(57) Abstract:The invention relates to new androstenone steroids of formula I
< / BR>where P1-oxo, -(-)hydroxy, -(-)-C1-4-alkoxy or -(-)benzyloxy; P2- C1-4-alkyl, hydroxy-C1-4-alkyl; P3missing or C1-4-alkyl; P4is hydrogen, oxo or hydroxy; P5- one or two hydrogen atoms, methyl or methylene; P6- hydrogen, which are ligand Poluchenie products, communicating with neuroepithelial receptor. 7 C.p. f-crystals, 1 tab., 24 Il. Background of the invention
References to related applications
This application is a partial continuation of application U.S. N 08/127908, filed September 28, 1993, which, in turn, is a partial continuation of application U.S. N 07/903604 filed June 24, 1992, which, in turn, is a partial continuation of application U.S. N 07/708936, filed may 31, 1991, which, in turn, is a partial continuation of application U.S. N 07/638185, filed January 7, 1991, now abandoned.The invention relates also to the partial continuation of other applications for U.S. patents N 07/903604, 08/077359 filed June 15, 1993, and to the pending application, in turn, is a partial continuation of application U.S. N 07/638743, filed January 7, 1991, now withdrawn), entitled "Extraname steroids as neurochemical initiators of change of the function of the human hypothalamus and related medications and treatments; and to the partial continuation of application for U.S. patent N 07/903525 transferred to the assignee and pending application U.S. patent N 08/077140 filed June 15, 1993, Each of the aforementioned patent applications U.S. is introduced into the present description by reference.Ultimately, this application may relate to a pending application for U.S. patent entitled "Aromatic drugs containing human pheromones", filed March 24, 1992, the application of the U.S. N 07/856435.The technical field
In General terms, the present invention relates to pharmaceutical compositions and methods for the implementation of changes in the hypothalamus of the person and thereby change the behavior and physiology mediated by the hypothalamus. More specifically, the invention relates to the use of certain androstenone steroids as neurochemical regulators of physiological behavioral R. the military connections, namely androstenone steroids, in particular androstenol steroids and related compounds, which will be described here, and to methods of using these compounds as poluchilisi products designed to change the function of the hypothalamus in order to impact on subsequent behavior and human physiology, for example to alleviate anxiety. Androstane steroids, a typical representative of which is testosterone, are characterized by a steroid structure, having four rings, and methylation in the 13-position and 10-position. Androstene are a subset of androstenol and have at least one double bond. In their work, which is included in the present description by reference Ohloff, G. et al. (Helv. Chim. Acta (1983), 66: 192-217) showed that several members of this group of steroids have smell, which varies depending on various isomeric, diastereomeric and enantiomeric forms. It was reported that some members of this group are the various species of mammals, like pheromone, such as 5-androst-16-EN-3-one and 5-androst-16-EN-3-ol in pigs (Melrose, D. R. et al. Br. vet J. (1971) 127: 497-502). These 16-androstene produced at the grunt call in sows response to spiritline characteristics of certain 16-androstenol (including 5-androst-16-EN-3-ol and 5-androst-16-EN-3-one), such as concentration, metabolism, and localization, are dimorphic gender (Brooksbank et al., J. Endocr. (1972) 52: 239-251, Claus, et al., J. Endocr. (1976) 68: 483-484; Kwan, et al., Med. Sci. Res. (1987) 15: 1443- 1441). So, for example, 5-androst-16-EN-3-ol and 5-androst-16-EN-3-one were found in various concentrations in the peripheral blood, saliva and in the axillary secretions of men and women (Kwan, T. K. et al., Med. Sci. Res. (1987) 15: 1443-1444) and it has been suggested that they function as a pheromone of a person affects, to some extent, on the selection and formation of judgment (Id.: see also Gower, et al., "The Significance of Odorous Steroids in Axillary Odour", in Perfumery, pp. 68-72, Van Toller and Dodd, Eds., Chap-man and Hall, 1988); Kirk-Smith, D. A. et al. Res. Comm. Psychol. Psychiat. Behav. (1978) 3:379). It was noted that androstenol (5-androst-16-EN-3-ol), which is present in men's Cologne and women's perfume, detects paramonotone activity (AndronTMfor men and AndronTMfor women, Jovan). Patent application Japan, owned by Koki relates to perfume compositions containing androstenol and/or its analogs. 5-androstadien-3-ol (and possibly 3-ol) were also found in the axillary secretions of a person (Gower, et al., see above on pages 57-60). On the other hand, in the literature there is little disagreement about playing the people. See: Beauchamp, G. K., et al., "The Pheromone Concept in Mammalian Chemical Communication: A Critique", in: Mammalian Olfaction, Reproductive Processes and Behaviour, Doty, R. L., Ed., Academic Press, 1976). See also above: Gower, et al., on pages 68-73.In one variation of its implementation of the present invention relates to a non-system intranasal introduction of certain androstenone and androstenone steroids for impacts on specific behavioral or physiological response in humans, for example to reduce negative emotional reactions, relieving depression and the impact on certain traits. In particular, the introduction through the nose provides communication neurochemical receptors is still not studied neuroendocrine patterns, commonly known as Coulter-nasal organ ("VNO"; also known as "Jacobsonís organ") with one or more steroids or drugs containing such(s) steroid(s). This body is available through the nostrils of most higher animals from snakes to humans and is associated, among other things, to the reception of pheromone certain species (see Muller-Schwarze and Siverstein, Chemical Signals, Plenum Press, New York (1980)). Axons of the neuroepithelium Coulter-nasal organ, above the sky, form a Coulter-noses who do they exercise mediated signal transmission from the follicles in the cortical-medial amygdala, basal forebrain and hypothalamus nucleus of brain cells. As neurochemical receptors in the VNO can also serve distal axons of nerve endings. Stensaas, L. J. et al., J. Steroid Biochem. and Molec. Biol (1991) 39: 353. This nerve has a direct synaptic connection with the hypothalamus.Johnson, A. et al., (J. Otolaryngology (1985) 14: 71-79) provide evidence for the presence of Coulter-nasal organ of most adults, but conclude that this body is probably nonfunctional. About the legality of this provision results reported Stensaas, L. et al.; and Moran, D. T., et al., Garcia-Velasco, J. and M. Mondragon; Monti-Bloch, L. and B. Grosser, J. Steroid Biochem. and Molec. Biol. (1991), 39, where it is assumed that the VNO is a functional homocysteine receptor.It is clear therefore that it would be desirable to identify and synthesize Poluchenie products and pheromones human, and to develop drugs and methods of their use for influencing the function of the hypothalamus. This invention is based on the unexpected discovery that by intra man, certain neurochemical ligands, in particular androstane steroids, more specifically androstenone steroids and related compounds or pharmaceutical compositions, seedling and nasal neuroepithelial cells, and this binding generates a number of neurophysiological reactions leading to changes in the hypothalamus of the individual. If appropriate, the impact of these compounds on the hypothalamus influences the function of the autonomic nervous system and the set of behavioral or physiological phenomena, including but limited to, anxiety, premenstrual syndrome, fear, aggression, hunger, blood pressure and other behavioral and physiological functions, usually regulated by the hypothalamus: Otto Appenzeller. The Autonomic Nervous System. An introduction of basic and clinical concepts (1990); Korner, P. I. Central nervous control of autonomic cardiovascular function, and Levy, N. M. and Martion, P. J. Neural control of the heart, both links are in the manual of physiology; Section 2: the Cardiovascular System - the heart. Vol. I, Washington Dc, 1979, American Physiological Society; Fishman, A. P., et al. editors, Handbook of Phisiology. Section 3, The Respiratory System, Vol. II. Control of breathing. Bethesda, M. D. 1986, American Physiological Society.In some cases, introducing one androstenone steroid or related connection, in other cases, introducing a combination androstenone steroids and/or related compounds.The invention
Accordingly, the purpose of the invention to provide a new steroid compounds, which are pheromones and what is is to obtain compounds which can be used to change the function of the hypothalamus, and which have the following advantages: 1) they can be entered directly into the chemoreceptors in the forward course and Coulter-nasal organ without the use of oral pharmaceutical forms or needle - i.e., non-invasive; 2) these drugs act on the nervous system, and not through the circulatory system that allows you to affect the function of the brain excluding the blood-brain barrier; 3) they directly affect the hypothalamus, as there is only one synapse between the receptors of the phenomenon and the hypothalamus; and 4) these medicines provide highly specific effect, resulting in greatly reduces the possibility of unwanted side effects, because sensory neurons transmit information in a specific area of the brain.Additional objectives, advantages and new features of the invention will be partially set forth in the following description and will be clear to experts in this field after reading this description or may be learned by practicing the invention in practice.
I: if "f" and "h" are absent and P2is stands, P5there can be two atoms of hydrogen;
II: if "h" is present, P3is a methyl group, P5is the R> (b) "d" may not be present if P1is oxo, "b" is present and "e" is missing;
(C) P4cannot be hydrogen if there is no "c" and "d" is "b" P1is oxo and P2is stands or hydroxymethyl;
(d) P4cannot be oxo, if there is no "e", "c" and "d", "b" is present, and P1is oxo;
(e) P4and P6cannot be hydrogen when P1is oxo, "e" and "b" are present, and "c" and "d" are absent;
(f) P4cannot be hydrogen when P1is-hydroxy, "c" is present and "a", "b", "e" and "d" are absent;
(g) P4cannot be hydrogen when P1is methoxy, "a" and "c" is present and "e", "a" and "d" are absent;
III: P4and P6cannot be hydrogen when P1is oxo, "b" is present, P6is methylene, and "a", "e", "c" and "d" are absent;
IV: P4and P6cannot be hydrogen when P1is-hydroxy, "c" is present, P5is methylene, and "a", "e", "b" and "d" are absent;
V: P4and P6cannot be hydrogen when P1is oxo, "b" and "f" are present, P5is stands, and "e", "a", "c", "d" and "h" is missing.
A = acetate 1,3,5(10),16-estracecream-3-Il,
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. 9 illustrates electroretinogram men and women, induced by stimulation of the OE olfacto stereoisomer E dealt separately in OE 20 subjects (men, and women) and registered each EVG reaction, as described. Olfactory, and E and B caused a significant (p < 0,01) local response. In: 400 fmoles of olfaction 1-carvone and cineole did not cause significant EVG reaction when filing in VNO men and women.Fig. 10 illustrates electrophysiological effects following vomeropherins on Coulter-nose body 20 women:
G = androst-4-EN-3-one,
H = androsta-4,16-Dien-3,6-dione,
J = 10,17-dimetilan-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 response,
EDA = electrical resistance of the skin,
ST = skin temperature.Fig. 11 illustrates electrophysiological effects vomeropherins on Coulter-nose body 20 men:
M = 1,3,5(10)-estratrien-3-ol.Fig. 12 illustrates the synthesis of examples 10-14.Fig. 13 illustrates a synthesis for examples 15-20.Fig. 14 illustrates a stage of synthesis for examples 22-24.Fig. 15 illustrates the synthesis of examples 25-26.Fig. 16 illustrates the synthesis of examples 27-28.Phi Is Fig. 17B shows the respiratory rate and ECG data for women when testing androsta-5,16-Dien-3,19-diol in the VNO.Fig. 18A, 18B and 18C show the data EVG, GSR and ST in the form of diagrams in women for four androstenol and androsta-5,16-Dien-3,19-diol.Fig. 19A, 19B and 19C show the data EVG, GSR and ST in the form of diagrams in men when testing five androstenol identified in Fig. 18.Fig. 20A and 20B show the EEG data for men and women for androstane A4/N3.Fig. 21A and 21B show the EEG data for men and women for androstane A3/N3.Fig. 22A and 22B show the EEG data for men and women for androstane A13/N1.Fig. 23A and 23B show the EEG data for men and women for androst-5,16-Dien-3-diol.Fig. 24A and 24B show the EEG data for men and women for androstane A6/N3.Detailed description of the invention
"Emotional reaction" is a short sensual state. Typical negative emotional reactions are feelings of nervousness, tension, shame, anxiety, irritability, anger, rage, etc. "Moods" are more long-lasting emotional States such as guilt, sadness, beznadezhnosti aspects of the individual personality. Typical negative character traits are thin-skinned, prone to constant repentance and judgment, stubbornness, irritability, bitterness, timidity, laziness, etc."Androstane steroids" are aliphatic polycyclic hydrocarbons, characterized chetyrehkolkoy steroid structure methylated in 10 - and 13-positions. Androsten is a subgroup of androstenol, which means that the connection has at least one double bond. Usually, if the connection is not gonna, it is assumed that it has an 18-carbon group. However, in this description 18-norandrosterone considered androstane steroids. In addition, all derivatives that are described above structural properties also apply to androstenone steroids."Chemoreceptor" represents the receptor molecule present on the surface of the "dynamics" neuroepithelial cells, which stereospecific manner associated with a specific ligand or ligands. This specific binding initiates a signal transduction that the incentive stimulates afferent nerve impulse. Chemoreceptors found, incidentally, in the flavor with the term "astronomie steroids" means aliphatic polycyclic hydrocarbons with chetyrehkolkoy steroid structure, at least one double bond in the A-ring methylated in the 10-position and with oxo, hydroxyl or hydroxyl derivative at the 3-position, such as alkoxy, ester, benzoate, cypionate, sulfate or glucuronide. Derivatives such structural characteristics also apply to astronomy steroids.The following structure represents chetyrehkolkoy steroid structure, which usually refers to the androstane and extrenely steroids. When describing the location of groups and substituents used the following numbering system:
< / BR>The term "sexually dimorphic" refers to a medicinal product, producing different actions or different responses in men and women.The term "effective amount" of a medicinal product means the interval quantities and/or concentrations which(th) causes the desired physiological and/or psychological impact upon the administration of a medicinal product to an individual in need of such treatment. In this case, such an individual is the individual's physiological or behavioral characteristic that is normally regulated by the hypothalamus, and if in this case it is desirable the frame means may vary depending on the function, influenced, the desired effect, method of administration etc., for example, if the steroid is injected in the form of a solution, which is applied to the skin of the human face, the effective concentration is from 1 μg/ml to 100 μg/ml, preferably from 10 to 50 μg/ml and most preferably from 20 to 30 ág/ml If the steroid is injected directly into the VNO, the effective amount is from about 1 PG (picograms) to about 1 ng (nanogram), more preferably from about 10 PG to about 50 PG. When the steroid is injected into the nasal passage in the form of ointment, cream, aerosol, etc.,, the effective amount is from 100 PG to about 100 μg (micrograms), preferably from about 1 ng to about 10 μg. Some medicines can be effective when they are administered in certain ways, but are ineffective when they are administered in other ways."The hypothalamus is a part of the intermediate brain, including the ventral wall of the third ventricle below the hypothalamic sulcus and comprising structure forming the bottom of the ventricle, including the optic chiasm, the gray matter of the hill brain, funnel and mastoid body. The hypothalamus regulates the autonomic nervous system and on the attack and retreat, sexual behavior, water balance, sugar and fat metabolism, hunger, regulates the body temperature, internal secretion and other functions. The hypothalamus is also the source of vasopressin, which regulates blood pressure, and oxytocin, which stimulates childbirth and milk production. All of hypothalamic functions potentially modeled by means described here polychemicals therapy.Used in the present invention, the term "ligand" is a molecule that acts as a chemical signal through specific binding to a receptor molecule present on the surface of the receptor cells, resulting in stimulation of signal transduction through the cell surface. Ligand binding to receptors that are sensitive to himioterpevticeski drugs, can be measured. The fabric is sensitive to himioterpevticeski drugs, such as Coulter-nasal neuroepithelium or olfactory neuroepithelium contains many cells of neuroreceptors, each of which has at least one receptor on their surface. Many receptor molecules have the same ligand specificity.Poetomu VNO poluchilisi products), can be measured by the total change of the receptor potential of the cell surface.Used in the present invention, the term "lower alkyl" means a branched or unbranched saturated hydrocarbon chain containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isobutyl, etc., In the present description, the term "alkoxy" is used in its conventional sense, that means the group-OR where R is alkyl, which is defined here."Pheromone" is a substance that enables a chemical means of communication between members of the same species through the secretion and nasal reception. Pheromones mammals are detected usually by means of receptors in the Coulter-nasal organ of the nose. Typically the pheromones act on development, reproduction and related behavior. "Poluchilisi product" is a more General term that includes pheromones and describes the substance from any source, which functions as the dynamics of the mediator; associated with specific neuroepithelial receptor and induces physiological or behavioral effects."Vomeropherins" is poluchilisi product, physiological effects cat who micrograms (mcg), microgram = 0.001 mg.II. Embodiments of the invention
A. Androstane used in the present invention
The invention is directed to a group of specific androstenone steroids. Typical androstane is testosterone (17-hydroxy-androst-4-EN-3-one).Androstane especially suitable for use in the present invention (see table at the end of the description) include compounds where independent: P1= oxo, hydroxy, hydroxy; P2= methyl, lower alkyl hydroxymethyl, hydroxyalkyl; P3= hydrogen or methyl; P4= hydrogen, hydroxy or oxo; P5= hydrogen or methyl; and usually in 4 - or 16-position at least one double bond.The preferred androstenone are androsta-4,16-Dien-3-one (P1= oxo, h = double bond, P2P3= methyl, P4P5P6= hydrogen, commercially available from Steraloids, Inc.), androsta-4,16-Dien-3-ol (P1= -HE, b, h = double bond, P2P3= methyl, P4P5P6= hydrogen, and 6-keto-androsta-4,16 - Dien-3-one (P1= oxo; b, h = double bond, P2P3= methyl, P5P6= hydrogen, P4= oxo), the synthesis of which is described here.Obviously, de (see the table at the end of the description) are indicated as follows: 17-methylene-androst-4-EN-3-ol (A3/N3), 17-methylene-6-oxo-androst-4-EN-3-one (A6/N3) and 6-Oh-androsta-4,16-Dien-3-one (A11/N1).The first Chapter includes androstane that sent the invention, but not limit its scope. Charts illustrate the synthesis the synthesis of intermediate and branch connections intended for obtaining such androstenol.New androstane.17-Medienanstalt-4-EN-3-ol (A4/N3)
6-Hydroxy-17-methyl-18-norandro-4,13(17) -Dien-3-one (A13/N4)
Androsta-5,16-Dien-3,19-diol (19-hydroxy A2/N1)
17-Methyl-18-norandro-4, 13(17)-Dien-3-ol (A4/N4)
17-Methyl-18-norandro-4, 13(17)-Dien-3-ol (A3/N4)
17-Methylandrosta-4-ene-3,6-dione (17-methyl derivative A6/N2)
6-Hydroxyandrost-1,4,16-triene-3-one (6-hydroxy A11/N1)
6-Hydroxy-17-methylandrosta-1,4-Dien-3-one (6-hydroxy A11/N3)
17-Methylandrosta-4-EN-3-ol (17-methyl derivative A4/N2)
17 Synthesis of substructures
In accordance with the table (see the end of the description) the following are examples of the synthesis of intermediate compounds in this series (A1 through A11) or column (N1 through N4)
< / BR>< / BR>A2:
< / BR>< / BR>This substructure is commercially available, for example from DEHYDRO EPI ANDROSTERONE.Further examples of the synthesis of intermediate compounds, see the end of the description.Methylandrostan.German Off. 2631915 describes how to get
< / BR>with a methyl group in any of the following provisions 1,2,4,6,6,7 and 16
< / BR>6-methylandrosta-4,6-Dien-3-one
5 German Off. 2428679.Synthesis of 17-methylandrostan
< / BR>< / BR>Daniel Bertin and Lucien Nedelac, Memories Presentes a la Societe Chimique, 1964, No. 345, p. 2140.Therefore, the synthesized compounds include those compounds together with those compounds that are derived from them: i.e., N1 with stands in 1,2,4,6,6,7 or 17, combined with A1, A3, A4, A5, A8, A9, A10 or A11 and A2 or A6 17-stands.Galogenangidridy see the end of the description.And
< / BR>The application for the European patent EP 208497.The synthesized compounds therefore include these compounds together with such compounds from which they are derived, i.e., (4-chloro, 4-bromo, 6-chloro, 6-N1 in combination with A1, A2, A3, A4, A5, A6, A8, A9, A10 or A11.B. synthesis Methods.1. Deriving compounds substituted in 3-, 5-, 6-, 18- and the 19-position.Compounds used in the methods of this invention, are androstane steroids substituted in 3-, 5-, 6-, 18- and 19-positions. Many 3 - and 5 - substituted steroids are known compounds which can be obtained from 17-hydroxy - 17-oxosteroid (which are commercially available and are produced, for example, the Aldrich Chemical company. by elimination or restoration to a 16-homolog. The synthesis of most of these compounds previously described Ohioff (Ohloff). As shown in Fig. 1, 17-hydroxy-5-androstane-3-one (I) and methylchloroform (a) in pyridine gives methylcarbonate, 17 methoxycarbonylamino-5-androstane-3-one (II), which provides the source material for 5-androst - 16-ene-(3-one and 3-tin) (Ohloff, on page 200).Alkoxybenzenes receive from their respective hydroxysteroids by reacting with an alkylating agent such as trimethyloxonium, triethylorthoformate or metalforlife in an inert chloropercha a solvent such as methylene chloride. Alternatively, alkylating agents, such as alkylhalogenide, and the led silver or barium oxide in polar aprotic solvents, for example, DMF (N, N-dimethylformamide), DMCO (dimethyl sulfoxide) and hexamethylphosphoramide.The usual methods for the synthesis of steroids known to specialists in this field. When should it be determined the time of reaction and temperature, you can define them in the usual method. After adding the reagents, the mixture was mixed in an inert atmosphere and hourly took aliquots. Aliquots were analyzed using chromatography, controlling thus the disappearance of the starting material since the beginning of the reaction. If the source material was not used within twenty-four hours, the mixture was heated to phlegmy and hourly, as before, were analyzed aliquots, until then, until starting material disappeared. In this case the mixture before starting the reaction was cooled.Purification of products was performed by the methods of chromatography and/or crystallization, known to specialists in this field.2. Getting 19-HE-derivatives.Synthesis of 19-Oh-androsta-4,16-Dien-3-one
This connection is described as an intermediate compound in the synthesis of 19-oxo-3-Aza-A-Homo-5-androstane (Habermehl, et al., Naturforsch. (1970) 25b: 191-195). The method of synthesis of this compound is shown below.the procedure changes the function of the hypothalamus of the individual. Another option is to change the Autonomous functions of the individual. These Autonomous functions include heart rate, breathing frequency, features electroencephalogram (% cortical alpha rhythm in the EEG), body temperature, but not limited to. Other options include ways to alleviate negative emotional reactions, a bad mood or correction of the negative traits of the individual. Another option is a method of treatment of premenstrual syndrome. All of these options shall be implemented by random insertion through the nose for certain 16-androstenone steroids or combinations of these 16-androstenone steroids.This method of introduction is different from alternative methods, such as oral administration or injection, several important features by which exercise direct control with the VNO, which are provided by nasal steroid ligand. In the methods of the present invention corresponding ligand injected directly into the chemoreceptors in the forward course and Coulter-nasal organ, without resorting to pills or needles, i.e. non-invasive. Baskimi receptors submitted neuroepithelial cells in the nose, preferably in the VNO. In addition, this method of drug action through the nervous system, and not through the circulatory system that allows you to affect the function of the brain excluding the blood-brain barrier. These treatments provide an opportunity to directly affect the hypothalamus through the nervous system, since there is only one synaptic connection between pheromone receptors and the hypothalamus. Because sensory neurons carry out signal transmission in a particular part of the brain, this method provides a highly specific action of the medicinal product, resulting in greatly reduces the possibility of unwanted side effects.Contact VNO is important because VNO associated with chemoreceptive/pheromone function. VNO consists of a pair of blind tubular diverticula, which are in the lower edge of the nasal septum. VNO neuroepithelium contains axons of which have direct synaptic contact with the almond-shaped body and from him in the hypothalamus. The existence of the VNO has been documented for many NASA dimentary body. (See below the specified reference Johnson et al.)
Ligand substances described in this application, or their sulphonated, Leonidovna, benzothiophene, propanediamine or glukuronidirovania derivatives can be entered directly, but is preferably introduced in the form of drugs. Get them in a liquid dosage form, such as solutions, suspensions or similar, preferably in the form of standard dosage forms suitable for single injection precisely defined doses. The dose of liquid drug can be introduced in the form of nose drops or as a spray.Alternative active connection can be obtained in the form of a cream or ointment that is applied topically to the nasal cavity. As another alternative, the supply of a medicinal product may be accomplished through the controlled release of these funds through their inclusion in a gelatin capsule in whole or in microscopic concentrations using synthetic polymers, such as silicone, and natural polymers such as gelatin and cellulose. The release rate can be adjusted by proper choice of the polymer system used for the regulation is about to dissolve in the substance, from about several minutes to several hours, whereas the silicone retains its integrity for several months. Such drugs include standard pharmaceutical carrier or excipient and one or more active androstenone compounds of formula I. in Addition, these parameters may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.The most appropriate means of delivery polychemicals ligand is the inhalation of naturally occurring pheromone present on the skin of another person. Several steroids 16-androstene, including 5-androst-16-EN-3-ol and 5-androst-16-EN-3-one, 4,16-androstadien-3-one, 5-androsta-Dien-3-ol and probably 5-androstadien-3-ol, are natural compounds found in humans and may be present on the skin. It is estimated that the maximum concentration of natural steroid man, 16-androstene present on the skin, ranging from 2 to 7 ng/cm2. Determined that during close contact, the person will be exposed to no more than 700 ng natural steroid. Since these compounds are relatively non-volatile, that is definitely, while b is Gogo person. This inhaled quantities of only 1% will achieve receptors Coulter-nasal organ. Therefore, the maximum estimated number of pheromones, the effect of which usually affects people in the most natural conditions should be 0,007 PG.The number entered polychemicals ligand will, of course, depend on the individual being treated, the severity of the disease, the route of administration, frequency of administration and pre-trial detention of a physician. However, single dose, consisting of at least about 10 PG and introduced directly into the cavity Coulter-nasal organ, is effective to provide temporary Autonomous reactions. When introduced into the nasal cavity dose of approximately from about 100 PG to about 100 μg, preferably from about 1 ng to about 10 μg, more preferably from about 10 ng to about 1 μg. The frequency of injection may range from an hourly rate to a monthly dose, preferably from 8 times/day up to 3 times a day. Ointments containing one or more active compounds and optional pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, etc. may ">The liquefied input pharmaceutical preparations can be obtained, for example, by dissolving, dispersing, etc. an active compound, as defined above and optional pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, and so on, with the formation of a solution or suspension. Optionally type the drug may also contain small amounts of non-toxic additives, such as wetting agents or emulsifiers, buffer solutions, etc., such as sodium acetate, sorbitanoleat, triethanolaminato, triethanolamine etc., Modern methods of preparing such dosage forms known in the art or can be found, for example, the manual Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton, PA, 15thEd. 1975. In any case, injected drugs or medicines will contain one or more active compounds in an amount effective to alleviate symptoms in the exposed treatment of the patient.When aerosol introduction the active ingredient is administered preferably in finely dispersed form, together with surface-active substance and dispersal is of 0.004 to 0.10%.Surfactants should be, of course, non-toxic and preferably soluble in the dispersant. 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 alcohol or its cyclic anhydride such as ethylene glycol, glycerin, aritra, Arabic, mannitol, sorbitol and the anhydrides of exit derived from sorbitol (esters sorbitan sold under the brand name "Spans") and polyoxyethylene and polyoxypropylene derivatives of these esters. Can be used combined esters, for example, mixed or natural glycerides. The preferred surfactants are the oleates or sorbitan, such as those sold under the brand name "Arlacel C" (sesquioleate sorbitan), "Span 80" (monooleate sorbitan). Surface-active agent may be 0.1-20% by weight of the composition, preferably 0.25 to 5%.The balance of the composition is usually the propellant. The liquefied propellant is usually the lower alkanes, containing up to five carbon atoms, such as butane and propane; fluorinated or ferroresonance alkanes, such as those sold under the brand name "Freon". Can also be used mixtures of the aforementioned substances.Upon receipt of the aerosol container, accompanied by an appropriate valve, fill a suitable propellant, containing finely ground active ingredient and a surfactant. Thus the ingredients support at high pressure up until they will not be released through the valve.Another method of introduction is the local application of a volatile liquid drug to the skin, preferably facial skin of the individual. This drug will typically contain alcohol, such as ethanol or propanol. The drug can also be included pleasant fragrant substance.D. Determination of conditions associated with emotional reactions, mood and personality.Emotional States associated with emotional reactions, mood and personality, is usually dened using a questionnaire. For example, the individual may be given a questionnaire that includes a number of characteristic presenoe through these adjectives for replies and determines the depth of feeling on the reference numerical scale. On the basis of systematization related adjectives and statistical analysis of the estimates of the subject for each adjective identify different emotional States.Alternatively, the emotional state can be determined through the autonomic changes, such as those used in printing estimates (galvanic skin response, pulse rate, etc.) Cabanac, M. Annual Review of Phisiology (1975), 37: 415, Hardy, J. D., "Body temperature Regulation", Chapter 59, pp. 1417. In: Medical Phisiology, Vol. II Ed.; VB Mountcastle (1980); Wolfram Bouscein. Electrodermal Activity (Plenum Press, 1992).In addition, can be estimated non-speech factors such as facial expressions and posture.III. Examples
The following examples are given to illustrate, but not limit, the invention. In these examples, we used the following abbreviations: aq (aqueous), RT = room temperature; PE = petroleum ether (boiling temperature (50 - 70oC)); DMF = N,N-dimethylformamide; DMCO = dimethyl sulfoxide; THF = tetrahydrofuran.Example 1. Androsta-4,16-Dien-3-one (4).This synthesis is illustrated in Fig. 1. For the conversion of testosterone in androsta-4,16-Dien-3-one known Nickelodeon received androsta-4,16-Dien-3-one with a yield of 90%. 17-Methoxycarbonyl-androst-4-EN-3-one (IV) was obtained by interaction of testerone (III) Fluka (Fluka) methylcarbamate/pyridine (a), with a yield of 76% (after recrystallization from MeOH). Melting point 140-141oC [a]D= +95,4o(C= 1,10). IR (CDCl3): 1740s, 1665s, 1450s, 1280s.1H NMR (360 MHz): 0,87 (s, 3H); of 1.20 (s, 3H); of 3.77 (s, 3H); 4.53-in (lat.t, J=8,1 N); of 5.75 (s, 1H). The solution methylcarbonate IV in toluene pyrolizer (b) as described for 1. Recrystallization of the crude product from acetone at room temperature gives the pure ketone 4 with 90% yield. So pl. 127-129,5oC [a]D= +118,9o(C=1,32) (, 131, 5mm square-133,5o(hexane), [a]D16= +1233,5o(C=1,03)). IR (CDCl3): 3050w, 1660s, m.1H NMR (360 MHz): 0,82 (s, 3H); 1,22 (s, 3H); 5,70 (m, 1H); 5,73 (s, 3H); of 5.84 (m, 1H).Example 2. Androsta-4,16-Dien-3-ol (5) and 3-ol (6).This synthesis is illustrated in Fig. 1. Androsta-4,16-Dien-3-one (4) was restored when -55oC using Tris(1,2-dimethylpropyl)hydridoborate lithium in THF, as described to obtain 2 (Fig. 1). The result chromatography on silica gel using as eluent CH2Cl2/ethyl acetate at a ratio of 9:1 received net axial alcohol 5 (exit 48%) and pure Equatorial alcohol 6 (yield 48%). Analytical sing a temperature of - to get 6).Data for 5. Melting point: 77-79oC [a]D= +120,6o(C=1,26). IR (CDCl3): 3620m, m Shir., M, 1595w.1H NMR (360 MHz): 0,79 (s, 3H); of 1.02 (s, 3H); 4,07 (m, w1/210, 1H); 5,48 (d x d, J 5 and 2, 1H); 5,71 (m, 1H); to 5.85 (m, 1H).Data for 6. Melting point: 116-119oC [a]D= +53,9o(C=1,28) ( : so pl. 116-118oC [a]D8= +59,3o(c=0.4)). IR (CDCl3): M, m Shire. , 3050 m, m, 1590w.1H NMR (360 MHz): 0,78 (s, 3H); 1,08 (s, 3H); 4,15 (m, w1/220, 1H); and 5.30 (m, w1/25, 1H); 5,71 (m, 1H); to 5.85 (m, 1H).Example 3. Androsta-5,16-Dien-3-ol (7).This synthesis is illustrated in Fig. 2. To a solution of alcohol 8 (545 mg, 2.0 mmol) in acetone (100 ml) at 0oC in an atmosphere of N2quickly added Jones reagent (i, 1.5 ml, about 4 mmol). After 5 minutes the mixture is poured into diluted phosphate buffer solution (pH 7,2, 1200 ml) and was extracted with simple ether. The extracts were washed with saturated aqueous NaCl, dried (NaSO4and boiled away, receiving, mainly androsta-5,16-Dien-3-one as an oily product (567 mg). The crude product was dissolved in THF (7 ml) and restored using Tris(1,2-dimethylpropyl)hydridoborate lithium (s) under 55oC, as described to obtain 2. The crude product (530 AI 4:1, receiving 280 mg (51%) of pure alcohol (with the first elution) and 13 mg of the original alcohol 8. A small sample of 7 at room temperature to recrystallize from acetone/water. Melting point: 1380oC [a]D= - 77,5o(s=1,2). IR (CDCl3): M, m, 1665w, 1590w.1H NMR (360 MHz): 0,80 (s, 3H); 1.06 a (s, 3H); was 4.02 (m, w1/28, 1H); 5,44 (m, 1H); 5,72 (m, 1H); 5,86 (m, 1H).Example 4. Androsta-5,16-Dien-3-ol (8).This compound is obtained with a yield of 73% using known techniques (Marx, A. F., et al., Ger. Offen. 2, 631, 915; Chem. Abst. 87: 23614p (1977) commercial (Fluka) 3-hydroxy-androst-5-ene-17-she (VII). Melting point 137oC [a]D= -71,9o(or=1.5) (: so pl. 140-141oC [a]D= 68o). IR (CDCl3): 3600 m Shir., 1670w, 1590w.1H NMR (360 MHz): 0,80 (s, 3H); of 1.05 (s, 3H); of 3.53 (m, w1/222, 1H); 5,38 (m, 1H); 5,72 (m, 1H); 5,86 (m, 1H). This synthesis is illustrated in Fig. 4.Example 5. Alternative synthesis of androsta-4,16-Dien-3-one (25).Subsequent synthesis method is shown in Fig. 3.Dehydroepiandrosterone-p-toluensulfonate (23)
Dehydroepiandrosterone (VII) (14.4 g, 50 mmol) and p - toluensulfonate (was 12.75 g, and 68.5 mmol) in dry methanol (300 ml) was heated in a flask under reflux for 20 hours. This mixture pianola (50 ml). By subsequent evaporation of the filtrate to 75 ml and 20 ml and implementation of crystallization after each evaporation got additional fee product. The total yield amounted to 21.6 g (95%).Androsta-5,16-Dien-3-ol (24)
Dehydroepiandrosterone-p-toluensulfonate (23) (22,8 g, 50.0 mmol) in dry tetrahydrofuran (1.0 l) was cooled in a bath with a mixture of dry ice / isopropanol. By adding n-utility (125 ml, 1.6 M solution in hexane, 200 mmol) and the mixture was stirred. The mixture was heated to room temperature and was stirred for 24 hours. Under ice cooling was added water (50 ml). The mixture was poured into a saturated solution of ammonium chloride/ice (500 ml) and was extracted with simple ether (x 2). The organic layers were washed with saturated sodium bicarbonate solution (500 ml) and saturated sodium chloride solution (500 ml), dried (MgSO4) and evaporated in vacuum, obtaining the crude product. It was purified flash chromatography on 190 g of silica gel 60, 230-400 mesh mesh, using as eluent ethyl acetate/hexane (at a ratio of 20: 80 to 50:50), thus obtained crystalline product. Product recrystallize from methanol (45 ml)/3% hydrogen peroxide (8 ml), washed with methanol (30 ml)/water (8 ml), this was pure toluene and 75 cm3cyclohexanone was subjected to distillation (gathered about 50 cm3distillate) to eliminate moisture, was added 5 g of Al(Opri)350 cm3toluene, and the solution for 1 hour was heated in a flask with reflux condenser. Then added water and by steam distillation removed the volatile impurities and the residue was extracted with chloroform. After evaporation of the dried extract and crystallization of the residue from chloroform-hexane got 7,53 g androsta-4,16-Dien-3-one (25). By chromatography of the mother liquor on a neutral alumina got 0.97 g of the compound (8.5 g, yield 86%).Example 6. Synthesis of androsta-3,5,16-triene-3-Eletropaulo ether (12).To a solution of androsta-4,16-Dien-3-one (1,00 g, 3,70 mmol) in 2,2 - dimethoxypropane (5.0 ml, 41 mmol) and 5 ml of DMF was added methanol (0.2 ml) and the monohydrate of p-toluenesulfonic acid (26,4 mg, 0,139 mmol). The mixture for 5 hours, heated in a flask with reflux condenser, after which it was cooled and added sodium bicarbonate (152,5 mg). The suspension is distributed between 50 ml of ice water and 50 ml of ethyl acetate. The organic layer was washed with two 50 ml portions of water and 50 ml of brine, dried over magnesium sulfate, filtered and concentrated in Panigale 60, with dimensions 12 mm x 30 mm, using 150 ml of hot hexane. The combined filtrates were concentrated under reduced pressure and recrystallized from acetone/methanol, was obtained white crystals (468,0 mg, 1,645 mmol, 44%), melting point 83-92oC.Example 7. Synthesis of 17-methylene-androst-4-EN-3-tins.To 20 ml of Comandante-4,17-Dien-3-one (119,0 mg, 0,4184 mmol) in 5 ml of methanol was added sodium borohydride (6.0 mg, 0.16 mmol) and 77 μl of water. After stirring for two hours additionally added sodium borohydride (32,0 mg, 0,846 mmol) and the mixture was stirred overnight. After concentration under reduced pressure (5% ethyl acetate/hexane, silica gel) received more polar (59,8 mg) and less polar (1.7 mg) product.Example 8. Synthesis of 17-methylene-6-oxo-androsta-4-EN-3-one.To a chilled solution of 20-Comandante-5,17-diene-3-ol (RUB 399.4 mg, KZT 1,394 mmol) in 50 ml of acetone was added to 2.67 M Jones reagent (2.0 ml, 5.3 mmol). After stirring for 1 hour the reaction mixture is abruptly cooled isopropanol (1.0 ml, 13 mmol) and poured into 100 ml of water. The mixture three times was extracted with 50 ml portions of ethyl acetate and the combined organic extracts were washed with 50 ml of saturated solution of bicarbonate is listed under reduced pressure. The residue was recrystallized from 95% ethanol, it was received almost white powder (of 177.8 mg, 0,5958 mmol, 43%), melting point 113-115oC.Example 9. Synthesis of 6-Oh-androsta-4,16-Dien-3-one.To a solution consisting of androsta-3,5,16-triene-3 - Eletropaulo ether (12) (200,5 mg, 0,7049 mmol) in 5 ml of 1,2 - dimethoxyethane (DME) and 1 ml of water, while stirring for 90 minutes dropwise added m-chloroperbenzoic acid (MJPBK, 77,4%, 173,2 mg, 0,776 mmol), suspended in a mixture consisting of 5 ml of dimethyl ether, 1 ml of water, 0.40 g of 5% (wt.) NaOH. After stirring for 18 hours at subsequent stirring for 1.5 hours dropwise added MJPBK (247,0 mg, 1.11 mmol), suspended in a mixture consisting of 10 ml of DME and 2 ml of water, 0.8 g of 5% (wt.) NaOH. The reaction mixture was stirred for 0.5 hours and then poured into 25 ml of saturated sodium bicarbonate solution. Water the mixture three times was extracted with 25 ml of simple ether and the combined organic extracts were washed with 50 g of 5% (wt.) sodium thiosulfate and three 50 ml portions of brine, dried over magnesium sulfate, filtered through celite and concentrated under reduced pressure. The resulting crystalline residue was purified preparative thin-layer chromatography (TLC) (35% of those who received the crystals in the form of shiny white plates (of 102.3 mg, 0,3571 mmol, 51%), melting point: 165-166oC.Example 10. 18-nor-17-methylandrosta-4,13(17)-Dien-3-ol, 2 (see Fig. 12).To a solution of 18-nor-17-methylandrosta-4,13(17)-Dien-3-one (1, 378,3 mg, 1,399 mmol) in 7.5 ml of anhydrous ether was added 59,7 g (1.57 mmol) of lithium aluminum hydride (AGL). After stirring the resulting suspension for 30 minutes
added to 2.00 g of Glauber's salt and the mixture was mixed for another 30 minutes. Then the mixture was filtered and was extracted with four 25 ml portions of simple ether. The combined filtrates were concentrated under reduced pressure, and then subjected to preparative thin-layer chromatography (silica gel GF, 1000 μm, as eluent used 5% ethyl acetate/methylene chloride), got a less polar fraction (Rf0,63, to 34.5 mg, to 0.127 mmol, 9%) and more polar fraction (Rf0,45, 273,8 mg, 1,005 mmol, 72%).(NA-1994A-209)
Example 11. 18-nor-17-methylandrosta-3,5,13(17)-trien-3 - ymetray ether, 3 (see Fig. 12).A solution of 18-nor-17-methylandrosta-4,13(17)-Dien-3-one (1, 0,86 g, 3.2 mmol) in 2,2-dimethoxypropane (4.3 ml, 35 mmol) and dimethylformamide (DMF), a 4.3 ml) containing anhydrous methanol (0.17 ml) and the monohydrate of p-toluenesulfonic acid (21,3 mg), heated for 4 hours in a flask with inverse x is a mixture of water with ice. The organic phase was washed with two 40 ml portions of water and 40 ml of saline solution and then filtered through a column of silica gel (200-400 mesh), with a height of 17 mm and a diameter of 30 mm After concentration of the combined filtrates and subsequent recrystallization their acetone/95% ethanol received a bright yellow crystals (489,6 mg, 1,721 mmol, 54%), melting point: 95-101oC. TLC (10% ethyl acetate/hexane on silica gel) showed the presence of the main product when Rf0,69, which was attended by trace amounts of impurities.Example 12. 18-nor-17-methylandrosta-4,13(17)-Dien-6-3-one, 4 (see Fig. 12).The reaction was carried out in a manner analogous to the method described by D. N. Kirk and J. M. Wiles, J. Chem. Soc., Chem. Commun. 1974, 927. To a stirred solution of 18-nor-17 - methylandrosta-3,5,13(17)-trien-3-Eletropaulo ether (477,0 mg, 1,677 mmol) in 1,2-dimethoxyethane (DME, 26 ml) within 88 minutes was added 77% m-chloroperbenzoic acid (MJPBK, 999,7 mg, 4,48 m-EQ) are suspended in DME (39 ml), water (8 ml) and 5% (wt.) the sodium hydroxide (7,1 ml). After stirring for 20 hours the reaction mixture was poured into saturated sodium bicarbonate solution (50 ml) and was extracted with three 50 ml portions of simple ether. The combined organic extracts were washed with 50 g of 5% (wt. ) Pentti through diatomaceous earth. The residue was washed with 25 ml of simple ether and the combined filtrates were concentrated under reduced pressure to obtain a yellow syrup. By purification using preparative TLC (silica gel GF, 1000 μm, as eluent used 35% ethyl acetate/hexane) received not quite white crystalline film (132,1 mg, 0,4612 mmol, 28%), while thin layer chromatography showed the presence of the main component (Rf0,23), and the impurity component (Rf0,18).(NA-1994A-223)
Example 13. 17-Methylandrosta-4-ene-3,6-dione, 6 (see Fig. 12).To a solution of 17-methylandrosta-5-EN-3-ol (5, 135,5 mg, 0,4697 mmol) (J. B. Jones, and K. D. Gordon, Can. J. Chem. 1972, 50, 2712-2718) in acetone (15 ml) was added Jones reagent (2.67 Meters, to 0.88 ml, 2.3 mmol) and within 45 minutes, the mixture was stirred. The reaction was suppressed by the addition of 2-propanol (of 0.44 ml). After stirring for a further 10 minutes the reaction mixture was poured into 30 ml of water and was extracted with three 15 ml portions of ethyl acetate. The combined organic extracts washed with 15 ml saturated sodium bicarbonate 15 ml of saline solution, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Using p the purpose of an aqueous solution of ethanol received brilliant, whitish crystals (37.5 mg, 0.125 mmol, 27%), melting point: 94-95oC, homogeneous according to TLC (25% ethyl acetate/hexane, silica gel, Rf0,39).(NA-1994A-298)
Example 14. 17-Methylandrosta-4-EN-3-ol, 8 (see Fig. 12).To a solution of 17-methylandrosta-4-EN-3-one (7, 143,2 mg, 0,4999 mmol) (J. B. Jones, and K. D. Gordon, Can. J. Chem. 1972, 50, 2712-2718) in 2.8 ml of anhydrous ether was added alumoweld lithium (21,3 mg, 0,561 mmol). After stirring the suspension for 30 minutes added Glauber's salt (0,76 g) and the mixture was stirred for another 0.5 hour. Added a simple ether (10 ml) and the suspension was filtered through diatomaceous earth. The residue was washed with three 10 ml portions of simple ether and the combined filtrates were concentrated under reduced pressure. Using preparative TLC (silica gel GF, 1000 μm, as eluent used 5% ethyl acetate/methylene chloride) the crude product was divided into more polar component (Rf0,30, 77.9 mg, 0,270 mmol, 54%) and less polar component (Rf0,43, 10,3 mg, 0,0357 mmol, 7%).(NA-1994A-300)
Example 15. 17-Medienanstalt-3,5-diene-3-ymetray ether, 10 (see Fig. 13).17-methylandrosta-4-EN-3-ONU (9, 2000, 7,0314 mmol) in 2,2-dimethoxypropane (9.4 ml, 76 mmol) and DMF (9.4 ml) was added and 0.37 ml of anhydrous mettanando the mixture was cooled and then distributed between 140 ml of hexane and 90 ml of water. The organic phase is washed two 90 ml portions of water and 90 ml of saline solution, dried over magnesium sulfate and filtered through a column of silica gel (200-400 mesh) having a diameter of 30 mm and a height of 37 mm, Then the elution was continued using 200 ml of hexane. After concentration of the combined filtrates under reduced pressure and recrystallization of the residue from acetone/methanol obtained pale yellow plates (1,5291 g, 5,1231 mmol, 73%), melting point 97-99oC, homogeneous according to TLC (25% ethyl acetate/hexane, silica gel, Rf0,72).(NA-1994A-226)
Example 16. 17-Methylandrosta-4-EN-6-ol-3-one, 11 (see Fig. 13).To a stirred solution of 17-methylandrosta-3,5-diene-3 - Eletropaulo ether (10, 500,1 mg, 1,676 mmol) in DME (10 ml) for 15 minutes added MJPBK (318,6 mg, 1,846 mmol) in DME (10 ml) and water (4 ml). After stirring for 30 minutes the mixture is poured into 50 ml saturated sodium bicarbonate and was extracted with three 50 ml portions of simple ether. The combined organic extracts were washed with 50 mg (wt.) pentahydrate sodium thiosulfate and three 50 ml portions of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue was washed with 25 ml of simple ether and the combined is imagele) and subsequent recrystallization from aqueous ethanol was obtained as pale-yellow crystals (187,1 mg, 0,6228 mmol, 37%), melting point 192-194oC, TLC (35% ethyl acetate/hexane on silica gel) showed the presence of primary (Rf0,17) and impurity (Rf0,13) components.(NA-1994A-232)
Example 17. 17-Methylandrosta-1,4-Dien-3-one, 12 (see Fig. 13).A solution of 17-methylandrosta-4-EN-3-one (9, 1,0001 g, 3,5160 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DH, 2,43 g of 10.7 mmol) in dioxane (60 ml, freshly distilled after heating in a flask under reflux overnight in the presence of sodium) was heated in a flask under reflux for 6 hours and then cooled with vortex mixing in tap water. Added tert-butyl ether (MTBE, 50 ml) and the suspension was filtered through diatomaceous earth. The residue is washed with two 50 ml portions of MTBE and the combined filtrates were concentrated under reduced pressure. After flash chromatography of the residue (20% ethyl acetate/hexane, silica gel) and subsequent recrystallization from 95% ethanol received whitish crystals (498,9 mg, to 1.767 mmol, 50%), melting point: 155-157oC.Example 18. 17-Methylandrosta-1,3,5-trien-3-yl-benzoate, 13 (see Fig. 13).The reaction was carried out by an adapted method described by R. W. Draper et al. , Arzneim.-Forsh, 1982, 32, 317-322, trail-1,4-Dien-3-one (12, 389,0 mg, 1,378 mmol), anhydrous pyridine (4,7 ml, 58 mmol) and benzoyl chloride (1.2 ml, 10 mmol). After cooling with ice, the reaction mixture was poured into 40 ml of a mixture of ice and 1 N. HCl, and was extracted with three 20 ml portions of methylene chloride. The combined organic extracts were washed with 40 ml of cold 1 N. HCl, 40 ml saturated sodium bicarbonate and 40 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue is washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. After flash chromatography of the residue (4% ethyl acetate/hexane, silica gel) has received a yellow solid (of 0.43 g, 1.1 mmol, 81%).(NA-1994A-284)
Example 19. 17-Methylandrosta-1,4-Dien-6-ol-3-one, 14 (see Fig. 13).The reaction was carried out by an adapted method described by R. W. Draper et al. , Arzneim. -Forsh, 1982, 32, 317-322, as follows: 17-methylandrosta-1,3,5-trien-3-yl-benzoate (13, of 0.43 g, 1.1 mmol) in 6.6 ml of DME for 20 minutes under stirring added MJPBK (211,4 mg, 1,225 mmol) in DME (6.6 ml) and water (2.7 ml). Stirring is continued for 30 minutes and then the reaction mixture was poured into 35 ml of saturated sodium bicarbonate. The mixture was extracted with three 35 ml portions of ethyl acetate. The combined organic alfacom magnesium and filtered through diatomaceous earth. The residue is washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. After making preparative TLC (silica gel GF, 1000 microns, 50% ethyl acetate/hexane as eluent) has received a yellow crystalline solid (83,7 mg, 0,280 mmol, 25%) homogeneous according to TLC (50% ethyl acetate/hexane, silica gel, Rf= 0,50).(NA-1994A-292)
Example 20. Androsta-1,4,16-triene-6-ol-3-one, 16 (see Fig. 13).In an oil bath (70-73oC) in argon atmosphere put androsta-1,4,16-triene-3-one (15, 500.0 mg, 1,863 mmol), anhydrous pyridine (6.4 ml, 79 mmol) and benzoyl chloride (1.6 ml, 14 mmol) and mixed for 18 hours. After cooling with ice, the mixture was poured into 50 ml of a mixture of ice and 1 N. HCl and was extracted with three 25 ml portions of methylene chloride. The combined organic extracts were washed with 50 ml of cold 1 N. HCl, 50 ml saturated sodium bicarbonate and 50 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue is washed with 10 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. After making flash chromatography of the residue (2% ethyl acetate/hexane, silica gel) has received a yellow crystals (of 0.47 g, 1.3 mmol, 68%) temporarily is giving 1 hour added additional amount MJPBK (239,5 mg, 1,388 mmol) and the reaction mixture was stirred for another one hour. The mixture is then washed with 30 g of 5% (wt.) pentahydrate, sodium thiosulfate, 30 ml saturated sodium bicarbonate, 30 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue is washed with 10 ml of chloroform and the combined filtrates were concentrated under reduced pressure. After making flash chromatography (40-45% ethyl acetate/hexane, silica gel) has received a yellow resin (106,1 mg, 0,3731 mmol, 29%), while thin layer chromatography (40% ethyl acetate/hexane on silica gel) showed the presence of a main component (Rf0,34) and impurity (Rf0,40) component.(NA-1994A-276)
Example 21. Androsta-4,16-Dien-6-ol-3-one, 16.To a solution of androst-3,5,16-triene-3-Eletropaulo ether 12 (200,5 mg, 0,7049 mmol) in 5 ml of 1,2-dimethoxyethane (DME) and 1 ml of water is added dropwise, with stirring, for 90 minutes was added m-chloroperbenzoic acid (MJPBK) (77,4%, 173,2 mg, 0,776 mmol), suspended in a mixture consisting of 5 ml of dimethyl ether, 1 ml of water, 0.40 g of 5% (wt.) NaOH. After stirring for 18 hours, dropwise with stirring over 1.5 hours added MJPBK (247,0 mg, 1.11 mmol), suspended in a mixture consisting of 10 ml of DME and 2 ml of water, 0.8 g of 5% (wt.ing the mixture three times was extracted with 25 ml of simple ether and the combined organic extracts were washed with 50 g of 5% (wt.) sodium thiosulfate, three 50 ml portions of brine, dried over magnesium sulfate, filtered through celite and concentrated under reduced pressure. The resulting crystalline residue was purified using preparative TLC (35% ethyl acetate/hexane, silica gel), which was carried out by 2-fold recrystallization from aqueous ethanol to obtain shiny white plates (of 102.3 mg, 0,3571 mmol, 51%), melting point: 165-166oC.< / BR>Example 22. 20-Comandante-4,17-Dien-3-one, 13 (see Fig. 14).To a solution of 20-Comandante-5,17-diene-3-ol (1,0001 g, 3,4911 mmol) in 100 ml of toluene and 20 ml (0,19 mmol) of cyclohexanone was added isopropoxide aluminum (2.00 g, 9,79 mmol) in 20 ml of warm toluene. After heating in a flask under reflux for 4 hours, the cooled reaction mixture was shaken for 1 minute with 5 ml of water and 12.5 ml of 3.6 N. sulfuric acid. The organic layer was washed with 50 ml of brine, dried over magnesium sulfate, filtered through celite and concentrated under reduced pressure. After the steam distillation, carried out to remove cyclohexanone, non-volatile residue was dissolved in two 10 ml aliquot of dichloromethane, dried over magnesium sulfate, filtered the barely) and recrystallization from aqueous acetone, the result obtained colorless needle crystals (238,8 mg, 0,8400 mmol, 24%), melting point: 130-134oC [lit. (B. S. Macdonald et al., Steroids, 1971, 18, 753-766) the melting point of 129-131oC].(NA-1993A-99, 103B)
Example 23. 20-Comandante-4,17-Dien-3-Ola, 14 (see Fig. 14).20-Comandante-4,17-Dien-3-ONU (119,0 mg, 0,418 mmol) in 5 ml of methanol was added sodium borohydride (6.0 mg, 0.16 mmol) and 77 μl of water. After stirring for two hours additionally added sodium borohydride (32,0 mg, 0,846 mmol) and the mixture was stirred overnight. After concentration under reduced pressure the residue was purified using preparative TLC (5% ethyl acetate/hexane, silica gel) has received more polar (59,8 mg) and less polar (1.7 mg) product.(NA-1993A-99, 110 A, B)
Example 24. 20-Comandante-4,17-Dien-3,6-dione, 15 (see Fig. 14).To a chilled solution of 20-Comandante-5,17-diene-3-ol (RUB 399.4 mg, KZT 1,394 mmol) in 50 ml of acetone was added to 2.67 M Jones reagent (2.0 ml, 5.3 mmol). After stirring for 1 hour the reaction mixture is abruptly cooled isopropanol (1.0 ml, 13 mmol) and poured into 100 ml of water. The mixture three times was extracted with 50 ml portions of ethyl acetate and the combined organic extracts were washed with 50 ml of saturated and concentrated under reduced pressure. The residue was recrystallized from 95% ethanol, this was almost white powder (of 177.8 mg, 0,5958 mmol, 43%) melting point: 113-115oC.(NA-1993A - 91B)
Example 25. to 6.19-Epoxy-17-identrust-4,16-Dien-3 - atlantal, 18 (see Fig. 15).A mixture of crude to 6.19-epoxy-17-identrust - 16-ene (17, 1,38 g, to 3.09 mmol) (G. Habermehl and A. Haaf, Z. Naturforsch, 1970, 25b, 191-195), ethylene glycol (0.97 g, 16 mmol), toluol (50 ml) and the monohydrate of p-toluenesulfonic acid (20,3 mg, 0,107 mmol), within 19 hours was heated in a flask under reflux for azeotropic removal of water (Deen-Stark). After cooling, was added ethyl acetate (100 ml) and the reaction mixture is washed with 100 ml saturated sodium bicarbonate and 100 ml of saline solution. The organic phase was dried over magnesium sulfate and filtered through diatomaceous earth. The residue is washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure, got a tan crystalline solid (1.47 g). The residue is suspended in anhydrous methanol (40 ml), was added potassium acetate (2,44 g, 24,9 mmol) and drove about 26 ml of methanol. The residue was concentrated under reduced pressure, added water (50 ml) and the mixture three times was extracted with 25 ml aliquot m is 10 ml of methylene chloride. After concentration of the combined filtrates under reduced pressure to a yellow solid which was then purified flash chromatography (5-7,5-10% ethyl acetate/methylene chloride on silica gel) and recrystallization from methanol obtained light yellow needle crystals (914,6 mg, 2,013 mmol, 65%), melting point: 187-189oC.1H-NMR: 6,13 , 1H, DD, 16-H; of 5.82 , 1H, s, 4-H; 4,71 , 1H, d, 6-H; 4,22 and 3,53 , 2H, AB, 19-H'; 4,10-3,28 , 4M, mult., 3-ketal H c; 0,83 , 3H, s, 18-Me.(NA-1994A-141C)
Example 26. Androsta-4,16-Dien-19-ol-3-one, 19 (see Fig. 15).Anhydrous ammonia (about 75 ml) drove through the CON column in drained flame three-neck 250-ml flask equipped with inlet, magnetic stirrer, condenser, cooled with dry ice/acetone, and tube. Added the solution to 6.19-epoxy-17-identrust-4,16-Dien-3 - atelectasia (18, 880,4 mg, 1,938 mmol) in anhydrous tetrahydrofuran (THF, 45 ml), and then sodium metal (0.20 g, 8,7 mg-atoms), cut into small pieces. After stirring under a pressure of argon for 30 minutes, the reaction mixture is abruptly cooled by the addition of absolute ethanol (1.0 ml). Ammonia is evaporated during the night, then added 50 ml of water and the mixture was extracted with three 5 ml Porti magnesium and filtered through diatomaceous earth. After washing the residue with 10 ml of methylene chloride the combined filtrates were concentrated under reduced pressure. Intermediate product ketal was directionspanel, but ultimately he was hydrolyzed by heating for 18 hours in a flask under reflux in the presence of 5 ml of chloroform and 2.5 ml of 4 N. hydrochloric acid. To the cooled obtained after hydrolysis of the mixture was added ethyl acetate (50 ml) and the layers were separated. The organic phase is washed with 25 ml saturated sodium bicarbonate, 25 ml of brine, dried over magnesium sulfate and filtered through diatomaceous earth. The residue is washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The obtained brown foam was purified using flash chromatography (50% ethyl acetate/hexane, silica gel) and then preparative TLC (50% ethyl acetate/hexane, silica gel GF, of a thickness of 1000 μm), got a semi-crystalline film (66,7 mg, 0,233 mmol, 12%).1H-NMR: of 5.92 , 1H, s, 4-H; by 5.87-5,64 , 2H, mult., 16,17-H; 4,10 and 3,94 , 2H, AB, 19-H; 0,79 , 3H, s, 18-Me.(NA-1994A-244D)
Example 27. Androst-5-ene-3,19-diol-17-(p-toluensulfonyl)- hydrazone, 2 (see Fig. 16).In a flask under reflux for 24 hours was heated suspension comprising the p-toluensulfonate (p-TsNHNH2, 392,1 mg, 2,105 mmol) in 2-propanol (6.0 ml). To the cooled reaction mixture was added 20 ml of a simple ether under reduced pressure, the solvent was removed. The residue was dissolved in 10 ml of simple ether and the solution was filtered through diatomaceous earth. To the filtrate was added 10 ml of hexane and the suspension was concentrated under reduced pressure. The residue was dissolved in 10 ml of hot benzene and cooled suspension was subjected to filtration. The filtrate was concentrated under reduced pressure and then subjected to flash chromatography (40% ethyl acetate/hexane, silica gel), when it got dark resin (0,69 g, 1.5 mmol, 87%).(NA-1993B-47)
Example 28. Androsta-5,16-Dien-3,19-diol, 3 (see Fig. 16).In a bath containing a mixture of ice / acetone, and in an argon atmosphere cooled solution of androst-5-ene-3,19-diol-17-(p - toluensulfonyl)hydrazone (2, 0,69 g, 1.5 mmol) in anhydrous tetrahydrofuran (THF, 35 ml) and dropwise with stirring over 1 minute was added n-utility (2.5 M in hexane, and 3.7 ml, 9.3 mmol). The reaction mixture was stirred for 4 days, during which time the mixture was gradually warmed to room temperature. Then the reaction mixture is poured into 50 ml saturated ammonium chloride with ice and the layers were separated. The aqueous layer was extracted twice elevage solution, was dried over magnesium sulfate and filtered through diatomaceous earth. The residue is washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. The residual yellow resin was subjected to flash chromatography (50-55-60% ethyl acetate/hexane, silica gel) was led from methyl tert-butyl ether/benzene, got a loose white crystals (of 92.5 mg, 0,361 mmol, 24%), melting point 169-171oC.(NA-1993B-66)
Example 29. Electrophysiology during stimulation of the androstane VNO and olfactory epithelium of man.At check local electrical potentials from Coulter-nasal organ (VNO) of man and from the olfactory epithelium (OE) was used non-invasive method. Localized gas stimulation was applied to both of the nasal structures using a specially designed catheter/electrode connected to multi-channel delivery system of the drug to the site of action. This electrode and the delivery system described Monti and Grosser (J. Steroid Biochem. and Molec. Biol. (1991) 39: 573) and under consideration of the national application U.S. 07/771414, which is introduced in the present description by reference. Local response VNO and OE correlated with the concentration of ligands dobrovolcev - 2 men and 8 women, aged 18 to 85 years. Studies were performed without General or local anesthesia.The catheter electrodes were designed to deliver a localized stimulus and simultaneous recording of responses. In the case of registration VNO researched the right nasal fossa of the individual using a nasal mirror (nasal dilators) and determined the location Coulter-nasal openings, which was near the intersection of the front edge of the vomer and the base of the nose. Catheter/electrode gently guided into the hole VNO and the tip of the electrode was placed in the cavity of the body at a distance from 1 to 3 mm from the hole. Then bow the mirror was removed. In the case of OE, the registration procedure was similar, except for the position of the catheter/electrode, which gently deeply placed in the lateral part of the medial lacrimal-nasal flow, reaching the olfactory mucosa.Through the catheter/electrode was carried out by the localized gas stimulation. Through the channel of the incentive system at room temperature continuously missed the thread clean humidified air, odorless. Stimulating ligand substances diluted propilenglikolem, what is the administration ensures the presence of about 25 PG steroid of ligand in the nasal cavity.The results of this study are presented in Fig. 4A, 4B and 4C. The response was measured in millivolts-seconds (mV x). Androsta-4,16-Dien-3-one causes a much stronger reaction VNO women, other than compound (Fig. 4A). In addition, the response of the VNO in androsta-4,16-Dien-3-one is sexually dimorphic, i.e., it is two times stronger in women than in men (Fig. 4B). In contrast, the reaction of the OE as in men, so women are insignificant in comparison with the behavior of a strongly odorous substance, such as carnation (Fig. 4C).Example 30. The dimension changes of the receptor potential of the VNO neuroepithelium in response to various steroids.The change of the receptor potential in response to five different ligands was measured in 40 women (Fig. 5A) and 40 men (Fig. 5B). Each person introduced 60 PG of each of the seven substances indicated on the drawings. Substances were administered separately for 1 second using the methods described in example 10. The change of potential of the VNO neuroepithelium registered depending on time and the integral of the change of potential averaged for each Iino dimorphic in their activity and that some ligand substances are stronger for men, while others are stronger for women.Example 31. Measurement of autonomic responses to stimulation of the VNO 16-androstenol.Women using the techniques described in example 10, was introduced androsta-4,16-Dien-3-one and record the various parameters of the Autonomous reactions. As the control substance was administered also propylene glycol. The ligand was introduced in the form of a one-second pulse. Change the offline feature was observed already after 2 seconds and continued over time to 45 seconds. As shown in Fig. 6, compared with the control substance propylene glycol androstane caused significant changes of the receptor potential in the VNO (Fig. 6A), galvanic skin response (Fig. 6B), skin temperature (Fig. 6C), % alpha-rhythm of the cerebral cortex, measured in the EEG (Fig. 6D), peripheral arterial pulse (Fig. 6E) and breathing frequency (Fig. 6F).Example 32. Comparison of the receptor potential changes induced by two androstane steroids.60 PG of each ligand and the control of the propylene introduced 5 women, as described in example 10.As shown in Fig. 7, androsta-4,16-Dien-3-ol caused large changes in relatii VNO-androstane.Psychophysiological effect of stimulation of the VNO-androstane measured by the coordinated introduction of pheromone and assess its state of the subject by means of a questionnaire before and after administration of drugs. The questionnaire included a set of adjectives to reply, used as part of, included in the standard questionnaire Derogatis Sexual Inventory.The study involved 40 women who is in good health at the age from 20 to 45 years. Women were arbitrarily divided into groups: 20 women received placebo and 20 women received about 20 picograms of androsta-4,16-Dien-3-one, entered as described above in example 10. Women were offered a questionnaire consisting of 70 points, which was estimated emotional state directly before the introduction and after 30 minutes after administration of placebo or test substance. The proposed questionnaire consisted of 70 characteristic adjectives, which subsequently were used for evaluation based on their relevance with respect to each mood, feeling, or personality. If this were the results: changes in such things as social adaptation, personal well-being, activity/excitability and aggression before the introduction of view 16-androstene, compared to the changes observed after injection of control. However, highly significant reduction in negative emotional reactions (nervous, tense, shy, restless, excitable, irritable, angry, as it was by the T-student test: p<0,0001 and variance analysis: p<0,04), reducing bad mood and correction of negative traits (sensitive, sad, blamable, faulting, full of remorse, sad, hopeless, hurt, worthless, wretched, unfortunate, bitter, fearful, as determined by the T-student test: p<0,0004 and variance analysis: p<0,06), as well as reducing the overall negativity (the combination of emotional reactions and character, as determined by the T-student test: p<0,0003 and variance analysis: p<0,05) was observed after the introduction of 16-androstene compared with controls.In General, these results suggest that androsta-4,16-Dien-3-one when his intranasal introduction of sedative and/or relieving anxiety and/or antidepressant effects.Example 34. Treatment of premenstrual syndrome in women.Women suffering from pigments is androsta-4,16-Dien-3-one or androsta-4,16-Dien-3()-ol), suitable for intranasal administration. This steroid was applied in the form of ointment at a concentration from about 1 μg/ml to about 0.1 ml Ointment was applied into each nostril three times a day. In a similar way to treat PMS use the aerosol product of the same tools. Aerosol spray in each nostril three times a day.Example 35. Electrophysiological studies.Subsequent electrophysiological studies were carried out with the participation of 60 clinically healthy volunteers of both sexes (30 men and 30 women), aged from 20 to 45 years. Anaesthetic is not used and pregnant women were excluded.System stimulation and registration consisted of "multifunctional minidoccia" (described in Monti-Bloch, L. and Grosser, B. I. (1991) "Effect of putative pheromones on the electrical activity of the human vomernasal organ and epithelium in humans", J. Steroid Biochem. Molec. Biol. 19: 573-582).The recording electrode was 0.3 mm silver ball attached to a small (0.1 mm) silver wire insulated with Teflon. The electrode surface was processed first in order to obtain the inner surface of silver chloride and then coated with gelatin. It is placed in a small calibrated Teflon Catete is a length of 10 cm and included the extension at the end for multi-channel delivery systems which ensured the delivery of a continuous stream of air bearing dynamics of discrete pulses of the stimulus. The air flow is initially entered the small chamber and barotiwala through a solution containing or vomeropherins or affectant in the diluent or diluent. To quickly change the direction of flow of air from the chamber along the path, bypassing the camera, used the solenoid. It was created in the air stream of discrete pulse stimulator. System catheter-electrode surrounded by a second outer Teflon tube with a diameter of 2 mm and its located in the center of the end was connected to the aspirator, which provided a continuous absorption of 3 ml/sec Is the concentric arrangement of the outer suction tube provided localization released homocystiene stimulus on the square, which the authors called "minipole" (diameter about 1 mm), which helped to avoid the diffusion of substances in the region outside of the site of stimulation or in the respiratory system. System stimulation and registration can be located either on the neurosensory epithelium in VNO or on the surface of the olfactory or respiratory epithelium.Electrophoretogram (EVG).Zapisanny mindtct first stabilized in the nasal cavity, using a nasal dilator is placed ahead of the nose. The reference electrode and grounded electrode consisted of a silver disks (8 mm), while both were located on the glabella.Sign in VNO or Coulter-nasal depression identified by the first dilation of nasal openings and the nasal vestibule. For the introduction of the Teflon tip of the catheter and the establishment of the electrode system into the hole VNO, where it stabilized in Coulter-nose hole to a depth of 1 mm, was used binocular loupe with a sixfold increase with halogen lighting. Test for adequate depolarization in response to the test substance indicated on the optimal placement of the recording electrode.Electrical signals from the recording electrode was admitted to the DC amplifier, and then converted into digital form, processed on a computer and saved. Measured full amplitude signals and integrated area under depolarization wave signal is continuously controlled on the computer screen and on a digital oscilloscope. Artifacts produced due to respiratory movements were eliminated by training individuals to breath through rowany cineole, 1-carvon and vomeropherins A, B, C, D, E and F. the Samples vomeropherins at a concentration of 25-800 fmol were delivered in a continuous stream of air for a period of time from 300 MS to 1 C. Each series of short pulses separated intervals from 3 to 5 minutes All components of the lines carrying the test stimulus were made of Teflon, glass or stainless steel before each use their carefully cleaned and sterilized.Electroretinogram (EOG). When you register olfactory epithelium used the same stimulating and recording multifunctional minicucci, which is used to VNO. The tip was slowly introduced until such time as the recording electrode does not touch the olfactory mucosa. Of adequate accommodation signaled depolarization in response to the pulse odorous test substance.The activity of the cerebral cortex was induced by stimulation of the VNO vomeropherins, and stimulation of the olfactory epithelium, odorous substances, provide a 300-millisecond air pulses. This activity was recorded using electroencephalography (EEG) electrodes placed in positions Cz-A1. and Tz-A1 international systems is expected (EDA) was recorded, using standard 8-mm silver electrodes in contact with the Palmar skin of the middle and ring fingers, passing through the gel interfacial surface. Skin temperature (ST) was registered using a small (1.0 mm) thermistor sensor, placed in the right lobe of the ear. Peripheral arterial pulse (PAP) registered with plethysmograph attached to the tip of the index finger. Breathing frequency (RF) was measured using an adjustable tenzimetricheskikh sensor placed near the lower part of the chest. All electrical signals are amplified (DC), converted into digital data (MP-100, Biopac Systems) and continuously controlled on the computer.The statistical analysis. Measured and statistically analyzed EVG or EOG, changes of amplitude and frequency changes of other parameters. The significance of the results was determined using bilateral T-test, t-test or analysis of variance (ANOVA).Influence vomeropherins on EVG. It was found that each of vomeropherins produces sexually dimorphic receptor potential (Fig. 8A - B). Performed account EVG for 30 men and 30 women (in vozrastnoi, components "b" minutes, in the case when the individuals in the survey were not able to "smell" or consciously feel any of vomeropherins. This discovery is consistent with the results reported in (Monti-Bloch, L. and Grosser, B. I. (1991) "Effect of putative pheromonenes on the electrical activity of the human vomernasal organ and epithelium in humans", J. Steroid Biochem. Molec. Biol. 39:573 - 582, in which it was stated that neither smell nor vomeropherins the test stimulus delivered to the VNO, does not cause tangible perceptions when your concentration.Fig. 8A illustrates the average response of men (aged 20 to 38 years) in the diluent and equimolar amounts (100 fmol) five vomeropherins (a, b, C, D, and F) and F, which is a stereoisomer f Profile response to each substance was the same for all individuals regardless of age, if this has not been found no significant difference using T-student test or analysis of variance. For example, A, C, and D had a significant impact (M15=11,4 MB, SD=3.6 mV; M76= 6,4 mV, SD=2,5 mV and M34=15,1 mV, SD=4.9 mV; p<0.01), which was in compliance with all individual cases. Other vomeropherins was depositfile VNO receptors is of n is negligible. Vomeropherins affecting men who have caused great response than the diluent (p<0,001). B, F and similar concentrations of olfaction caused a significantly smaller response in VNO men (Fig. 8A and 9)
Similar experimental data were obtained for 30 women (aged 20-45 years). From vomeropherins, F (100 fmol) was caused by the effect with the largest significant difference within the group (Fig. 8B), AND induced a slight effect, which was significant difference from the effects of F (p<0,01). In both groups of individuals, active vomeropherins evoked response of the receptor response with large standard deviations (Fig. 8). When studying the frequency distribution of effects a and F, respectively, in men and women, the authors found a bimodal distribution. In the present studies concerning the significance of these observations.E, which is a stereoisomer F, does not stimulate the VNO in women, whereas F has such an effect (Fig. 8B). This is proof of the specificity of VNO-recognition vomeropherins. In this respect it is interesting to note that while F is an excellent vomeropherins, E has a stronger effect on the olfactory epithelium, and the total receptor potential from the olfactory epithelium (OE). In contrast, the sensitivity of the VNO to vomeropherins, OE is less sensitive to these substances. This is equally true for both men and women. The average amplitude of the receptor potential was in the range from 2.3 MB to 0.78 mV. In this study, B is the only vomeropherins having a significant impact on OE (p<0,02). Of the individuals interviewed regarding the perception of odors, 16 reported no olfactory perception, while three men and one woman described B as having an unpleasant odor. The data obtained show that at the concentrations used in our study, most vomeropherins is inefficient stimulants olfactory receptors, but have a clear impact on receptors Coulter-nasal organ.The influence of olfaction on EVG and EOG. In contrast vomeropherins olfactory 1-carvon and cineole cause only a slight local reaction in the VNO (Fig. 9B). This is equally true for both men and women. As expected, these olfactory the local introduction in OE evoke a strong response in both men and women (p<0,01) (Fig. 9A). The diluent dlego perception.Reflex effects vomeropherins. Studies were performed to determine the reflex reactions of the Central nervous system (CNS) stimulation of the VNO vomeropherins. Sexually dimorphic local reactions caused vomeropherins (Fig. 8A and B), shown in Autonomous reactions of men and women. In men (Fig. 8C) and C reduced skin resistance (electric activity = EDA) (p<0,01, n=30). In women (Fig. 8B) F and caused a greater decrease in EDA than a or C (p<0,01, n=30).Vomeropherins a and C caused a significant increase in skin temperature (ST) (Fig. 8G) 30 men (p<0,01); however, D caused a significant decrease in temperature (p<0,01). In 30 women (Fig. 8H) and F caused a significant increase in temperature (ST) (p<0.01) compared with a and C. In men vomeropherins caused the change in EDA and ST with larger standard deviations than in women.Men and women during the introduction VNO air pulses (300 MS to 1 s) containing 200 fmol vomeropherins (Fig. 8G and H), recorded cortical activity from Cz and Tz. In men (Fig. 8E) A, C and D significantly increased the activity of cortical alpha rhythm delay 270-380 MS. D and And caused the strongest effect (p<0,01). After the filing of a single pulse actimol) B and F, supplied in VNO caused an increase in the cortical alpha rhythm regardless of the response of the olfactory receptors. The authors found characteristic specificity in response human VNO and olfactory epithelium, suggesting that they are independent functional systems having separate communication with the Central nervous system (CNS). (Brookover, C. (1914). The nervus terminalis in adult man. J. Comp. Neurol. 24:131-135). There is also preliminary evidence that the EVG is not associated with nocireceptors endings of the trigeminal nerve, as the use of local anesthesia (2% lidocaine) in the respiratory epithelium of the nasal septum does not lock and does not reduce EVG (Monti-Bloch, L. and Grosser, B. I. (1991) "Effect of putative pheromonenes on the electrical activity of the human vomernasal organ and epithelium in humans", J. Steroid Biochem. Molec. Biol. 39: 573-582).The authors conducted additional tests, which used androsta-5,16-Dien-3,19-diol and four other androstane identified by their positions on the chart. The results are shown in Fig. 10-24. EEG, RF and EKG-reaction on androsta-5,16-Dien-3,19-diol were stronger in women than in men, while the ST, GSR and EVG-reactions were stronger in men. Some women, who had entered the compound, said the more high RF data and GSR, than those shown in Fig. 18B and 18C.It is obvious that the VNO receptors are more sensitive to vomeropherins than to any of the subjects of olfaction; for olfactory receptors is just the opposite proposition. OE (olfactory epithelium) may have cellular receptors for some vomeropherins, however, the specificity of the reaction VNO undoubtedly differs from the reaction OE. Sex differences were noted in regard to specificity and effects of two groups vomeropherins A, C, and D; and B and F. This suggests a possible sexual dimorphism associated with receptors. The discovery of this fact suggests that stimulation of the VNO vomeropherins leads to activation of components of the autonomic nervous system in adults.In addition, the results indicate that stimulation of the VNO vomeropherins causes synchronization of the EEG (Fig. 8G and 8H). Thus, these results suggest that Coulter-nasal system responds to many homocysteine stimuli and that some of them can cause reflex autonomic activity. 1. Androstane General formula
< / BR>where P1selected from the group consisting of oxo, -()-gianrossi-C1-4alkyl;
P3missing or C1-4alkyl;
P4denotes hydrogen, oxo or hydroxy;
P5indicates one or two substituent, where P5represents one or two atoms of hydrogen, methyl or methylene;
a, b, c, d, e, f, h are alternative sites for optional double bonds,
provided that 1) cannot simultaneously be the following: a, c, d, e and f are absent, b and h are present, P1represents oxo, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
2) cannot simultaneously be the following: a, b, d, e and f are absent, c and h are present, P1means-hydroxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
3) cannot simultaneously be the following: a, c, d, e and f are absent, b and h are present, P1means-hydroxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
4) cannot simultaneously be the following: a, c, d, e, and f is ethyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
5) cannot simultaneously be the following: a, c, e and f are absent, b, d and h are present, P1represents oxo, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
6) cannot simultaneously be the following: a, c, d, e and f are absent, b and h are present, P1represents oxo, P2denotes methyl, P3denotes methyl, P4represents oxo, P5represents hydrogen and P6denotes hydrogen;
7) cannot simultaneously be the following: a, c, d, e and f are absent, b and h are present, P1represents oxo, P2represents hydroxymethyl, P3denotes methyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
8) cannot simultaneously be the following: b, d, e and f are absent, a, c, and h are present, P1denotes methoxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5represents hydrogen and P6denotes hydrogen;
9) cannot simultaneously be the following: a, c, d, and f are absent, b, e and h are present, P16denotes hydrogen;
10) cannot simultaneously be the following: a, c, d, e, f and h are absent, b is present; P1represents oxo, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
11) cannot simultaneously be the following: a, b, d, e, f and h are absent, c is present, P1means-hydroxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
12) cannot simultaneously be the following: a, c, d, e, f and h are absent, b is present; P1means-hydroxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
13) cannot simultaneously be the following: a, c, d, e, f and h are absent, b is present; P1means-hydroxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
14) cannot simultaneously be the following: a, c, e, f and h are absent, b and d are present, P1represents oxo, P26denotes hydrogen;
15) cannot simultaneously be the following: a, c, d, e, f and h are absent, b is present; P1represents oxo, P2denotes methyl, P3denotes methyl, P4represents oxo, P5means 2 hydrogen atoms and P6denotes hydrogen;
16) cannot simultaneously be the following: b, d, e, f, and h are absent, a and C are present, P1denotes methoxy P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
17) cannot simultaneously be the following: a, c, d, f and h are absent, b and e are present, P1represents oxo, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
18) cannot simultaneously be the following: a, c, d, f and h are absent, b and e are present, P1means-hydroxy, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5means 2 hydrogen atoms and P6denotes hydrogen;
19) cannot simultaneously be the following: a, c, d, e, f and h are absent, b is present; P1represents oxo, P2UB>6denotes hydrogen;
20) cannot simultaneously be the following: a, c, d, e, f and h are absent, b is present; P1represents oxo, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5denotes methylene, and P6denotes hydrogen;
21) cannot simultaneously be the following: a, b, d, e, f and h are absent, c is present, P1represents oxo, P2denotes methyl, P3denotes methyl, P4denotes hydrogen, P5denotes methylene, and P6denotes hydrogen and
22) cannot simultaneously be the following: a, c, d, e, and h are absent, b and f are present, P1represents oxo, P2denotes methyl, P3missing, P4denotes hydrogen, P5denotes methyl and P6denotes hydrogen.2. Connection on p. 1, where c and h are double bonds.3. Connection on p. 2, where P2is hydroxymethyl and P1is hydroxy.4. Connection on p. 1, where b is a double bond, and P5is methylene.5. Connection on p. 4, where P1is hydroxy or oxo and P4optional is oxo.6. Connection on p. 1, where b and h are Gruppo.8. Connection on p. 1, selected from the group including: 17-methylene-androst-4-EN-3-ol; 17-methylene-6-oxo-androsta-4-EN-3-one; 6-hydroxyandrost-4,16-Dien-3-one; 18-nor-17-methylandrosta-4,13(17)-Dien-3-ol; 18-nor-17-methylandrosta-3,5,13(17)-trien-3-yl methyl ether; 18-nor-17-methylandrosta-4,13(17)-Dien-6-ol-3-one; 17-methylandrosta-4-ene-3,6-dione; 17-methylandrosta-4-EN-3-ol; 17-medienanstalt-3,5-Dien-3-yl methyl ester; 17-medienanstalt-4-EN-6-ol-3-one; 17-medienanstalt-1,4-Dien-3-one; 17-medienanstalt-1,3,5-triene-3-eventout; androsta-1,4,16-triene-6-ol-3-one; androsta-4,16-Dien-6-ol-3-one; 17-medienanstalt-4-ene-3,6-dione and androsta-5,16-Dien-3,19-diol.
< / BR>where Z denotes-CO-CH3; -CO-O-C2H5; -CO-NH-phenyl; -CO-NH-C2H5; -CH3or-CO-phenyl,
and the way they are received by esterification of the corresponding 11-benzaldoxime-östra-4,9-Dien-3-one to a complex or a simple ester
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a pharmaceutical composition as a capsule for oral administration that comprises testosterone undecanoate as an active component dissolved in pharmaceutically acceptable liquid carrier wherein liquid carrier involves at least 50 wt.-% of castor oil. Using castor oil as a liquid carrier in combination with testosterone undecanoate as androgen provides preparing a solution that can contain about 200-250 mg of testosterone undecanoate/ml that represents the new achievement for testosterone solution for oral administration. Solution can contain lipophilic surface-active substance, such as lauryl glycol also. The composition shows good absorption in human body and elicits higher activity as compared with the known composition of undecanoate.
EFFECT: improved and valuable properties of composition.
7 cl, 1 ex
SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.
EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.
41 cl, 13 dwg, 4 tbl
SUBSTANCE: a patient with systemic lupus erythematosus (SLE) should be prescribed to apply efficient quantity of pharmaceutically active form of dehydroepiandrosterone (DHEA) and then, after prescription it is necessary to detect the values for disease activity and total symptoms of the process that characterizes SLE-patient's state, such as: index of SLE activity (IASLE), degree of SLE activity (DSLE), patient's visual analog scale (VAS) and coefficient of Krupp's severity degree (CSDK) to determine the difference between these above-mentioned values obtained before treatment and those taken during therapy, moreover, the decrease of three out of these four values or either the decrease of stabilization or the increase being not higher than by 5% in the fourth value shows that patients reacts to the intake of DHEA.
EFFECT: higher efficiency of therapy.
13 cl, 1 dwg, 8 tbl
FIELD: organic chemistry, steroids, medicine, chemical-pharmaceutical industry.
SUBSTANCE: invention relates to an agent exhibiting structure 7β-hydroxyepiandrosterone or 7β-dehydroepiandrosterone, or their pharmaceutically acceptable esters of the structural formula (I) used for protection of neurons against their damages. Compounds elicit high effectiveness and bioavailability.
EFFECT: valuable medicinal properties of compounds.
15 cl, 3 dwg, 3 tbl, 22 ex
SUBSTANCE: disclosed is application of 7-hydroxyepiandrosteron as active agent for protection from acute or chronic neuron damage caused by hypoxia, ischemia, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, or spinal cord damage. 7-Hydroxyepiandrosteron increases number of pyramidal cell survivor after ischemia or hypoxia.
EFFECT: new agent with neuroprotective activity.
6 cl, 1 dwg, 2 tbl, 8 ex
FIELD: medicine, urology, pharmaceutical industry, pharmacy.
SUBSTANCE: method for correction of PADAM involves oral administration of testosterone or its pharmacologically acceptable derivatives for 22-24 h as a preparative formulation providing onset of release of abovementioned medicinal substance in 4-7 h after its administration, and prolonged effect for 24 h. The testosterone preparative formulation comprises a core and envelope that is insoluble in stomach. A core comprises components in the following ratio, mas. p.: testosterone undecanoate, 1; magnesium basic carbonate, 82-100; sugar, 21.6-26.4; Eudragit E, 2.16-2.64, and calcium stearate, 1.08-1.32. A core is covered by envelope that is difficultly soluble in intestine and providing onset in a medicinal agent releasing in 4-7 h after its administration. Invention provides the testosterone level in a patient that repeats its physiological daily modulation completely. Invention can be used in treatment of patients suffering from partial age androgen deficiency (PADAM) and in production of testosterone preparations or its pharmacologically acceptable derivatives.
EFFECT: improved method of correction of deficiency.
6 cl, 2 tbl, 2 dwg
SUBSTANCE: system has at least one steroid hormone and propylene glycol monocaprylate as penetration accelerator. The steroid hormone is enclosed into polymer matrix. Transdermal system is to be used as hormone-substituting therapy and contraception means.
EFFECT: increased steroid hormone penetration through skin; reduced transdermal system application area.
FIELD: medicine, oncology, organic chemistry, antibiotics.
SUBSTANCE: invention proposes a combination and corresponding method for treatment of tumors that are positive with respect hormone receptors. Combination comprises rapamycin or 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin, or ABT578, or compound of the formula (1): or an aromatase inhibitor: atamestan, exemestan, formestan, aminoglutetinide, rogletimide, pyridoglutemife, trilostan, testolactone, ketocona-zol, vorozol, fandrozol, anastrozol or letrozol. In the formula (1) R1 means -CH3 or (C3-C6)-alkynyl; R2 means hydrogen atom (H) or -CH3-CH3-OH; X means oxygen atom (O), (H, H) or (H, -OH) under condition that R2 doesn't mean H if X means O, and R1 means -CH3. Proposed composition shows synergism in suppression of breast cancer proliferation.
EFFECT: valuable medicinal properties of combination.
FIELD: medicine, steroids, pharmacy.
SUBSTANCE: invention describes a pharmaceutical composition based on oil for injection contraception and/or for substitution hormonal therapy. The composition comprises the effective amount of ethonogestrel decanoate and/or ethonogestrel undecanoate, and/or ethonogestrel dodecanoate taken in the effective contraception and/or therapeutic acting doses. Also, invention describes a method for carrying out the contraception and/or substitution hormonal therapy. Use of specific ethonogestrel esters provides good pharmacokinetic pattern and gives the possibility for using progestogen in a single dose with the prolonged period of effect.
EFFECT: improved and valuable medicinal and pharmaceutical properties of compounds.
10 cl, 2 tbl, 6 dwg, 4 ex
SUBSTANCE: described oil solution for injection to patient is characterised by the fact that it includes 25-200 mg/ml of the first component which is ethonogestrel ether and 50-400 mg/ml of the second component which the fatty acid ether with chain length within C6 to C12 and 7-alpha-methyl-19-nortestosterone, where progesterone ether and androgen ether are dissolved in ethylundecanoate. Besides, related introduction device is described.
EFFECT: high level of predisposition to treatment implying infrequent painless introduction without by-effects and local reactions.
2 cl, 2 tbl, 6 ex, 15 dwg