that the result of this procedure in the nasal cavity receives about 25 PG mixture of steroid and ligand.

Example 53

The dimension changes of potential receptors in the vomeronasal neuroepithelium of the body under the action of various steroids

The change of potential receptors under the influence of several different ligands were measured in 40 women (Fig. 3A) and 40 men (Fig. 3B). Each test was administered to 60 PG of each of the seven substances indicated on the figures. These substances were injected separately for 1 second, using the procedure described in example 20. The change of potential of the vomeronasal neuroepithelium of the body were recorded within a certain period of time and produced average price. The comparison of Fig. 3A and 3B shows that the impact of each steroid differs sexual dimorphism and that some ligands have a stronger effect on men and women.

Example 54

Measuring reactions of the autonomic nervous system to stimulation by astronom vomeronasal organ

With the introduction of 1,3,5(10),16-estracecream-3-yl-acetate 40 men in accordance with the procedure described in example 20, was controlling different functions of the autonomic nervous system. As a control substance used propylene glycol. The ligand was introduced in the form of a pulse with duration of 1 second. The changing role of the autonomic nervous system was noted in the first 2 seconds, and it lasted for 45 seconds. As shown in Fig. 4, when compared with propylene glycol, which was the control connection, Estrin caused a significant change in the total potential receptors in the vomeronasal organ (4A), galvanic skin response (4B) and skin temperature (4C).

Example 55

Comparison of changes of potential receptors under the influence of two astramovich steroids

60 PG of each steroid and propylene glycol as control compounds were administered to a subject Murci ether caused a greater change of potential receptors, than 1,3,5(10),16-estracecream-3-yl-acetate.

Example 56

Psychophysiological effects of stimulation of astronom vomeronasal organ

Psychophysiological effects of stimulation of astronom vomeronasal organ was measured by introducing pheromone and evaluation test its state based on the questionnaire before and after the introduction. The questionnaire included several adjectives used for the routine assessment of emotional state (Derogatis Sexual Inventory).

Forty (40) subjects with good health were randomly divided into two groups: 20 people in the first group received placebo, and 20 subjects in the second group received 20 picograms 1,3,5(10),16-estracecream-3-ol, which was introduced in accordance with the description given in example 3. Subjects were given a questionnaire consisting of 70 adjectives, which made it possible to assess the emotional state immediately before and 30 minutes after administration of placebo or experimental substances. All adjectives were placed in the questionnaire completely at random, and after the survey were grouped to assess on the basis of their relationship to each mood, emotional state or trait of character.

Example 57

El is the ratio of 60 clinically healthy volunteers of both sexes (30 men and 30 women) aged 20 to 45 years. Anesthesia was not used, and pregnant women from the study were excluded.

System irritation and registration was a "multifunctional minisonde", described in the scientific literature (Monti-Bloch L. and Grosser C. L. (1991) "Effects of putative pheromones on the electrical activity of the human vomeronasal organ and epithelium in humans", J. Steroid Biochem. Molec. Biol. 39:573-582). The recording electrode was a silver ball of 0.3 mm, attached to a short (0.1 mm) silver wire with Teflon coating Teflon). The electrode surface was first treated with the aim of obtaining a layer of silver chloride, and then covered with gelatin. This electrode was placed in a small Teflon catheter (diameter = 5 mm) so that the tip of the electrode was performed approximately 2 mm Teflon catheter with a length of 10 cm was a long end of the multi-channel input system, which were feeding a continuous stream of air containing the individual pulses of the dynamics of the stimulus. The air flow first got into the little chamber where he was barbotirovany through the solution containing vomeropherins or affectant in the solvent or solvent. To quickly change the direction of airflow to bypass this camera used solenoidality second outer Teflon tube with a diameter of 2 mm, the Central end of which was connected with a suction device that provides continuous suction with a speed of 3 ml/sec. Such a concentric arrangement of an outer suction tube was allowed to submit dynamics of the stimulus on a site called "minipolis" (approximate diameter = 1 mm), it was eliminated the ingress of substances into the area that is located outside of the proposed site irritation, or respiratory system. All device irritation and registration can be placed on the neurosensory epithelium in the vomeronasal organ or on the surface of the olfactory or respiratory epithelium.

Electrophoretogram (EVG): the Registration was made in a soundproof room in subjects lying on the back; multifunctional minisand first stabilized in the new cavity with a nasal retractor placed in the vestibule of the nose. Reference and ground electrodes consisted of silver discs (8 mm), which was placed on the glabella.

The entrance of the vomeronasal organ or the vomeronasal pit identified by extending the nasal openings and the nasal vestibule. Then, using a binocular magnifier with a sixfold increase and what their vomeronasal organ where it was fixed at a depth of 1 mm in the vomeronasal course. Regarding the exact location of the recording electrode testified a certain depolarization potential reactions to the substance under test after the test.

Electrical signals from the recording electrodes, were sent to the DC amplifier, and then using the computer produced their digital processing and stored in the storage device. Measured double amplitude signals and integrated the area under the wave of depolarization during continuous monitoring of the signal on the computer screen, and a digital oscilloscope. False signals created by the respiratory movements were eliminated by training the subjects breathing through the mouth when the velopharyngeal closing.

Dynamics of stimuli: as substances for studies of the olfactory epithelium was used cineole and 1-carvon; vomeropherins were a, b, C, E, and F. (Vomeropherins were provided by the Corporation Pherin Corporation, Menlo Park, PCs California). Sample vomeropherins concentration of 25-800 Foley was applied in a continuous stream of air for a period of time from 300 milliseconds to 1 second. A series of short test pulse, the yli made of Teflon), glass or stainless steel and were thoroughly cleaned and sterilized before each use.

Electroretinogram (EOG): For registration olfactory reactions used the same multi-function minisand for irritation and registration, which is used for research vomeronasal organ. The tip was slowly introduced until such time as the recording electrode is not in contact with the mucous membrane of the olfactory epithelium. The correct position was confirmed by depolarization potential response to the pulse odorous test substance.

The activity of the cerebral cortex caused by irritation of vomeronasal organ vomeropherins, and olfactory irritation produced by odorous substances supplied in the form of air pulses with a duration of 300 msec. Registration was made standard electrodes used for electroencephalogram (EEG), which are consistent with the positions Cz-AI and Tz-AI international system 10120; the ground electrode was placed in the region of the mastoid process. The electrical resistance of the skin (EDA) was recorded through a conductive gel using standard 8 mm cerebrovascu small (1.0 mm) temperature resistant probe, attached to the tip of the right ear. The pulsation of the peripheral arterial system (PAP) was controlled using plethysmograph attached to the tip of the index finger. Breathing frequency (RF) was measured using the controlled tensiometer, covering the lower part of the chest. All electrical signals were amplified using amplifier DC were subjected to digital processing (MP-100, Biopac Systems) and continuously controlled by the computer.

Statistical analysis: Electrophoretogram or electroretinogram, change dual amplitude and frequency of other parameters were measured and subjected to statistical analysis. The significance of the results was determined using the paired t-test t-test or analysis of variance (ANOVA).

Impact vomeropherins on electrophoretogram: it Was found that the potential receptors caused all vomeropherins, characterized by sexual dimorphism (Fig. 6A-C). Electrophoretogram registered in 30 men and 30 women (aged 20 to 45 years). Vomeropherins was dissolved and injected in the form of pulses with a duration of 1 second in the vomeronasal organ with intervals between pulses 6 minutes. Nobody could PTY are consistent with previously presented results (Monti-Bloch L. and Grosser C. L. (1991) "Effect of putative pheromones on the electrical activity of the human vomeronasal organ and epithelium in humans", J. Steroid Biochem. Molec. Biol. 39: 573-582), which suggests that neither olfactory stimuli, nor vomeropherins directed to the vomeronasal organ, not felt at these concentrations.

In Fig. 6A presents the average response of subjects men (aged 20 to 38 years) in the solvent and in equimolar amounts (100 fmoles) five vomeropherins (a, b, C, D and F) and vomeropherins E, stereoisomer vomeropherins F. Profiles in response to each substance were identical for all subjects regardless of age, with no significant differences using t-test t-test and by ANOVA. For example, vomeropherins a, C and D had a significant impact (M15= 11,4 MB, standard deviation = 3.6 mV; M76= 6,4 mV, standard deviation = 2,5 mV and M84= 15,1 mV, standard deviation = 4.9 mV; p<0,01), which was comparable in all cases. Other vomeropherins caused depolarization of the receptor vomeronasal organ to a much lesser extent, but with comparable amplitudes of the average response in all subjects. Vomeropherins actively influencing men who caused the pain is sustained fashion smaller reaction in the vomeronasal organ of the male (Fig. 6A and Fig. 7A).

A similar experimental procedure was performed in 30 subjects women (aged 20 to 45 years). Among vomeropherins F (100 fmoles) caused the biggest differences in this group (Fig. 6B). Vomeropherins And caused a small reaction, which differed significantly from the response to vomeropherins F (p<0,01). In both test groups active vomeropherins caused reactions of receptors with large standard deviations (Fig. 6). After studying the frequency distribution of impacts vomeropherins a and F in men and women was found a bimodal distribution. Currently, we study the significance of this phenomenon.

Vomeropherins E, stereoisomer vomeropherins F, did not cause irritation vomeronasal organ in women, which was typical vomeropherins F (Fig. 6B). This demonstrates the specificity of the vomeronasal organ in relation to the recognition vomeropherins. In this connection it is interesting to note that although F is the highest vomeropherins, E has stronger olfactory effect than F (Fig. 6B and Fig. 7).

Impact vomeropherins on electroretinogram: Summed potential receptors of the olfactory epithelium (OE) was detected in 20 of them the olfactory epithelium is less sensitive to these substances. This conclusion is true for both men and women (Fig. 7A). The average amplitude of potential receptors is in the range from 2.3 MB to 0.78 mV. In this study, vomeropherins In was the only substance that had a significant effect on the olfactory epithelium (p<0,02). In response to the question about the sense of the odorous substances which asked subjects after entering each stimulus, 16 people have pointed to the absence of olfactory perception, while three men and one woman noted that vomeropherins In has an unpleasant smell. The result suggests that at the concentrations used in our study, most vomeropherins are not effective stimuli olfactory receptors, but have a distinct impact on the receptors, vomeronasal organ.

The impact of olfaction on electrophoretogram and electroretinogram: unlike vomeropherins such olfactory as 1-carvon and cineole, cause minor local reaction in the vomeronasal organ (Fig. 7B). This conclusion is true for both men and women. As expected, these olfactory caused a strong reaction among men and women (p<0.01), and EOF to a much lesser extent, than cineole or 1-carvon (p<0,01), while it was not felt olfactory organs.

Reflex effects vomeropherins: studies Were conducted to determine reflex reactions of the Central nervous system (CNS) irritation vomeropherins vomeronasal organ. Local reactions caused vomeropherins (Fig. 6A and B), which was characterized by sexual dimorphism, reflected in the reaction mitigative nervous system of subjects men and women. The subjects men (Fig. 6C) vomeropherins and With reduced electrical resistance of the skin (EDA) (P<0,01, n = 30). In subjects women (Fig. 6B) vomeropherins F and caused a greater reduction in electrical resistance of the skin than a or C (p<0,01, n = 30).

Vomeropherins a and C caused a significant increase in skin temperature (ST) (Fig. 6G) thirty subjects men (p<0,01); however, vomeropherins D caused a significant reduction in temperature (p<0,01). 30 subjects women (Fig. 6H) vomeropherins In and F stronger increased skin temperature (p<0,01) than a and C. In women vomeropherins caused changes in the electrical resistance and temperature of the skin at a higher standard deviation than those of men.

The activity of the cerebral cortex Regis what eTelestia from 300 msec to 1 sec), containing 200 fmole vomeropherins (Fig. 6G and H). In men (Fig. 6E) vomeropherins a, C and D were significantly increased alpha rhythm of the cerebral cortex, which was not shown during 270-380 msec. Vomeropherins D and a had the strongest effect (p<0,01). Synchronization of the EEG was delayed by 1.5 to 2.7 minutes after the introduction of the one pulse of the active substance. In women (Fig. 6F) one pulse (200 fmole) vomeropherins In or F directed in the vomeronasal organ, increased alpha rhythm of the cerebral cortex regardless of the response of the olfactory receptors. We found the specificity of the reaction vomeronasal organ and olfactory epithelium, which suggests that they represent independent functional systems with Autonomous communication with the Central nervous system (Brookover C. (1914) The nervus terminalis in adult man. J. Comp. Neurol. 24:131-135). In addition, there is preliminary evidence suggesting that electrophoretogram has nothing to do with the endings nocireceptors of the trigeminal nerve, because local anesthesia (2% lidocaine) respiratory epithelium of the nasal septum is not hindered in obtaining efficiency electrophoretogram (Monti-Bloch L. and Grosser C. L. (1991) "Effect of putative pheromon pain procedures irritation.

Additional tests to verify settings electrophoretogram, galvanic skin response, skin temperature and electroencephalogram men and women were executed in relation to 13 estreno in table 1 and Fig. 20. Steroid E12/N1 evoked the highest alpha rhythm of the cerebral cortex on the electroencephalogram in men. Steroid E8/N1 evoked the best beta-rhythm of the cerebral cortex on the electroencephalogram in men. Steroid E7/N1 evoked the best alpha rhythm in the EEG in men. In addition, it should be noted that steroid E7/N1 evoked great response, as is shown in the data electrophoretogram, males (Fig. 21A) and women (Fig. 20A), but there were differences depending on gender-related effects on the Central nervous system (high alpha rhythm of the cerebral cortex on the electroencephalogram in women and high beta-rhythm of the cerebral cortex on the electroencephalogram in men, Fig. 31A and b).

Receptors, vomeronasal organ, no doubt, are more sensitive to vomeropherins compared with all tested olfactorily; for olfactory receptors characterized by the opposite effect. Although the olfactory epithelium of the constituent body opposite.

On the specificity and the influence of two groups vomeropherins, A, C, and D, and and F was influenced by sex differences. From this we can conclude about a possible sexual dimorphism associated with receptors. The obtained results confirm the possibility of activation of components of the autonomic nervous system in adult men by irritation of vomeronasal organ vomeropherins.

In addition, the obtained results allow to conclude that the irritation of the vomeronasal organ vomeropherins causes synchronization of the EEG (Fig. 6G and H). Thus, the data presented here suggest that the vomeronasal system reacts to different dynamics of the stimuli and that some of them can cause reflex activity of the autonomic nervous system.

1. Steroid compound of the formula I ( see text),

where R1selected from the group comprising one or two atoms of hydrogen, methyl and methylene;

R2absent or selected from the group comprising hydrogen or methyl;

R3selected from the group consisting of oxo, hydroxy, lower alkoxy, lower acyloxy;

R4selected from the group comprising hydrogen, hydrox who is hydrogen;

and represents optional aromatic unsaturation of ring And specified steroid, or b, c, and d each represent an optional double bond:

e, f, g, h, i and j each represent an optional double bond; provided that

(1) when a is present, R3denotes hydroxy, lower alkoxy or lower acyloxy, j, i, g, and h are all absent, then (a) R4cannot be hydrogen; or (b) R4cannot be hydrogen or oxo, if e and f are absent;

(II) when a is present, R3denotes hydroxy, j, i and g are absent, and h is present, then R1cannot be methylene;

(III) when a, h and i are present, then (a) at least one of e or f is present, or (b) R1is not hydrogen, or (C) R1is not a methylene;

(IV) when b is present, R3represents oxo, g, h, i, j all absent and R5is hydrogen, then (a) R1there can be one or two hydrogens, if f is missing, or (b) if f is present, R1may not be the stands;

(V) when b and j are present and R3represents oxo, then (a) at least one of e or f must be present, or (b) R1must be methylene;

(VI) when present, 1 must be methylene;

(VII) when C and d are present, and R3denotes methoxy, then (a) at least e or f must be present, or (b) R1must be methylene;

(VIII) when b is present, R3denotes hydroxy and R5denotes hydrogen, then (a) at least e or f must be present, or (b) R1must be methylene;

(IX) when R3- lower alkoxy or lower acyloxy, then R1cannot be methylene;

(X) when R1denotes methyl, R4and R6are not both hydrogen;

(XI) when a and e are present, j, i, g, h and f are absent, R2denotes methyl and R3denotes hydroxy, then R1, R4and R6are not both hydrogen;

(XII) when e is present, R2denotes methyl, R5denotes hydroxy and a, C, d, f, g, h, i and j are absent, then R6, R4and R1can't all denote hydrogen.

2. Connection on p. 1, where a is present and one or more of g, h or i are optional double bonds.

3. Connection on p. 1, where b denotes a double bond.

4. Connection on p. 1, where C and d represent double bonds.

5. Connect the config steroid selected from the group including östra-1,3,5(10), 6,16-pentaen-3-ylacetic; östra-1,3,5(10), 7-tetraen-3-ol; 17-methyltetra-1,3,5(10), 7,9-pentaen-3-ol; 17-methylene-6-exestr-1,3,5(10)-triene-3-ylacetic; östra-1,3,5(10), 7,9,16-hexaen-3-ol; östra-1,3,5(10), 6-tetraen-3-ol; 17-methyltetra-1,3,5(10),7-tetraen-3-ol; östra-1,3,5(10), 7,9,16-hexaen-3-ylacetic; östra-1,3,5(10), 7,16-pentaen-3-ol; 17-methyltetra-1,3,5(10)-triene-3,6-diol; östra-1,3,5(10),7,16-pentaen-3-ylacetic; östra-1,3,5(10),6,16-pentaen-3-ol and 17-methyltetra-1,3,5(10),7-tetraen-3-ylacetic.

7. Connection on p. 3, where the specified steroid is östra-4,16-Dien-3-ol; 17-methylgene-4,13(17)-Dien-3-ol and 17-methylenethf-4-EN-3-ol.

8. Connection on p. 4, where the specified steroid selected from the group comprising 3-petoksista-2,5(10),16-triene and 3-Mexi-17-methyltetra-2,5(10)-diene.

9. Connection on p. 5, where the specified steroid selected from the group comprising 3-hydroxyestra-1,3,5(10), 16-tetraen-6-he; 6-exestr-1,3,5(10),16-tetraen-3-ylacetic; östra-1,3,5(10), 16-tetraen-3,6-diol; 6-hydroxyestra-1,3,5(10), 16-tetraen-3-ylacetic; östra-4,9,16-triene-3-one; östra 5(10),16-Dien-3-ol and östra 5(10),16-Dien-3-ol.

10. Connection on p. 8, which represents a 3-petoksista-2,5(10),16-triene.

11. Connection on p. 9 representing östra-1,3,5(10),16-tetraen-3,6-diol.

 

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