Neuroactive steroids, pharmaceutical product, the method of treatment or prevention of various disorders, the method induction of sleep and way of induction of anesthesia with their use, the method of complex modulation of gabaa receptor-chloride ionophor

 

(57) Abstract:

The invention describes new neuroactive steroids of some of the androstane or pregnane General formula I or their physiologically acceptable complex 3-esters where R is H or lower alkoxygroup, R1- H, C1-10alkyl, C2-10alkenyl,2-10quinil, halogen WITH1-10alkyl, trihalogen-C1-10alkyl, hydroxy-C2-10quinil, alkoxy-C1-10alkyl, optionally substituted phenylalkyl, complex gemify hydroxyhomosildenafil acid; R2- N or ketogroup, R3- optionally substituted alkoxy, alkyloxy-, optionally substituted phenylalkylamine, -C(O)-CH2-Y-G, C(O)-CH2-O-D, -C(O)-CH2-O-E, -C(O)-CH2-Z-G or-C(O)-CH2-Y-Z-A, where Y IS O, S, SO or SO2; Z1-10alkyl, and G is pyridyl or optionally substituted phenyl, D - quinoline attached to the carbon atom; E is optionally substituted phenyl, AND-HE, carboxyl or sulfonate; R4Is h or methyl; R5- N; R6- N; R7- H or HE; R8- N; R9- N; R10- N, provided that when R3- C1-3alkoxygroup and R - N, R1different from N; when R3- C1-4alkoxy (C1-4) alkoxygroup, R1- otlichie from N or C1-10of alkyl; or when R3- - (O)-CH2-Z-G, R1differs from N. The compounds I can affect the excitability of the brain in such a way as to alleviate the stress, anxiety, insomnia, mood disorders due to active against GRC agents. 10 C. and 29 C.p. f-crystals, 1 Il., 10 table.

The technical field

The invention relates to new steroid derivatives of the androstane series and pregnane, as well as to pharmaceutical preparations and methods for modulation of excitability of the brain. More specifically the invention relates to 3-hydroxy, 17-(UN)substituted derivatives of a number of androstane and 3-hydroxy, 21-substituted derivatives of a number of Pregnana.

Art

The excitability of the brain is defined as the level of arousal of the animal, condition ranging from coma to convulsions, and are subject to various neurotransmitters. In the General case, the neurotransmitter responsible for regulating the conduction of ions through the neuronal membrane. In the resting state neural membrane has the potential (or membrane voltage) approximately -80 mV, the internal portion of the cell is negatively charged compared to the outside of the cell. The potential of what they have water resistant neural membrane. Neurotransmitters are found in the presynaptic vesicles and are released under the influence of the action potentials of a neuron. When entering the synaptic deepening chemical mediator of irritation, such as acetylcholine, will cause membrane depolarization (change of potential from -80 to -50 mV). This effect is transmitted to postsynaptic nicotinic receptors, which are stimulated by acetylcholine, with the aim of increasing the membrane permeability for ions of Na+. Reduced membrane potential stimulates neural excitation in the form of a postsynaptic potential actions.

In the case of the complex of the GABA receptor (GRC) effect of excitability of the brain is carried by the neurotransmitter GABA. GABA has a strong impact on the overall excitability of the brain, because up to 40% of brain neurons use GABA as a neurotransmitter. GABA regulates the excitability of individual neurons change in conductivity chloride ions across the neuron membrane. GABA interacts with your site recognition at GRC to facilitate the penetration of chloride ions on the electrochemical gradient GRC in a cage. The increase in the concentration of this anion inside the cell causing hyperpolarization of transmembrane poten). In other words, the higher the concentration of chloride ion in the neuron, the lower the excitability of the brain (the excitation level).

Widely described that the GRC is responsible for the manifestation of anxiety, pripadochnaya activity and sedative effect. Thus, GABA and medicines, which act as GABA or facilitate the effects of GABA (e.g., therapeutically used barbiturates and benzodiazepines (BZs), such as valium), show their therapeutically useful effects when interacting with specific regulatory sites on GRC.

Accumulated evidence now indicate that in addition to binding site of the benzodiazepine and barbiturate GRC contains a separate section for neuroactive steroids (Lan N. C. et al., Neurochem. Res. 16:347-356 (1991)). The most active endogenous neuroactive steroids are 3-hydroxy-5-rebuilt by pregnan-20-he 3,21-dihydroxy-5-rebuilt by pregnan-20-he, metabolites of hormonal steroids progesterone and hypertension, respectively. The ability of these steroid metabolites to alter the excitability of the brain was discovered in 1986 (Majewska, M. D. et al., Science 232: 1004-1007 (1986); N. Harrison L, et al., J. Pharmacol. Exp. Ther. 241: 346-353 (1987)). However, therapeutic field, working in this area, due to incomplete understanding of the activity and scope of these neuroactive steroids. The invention of applicants, partly due to the pharmaceutical application of knowledge derived from a more complete understanding of the activity and scope of certain steroid compounds.

It was demonstrated that the ovarian hormone progesterone and its metabolites have a strong effect on the excitability of the brain (Backstrom T. et al., Acta Obstet. Gynecol. Stand. Suppl. 130:19-24 (1985); Pfaff D. W. and McEwen B. S., Science 219:808-814 (1983); Gyermek et al., J. Med. Chem. 11:117 (1968); J. Lambert et al., Trends Pharmacol. 8:224-227 (1987). The levels of progesterone and its metabolites vary depending on the phase of the menstrual cycle. It was widely described that the content of progesterone and its metabolites is reduced before the onset of menstruation. Monthly repetition of certain physical symptoms before menstruation has also been described. These symptoms, which were associated with premenstrual syndrome (PMS) include stress, anxiety, and migraine (Dalton K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago: Chicago yearbook, 1984). Patients with PMS have a monthly recurrence of symptoms that occur before menstruation and is missing after menstruation.

The syndrome is also associated with low levels of progesterone, is postnatal depression (PND). Immediately after birth, progesterone levels drop sharply, leading to the beginning of the PND. The PND symptoms vary from mild depression to psychosis requiring hospitalization; PND is associated with a state of acute anxiety and irritability. PND-associated depression cannot be treated by classical antidepressants, and women with PND increased incidence of PMS (Dalton K., Premenstrual Syndrome and Progesteron Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).

Taken together, these observations imply a significant role of progesterone and desoxycortisol the traveler is manifested as increased epileptic activity or symptoms, associated with menstrual epilepsy, PMS and PND. The correlation between reduced levels of progesterone and symptoms associated with PMS, PND and menstrual epilepsy (Backstorm et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983); K. Dalton, Premenstrual Syndrome and Progesteron Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)), suggested the use of progesterone in their treatment (Mattson et al., "Medroxyprogesteron Therapy of catamenial epilepsy" in Advances in epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), 279-282, 1984 and K. Dalton, Premenstrual Syndrome and Progesteron Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not constantly effective in the treatment of the above-mentioned syndromes. For example, there is no relationship the dose-response to progesterone in the treatment of PMS (Maddocks running etal., Obstet. Gynecol. 154:573-581 (1986); Dennerstein, et al., Brit. Med. J., 290:16-17(1986)).

Templeton et al., Steroids 48:339-346 (1986) describe the stereoselective and regioselective recovery of steroid ketones with the formation of axial alcohols at C-3. The compound 17-methoxy-2-methyl-5-androstane-3-ol obtained from 17-methoxy-2, 3-epoxy-5-androstane.

Grieco et al., J. Am. Chem. Soc. 11:7799-7801 (1990) describe the use of the 17-methoxy-5-androstane-3-ol as a starting material for the production of conjugates containing metalloporphyrins associated with steroid substrates.

Babcock et al., U.S. patent 4297350 is the firmness of male contraceptives.

Neef et al. Tetrahedron Letters 21:903-906 (1980) describe the connection 17 methoxyethoxy-3-(1-PROPYNYL)-5-androsten-3-ol as an intermediate connection when receiving steroid derivatives.

FR 1437361, published may 6, 1966, and U.S. Patent 3135744, issued June 2, 1964, describe 17-(2-methyl-2-butenyl)marketing and cycloalkenyl esters-androstane-3, 17-diol and 3-esters of lower alkanols. It is shown that the compounds possess androgenic and/or anabolic activity.

Phillips et al., U.S. patent 4197296, issued April 8, 1980, describe the steroids of some of the androstane, which contain 3-hydroxy-group, 5 - or 5-atom of hydrogen, and 11 is replaced by the amino group, in which position 17 may be unsubstituted. Describes the connection 11-N, N-dimethylamino-2-ethoxy-5-androstane-3-ol. The patent describes that such compounds possess anaesthetic activity.

Phillips et al., U.S. patent 3882151, issued may 6, 1975, and Phillips et al. , U.S. patent 3969345, issued July 13, 1976, describes the 21-esters of 3-oxygendemanding Pregnana containing 3-hydroxyl or ether, keto group in position 20 and esterified hydroxyl in position 21. 21-ether Deputy preferably presents alkoxy, cycloalkane-Allakaket or aryloxy group, Kotor, the overall activity.

Phillips et al., U.S. patent 3959260, issued may 25, 1976, describe steroid anesthetic compounds from the ranks pregnane and 19-norpregnane, which contain the 3-hydroxyl, a 20-oxo group in position 21 - residue containing sulfur of the nucleophile or sulfonic or sulfoxide group. 3-Deputy may be either hydrogen or alkyl.

Clayton et al., U.S. patent 3822298, issued July 2, 1974, describe the method of obtaining 3-hydroxy-5-steroid. The patent describes obtaining 21-benzyloxy-3-hydroxy-5-pregnan-11,20-dione.

This application is a partial continuation of application 08/467404, filed June 6, 1995, the contents of which are fully incorporated by reference.

The invention

The present invention concerns new steroid derivatives of the androstane series and pregnane, as well as pharmaceutical preparations and methods of modulating the excitability of the brain. More specifically, the invention relates to 3-hydroxy, 17-(UN)substituted derivatives of a number of androstane and 21-substituted derivatives of a number of Pregnana. These derivatives can act on the newly identified site on GRC, modulating, therefore, the excitability of the brain in such a way as to facilitate stresser, depression), and epileptic activity.

Neuroactive steroid derivatives presented in this invention have the General structural formula (I),

< / BR>
where R is hydrogen or lower alkoxygroup;

R1means hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil, halogen-C1-10alkyl, trihalogen1-10alkyl, hydroxys2-10quinil, alkoxyl1-10alkyl, optionally substituted phenyl, alkoxyl2-10quinil, oxoalkyl or ketal, optionally substituted phenylalkyl, complex gemify hydroxyhomosildenafil acid;

R2means hydrogen or ketogroup;

R3means optionally substituted alkoxy, alkyloxy-, optionally substituted by phenylalkylamine, -C(O)-CH2-Y-G-C(O)-CH2-O-D, -C(O)-CH2-O-E, -C(O)-CH2-Z-G or-C(O)-CH2-Y-Z-A, where

Y represents O, S, SO or SO2;

Z represents C1-10alkyl;

G denotes pyridyl or optionally substituted phenyl;

D denotes the quinoline attached to the carbon atom;

E is optionally substituted phenyl;

And denotes hydroxyl, carboxyl or sulfonate;

R4denotes hydrogen or methyl;
IS;

R9is hydrogen;

R10is hydrogen;

provided that:

when R3- C1-3alkoxygroup and R is hydrogen, R1different from hydrogen. The structure having formula I, includes androstane, pregnane (R4= methyl), 19-norandrosterone and norpregnane (R4= N).

The present invention also includes pharmaceutically acceptable esters and salts of compounds of formula I, including salts of acids. Consider that the 3-hydroxyl can also be disguised pharmaceutically acceptable ether, due to the fact that the ether will be split as proletarienne substance turns into a dosage form. In the description of them is designated as biodegradable esters.

The compounds presented in this invention are modulators of excitability of the Central nervous system, as follows from their ability to regulate the channels of chloride ions associated with the GABA receptor. In the experiments, applicants found that these compounds have activity against seizures, anxiety and sedative hypnotic activity similar to known agents such as BZ (benzodiazepines), but they operate on a different site on the GRC.

The desired objects of pharmaceutical preparations and methods presented in this invention are the treatment of stress, anxiety, PMS, PND and seizures, such as caused by epilepsy, to facilitate or prevent anxiety attacks, muscle tension and depression, which is common for patients suffering from these anomalies of the Central nervous system. Additional desirable object of drugs and methods is the treatment of insomnia and receiving hypnotic action. Another desirable object of the compounds and methods is the induction of anesthesia, especially by intravenous injection. The present invention is directed to new compounds and their use in pharmaceutical preparations and methods of treatment of such disorders by modulation of excitability of the brain.

Another aspect of the present invention relates JV is provided during normal sleep, when not induced reactive, as defined here, insomnia. This method requires the introduction of an effective amount of the compounds presented in the invention. The compounds presented in the invention can extend NREM (slow) sleep and total sleep time without significant effect on the amount of REM sleep.

List of figures

The present invention may be better understood and its advantages appreciated with the accompanying drawing, which is given to the scheme depending on the time antipersonnel activity of prodrugs of 3-hydroxy-17-methoxy-5-androstane (injected intraperitoneally at a dose of 20.0 mg/kg).

Information confirming the possibility of carrying out the invention

The compounds presented in this invention are derivatives of different 3-hydroxylated-pregnane and 3-hydroxylated androstenol and their ethers or esters, sulfonates, sulfates, phosphonates, phosphates, Joksimovi, thiosulfate, heterocyclic and heteroaryl derivatives, and derivatives, which are described as prodrugs. The expression "prodrug" refers to a derivative of the known medicines direct action, kestvam and transformed into an active drug enzymatic or chemical means; see Notari, R. E., Methods in Enzymology, 112: 309-323 (1985); N. Bodor, Drugs of the Future, 6(3):165-182 (1981) and H. Bundgaard, "Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities," in Design of prodrugs, H. Bundgaard, ed., Elsevier, New York (1985). It should be noted that some of the synthetic derivatives constituting part of the present invention may not be true prodrugs, because in addition to the above characteristics, they also have their own activity. However, under this proposal they will be referred to as prodrugs.

Early studies (Gee, K. W. et al., European Journal of Pharmacology, 136: 419-423 (1987) demonstrated that gidroksilirovanii steroids by several orders of magnitude more active as modulators GRC than previously described (Majewska, M. D. et al. Science 232:1004-1007 (1986); N. L. Harrison et al., J. Pharmacol Exp. Ther. 241:346-353 (1987)). Majewska, M. D. et al. and Harrison, N. L. et al. showed that 3-gidroksilirovanii-5-rebuilt steroids can give significantly lower levels of efficiency. Experimental data in vitro and in vivo demonstrate that the high activity of these steroids allows their therapeutic use for the modulation of excitability of the brain through GRC (Gee, K. W. et al., European Journal of Pharmacology, 136: 419-423 (1987)); Wieland et al., Psychopharmacology 118(1):65-71 (1995)). Various synthetic steroids were poluchaetsya steroid compounds, used to treat stress, anxiety, epileptic disorders and mood disorders susceptible agents active against GRC, such as depression, therapeutically favorable way. Further, it has been previously shown that these steroids interact with unique stretch of GRC, which differs from other known sites of interaction (i.e., barbiturates, BZ and GABA), for which the previously installed therapeutically beneficial effect on stress, anxiety, sleep, mood disorders and epileptic disorders (Gee, K. W., Yamamura H. I. Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders in Central Nervous System Disorders, D. C. Horvell, ed., Marcel-Dekker, New York (1985), 123-147; Lloyd K. G. and P. L. Morselli, Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, ed. Raven Press, N. Y. (1987), 183-195, and Gee, K. W. et al., European Journal of Pharmacology, 136: 419-423 (1987). These compounds are desirable due to the length of their actions, the effectiveness and activity of the oral application (along with other forms of administration).

Definition

In accordance with this invention and as used here, the following terms, which appear separately or as part of a whole, have the following meanings, unless otherwise clearly.

Hppy with unbranched chain, branched chain and cyclic groups, all of which may be optionally substituted. Preferred alkyl groups contain 1-10 carbon atoms. Suitable alkyl groups represented by stands, ethyl and similar groups can be optionally substituted.

The term "alkenyl", as used here in all cases, refers to unsaturated groups which contain at least one carbon-carbon double bond, and includes groups with an unbranched chain, branched chain and cyclic groups which may be optionally substituted. Preferred alkeneamine group contains 2-10 carbon atoms.

The term "quinil", as used here in all cases, means an unsaturated hydrocarbon groups which contain at least one carbon-carbon triple bond, and includes groups with an unbranched chain and branched chain, which may be optionally substituted. Preferred alkyline groups contain from two to eighteen carbon atoms. More preferred alkyline groups contain from two to twelve carbon atoms. The most preferred alkyline groups contain from two to seven atomo the which can be optionally substituted by cyano, acetoxy-, halo-, hydroxy - or catography.

The term "alkoxy" means an ether-O-alkyl, where alkyl is defined above.

The term "aryloxy" means the ether-O-aryl, where aryl, as defined below.

The term "aryl" means an aromatic group that contain at least one cycle with conjugated PI-electron system and includes carbocyclic aryl, and biaryl, both of which can be optionally substituted. Preferred aryl groups contain 6 to 10 carbon atoms. Suitable arily represented by phenyl and naphthyl.

The term "carbocyclic aryl" means a group in which atoms of the aromatic cycle are carbon atoms. Carbocyclic aryl groups include phenyl and raftiline group which may be optionally substituted. Substituted phenyl preferably contains from one to three, four or five substituents, mainly represented by the lower alkyl, amino group, aminocarbonyl, cyano, carboxypropanoyl ether, hydroxyl, lower alkoxyl, halogen, lower acyl and nitrogroup.

The term "arylalkyl" means alkyl group, substituted aryl group. Suitable arylalkyl grouppolicy group" means-O-C(O)Rawhere Ra- alkyl, alkenyl, quinil or aryl-alkyl.

The term "carbalkoxy group" means-O-C(O)Rbwhere Rb- alkyl, alkenyl, quinil or arylalkyl.

The term "carboxamide" means-O-C(O)NRcRdwhere Rcand Rdindependently selected from hydrogen, alkyl, alkenyl, quinil, aryl or arylalkyl.

The term "amino" means-NRhRiwhere Rhand Riindependently represented by hydrogen or a lower alkyl or linked together with the nitrogen atom to which they are attached form a 5 - or 6-membered cycle, for example, pyrolidine, morpholinyl or piperidinyl cycles. The term "dialkylamino" means NReRfwhere Reand Rfindependently represented by lower alkyl groups, or together with the nitrogen atom to which they are attached, form a residue morpholino group. Suitable dialkylamino presents dimethylamino, diethylamino and morpholino groups.

The term "tighrope" means-SRmwhere Rmis hydrogen, alkyl, alkenyl, quinil or aryl(lower)alkyl.

The term "sulfinil" means-SORnwhere Rn- alkyl, alkenyl, quinil or aryl(lower)alkyl.

The term "sulfamidihappo" means-SO2NRkRlwhere Rkand Rlis independently hydrogen or lower alkyl.

The term "optionally substituted" or "substituted", unless specifically indicated otherwise, refers to groups substituted by one to five substituents, independently selected from lower alkyl (acyclic or cyclic), aryl (carbaryl or heteroaryl), alkenyl, quinil, alkoxyl, halogen, halogenoalkane (including trihalomethyl, for example trifluoromethyl), amino-, mercapto-, alkylthio, alkylsulfonyl-, alkylsulfonyl-, nitro, alkanoyl, alkanoyloxy, alkanolamine, alkoxycarbonyl, carbalkoxy (-COORjwhere Rjlower alkyl), carboxamido (-CONRkRlwhere Rkand Rlabove), formyl, carboxyl, hydroxyl, ceanography, azido and ketogroup and its cyclic ketals, alkanolamides, heterokaryosis, hemerocallidaceae and salts of ether hemisuccinate.

The term "lower" as outlined here in relation to organic radicals or compounds, means those containing up to ten inclusive, preferably up to six, inclusive, preimushestvenno is practical.

The term "heterocyclic" means a carbon-containing radicals with three-, four-, five-, six - or semifinali cycles and one or two heteroatoms O, N or S, for example, thiazolidin, tetrahydrofuran, 1,4-dioxane, 1,3,5-trioxane, pyrrolidine, piperidine, Hinkley, Titian, tetrahydropyran-caprolacton, -caprolactam, cicaplast and morpholine.

The term "heteroalkyl" means carbon containing 5-14-membered unsaturated cyclic radicals containing one, two, three or four atoms O, N or S, and having 6, 10 or 14-electrons delocalized in one or more cycles, for example pyridine, oxazole, indole, purine, pyrimidine, imidazole, benzimidazole, indazole, 2H-1,2,4-triazole, 1,2,3-triazole, 2H-1,2,3,4-tetrazole, 1H-1,2,3,4-tetrazol, benzotriazole, 1,2,3-triazolo[4,5-] pyridine, thiazole, isoxazol, pyrazole, quinoline, cytosine, thymine, uracil, adenine, guanine, pyrazin, picolina acid, picoline, Turaeva acid, furfural, furrowy alcohol, carbazole, N-pyrido[3,4-a]indole, isoquinoline, pyrrole, thiophene, furan, 9(10H)-acridone, phenoxazin and phenothiazines, each of which may be optionally substituted as discussed above.

The term "Quaternary ammonium salt" means the Quaternary ammonium salts of amino compounds and heteroaryl is possible with an electrophilic reagent, such as alkyl, alkenyl, quinil, cycloalkenyl, aryl-alkyl or aryl-quinil, halide, tosylate, sulfate, mesilate or similar. Specific examples of electrophilic reagents include methyliodide, ethyliodide, n-butylated and penetrated.

The term "ED" means Ethylenediamine.

The term "pharmaceutically acceptable ester or salt means an ester or salt of formula I, obtained by the combination of the combination of the compounds presented in this invention and an organic or inorganic acid or base. Basic salts obtained by mixing a solution of a compound in this invention, a solution of the pharmaceutically acceptable non-toxic base such as the hydroxide of sodium, potassium hydroxide, sodium bicarbonate, sodium carbonate or amino compounds, such as choline hydroxide, Tris, bis-Tris, N-methylglucamine, lysine and the like. Sour salt is produced by mixing a solution of a compound in this invention, a solution of the pharmaceutically acceptable non-toxic organic acids or dicarboxylic acids, such as acetic, propionic, maleic, fumaric, ascorbic, Emelyanova, amber, glua, gluconic, Takanawa, glycolic, p-aminobenzoic, aspartic, glutamina, -amino, -(2-hydroxyethylamino)propionic, glycine and other amino acids, phosphoric, sulfuric, glucuronic and 1-methyl-1,4-digitaleconomy. Esters derived from starodniprovs and appropriately activated acids. Esters are discussed below.

The term "dicarboxylic acid" means1-5alkylene group substituted by two carboxy, for example, malonic acid, succinic acid, glutaric acid, adipic acid, Emelyanova acid and subernova acid. Hemi-ester salts of dicarboxylic acids include salts of sodium, lithium, potassium, magnesium and calcium.

In accordance with this invention the ketals include the diesters of lower alkanols, such as dimethyl - and diethylketone and cyclic ketals, which are represented by the diesters1-3alkanediols, which may be optionally substituted, for example etelemetry and propellantto.

A variant of the invention, 1A.

In its broadest aspect the present invention relates to steroid derived from the basic formula I

< / BR>
where R is hydrogen, amino, thio-group, sulfinil, sulfo - hydrogen, alkyl, alkenyl, quinil, halogen-alkyl, dihalogen-alkyl, trihalogen-alkyl, optionally substituted aryl-quinil, alkoxyalkyl, aminoalkyl, cyano group, cianelli, thiocyanates, azidoethyl, optionally substituted arylalkyl, arylalkyl, optionally substituted aryl, optionally substituted arylalkylamines, alkanoyloxy, optionally substituted heteroarylboronic, oxoalkyl or ketal, cyanoacetyl, optionally substituted heteroarenes, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, mercaptoamines, genifer hydroxyalkanoates dicarboxylic acid or its salt or alkyloxyalkyl;

R2is hydrogen, hydroxyl, alkoxyl, alkanoyloxy group, carbalkoxy group, ketogroup or amino group;

R3is hydrogen, alkoxy, substituted alkoxy, alkenylamine group, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, sulfinil, sulfonyl, tigroup, sulfonamide group, alkyloxy group, optionally substituted aryloxy, optionally substituted arylalkylamines, optionally substituted 1,3-dioxolane-4-one acetyl group, optionally substituted 1,3-dioxane-4-one acetyl group, pobystromu, -O-C(O)-NR'R R", -C(O)-CH2-Y-G-C(O)-CH2-O-D, -C(O)-CH2-O-E, -C(O)-CH2-Z-G, -C(O)-CH2-Y'-Z-G, -C(O)-CH2-Y'-Z-A, where

R' and R" independently represented by hydrogen or optionally substituted alkyl, or together with the nitrogen to which they are attached, form a 3-6-membered heterocyclic ring;

Y is S, SO or SO2;

Y' is O, S, SO or SO2;

Z - alkyl, alkenyl or quinil;

G - heteroaryl attached to the carbon atom, optionally substituted aryl, salt of the Quaternary ammonium nitrogen-containing heteroaryl group or a Quaternary salt of amino-substituted aryl group;

D - heteroaryl attached to the carbon atom, or a salt of the Quaternary ammonium nitrogen-containing heteroaryl group;

E is optionally substituted aryl or salt of Quaternary ammonium aminosilanes aryl group;

A - amino-, amido-, cyano-, thiocyano, azido-, nitro-group, hydroxyl, halogen, carboxyl, alkoxygroup, alkoxycarbonyl, alkanoyloxy group, hydrogen, sulfate, thiosulfate, sulfonate, allylthiourea, alkylsulfonyl-, alkylsulfonyl or mercaptopropyl;

R4is hydrogen or lower alkyl;

R5is hydrogen or, if a double bond is present between C4 and C5 steroid CEC;

R7is hydrogen, halogen, hydroxyl, alkoxy, alkanoyloxy or carbalkoxy;

R8is hydrogen or halogen;

R9is hydrogen, halogen, alkyl, alkoxy, Allakaket - or amino group;

R10is hydrogen, halogen, alkyl, halogenated, hydroxyl, alkoxy, alkanoyloxy, carbalkoxy-, cyano-, thiocyano or mercaptopropyl; and the dotted lines denote that may be simple or double bond;

provided that:

when R3- C1-3alkoxygroup or1-6alkenylacyl and R is hydrogen or methyl, R1Deputy other than hydrogen; or

when R3- C1-4alkoxy(C1-4)alkoxygroup, R1Deputy other than hydrogen or 1-propenyl; or

when R3is hydrogen and R2is hydrogen, hydroxyl, ketogroup or amino group, R1is not hydrogen, alkyl or cyanoacrylat; or

when R3- aminocarbonyl, monoalkylamines, dialkylaminoalkyl, R1is not hydrogen or alkyl; or

when R3IS-C(O)-CH2-Y-G and G - heteroaryl attached to the carbon atom, or optionally substituted aryl, R1different from hydrogen or alkyl; or

when R3IS-C(O)-CH2-Y'-Z-G, and Y' Is O, and G is aryl, R1different from hydrogen; or

when R3IS-C(O)-CH2-Y'-Z-G, and Y' IS S, SO or SO2and G is aryl, R1different from hydrogen or alkyl; or

when R3IS-C(O)-CH2-Z-G, R1different from hydrogen; or

when R3IS-C(O)-CH2-Y'-Z-A and Y' Is O and a is hydrogen, halogen, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino group, R1different from hydrogen; or

when R3IS-C(O)-CH2-Y'-Z-A and Y' IS S, SO or SO2and a - hydrogen, halogen, carboxyl, alkoxycarbonyl, or amino group, then R1different from hydrogen or alkyl.

The present invention also includes pharmaceutically acceptable esters and salts of compounds of formula I, including salts of acids. Suppose that the 3-hydroxyl can be protected in the form of a pharmaceutically acceptable ether complex due to the fact that the ether will be chipped off, as the conversion of prodrugs in the pharmaceutical form. Here they are referred to as split ethers.

A variant of the invention, 1b.

One group of useful compounds covered by the broad aspect the present invention provides compounds of formula I, where:

the relationship between C4 and C5 with the, alseny alkyl, quinil or substituted quinil;

R1, R2, R4, R6, R7, R8, R9and R10as defined above;

R3is hydrogen, alkoxy, substituted alkoxy, alkenylacyl, alkyloxy-, optionally substituted, aryloxy-, optionally substituted arylalkylamine, -O-C(O)-NR'r R", -C(O)-CH2-Y-G-C(O)-CH2-O-D-C(O)-CH2-O-E, -C(O)-CH2-Y'-Z-G or-C(O)-CH2-Y'-Z-A, where

R' and R" independently represent hydrogen or optionally substituted alkyl, or together with the nitrogen to which they are attached, form a 5 - or 6-membered heterocyclic ring;

Y, Y', Z, G, D, E and A, as defined above;

R5is hydrogen; and where the

all pertinent conditions as described above for Option 1A, applicable to this type of compounds.

Embodiments of the invention, 1A' and 1b'.

In preferred aspects of Options 1A and 1b steroid derivatives have the basic formula I, where R, R1, R2, R3, R', R", Y, Y', Z, G, D, E, A, R4, R5, R6, R7, R8, R9and R10defined above for Options 1A or 1b. However, the following conditions apply to each of the earlier variants:

when R3- C1-6- the hydrogen and R2is hydrogen, hydroxyl, keto or amino group, R1is not hydrogen, alkyl or cyanoacrylat; or

when R3IS-C(O)-CH2-Y-G and G - heteroaryl attached to the carbon atom, or optionally substituted aryl, R1Deputy other than hydrogen or alkyl; or

when R3IS-C(O)-CH2-Z-G, R1different from hydrogen or alkyl; or

when R3IS-C(O)-CH2-O-E and E is optionally substituted aryl, R1other than hydrogen or methyl; or

when R3IS-C(O)-CH2-Y'-Z-G, and G is optionally substituted aryl, R1Deputy other than hydrogen or alkyl; or

when R3IS-C(O)-CH2-Y'-Z-A and Y' Is O and a is hydrogen, halogen, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino group, R1Deputy other than hydrogen or alkyl.

Preferred values for all embodiments of the invention

Each of the following groups are preferred values applies to all variants of the present invention, unless specifically stated otherwise. Preferred compounds of formula I are compounds in which R is hydrogen or lower alkoxyl where odgp; R5, R6, R7, R8, R9and R10are hydrogen; and R1is replaced by arylalkyl, for example, R14 - substituted phenylalkyl, such as 4-acetylphenylalanine, 4-methoxyphenethyl, 4-N, N-dimethylaminopyridine, 4-cyanoaniline, ethyl ester 4-carboxypentyl, 4-N,N-dialkylaminomethyl, or where R1- oxoalkyl, hydroxyalkyl, acetoxyacetyl, cyanoacetyl or alkoxyalkyl.

Other preferred compounds are the compounds of formula I in which R is hydrogen, halogen, lower alkoxy, quinil or substituted quinil; R1- substituted arylamines; R2- hydrogen, ketogroup or dimethylaminopropan; R4is hydrogen or methyl; each of R5, R6, R7, R8, R9and R10is hydrogen and all dotted lines represent simple relationships.

Further preferred compounds are the compounds of formula I, which represents the esters of hydroxyl groups in position 3. Preferred esters are those derived from their corresponding acids and dicarboxylic acids: acetic, propionic, maleic, fumaric, ascorbic, pipelinewall, away, citric, gluconic, takenaway, glycolic acid, para-aminobenzoic, aspartic, glutamic, gamma-aminobutyric, -(2-hydroxyethylamino)propionic, glycine and other amino acids, phosphoric, sulfuric, glucuronic and 1-methyl-1,4-dihydrocodeinone.

17-ester derivatives of 3-hydroxyandrost.

The first subgenus of the compounds according to the present invention contains a 17-ester derivatives of 3-hydroxyandrost. Steroid derivatives according to this aspect of the present invention contain compounds having structural formula I as shown above, where

R, R1, R2, R4, R5, R6, R7, R8, R9and R10as defined above for Option 1A; and

R3- alkoxy, substituted alkoxy, alkenylacyl, alkyloxy-, optionally substituted, aryloxy-, optionally substituted, arylalkylamine-group or-OC(O)NR'r R", where

R' and R" independently represented by hydrogen, optionally substituted alkyl or together form a 5 - or 6-membered heterocyclic ring;

provided that:

when R3- C1-6alkoxy or C1-6alkenylacyl-group and R is hydrogen or methyl, R1different from hydrogen; and

when R3-
R3- alkoxygroup, such as methoxy, ethoxy - or propoxy - or substituted alkoxygroup, such as-OCH2CH2OH, -OCH2CCH or-OCH2CC-PhCOMe;

R4is hydrogen or lower alkyl, more preferably hydrogen or methyl;

R5, R6, R7, R8, R9and R10- each preferably hydrogen; and

all dotted lines represent simple relationships.

Preferred substances according to this aspect of the present invention are: 3-hydroxy-3-phenylethynyl-17-methoxy-5-androstane; 3-hydroxy-3-phenylethynyl-17-methoxy-5-androstane; 3-hydroxy-3-(3', 4'-acid)ethinyl-17-methoxy-5-androstane; 3-hydroxy-3(4'-were)ethinyl-17-methoxy-5-androstane; 3-hydroxy-3(2'-methoxyphenyl)ethinyl-17-methoxy-5-androstane; ethyl ester of 3-hydroxy-3(4'-carboxyphenyl)ethinyl-17-methoxy-5-androstane; 3-hydroxy-3(4'-acetoxyacetyl))ethinyl-17-methoxy-5-androstane; 3(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3(4'-dimethylaminophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3(4'-biphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3 is-5-androstane; 3(4'-triptoreline)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3(4'-chlorophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3(4'-cyanophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane;3(4'(R/S)-hydroxypentanal)-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-phenyl-17-methoxy-5-androstane; 3-hydroxy-3-benzyl-17-methoxy-5-androstane;3-hydroxy-3-(2'-phenylethyl)-17-methoxy-5-androstane; 3-hydroxy-3-[2-(3', 4'-acid)ethyl]-17-methoxy-5-androstane; 3-hydroxy-3-[6'-oxo-1'-heptenyl]-17-methoxy-5-androstane;

3-hydroxy-3-(7'-oxo-1'-octenyl)-17-methoxy-5-androstane; 3-hydroxy-3-(4'-oxo-1'-pentenyl)-17-methoxy-5-androstane; 3-[5'-(R/S)-hydroxyhexyl] -3-hydroxy-17-methoxy-5-androstane; 3-(4'-hydroxybutyl)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-hydroxybutyl)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetoxyphenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetylphenylalanine)-3-hydroxy-19-nor-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxypentyl)-3-hydroxy-19-nor-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxypentyl)-3-hydroxy-17-methoxy-5-androstane; 3-[4'-(N,N-diethylcarbamyl)phenyl] ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-[5-oxo-1-hexenyl] -17-methoxy-5-androstane; 3-hydroxy-3-[5'-oxo-1'-hexenyl]-17-methoxy-5-androstanolone 5'-(1,2-atendee the Academy of Sciences; 3-(6-hydroxy-1-hexenyl)-3-hydroxy-17-methoxy-5-androstane; sodium

Sol'-hemisuccinate-(6'-hydroxy-1'-hexenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(5'-hydroxy-1'-pentenyl)-3-hydroxy-17-methoxy-5-androstane; sodium salt of 5'-hemisuccinate 3-(5'-hydroxy-1'-pentenyl)-3-hydroxy-17-methoxy-5-androstane; sodium salt of 4'-hemisuccinate 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-cyano-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(5'-acetoxy-1'-pentenyl)-3-hydroxy-17-methoxy-5-androstane;3-(4'-acetoxy-1'-butenyl)-3-hydroxy-177-methoxy-5-androstane; 3-(4'-acetoxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(6'-acetoxy-1'-hexenyl)-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-[3-(2'-propenyloxy)-1-PROPYNYL] -17-methoxy-5-androstane; 3-hydroxy-3-(3-methoxy-1-PROPYNYL] -17-methoxy-5-androstane; 3-hydroxy-3-(3-methoxy-1-PROPYNYL]-17-methoxy-5-androstane; 3-hydroxy-3-[3-(4'-pyridyloxy)-1-PROPYNYL] -17-methoxy-5-androstane; 3-hydroxy-3-[3-(1 N-1,2,3-triazole-1'-yl)-1-PROPYNYL] -17-methoxy-5-androstane; 3-hydroxy-3-[3-(2 N-1,2,3-triazole-2'-yl)-1-PROPYNYL]-17-methoxy-5-androstane; 3-hydroxy-3-(2'-thienyl)ethinyl-17-methoxy-5-androstane; 3-hydroxy-3-(3'-phenyl-1'-PROPYNYL)-17-methoxy-5-androstane; 3-hydroxy-3-(3'-phenylpropyl)-17-methoxy-5-androstane;

3-hydroxy-3-[3-(1 N-pyrazole-1'-yl)-1-penyl)-3-hydroxy-17-methoxy-5-androstane.

More preferred neuroactive steroids according to this aspect of the present invention are 3-(4'-

acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-19-norandrosterone; ethyl ester of 3-(4'-carboxylphenyl)ethinyl-3-hydroxy-17-methoxy-5-19-norandrosterone;

3-(4'-dimethylaminophenyl)ethinyl-17-methoxy-5-androstane; 3-(4'-biphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-(4'-methoxyphenyl)ethinyl-17-methoxy-5-androstane; 3-(4'-triptoreline)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-chlorophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-[4'(R/S)-hydroxypentanal] -3-hydroxy-17-methoxy-5-androstane; 3-(4'-hydroxybutyl)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-hydroxybutyl)-3-hydroxy-17-methoxy-5-androstane and 3-hydroxy-3-[3-(2 N-1,2,3-triazole-2'-yl)-1-PROPYNYL] -17-methoxy-5-androstane.

Especially preferred neuroactive steroids on this aspect of the present invention are 3-(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-is droxi-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxyphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-dimethylaminophenyl)ethinyl-17-methoxy-5-androstane; 3-(4'-biphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-hydroxybutyl)-3-hydroxy-17-methoxy-5-androstane;

3-(4'-

hydroxybutyl)-3-hydroxy-17-methoxy-5-androstane;3-hydroxy-3-[3-(2 N-1,2,3-triazole-2'-yl)-1-PROPYNYL] -17-methoxy-5-androstane; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-19-norandrosterone and 3-[4'(R/S)-hydroxypentanal]-3-hydroxy-17-methoxy-5-androstane.

Derivatives of 3-hydroxyandrost

The second preferred subgenus of the substances according to the present invention contains 3-hydroxy-derivatives of androstane, which are not substituted in position 17 of the steroid cyclic system, that is, R3represents hydrogen. Steroid derivatives according to this aspect of the present invention include those having the structural Formula I as shown above, where

R3is hydrogen; and R, R1, R2, R4, R5, R6, R7, R8, R9and R10as defined above for Option 1A;

provided that:

R1is not hydrogen, alkyl or lanakila.

Preferred values for R, R1, R2, R

Derivatives 21-substituted 3-hydroxypropane

The third category of useful compounds according to the present invention, contains derivatives of 3-hydroxypropane, which contain 21 essential or 21-thioester, or 21-alkyl, 21-alkanniny or 21-alkynylaryl deputies. Compounds that can be used according to this aspect of the present invention, include those having the structural Formula I above, where

R, R1, R2, R4, R5, R6, R7, R8, R9and R10defined above for Formula I;

R3IS-C(O)-CH2-Y-G-C(O)-CH2-O-D, -C(O)-CH2-O-E, -C(O)-CH2-Y'-Z-G, -C(O)-CH2-Y'-Z-A;

Y is S, SO or SO2;

Y' is S, SO or SO2;

Z - alkyl, alkenyl or quinil;

G - heteroaryl attached to the carbon atom, optionally substituted aryl, salt of the Quaternary ammonium nitrogen-containing heteroaryl group, or a salt of the Quaternary ammonium aminosilanes aryl group;

D - heteroaryl attached to the carbon atom, or a salt of the Quaternary ammonium nitrogen-containing heteroaryl group;

E is optionally substituted aryl or salt of Quaternary ammonium aminosilanes aryl group;

And Amin is xygraph, hydrogen, sulfate, thiosulfate, sulfonate, allylthiourea, alkylsulfanyl, alkylsulfonyl or mercaptopropyl;

provided that

when R3IS-C(O)-CH2-Y-G and G - heteroaryl attached to the carbon atom, or optionally substituted aryl, R1different from hydrogen or alkyl; or

when R3- - (O)-CH2-O-S, R1different from hydrogen; or

when R3IS-C(O)-CH2-Y'-Z-G, and Y', and G is aryl, R1different from hydrogen; or

when R3IS-C(O)-CH2-Y'-Z-G, and Y' IS S, SO or SO2and G is aryl, R1different from hydrogen or alkyl; or

when R3IS-C(O)-CH2-Y'-Z-A, and Y'Is Oh and a is hydrogen, halogen, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino group, R1different from hydrogen; or

when R3IS-C(O)-CH2-Y'-Z-A, and Y' IS S, SO or SO2and A - hydrogen, halogen, carboxyl, alkoxycarbonyl or amino group, R1different from hydrogen or alkyl.

Alternative R3may also be-C(O)-CH2-Z-G, where Z and G are defined above, provided that when R3IS-C(O)-CH2-Z-G, R1different from hydrogen.

When D or G - heteroaryl attached to the carbon atom, heteroaryl structure preferably is benzimidazolyl and ethenolysis.

When F or G is substituted aryl, preferred groups are phenyl substituted one, two or three, most preferably one, nitro-, amino-, dimethylaminopropoxy, carboxyla, stands, hydroxyl, methoxy group, fluorine, chlorine, bromine, cyano or pyrrolidinium.

Examples of suitable values for substituents which may be applicable in the R3in this aspect of the invention, represent-COCH2S-(4-PhNH2), THE PINES2O-(4-hN+IU3)l--THE PINES2O-4-pyridyl, -PINES2O-3-pyridyl, -PINES2S-(4-pyridyl)-N-methyliodide, the PINES2S2CH2HE, -COCH2OCH2CH2OH, -COCH2SCH2CH2CH2OH, THE PINES2S2CH2CH2HE, -COCH2SO2CH2CH2CH2OH,

-COCH2SCH2COO-Na+, -COCH2SCH2CH2COO-Na+, -COCH2SCH2CH2OSO3-TMA+(TMA - abbreviation trimethylammonium), -COCH2SCH2CH2CH2OSO3-Na+, -COCH2SCH2CH2SO3-Na+, -COCH2SCH2CH2CH2SO3-Na+, -COCH2SO2CH2CH2<2">

Additional suitable values represent-COCH2S-(4-forfinal), the PINES2O-(6-chinoline), the PINES2SO2-(4-forfinal), -COCH2SO2-(4-pyrrolidinyl), the PINES2CH2-(4-pyridyl)- the PINES2O-(4-nitrophenyl)- the PINES2O-(4-dimethylaminophenyl), the PINES2SO-(4-nitrophenyl)- COCH2SO2-(4-nitrophenyl).

Preferred compounds according to this aspect of the present invention are: 3-hydroxy-3-(4-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-21-(pyrid-4-yloxy)-5-pregnan-20-he; sodium salt of 3-hydroxy-2-propoxy-21-thiopropionate-5'-pregnan-20-it; 3-ethinyl-3-hydroxy-21-(3'-hydroxypropylamino)-5-pregnan-20-he; sodium salt of 3-ethinyl-3-hydroxy-21-(thiopropionate)-5-pregnan-20-it; 3-hydroxy-2-propoxy-21-(pyrid-4-ylthio)-5-pregnan-20-he-N-methyliodide; 3-hydroxy-21-(2'-hydroxyethylthio)-5-pregnan-20-he; 3-ethinyl-3-hydroxy-21-(2'-hydroxyethylthio)-5-pregnan-20-he; 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he-N-methyliodide; 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he-N-methyliodide; trimethylammonio salt of 3-ethinyl-3-hydroxy-21-titansilver-5-pregnan-20-it; 3-hydroxy-3-methoxymethyl-21-(pyrid-

4 ylthio)-5-pregnan-20-he; 21-(4'-aminophenylthio)-3-hydroxy-3-metoxi the-21-(4'-nitrophenylthio)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-he; 21-(4'-dimethylaminoethoxy)-3-hydroxy-3-methyl-5-pregnen-20-he; 3-hydroxy-3-methyl-21-(4'-nitrophenoxy)-5-pregnan-20-he; iodide 3-hydroxy-3-methyl-21-(4'-trimethylammonio)-5-pregnan-20-it; sodium salt of 3-ethinyl-3-hydroxy-21-thiopropionate-5-pregnan-20-it; 3-ethinyl-3-hydroxy-21-(3'-hydroxypropanesulfonic))-5-pregnan-20-he; 3-hydroxy-21-(3'-hydroxypropylamino)-2-propoxy-5-pregnan-20-he; 3-hydroxy-21-(3'-hydroxypropanesulfonic)-2-propoxy-5-pregnan-20-he; sodium salt of 3-hydroxy-2-propoxy-21-sulfonylureatolerant-5-pregnan-20-she; 21-(4'-forfinally)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he; 3-ethinyl-3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; iodide 3-hydroxy-2-propoxy-21-(4'-N,N, N-trimethylammoniumphenyl)-5-pregnan-20-it; 3-hydroxy-3-methyl-21-(4'-quinoline-6-yloxy)-5-pregnan-20-he-N-methyliodide;3-hydroxy-3-methyl-21-(4'-quinoline-6-yloxy)-5-pregnan-20-he; 21-(4'-forfinal)sulfonyl-3-hydroxy-3-methoxymethyl-5-pregnan-20-he and 3-hydroxy-3-methoxymethyl-21-(4'-pyrrolidinyl)sulfonyl-5-pregnan-20-he.

More preferred neuroactive steroids according to the-4-ylthio)-5-pregnan-20-he; 3-hydroxy-21-(pyrid-4-yloxy)-5-pregnan-20-he; sodium salt of 3-hydroxy-2-propoxy-21 - thiopropionate - 5-pregnan-20-it; 3-ethinyl-3-hydroxy-21-(3'-hydroxypropylamino)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-he; 3-hydroxy-3-methyl-21-(4'-nitrophenoxy)-5-pregnan-20-he;3-hydroxy-21-(3'-hydroxypropylamino)-2-propoxy-5-pregnan-20-he;3-hydroxy-21-(3'-hydroxypropanesulfonic)-2-propoxy-5-pregnan-20-he and the sodium salt of 3-hydroxy-2-propoxy-21-sulfonylureatolerant-5-pregnan-20-it.

Especially preferred neuroactive steroids according to this aspect of the present invention are: 3-hydroxy-3-(4-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-21-(3'-hydroxypropanesulfonic)-2-propoxy-5-pregnan-20-one-hydroxy-21-(pyrid-4-yloxy)-5-pregnan-20-he.

Diastereoisomer

For professionals it is obvious that the above compounds can be present as mixtures of diastereoisomers, which can be divided into individual diastereoisomer. Division diastereoisomerism not otherwise stated, the links in the description and the claims is meant that the compounds presented in the invention, as discussed above, include all isomers, as separated, and mixtures thereof.

When isomers are separated, the desired pharmacological activity often will prevail in one of diastereoisomers. As here shown, these compounds show a high level of stereospecificity. In particular, those compounds which have the greatest affinity for the complex of the GABA receptor, are compounds with steroid skeletons of 3-substituted-3-hydroxypropan.

Methods of synthesis of

The substances according to the invention can be obtained by any suitable means, for example, using known methods, such as described in Djerassi, Steroid reactions, Holden-Day, Inc., San Francisco (1963), or Fried and Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand-Reinhold Co., New York (1972).

C17-esters in the present invention, derived from 17-hydroxy compounds by methods well known in the art to obtain the esters of the corresponding alcohols. Most of these methods are described in Larock, Comprehensive Organic Transformations VCH Publishers, New York (1989). 17-hydroxy-source materials well known in the art. It is desirable to protect 3-katoh is reattaching the C17-ether and hydrolysis of ketala get 3-keto-17-ether compounds. Various nucleophiles can be added to 3-ONU of these compounds for the preparation of 3-substituted-3-hydroxy-17-ether derivatives.

Another way to get C17-ester is a reaction C17-ketals derived from the corresponding 17-ones, with sociallyengaged and ll3as described by Cross et al., Steroids 5:557 (1965).

Phenylethylene substituents can be obtained by catalyzed by palladium (Pd) linking relevant etinilnoy derivatives with vinylidene or phenylpropene in the presence of amine.

All C21-bromides used in the examples as starting materials were prepared by the method used to obtain a-bromo-ketones from methylketones. This method is well known to specialists.

Pharmaceutical application

The compounds presented in the invention and used in it, being non-toxic, pharmaceutically acceptable, natural and synthetic, are directly applicable and proletarienne" forms are unknown to date activity in the brain in relation to complex receptor GABAA. The present invention takes advantage of this, previously unknown, the milling is known dosage forms through the introduction of active compounds, in the present invention, or a mixture of such substances, non-toxic pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to obtain the desired pharmacodynamic activity in the object, animal or person. Preferably the composition contains the active ingredient in an active but nontoxic amount selected from a range from approximately 1 mg to approximately 500 mg of the active ingredient on a standardized dose. This number depends on the desired specific biological activity and condition of the patient.

Applied pharmaceutical carrier may be, for example, either solid, liquid or delayed allocation (see Remington''s Pharmaceutical Sciences, 14th Edition (1970)). Representatives of solid carriers are lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum, magnesium stearate, stearic acid, microcrystalline cellulose, polymeric hydrogels, etc., a Typical liquid media are propylene glycol, glycoluril, aqueous solutions of cyclodextrins, syrup, peanut butter and olive oil, and the like emulsion. Similarly, the carrier or diluent may include any material with decreasing the do with wax, the microcapsules, microspheres, liposomes, and/or hydrogels.

Can be used in a wide range of pharmaceutical forms. So, when using solid media, the drug can be raw, powdered, micronized contained in the oil, tableted, placed in a hard gelatin capsule or the capsule shell for oral administration in micronized powder or in pill form or in the form of a tablet or pellet. The compounds presented in this invention can also be applied in the form of suppositories for rectal administration. The compounds can be mixed with materials such as cocoa butter and polyethylene glycols, or other suitable non-irritating material, solid at room temperature, but liquid at rectal temperature. When using a liquid medium, the drug can be in the form of a liquid, as liquid form or as an aqueous or nonaqueous liquid suspension. Liquid dosage forms also need pharmaceutically acceptable preservatives. In addition, due to the fact that it requires a low dose, as substantiated data presented here, parenteral, nasal spray, sublingual and protection forms for local use.

Method of inducing anti-anxiety, anticonvulsant, mood-altering (such as antidepressant or hypnotic activity, in accordance with the present invention, provides for the introduction of the object in need of such activity, the compounds presented in the invention is usually prepared in the preparation, as described above, in combination with a pharmaceutical carrier, in a nontoxic amount sufficient to obtain the specified action.

During menstruation, the levels of secreted metabolites of progesterone change approximately four times (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986). Thus, controlling the symptoms therapy involves keeping the patient has elevated levels of metabolites of progesterone, compared with normal pre-menstrual status in patients with PMS. The levels of active and major metabolites in plasma observed during the pre-menstrual and post-menstrual periods in a patient. The number of input connections presented in the invention, both separately and as mixtures thereof, calculated in such a way as to reach the level that gives the activity of GABAA-the receptor is equal to or greater than the level metabolite maintain substantially level REM-sleep, found in normal sleep, when not induced significant reactive insomnia, in accordance with the present invention, provides for the introduction of requiring such activity to the subject effective amounts described herein steroid derivative. The compounds presented in the invention can increase the period of NREM-sleep and total sleep time, without affecting significantly the duration of REM-sleep. Reactive insomnia is defined as a reduction of NREM-sleep after widespread effects of treatment returned to control levels. Methods of evaluating the effects of the compounds presented in the invention, REM - and NREM-sleep presented in WO94/27608, published on December 8, 1994, the contents of which are fully included here by reference.

The method of administration may be any method that efficiently delivers an active connection to the receptors GABAAsubject stimulation. The introduction can be carried out parenterally, orally, rectally, vnutrivaginalno, intracutaneous, intramuscular, sublingual, or nasal; preferred are oral, intramuscular and transdermal methods. For example, one dose in skin patch can deliver activetitle.

The following examples illustrate but do not limit, the method and products of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters that occur usually obvious to the experts, are within this invention.

Example 1

3-hydroxy-17-methoxy-3-(3'-methylbut-3'-EN-1'-inyl)-5-androstane

A solution of 2-methyl-1-butene-3-in (150 mg, of 0.21 ml, 2.25 mmol) in dry THF (tetrahydrofuran) (20 ml) is treated with n-BuLi (2.5 M in THF, 2.25 mmol, 0.9 ml) at -70oC. After stirring the mixture at a temperature of -75oC for 0.5 h add a solution of 17-methoxy-5-androstane-3-one (228 mg, 0.75 mmol) in THF (20 ml) and the mixture is stirred at a temperature of -78oC for 30 minutes the Cooling bath removed and the mixture is quenched with a solution of NH4Cl (2 ml). The solvent is removed and the residue extracted with tO. The organic layer is washed with water and then brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane: acetone (9: 1) gives 3-hydroxy-17-methoxy-3-(3'-methylbut-3'-EN-1'-inyl)-5-androstane as a colourless solid p is hydroxy-17-methoxy-5-androstane 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane

A solution of 3-butyn-1-ol (0,114 ml, 1.5 mmol) in dry THF (15 ml) is treated with n-BuLi (1.2 ml, 2.5 M in THF, 3 mmol) at -75oC. After stirring the mixture at a temperature of -78oC for 0.5 h add a solution of 17-methoxy-5-androstane-3-one (152 mg, 0.5 mmol) in THF (20 ml) and the mixture is stirred at a temperature of -78oC for 30 minutes the Cooling bath is removed and stirring is continued at room temperature for 45 minutes the Mixture was then quenched with a solution of NH4Cl (5 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene:acetone (4:1) gives 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane (20 mg) and then 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane (70 mg) as a colourless solid product; So pl. 132-134oWITH TCX-Rf(toluene:acetone 4:1)=0,19.

Example 3

4'-hemisuccinate 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane and its sodium salt

A solution of 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane (350 mg). The mixture is heated to 70-75oC for 3 hours TLC shows 100% conversion. The mixture is cooled to room temperature and poured into ice-cold 2N HCl. The organic residue was extracted with tO. The organic layer is washed with 0.2 N HCl, water and brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane: acetone (7:3) gives 4'-hemisuccinate 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane (360 mg).

A mixture of the above hemisuccinate (360 mg, from 0.76 mmol), NaHCO3(64 mg, from 0.76 mmol), water (3 ml) and CH2Cl2(5 ml) is mixed at room temperature for 1 hour. The solvent is removed and the residue is suspended in acetone (5 ml). Then filtering obtain a white solid product, and dried to obtain sodium salt in the form of a colourless solid (210 mg).

Example 4

3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane

A solution of 3-butyn-1-ol (0.15 ml, 2 mmol) in dry THF (15 ml) is treated with n-uLi (1.6 ml, 2.5 M in THF, 4 mmol) at -75oC. After stirring the pH (20 ml) and the mixture is stirred at a temperature of -78oC for 5 minutes the Cooling bath is removed and stirring is continued at room temperature for 45 minutes the Mixture was then quenched with a solution of NH4Cl (5 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and then brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene:acetone (4:1) gives 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane (50 mg); So pl. 184-186oWITH TLC-Rf(toluene: acetone 4:1)=0,35; and then 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane (225 mg) as a colourless solid product; So pl. 185-187oWITH TCX-Rf(toluene: acetone 4:1)=0,24.

Example 5

3-hydroxy-17-methoxy-3-methyl-5-androstane and 3-hydroxy-17-methoxy-3-methyl-5-androstane

A solution of 17-methoxy-5-androstane-3-one (101 mg, 0.33 mmol) in dry THF (20 ml) is treated with MeLi (1 ml, 1.5 M in THF, 1.5 mmol) at -75oC. After stirring the mixture at -78oC for 0.5 h the mixture was quenched with a solution of NH4Cl (5 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and then soleares then dissolved in a small amount of CH2CL2and put on a column of silica gel. Elution with a mixture of toluene: acetone (95: 5) gives 3-methyl-3-hydroxy-17-methoxy-5-androstane (35 mg); So pl. 151-154oWITH TLC-Rf(hexane:acetone 7:3)=0,43; and then 3-methyl-3-hydroxy-17-methoxy-5-androstane (30 mg) as a colourless solid; TCX-Rf(hexane:acetone 7:3)=0,27.

Example 6

3-hydroxy-17-methoxy-3-trifluoromethyl-5-androstane and 3-hydroxy-17-methoxy-3-trifluoromethyl-5-androstane

A solution of 17-methoxy-5-androstane-3-one (220 mg, 0.75 mmol) in dry THF (20 ml) is treated with triftoratsetilatsetonom (3 ml, 0.5 M in THF, 1.5 mmol) and tetrabutylammonium fluoride (TBAF) (10 mg) inoC. After stirring the mixture at 23oC for 2 h the mixture was re-cooled to 0oC. the Mixture is stirred at room temperature for 10 min, then quenched with a solution of NH4Cl (5 ml). The solvent was removed and the residue extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of hexane: ethyl acetate (9:1) gives 3-trifluoromethyl-3-hydroxy-17-methoxy-5-androstane the aqueous solid product; TCX-Rf(hexane: EtOAc 8:2)=0,45.

Example 7

3-hydroxy-17-methoxy-3-trifluoromethyl-5-androstane

A solution of 17-methoxy-5-androstane-3-one (304 mg, 1 mmol) in dry THF (20 ml) is treated with triftoratsetilatsetonom (7 ml, 0.5 M in THF, 3.5 mmol) and TBAF (10 mg) at 0oC. After stirring the mixture at 23oC for 2 h the mixture was re-cooled to 0oC. Add a solution TBAF (1M in THF, 3.5 ml, 3.5 mmol). The mixture is stirred at room

temperature for 10 min and then quenched with a solution of NH4Cl (5 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of hexane: ethyl acetate (9:1) gives 3-trifluoromethyl-3-hydroxy-17-methoxy-5-androstane (220 mg); So pl. 122-127oWITH TCX-Rf(hexane: tO 8:2)=0,38.

Example 8

3-hydroxy-17-methoxy-5-androstane

A solution of 17-methoxy-5-androstane-3-one (130 mg, 0.42 mmol) in dry THF (15 ml) is treated with a hydride Lititz(tert-butoxy)aluminum (1 ml, 1M in THF, 1 mmol) at -73oC. After stirring the MCA is if removed, and the residue is extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene: acetone (9:1) gives 3-hydroxy-17-methoxy-5-androstane (107 mg); So pl. 151-156oWITH TCX-Rf(hexane:acetone 7:3)=0,18.

Example 9

17-(2-propenyloxy)-5-androstane-3-one

A solution of cyclic 3-(1,2-candirectly) 17-hydroxy-5-androstane-3-one (of 1.03 g, 3 mmol) in dry THF (20 ml) is treated with KOt-Bu (12 ml, 1M in THF, 12 mmol) at 23oC. After stirring the mixture at 55oC for 2.5 hours, it is cooled to -50oC. Add propylbromide (80% solution in toluene, 1.3 ml, 11 mmol) and continue stirring at 50-55oC for 2.5 hours, the Solvent removed and the residue is treated with acetone (25 ml). After acidification of the mixture of 2N HCl it is stirred at room temperature for 15 hours, the Mixture is neutralized 2N NaOH solution. The solvent was removed and the residue extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting the cheese is SIA a mixture of hexane:acetone (8:2) to give 17-(2-propenyloxy)-5-androstane-3-one (700 mg).

Example 10

3-hydroxy-3-methyl-17-(2-propenyloxy)-5-androstane-methyl-17-(2-propenyloxy)-5-androstane

A solution of 17-(2-propenyloxy)-5-androstane-3-one (230 mg, 0.7 mmol) in dry THF (20 ml) is treated with MeLi (5 ml, 1 M in THF, 5 mmol) at -70oC. After stirring the mixture at -70oC for 0.5 h the cooling bath removed and the mixture is heated to 10oC. the Mixture was then quenched with a solution of NH4Cl (5 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene: acetone (98: 2) gives 3-hydroxy-3-methyl-17-(2-propenyloxy)-5-androstane (40 mg); TCX-Rf(toluene: acetone 95:5)=0,31; and then 3-methyl-17-(2-propenyloxy)-5-androstane (70 mg) as a colourless solid; TCX-Rf(hexane:acetone 7:3)=0,27.

Example 11

17-[3-(4-acetylphenyl)-2-propenyloxy]-3-hydroxy-3-methyl-5-androstane

A solution of 4-iodoacetate (16 mg, 0.06 mmol), 3-hydroxy-3-methyl-17-(2-propenyloxy)-5-androstane (22 mg, 0.06 mmol) in dry the degassed triethylamine (1 ml) is stirred in an atmosphere OI temperature for 45 minutes Add CH2Cl2(4 ml) and the mixture was stirred at 23oC for 1 h When TLC shows 100% conversion of the starting material, the solvent is removed and the residue purified by chromatography on silica gel. Elution with hexane: acetone (85:15) to give 17-[3-(4-acetylphenyl)-2-propenyloxy] -3-hydroxy-3-methyl-5-androstane (19 mg) as a colourless solid precipitate; So pl. 52-55oWITH TLC-Rf(hexane:acetone 85:15)=0,15.

Example 12

17-(2-hydroxyethoxy)-3-hydroxy-5-androstane

The circular solution of 17-(1,2-candirectly) 3-hydroxy-5-androstane-17-she (166 mg, 0.5 mmol) in dry THF (10 ml) was treated with LAH (18 mg, 0.5 mmol) and ll3(266 mg, 2 mmol) at 23oC. After stirring the mixture at 45oC for 2 h in its quenched with a solution of NH4Cl (2 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with diluted HCl, water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane: acetone (8: 2) to give 17-(2-hydroxyethoxy)-3-hydroxy-5-androstane (123 mg); So pl. 181-183oWITH TCX-Rf(hexane:acetone 7:3)=0,31.

Primall (10 ml) is treated with n-BuLi (16.4 ml, 2.4 M in THF, to 39.4 mmol) at -75oC. After stirring the mixture at -78oC for 0.25 h add a solution of 17-methoxy-5-androstane-3-one (2 g, to 6.57 mmol) in THF (20 ml) and the mixture was stirred at -78oC for 15 minutes the Cooling bath is then removed and the mixture is quenched with a solution of NH4Cl (3 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene:acetone (95:5) gives 3-ethinyl-3-hydroxy-17-methoxy-5-androstane (1.70 g) as a colourless solid product; So pl. 62-65oWITH TCX-Rf(toluene:acetone 95:5)=0,23.

Example 14

3-(4'-acetylphenylalanine)-3-hydroxy-17-methoxy-5-androstane

A solution of 4-iodization (112 mg, 0.45 mmol) and 3-ethinyl-3-hydroxy-17-methoxy-5-androstane (155 mg, 0.45 mmol) in dry the degassed triethylamine (1 ml) is stirred under argon at 23oC. Add the chloride bis(triphenylphosphine)palladium (5 mg) and Cul (5 mg) and stirred the mixture at this temperature for 45 minutes Add CH2Cl2(5 ml) and the mixture was stirred at 23oWITH TCX-Rf(hexane:acetone 4:1)=0.31 in.

Example 15

3-ethinyl-3-hydroxy-17-methoxy-5-androstane and 3-ethinyl-3-hydroxy-17-methoxy-5-androstane

A solution of 1,2-dibromoethylene (1.7 ml, 21 mmol) in dry THF (25 ml) is treated with n-BuLi (16,8 ml, 2.5 M in THF, 42 mmol) at -65oC. After stirring the mixture at -70oC for 0.25 h add a solution of 17-methoxy-5-androstane-3-one (2,128 g, 7 mmol) in THF (22 ml) and the mixture was stirred at -78oC for 30 minutes the Cooling bath is then removed and the mixture is quenched with a solution of NH4Cl (3 ml). The solvent was removed and the residue extracted with tO. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene:acetone (95:5) gives 3-ethinyl-3-hydroxy-17-methoxy-5-androstane (100 mg) as a colourless solid product; So pl. 138-145oWITH TCX-Rf(hexane: acetone 7: 3)= 0,45; and then 3-ethinyl-3-hydroxy-17-methoxy-5-androstane (1.6 g) as a colourless TV is metilen (0.9 ml, 2.0 g, 10,85 mmol) in dry THF (10 ml) is treated with n-BuLi (9 ml, 2.4 M in THF, and 21.7 mmol) at -75oC. After stirring the mixture at -70oC for 0.25 h add a solution of 17-methoxy-19-nor-5-androstane-3-one (1 g, 3.62 mmol) in THF (20 ml) and the mixture was stirred at -78oFor 20 minutes the Cooling bath is then removed and the mixture is quenched with a solution of NH4CL (3 ml). The solvent was removed and the residue extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with a mixture of toluene: acetone (98: 2) gives 3-ethinyl-3-hydroxy-17-methoxy-19-nor-5-androstane (750 mg) as a colourless solid product; So pl. 152-154oWITH TCX-Rf(hexane:acetone 7:3)=0,58.

Example 17

3-(4'-acetylphenylalanine)-3-hydroxy-17-methoxy-19-nor-5-androstane

A solution of 4-iodization (117 mg, 0.47 mmol) and 3-ethinyl-3-hydroxy-17-methoxy-19-nor-5-androstane (150 mg, 0.47 mmol) in dry the degassed triethylamine (1 ml) is stirred under argon at 23oC. Add the chloride bis(triphenylphosphine)palladium (5 mg) and Cul (5 mg) and stirred the mixture at this temperature, which showed 100% conversion of starting material, the solvent is removed and the residue purified by chromatography on silica gel. Elution of toluene:acetone (95:5) gives 3-(4'-acetylphenylalanine)-3-hydroxy-17-methoxy-19-nor-5-androstane (105 mg) as a colourless solid product; So pl. 148-150oWITH TCX-Rf(hexane:acetone 4:1)=0,52.

Example 18

3-hydroxy-17-methoxy-3-trifluoromethyl-19-nor-5-androstane

A solution of 17-methoxy-19-nor-5-androstane-3-one (300 mg, of 1.08 mmol) in dry THF (15 ml) is treated with triftoratsetilatsetonom (5 ml, 0.5 M in THF, 2.5 mmol) and TBAF (5 mg) at 0oC. After stirring the mixture at 23oC for 2 h the mixture was again cooled to 0oC. Add a solution TBAF (1M in THF, 3.5 ml, 3.5 mmol). The mixture is stirred at room temperature and then quenched with a solution of NH4CL (5 ml). The solvent was removed and the residue extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane:acetone (9:1) gives 3-hydroxy-17-methoxy-3-trifluoromethyl-19-nor-5-androstane (210 mg); So pl. 40-42oWITH TCX-Rf(hexane:acetone 7:3)=0,66.

Example 19

3(R)-thought) in dry THF (40 ml) is stirred under reflux for 2 hours After cooling to room temperature, add 17-methoxy-5-androstane-3-one (UAH 2.432 g, 8 mmol) and the mixture is stirred at this temperature for 3 hours Then quenched with water (5 ml). The solvent was removed and the residue extracted with EtOAc. The organic layer is washed with diluted HCl, water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, receiving raw 3(R)-Spiro-2'-oxiran-17-methoxy-5-androstane (2.5 g). This raw then used for the next stage.

Example 20

3-hydroxy-17-methoxy-3-(2-PROPYNYL)-5-androstane

A solution of crude 3(R)-Spiro-2'-oxiran-17-methoxy-5-androstane (318 mg, 1 mmol) and complex litigation EDA (95%, 485 mg, 5 mmol) in DMSO (10 ml) was stirred at room temperature for 15 hours Then quenched with water (30 ml) and extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then

dissolve in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane: acetone (8: 2) gives 3-hydroxy-17-methoxy-3-(2-PROPYNYL)-5-androstane (200 mg); So pl. 145-150oWITH TCX-Rf(hexane:acetone 7: 3)=0,6.

Example 21

8 mg, 1 mmol) and sodium (29 mg, 1.3 mmol) in Meon (10 ml) is heated under reflux for 2.5 h Then quenched with water (1 ml). The solvents were removed and the residue extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane:acetone (8:2) gives 3-hydroxy-17-methoxy-3-methoxymethyl-5-androstane (230 mg); So pl. 93-99oWITH TCX-Rf(hexane:acetone 7:3)=0,56.

Example 22

3-chloromethyl-3-hydroxy-17-methoxy-5-androstane

A solution of crude 3(R)-Spiro-2'-oxiran-17-methoxy-5-androstane (318 mg, 1 mmol), chloride of Tetramethylammonium (166 mg, 1.5 mmol) and acetic acid (0.5 ml) in DMF (dimethylformamide) (10 ml) was stirred at 90-95oC for 2.5 hours It is cooled to room temperature and then quenched with water (25 ml). After neutralization with 2N NaOH, the mixture is extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel is-Rf(hexane:acetone 8:2)=0,26.

Example 23

3-ethynyl-3-hydroxy-17-methoxy-5-androstane

The iodide solution trimethylsilane (632 g, 3.1 mmol) in dry THF (10 ml) is treated with n-BuLi (2.5 M in THF, 3 mmol, 1.2 ml) at -5oC. After stirring the mixture at 0oC for 0.5 h add a solution of 3(R)-Spiro-2'-oxiran-17-methoxy-5-androstane (318 mg, 1 mmol) in THF (10 ml). The cooling bath is removed and the mixture is stirred at room temperature for 2 hours the mixture is Then quenched with a solution of NH4Cl (2 ml). The solvent was removed and the residue extracted with EtOAc. The organic layer is washed with water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica gel. Elution with hexane:acetone (7:3) gives 3-ethinyl-3-hydroxy-17-methoxy-5-androstane (220 mg) as a colourless solid product; So pl. 104 to 111oWITH TCX-Rf(hexane:acetone 7:3)=0,5.

Example 24

3-hydroxy-2-isopropoxy-17-methoxy-5-androstane

A solution of 17-dimethylacetal 3-hydroxy-2-isopropoxy-5-androstane-17-she (prepared by opening the epoxy group, 2,3-epoxy-5-androstane-17-she isopropoxide with the last mmol) at -30oC. After stirring the mixture at 23oC for 1 h in its quenched with a solution of NH4Cl (2 ml). The solvent was removed and the residue extracted with EtOAc. The organic layer is washed with diluted HCl, water and brine. After drying over anhydrous gSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2CL2and put on a column of silica gel. Elution with hexane:acetone (9:1) gives 3-hydroxy-2-isopropoxy-17-methoxy-5-androstane (43 mg) as a foam; TCX-Rf(hexane:acetone 7:3)=0,41.

Example 25

3-hydroxy-3-(4-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-he

A solution of 21-bromo-3-hydroxy-3-(4-hydroxybutyl)-5-pregnan-20-she (230 mg, 0,494 mmol), 4-mercaptopyridine 90% (77 mg, 0,618 mmol) and triethylamine (86 μl, 0,618 mmol) in 10 ml of acetonitrile was stirred at K. T. for 3 h the Mixture was distributed between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried with Na2SO4and concentrate under vacuum. Raw is subjected to chromatography on evaporative column. Elution with 35-50% acetone in CH2Cl2results 3-hydroxy-3-(4-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-she (196 mg) as a yellow foam. TCX-RfoWITH TLC-Rf(hexane:EtOAc 1:1)=0,11;

3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; So pl. 154-156oWITH TLC-Rf(CH2Cl2:acetone 4:1)=0,18;

3-hydroxy-3-methoxymethyl-21-(pyrid-4-ylthio)-5-pregnan-20-he;

21-(4'-aminophenylthio)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he; So pl. 150-156oWITH TLC-Rf(hexane:EtOAc 3:1)=0,045;

3-hydroxy-3-methoxymethyl-21-(4'-nitrophenylthio)-5-pregnan-20-he; TCX-Rf(hexane:EtOAc 3:1)=0,17;

21-(4'-forfinally)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he; TCX-Rf(hexane:acetone 85:15)=0,25;

3-ethinyl-3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; TCX-Rf(hexane:EtOAc 1:1)=0.26 and

3-(4'-acetylphenyl)ethinyl-3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; TCX-Rf(hexane:EtOAc 2:1)=0,15.

Example 26

N-methyliodide 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-it

A solution of 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-she (62 mg, 0,145 mmol) and 1 ml under the conditions in 5 ml of EtOAc heated under reflux for several hours until the end of the reaction, confirmed by TLC. The mixture was then cooled to room temperature and concentrate under vacuum to education raw. The residue is ground to powder with ether and dried under vacuum to obtain N-under the conditions of 3-hydroxy-21-(pyrid-4-iltaasi-21-(pyrid-4-ylthio)-5-pregnan-20-it

A solution of 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-she (29 mg, 0,068 mmol) and 100 µl under the conditions in 5 ml of THF is heated under reflux. After 15 minutes, the precipitated solid product and the reflux continued for several hours. The mixture is cooled to room temperature and allow the excess to evaporate under the conditions. The solid product is filtered, washed with cold THF, resulting in an N-under the conditions of 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-it is in the form of a solid light orange color.

Example 28

N-methyliodide 3-hydroxy-2-propoxy-21-(pyrid-4-ylthio)-5-pregnan-20-it

A solution of 3-hydroxy-2-propoxy-21-(pyrid-4-ylthio)-5-pregnan-20-she (50 mg, 0,103 mmol) and 130 μl under the conditions in 5 ml of THF is heated under reflux for several hours until the end of the reaction is not confirmed by TLC. The mixture was then cooled to room temperature and concentrate under vacuum, resulting in an N-under the conditions of 3-hydroxy-2-propoxy-21-(pyrid-4-ylthio)-5-pregnan-20-she (64 mg) as a light yellow solid product.

Similarly, get:

iodid-hydroxy-3-methyl-21-(4'-trimethylammonio)-5-pregnan-20-it;

iodide 3-hydroxy-2-propoxy-21-(4'-N, N, N-the and.

Example 29

3-ethinyl-3-hydroxy-21-hydroxyethylthio-5-pregnan-20-he

A solution of 21-bromo-3-ethinyl-3-hydroxy-5-pregnan-20-she (150 mg, 0,356 mmol), 2-mercaptoethanol (31 μl, 0,445 mmol) and triethylamine (62 μl, 0,445 mmol) in 5 ml THF was stirred at room temperature overnight. The mixture was separated between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried PA2SO4and concentrate under vacuum, resulting in 3-ethinyl-3-hydroxy-21-hydroxyethylthio-5-pregnan-20-she (141 mg) as a white solid product; So pl. 122-126oWITH TCX-Rf(hexane: acetone 3:1)=0,11.

Similarly, get:

3-ethinyl-3-hydroxy-21-hydroxypropyl-5-pregnan-20-he; TLC Rf(hexane:acetone 3:1)=0,12;

3-hydroxy-21-hydroxypropyl-2-propoxy-5-pregnan-20-he; So pl. 133-136oWITH TCX-Rf(hexane:acetone 3:1)=0,175 and

3-hydroxy-21-hydroxyethylthio-5-pregnan-20-he; So pl. 150-152oC.

Example 30

Sodium salt of 3-ethinyl-3-hydroxy-21-titanat-5-pregnan-20-it

A solution of 21-bromo-3-ethinyl-3-hydroxy-5-pregnan-20-she (150 mg, 0,356 mmol), mercaptohexanol acid (31 μl, 0,445 mmol) and triethylamine (62 μl, 0,445 mmol) in 5 ml DMF was stirred at room temperature for several hours>O4and concentrate under vacuum to sediment. The residue is dissolved in 5 ml of CH2Cl2and add 1 EQ. sodium bicarbonate in 1 ml of water. The mixture is stirred for 30 min and then concentrated to dryness under high vacuum, resulting sodium salt of 3-ethinyl-3-hydroxy-21-titanat-5-pregnan-20-she (120 mg) as a white solid product; Different.>120oC.

Similarly, get:

sodium salt of 3-ethinyl-3-hydroxy-21-thiopropionate-5-pregnan-20-it;

sodium salt of 3-ethinyl-3-hydroxy-21-tibetanculture-5-pregnan-20-it; decomp.>85oWITH TCX-Rf(chloroform:methanol 4:1)=0,25;

retrieval-ethinyl-3-hydroxy-21-thiopropionate-5-pregnan-20-it; TCX-Rf(chloroform:methanol 4:1)=0.21 and

retrieval-hydroxy-2-propoxy-21-thiopropionate-5-pregnan-20-it; TCX-Rf(chloroform:methanol 85:15)=0,22.

Example 31

Trimethylammonium salt of 3-ethinyl-3-hydroxy-21-tibetanculture-5-pregnan-20-it

A solution of 3-ethinyl-3-hydroxy-21-hydroxyethylthio-5-pregnan-20-she (140 mg, 0,335 mmol), the complex of sulfur trioxide with trimethylamine (100 mg, 0,736 mmol) and a complex of sulfur trioxide with pyridine (50 mg) in 4 ml of chloroform was stirred at room temperature for but the evaporation column. Elution with a mixture of chloroform:methanol 85:15 leads to the production of the ammonium 3-ethinyl-3-hydroxy-21-tibetanculture-5-pregnan-20-she (69 mg) as a solid product; Different.>120oC.

Example 32

Retrieval-ethinyl-3-hydroxy-21-thiopropionate-5-pregnan-20-it

A solution of 3-ethinyl-3-hydroxy-21-hydroxypropyl-5-pregnan-20-she (50 mg, 0,115 mmol) and a complex of sulfur trioxide with trimethylamine (19 mg, 0,139 mmol) in 0.5 ml of pyridine was stirred at room temperature overnight. The mixture was diluted with chloroform and washed with 2N HCl, saturated aqueous NaCl, dried with Na2SO4and concentrate under vacuum to education raw. The residue is subjected to chromatography on evaporative column. Elution of chloroform:methanol 85: 15 leads to the production of sodium salt of 3-ethinyl-3-hydroxy-21-thiopropionate-5-pregnan-20-it (20 mg) as a solid product; TCX-Rf(chloroform:methanol 85:15)=0,12.

Similarly receive sodium salt of 3-hydroxy-2-propoxy-21-sulfonylureatolerant-5-pregnan-20-it; TCX-Rf(chloroform:methanol 85:15)=0,15.

Example 33

3-ethinyl-3-hydroxy-21-hydroxypropanesulfonic-5-pregnan-20-he

A suspension of 3-ethinyl-3-hydroxy-21-hydroxypropyl-5-pregnan-20-she (90 mg, 0,208 mm is Oh in the night. The mixture is concentrated to a small volume, and it is distributed in EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried with Na2SO4and concentrate under vacuum, resulting in 3-ethinyl-3-hydroxy-21-hydroxypropanesulfonic-5-pregnan-20-she (83 mg) as a foam; TCX-Rf(hexane:acetone 2:1)=0,035.

Similarly receive sodium salt of 3-hydroxy-2-propoxy-21-sulfonylureatolerant-5-pregnan-20-it.

Example 34

3-ethinyl-3-hydroxy-21-hydroxypropanesulfonic-5-pregnan-20-he

To a solution of 3-ethinyl-3-hydroxy-21-hydroxypropanesulfonic-5-pregnan-20-she (65 mg, 0,145 mmol), msrv 57-86% (42 mg) is added and the sodium bicarbonate solution (at the tip of a spatula) in 5 ml of CH2Cl2, the resulting mixture is stirred at a temperature of from 0oWith up to room during the night. The mixture was partitioned between CH2Cl2and aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous NaCl, dried with

Na2SO4and concentrate under vacuum to dry, resulting in 3-ethinyl-3-hydroxy-21-hydroxypropanesulfonic-5-pregnan-20-she (66 mg) as a white solid product; TCX-Rf(CH2CL2:acetone 1:1)=0,061.

Similarly receive the

Example 35

3-hydroxy-21-(pyrid-3-yl)oxy-5-pregnan-20-he

To a solution of 3-hydroxy-21-bromo-5-pregnan-20-she (300 mg, from 0.76 mmol) in DMF (5 ml) is added 3-hydroxypyridine (215 mg, of 2.27 mmol) and K2CO3(313 mg, of 2.27 mmol) and the resulting mixture was stirred at 25oC for 0.5 hours, the Reaction mixture is then poured into a separating funnel containing water (30 ml) and the mixture extracted with EtOAc (335 ml). The combined extracts washed with water (225 ml) and then dried with Na2SO4. Removal of the solvent under vacuum leads to the formation of raw sugar, which is purified by chromatography on evaporative column on silica gel, the result is pure 3-hydroxy-21-(pyrid-3-yl)oxy-5-pregnan-20-he (50 mg); So pl. 63-66oC; TCX-Rf(MeOH: CH2Cl25:95)=0,15.

Example 36

2 isopropoxy-3-hydroxy-5-androstane

A. 2 isopropoxy-3-hydroxy-5-androstane-17-one-tazelgettaze

To a mixture of 2-isopropoxy-3-hydroxy-5-androstane-17-she (700 mg, 2.0 mmol) and p-toluensulfonate (450 mg, 2.4 mmol) are added ethanol (2 ml) and the resulting mixture heated under reflux for 12 hours Then the reaction mixture was dissolved in CH2Cl2(150 ml) and washed with water (445 ml). Then it is dried with Na2SO4and UD is trasona (1,113 g), which is used without further purification for the next stage.

b. 2 isopropoxy-3-hydroxy-5-androstane

To a mixture of 2-isopropoxy-3-hydroxy-5-androstane-17-one-dailydata (300 mg), NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) is added DMF) and sulfolane (1: 1.3 ml) and the resulting mixture was heated to 110oC for 3 hours Then add an additional amount of NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) and heated for 1 h Then water is added and the mixture extracted with EtOAc (245 ml). The combined extracts are dried with Na2SO4and raw, obtained by removing the solvent, purified by chromatography on evaporative column on silica gel, resulting in a pure 2-isopropoxy-3-hydroxy-5-androstane (37 mg); TCX-Rf(EtOAc:hexane 1:9)= 0,17.

Example 37

3-hydroxy-5-19-norandrosterone

A. 3-hydroxy-5-19-norandrosterone-17-he

To a solution of 5-19-naranjestan-3,17-dione (0,76 g, 2.77 mmol) in THF (30 ml) at -78oTo add a solution of hydride Lititz(tert-butoxy)aluminum. The reaction mixture is then poured into a separating funnel containing a solution of NH4Cl (50 ml), and extracted with product EtOAc (350 ml). The combined extracts are dried with Na2SO4and remove Rasta silica gel to obtain pure 3-hydroxy-5-19-norandrosterone-17-she (605 mg); So pl. 159-161oC; TCX-Rf(hexane:acetone 7:3)=0,30.

b. 3-hydroxy-5-19-norandrosterone

To a mixture of 3-hydroxy-5-19-norandrosterone-17-she (0,59 g, 2,13 mmol) and p-toluensulfonate (480 mg, 2.6 mmol) are added ethanol (2 ml) and the resulting mixture heated under reflux for 5 hours Then the reaction mixture was dissolved in CH2Cl2(100 ml) and washed with water (230 ml). Then it is dried with a PA2SO4and removing the solvent under vacuum leads to the formation of raw material (1.0 g). This raw mix with NaBH3CN (555 mg) and p-toluenesulfonic acid (68 mg) and a mixture of DMF and sulfolane (1:1, 10 ml) and the resulting mixture is heated to 130oC for 2 hours Then add an additional amount of NaBH3CN (200 mg) and paratoluenesulfonyl acid (30 mg) and heated for 1 hour Then add water (80 ml) and the mixture extracted with EtOAc (350 ml). The combined extracts are dried with Na2SO4and raw, obtained by removing the solvent, purified by chromatography on evaporative column on silica gel, resulting in a pure 3-hydroxy-5-19-norandrosterone (217 mg); So pl. 129-132oC; TCX-Rf(EtOAc:hexane 1:9)=0,30.

Example 38

3-hydroxy-3-ethinyl-5-19-norandrosterone

A. 5-19-naranjestan-3-åmål) and RCA (520 mg, 2.4 mmol) and the resulting mixture was stirred at 25oC for 1 h Then the reaction mixture was filtered through a cake of Florisil (15 g) in a Buechner funnel, filled with a mixture of solvents: ether and CH2Cl2(1:1, 70 ml). The solvent is then removed under vacuum and the crude thus obtained, purified by chromatography on evaporative column on silica gel to obtain pure 5-19-naranjestan-3-one (190 mg); TCX-Rf(EtOAc:hexane 5:95)=0,20.

b. 3-hydroxy-3-ethinyl-5-19-norandrosterone

To a solution of 1,2-dibromoethylene (410 mg, 2.2 mmol) is added n-BuLi (2.5 M, 1.8 ml, 4.4 mmol) at -78oC and the reaction mixture is stirred at this temperature for 45 minutes Then added dropwise a solution of 5-19-naranjestan-3-one (190 mg, 0.73 mmol) in THF (10 ml) to the resulting lithium reagent. The reaction mixture is then poured into a separating funnel containing a solution of NH4Cl (50 ml), and extracted with product EtOAc (340 ml). The combined extracts are dried with Na2SO4and raw, obtained by removing the solvent, purified by chromatography on evaporative column on silica gel to obtain pure 3-hydroxy-3-ethinyl-5-19-norandrosterone (120 mg); So pl. 152-154oC; TCX-Rf(EtOAc:hexane 1:9)=0,19.

Example 39

3-GL), 4-iodization (115 mg, 0.46 mmol), chloride

bis(triphenylphosphine)palladium (II) (catalytic amount) and copper iodide (I) (catalytic amount) is added triethylamine (1.5 ml) and the resulting mixture stirred under argon for 45 min in a flask wrapped in aluminum foil. Then add CH2Cl2(5 ml) and the reaction mixture is stirred for 3 hours Then the solvent is removed under vacuum and the residue purified by chromatography on evaporative column on silica gel to obtain-hydroxy-3- (4'-acetylphenyl)ethinyl-5-19 - norandrosterone (37 mg); TCX-Rf(EtOAc:hexane 15:85)=0,2.

Example 40

3 isobutyryloxy-17-methoxy-5-androstane

A solution of 3-hydroxy-17-methoxy-5-androstane (250 mg, 0.82 mmol) in dry pyridine (2 ml) is treated with Isobutyraldehyde (0,12 ml, 1.15 mmol) and N, N-dimethylaminopyridine (5 mg) in 5oC. After stirring the mixture at 5-10oC for 1 h the mixture was quenched with a solution of HCl (0.5 N, 25 ml). The mixture is extracted with EtOAc. The organic layer is washed with diluted HCl, water and brine. After drying over anhydrous MgSO4the solution is filtered and evaporated, getting raw. This raw then dissolved in a small amount of CH2Cl2and put on a column of silica>
(hexane:acetone 9:1)=0,6.

Example 41

3-hydroxy-21-(pyrid-4-yloxy)-5-pregnan-20-he

A solution of 21-bromo-3-hydroxy-5-pregnan-20-she (500 mg, of 1.26 mmol), 4-hydroxypyridine (144 mg and 1.51 mmol) and triethylamine (200 μl) in 10 ml THF is heated under reflux for 4 hours the Mixture is cooled to room temperature, and it is distributed between EtOAc and water. The organic layer was washed with aqueous saturated NaCl, dried with gSO4and concentrate under vacuum. Raw is subjected to chromatography on evaporative column. Elution of 50% acetone in CH2CL2gives 3-hydroxy-21-(pyrid-4-yloxy)-5-pregnan-20-he (40 mg) as an oily solid product; TCX-Rf(acetone:CH2CL21: 1)=0,28.

Example 42

3-hydroxy-3-methyl-21-(4'-nitrophenoxy)-5-pregnan-20-he

A solution of 21-bromo-3-hydroxy-3-methyl-5-pregnen-20-she (250 mg, 0.61 mmol), 4-NITROPHENOL (127 mg, 0,912 mmol), triethylamine (127 μl, 0,912 mmol) and a small amount of sodium iodide in a mixture of acetonitrile:DMF (2:1) is stirred with heating to ~ 60oC for 6 hours the Mixture was distributed between EtOAc and water:saturated aqueous sodium bicarbonate (1:1). The organic layer was washed with 2N HCl, water, and aqueous saturated NaCl, dried with Na2SO4and kontsentriruitesi-3-methyl-21-(4'-nitrophenoxy)-5-pregnan-20-he (147 mg) as a solid product; So pl. 169-172oC; TCX-Rf(hexane:acetone 4:1)=0,35.

Similarly, a 3-hydroxy-3-methyl-21-(quinoline-6-yloxy)-5-pregnan-20-he; TCX-Rf(hexane:acetone 3:1)=0,22.

Example 43

21-(4'-dimethylaminoethoxy)-3-hydroxy-3-methyl-5-pregnen-20-he

A solution of 3-hydroxy-3-methyl-21-(4'-nitrophenoxy)-5-pregnan-20-it (100 mg, 0,213 mmol), formaldehyde (37% solution in water, 800 ml) and 5% Pd/C (30 mg, catalytic amount) in ethanol was placed in the atmosphere of H2at 53 F./inch2the vibrator Parra during the night. The catalyst is filtered off washing with EtOAc, and the filtrate is washed in a separating funnel with water and saturated aqueous NaCl. The organic layer is dried with Na2SO4and concentrate under vacuum. Raw is subjected to chromatography on evaporative column. Elution with 20% acetone in hexane gives 21-(4'-dimethylaminoethoxy)-3-hydroxy-3-methyl-5-pregnen-20-he (64 mg) as a foam product; TCX-Rf(hexane:acetone 2: 1)=0,55.

Similarly receive 21-(4'-dimethylaminophenyl)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he; TCX-Rf(hexane:acetone 3:1)=0,35.

Example 44

3-hydroxy-3-methoxymethyl-21-(R)-(4'-nitrophenyloctyl)-5-pregnan-20-he;

3-hydroxy-3-methoxymethyl-21-(S)-(4'-nitrophenyloctyl)-5-prés is oxymethyl-21-(4'-nitrophenylthio)-5-pregnan-20-she (120 mg, 0.23 mmol), msrv 57-86% (111 mg) and Panso3(80 mg, 4 equiv.) in CH2Cl2stirred at room temperature for 2 hours, the Reaction mixture was partitioned between CH2Cl2and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaCl, then dried with Na2SO4and concentrate under vacuum. Raw is subjected to chromatography on evaporative column. Elution of 40-50% EtOAc in hexane yields 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-he (65 mg) as a solid product, TCX-Rf(hexane: EtOAc 1: 1)= 0,38, then 3-hydroxy-3-methoxymethyl-21-(R)-(4'-nitrophenyloctyl)-5-pregnan-20-he and 3-hydroxy-3-methoxymethyl-21-(S)-(4'-nitrophenyloctyl)-5-pregnan-20-he in undetectable amounts.

Similarly receive 21-(4'-forfinal)sulfonyl-3-hydroxy-3-methoxymethyl-5-pregnan-20-he.

Example 45

3-hydroxy-3-methoxymethyl-21-(4'-pyrrolidinyl)sulfonyl-5-pregnan-20-he

Rastvor-(4'-forfinal)sulfonyl-3-hydroxy-3-methoxymethyl-5-pregnan-20-it (100 mg, 0,192 mmol) and pyrrolidine (21 μl, 0.25 mmol) in 5 ml of DMSO is heated on an oil bath at 100oC for 5 h, then stirred at room temperature overnight. Water is added and the mixture extracted with CH2Cl2. Org is and evaporative column, elwira a mixture of hexane:EtOAc to obtain the substances indicated in the title (62 mg) as a solid yellow color.

Example 46

3-hydroxy-21-(4-pyridylmethylene)-5-pregnan-20-he

The solution ethoxide sodium prepared from 300 mg of sodium and 10 ml of ethanol, a pipette added to a solution of 3-hydroxy-5-pregnan-20-she (500 mg, 1.57 mmol) and pyridine-4-carboxaldehyde (165 μl, of 1.73 mmol) in 10 ml of ethanol. The mixture is vigorously stirred at room temperature for 30 hours Solid product precipitated, filtered and washed with ethanol, then dried under vacuum, resulting in substances indicated in the title (260 mg).

Example 47

3-hydroxy-21-(4-pyridylmethyl)-5-pregnan-20-he

A solution of 3-hydroxy-21-(4-pyridylmethylene)-5-pregnan-20-it (100 mg, 0,245 mmol) in 4 ml of ethanol and 4 ml of THF containing 20 mg of 5% Pd/C, soak in the atmosphere of hydrogen from a balloon and stirred for 5 hours the Catalyst was then filtered off and the solution concentrated under vacuum. The residue is subjected to chromatography on evaporative column elwira a mixture of hexane:acetone, which leads to the production of substances indicated in the title (38 mg), in the form of a solid product; TCX-Rf(hexane:acetone 2:1)=0,28.

Example 48 the 3-hydroxy-3-trifluoromethyl-5-19-norpregna-20-she (1.0 g, 2.68 mmol), dimethyl-L-tartrate (1.0 g, 5,61 mmol), monohydrate paratoluenesulfonyl acid (13 mg, 0,068 mmol) and triethylorthoformate (10,35 ml) in 15 ml of toluene is heated under reflux with azeotropic removal of water. After 1 h the reaction is cooled to room temperature and add solid Panso3(130 mg). The final mixture is distributed between saturated aqueous NaHCO3and ethyl acetate. The aqueous layer was separated and washed twice with ethyl acetate (220 ml). The combined ethyl acetate layers washed with saturated NaCl solution, dried (Na2SO4) and concentrate under vacuum. The remainder chromatographic (17,5% acetone/hexane) to give a white foamy product which is ground to powder with hexane, obtaining a complex of dimethyl ether as a white solid product. The solution diapir in methanol (2 ml) and water (1 ml) is treated with solid KOH (78 mg). After stirring over night the reaction mixture was concentrated to dryness, obtaining the substance indicated in the title, in the form of a solid product is light yellow in color.

Example 49

The pharmacological activity

The activity and effectiveness of the GRC website

In vitro and in vivo experimental data show that deistvuut with high affinity with a new and specific site recognition at GRC to facilitate conductivity chloride ions across neuronal membranes, sensitive to GABA (Gee, K. W. et al., European Journal of Pharmacology, 136:419-423 (1987); N. L. Harrison et al., J. Pharmacol. Exp. Ther. 241:346-353 (1987)).

Experts know that the modulation of the binding of [35S]t-butylbenzylphthalate([35S]TBPS)is a measure of the activity and efficacy of drugs acting on GRC, these drugs may have potential therapeutic value in the treatment of stress, anxiety and epileptic disorders (Squires, R. F., et al., Mol. Pharmacol., 23: 326 (1983); Lawrence J. L., et al., Biochem. Biophys. Res. Comm. 123: 1130-1137 (1984); Wood et al., Pharmacol. Exp. Ther., 231:572-576, (1984)). Previously conducted a series of experiments to establish the nature of the modulation of [35S] TBPS when the effects of neuroactive steroids. It was shown that these compounds interact with the new site on GRC, which does not overlap with barbiturates, benzodiazepine, or any other previously known sites. Moreover, these compounds have high activity and effectiveness in terms of the GR complex, with strict structural requirements for the activity.

Procedures for conducting this analysis is fully discussed in (1) Gee, K. W. et al. , European Journal of Pharmacology, 136:419-423 (1987); and (2) Gee et al., Molecular Pharmacology, 30:218 (1986). These procedures are carried out as described below:

Gogent P2prepared as described previously (Gee et al., Molecular Pharmacology, 30:218 (1986). Briefly, the cerebral cortex gently homogenized of 0.32 M sucrose followed by centrifugation at 1000g for 10 minutes the Supernatant is collected and centrifuged at 9000g for 20 minutes. The precipitate P2suspended up to 10% (original wet weight/volume) suspension in 50 Mm Na/K phosphate buffer (pH 7.4) with 200 Mm NaCl to obtain a homogenate.

Aliquots hundred microliters (ml) of the homogenate Pg (0.5 milligrams (mg) protein) incubated with 2 nanomolar (Nm) [35S]TBPS (TBPS - t-butylbenzylphthalate) (70-110 CI/mm; New England Nuclear, Boston, MA) in the presence or in the absence of the tested natural steroids or their synthetic derivatives. Test compounds dissolved in dimethyl sulfoxide (Baker Chem. Co., Phillpsbury, NJ) and added to the incubation mixture in a 5 µl aliquot. The incubation mixture was adjusted with buffer to a final volume of 1 ml Nonspecific binding observed as binding in the presence of 2 Mm TBPS. The effect and specificity of GABA (Sigma Chem. Co., St. Louis, MO) estimate, conducting all the tests in the presence of GABA + bicucullin (Sigma Chem. Co.). Incubation was conducted at 25oC for 90 minutes (in constant terms), finish BST quantify liquid scintillation spectrophotometry. Data on the kinetics and curves dose response for compound [35S]TBPS analyze the nonlinear regression method using a computerized duplicate procedure to obtain values of rate constants and IC50(concentration of the compound, which is half the maximum inhibition of the primary binding of [35S]TBPS).

Conduct screening of various compounds, in order to establish their activity as modulators of the binding of [35S]TBPS in vitro. These tests conducted in accordance with the above procedures. Based on these analyses establish the requirements for structure-activity for a specific interaction at the GRC and the order of their activity and efficiency. Experimental data obtained using this analysis for a number of derivatives of 3-hydroxypregn-20-it, discuss Gee, K. W. et al., European Journal of Pharmacology, 136:419-423 (1987) and in U.S. Patent 5232917. In table. 1 presents the values of the IC50and maximum inhibition (Imaxfor many compounds, including examples of the compounds described and claimed here. IC50defined as the concentration of compounds inhibitory to 50% of control binding of [35S]TBPS. It is an indicator of active the table.1, 3-hydroxy-5-pregnan-20-he, 3,21-dihydroxy-5-pregnen-20-he and compounds presented in this invention have a low value IC50, which is the concentration required to achieve 50% of maximum inhibition of binding of [35S]TBPS, while compounds such as sex steroids (R5020, estradiol and progesterone), glucocorticoids (corticosterone) and cholesterol, having high value IC50are mostly inactive. So, take that hormonal steroids and cholesterol per se will not have any therapeutic value described herein. In order to distinguish this unique class of steroids and hormonal steroids, they are now called "neuroactive steroids". However, sex steroids, such as progesterone, can be metabolised in the body in the steroid, similar to the 3-hydroxy-5-pregnan-20-ONU. Thus, progesterone can be considered as "neuroactive steroids" prodrug. Data TBPS correlate with the absorption ion36Cl, potentiated different 3-gidroksilirovanii steroids described Purdy R. H. et al., J. Med. Chem 33:1572-1581 (1990). These data also correlate well with electrophysiological dannydjeljosevic receptors GABA person, as described by J. E. Hawkinson et al. Vol. Pharmacol. 46:977-985 (1995). This indicates that the analysis of TBPS is a suitable way of measuring the ability of steroids to allosteric modulation of the activity of the channel Cl-.

Connection with limited activity

To the extent that the desired therapeutic activity would be provided to the patient with minimal unwanted side effects, this invention also includes the discovery of new agonists with partial activity. (PL. 1, the connection with the Imax<110%). For patients who wish to alleviate anxiety or convulsions, hypnotic effect. For patients who wish to insomnia, adverse effects of anesthesia. It is expected that the compounds described as agonists with partial activity, have the desired effect with minimal unwanted side effects.

Advantages progesterone

Correlation between reduced levels of progesterone and symptoms associated to PMS, PND and menstrual epilepsy (Backstrom et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983); K. Dalton, Premenstual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yaerbook, Chicago (1984)), led to the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy ition, Chicago Yaerbook, Chicago (1984) 1984). However, progesterone is not consistently effective in the treatment of the above-mentioned syndromes. For example, progesterone there is no relationship dose-response in the treatment of PMS (Maddocks running et al., 1986). These results are predictable in light of the results of our in vitro studies that demonstrate that progesterone has a very low activity against GRC, as can be seen from the table. 1, compared with neuroactive steroids described in this invention.

The favorable effect of progesterone may be associated with different transformations of progesterone in the active metabolites of progesterone, which act on the receptor GABAA. Application specific neuroactive steroids in the treatment of the above-mentioned syndromes clearly superior to the use of progesterone due to the high activity and efficiency of these compounds (See. Gee et al., European Journal of Pharmacology, 136:419-423 (1987) and table. 1).

No hormonal side effects

Demonstrated that neuroactive steroids are no hormonal side effects due to the lack of affinity for progesterone and other steroid hormone receptors (table. 2-5). Presented data are obtained, conducting analysis is svodnik and progestin R5020 binding [3H]R5020 with progesterone receptors in the uterus of rats (Gee et al. Journal of Pharmacology and Experimental Therapeutics 246:803-812 (1988).

3H-progesterone (0,15 nm) incubated with the cytosol of the uterus of rats in the presence of test compounds. Specific binding set after incubation and compared with the control incubation without connections. The results are expressed as the percent inhibition of binding. If the connection is associated progesterone receptor with high affinity, we would expect a 100% inhibition of binding at the tested concentration.

Various hormonal activity of representatives of neuroactive steroids further study testing their potential estrogenic, mineralocorticoid and glucocorticoid activities. These activities analyzed by monitoring the ability of compounds to inhibit the binding of steroid hormones with their respective hormone receptors. The results are presented in table. 3-5. Their expressed as the percentage inhibition of binding3H-ligand with various steroid hormone receptors for compounds at a concentration of 10-6M. reference values are binding in the absence of test compounds.

wow receptor prepare faction cytosole brain as described by Gee et al., Journal of Pharmacology and Experimental Therapeutics 246:803-812 (1988). Medicines incubated with 3 nm 3H-aldosterone (specific ligand mineralocorticoid receptor) in the presence of a selective agonist of type II RU28362 (0.5 µm), which blocks the binding3H-aldosterone (glucorticoids) receptor type II.

For the table. 4 fraction of cytosol brain gain, as for the table. 3, and the connection incubated with 3 nm3H-dexamethasone (specific ligand of the glucocorticoid receptor).

In table. 5 represent the inhibition of binding3H-estradiol (specific ligand of the estrogen receptor) with uterine cytosol cows, prepared as described previously Gee et al., Journal of Pharmacology and Experimental Therapeutics 246:803-812 (1988).3H-estradiol (0,15 nm) incubated with cytosol in the presence of compounds.

The results of these experiments clearly show that neuroactive steroids do not have a strong affinity to any of the aforementioned steroid receptors. Thus, they will not give hormonal side effects that would be associated with steroid receptors. Neuroactive steroid 3-hydroxy-3-methyl-5-pregnen-20-he further tested in vivo and positivisation activity

Conduct experiments to establish the physiological correlates of the interaction neuroactive steroid and receptor GABA by assessing the ability of the compounds presented in the invention, to prevent induced metrazol convulsions in mice. Mice injected with varying doses of the tested compounds presented in the invention, for 10 minutes before injection of metrazol. The start time of myoclonia (presence of clonic activity of the forelimbs), induced metrazole determine by observing each mouse within 30 minutes. The control mice metrazol (85 mg/kg) to induce convulsions in 95% of the animals. The ability of some compounds of the invention and used to protect mice against seizures are shown in table. 6.

The ability of synthetic neuroactive steroids to protect animals from other chemical agents that cause convulsions, further demonstrated for several of the compounds presented in this invention. Tests on anticonvulsant activity similar to the above. Use the following chemical agents that cause seizures: metrazol (85 mg/kg); Scullin (2.7 mg/kg); picrotoxin (3.15 mg/kg); strychnine (1.25 mg/kg) or vehicle (0.9% saline, restart. Record the number of animals with tonic and/or clonic convulsions. In the test using maximal electroshock 50 mA, 60 Hz down through corneal electrodes for 200 MS with the aim of inducing tonic seizure. The ability of compounds to eliminate the tonic component is defined as the end point. The total potential depression of the Central nervous system (CNS) establish test of the rotating rod 10 minutes after the injection of compounds, which determine the number of mice remaining on the rotating rod (6 rpm) after 1 minute in one of three experiments. ED50(the dose at which there is half of the maximum effect) set for each test and are in the table. 7 infra. The results demonstrate that neuroactive steroids in comparison with other used in the clinic anticonvulsant agents are highly effective and have profiles similar to those of clonazepam from the group of benzodiazepines. These observations suggest therapeutic suitability of these compounds as modulators of excitability of the brain, which is consistent with their high affinity interaction with complex GRC in vitro.

Calming effect

Following the Expo is Ivanushki agents for humans in two animal models. The results of these definitions relative to other compounds presented in this invention, are presented in table. 8 and 9. Two animal models used to measure the behavioral effects of compounds against anxiety, are elevated plus maze and conflict test Geller-Seifter.

A. Elevated plus maze

theoretical basis for the test with an elevated cross maze close to that of the test moves from light to dark. As described by Pellow et al. , J. Neurosci. Meth. 14:149-167 (1985), the device is elevated cross maze designed to use natural avoidance mice open spaces. The device consists of two open corridors and two closed corridors. The test using the elevated cross maze allows you to make two dimensions of anxiety - define the number of outputs in open corridors and the time spent in the open corridors, which are expressed in percentage of the total number of outputs and the time spent in open and closed corridors.

Male mice N. I. H. Swiss-Webster (Harlan, Indianapolis, IN) weighing 15-20 g placed four/cage in plastic cages with coating/dark (0600-1800 h). Feed and water given ad libitum except during testing. Experiments conducted during 0700-1500 hours, and group balance on time of day effects. Mice only imposed once the drug or the media.

Used the method described previously (Lister, Psychoparmacol. 92:180-185 (1987)). The device includes two open corridor perpendicular to the two closed corridors, which are raised from the floor on 50 see Each corridor has a length of 50 cm and a wall at the closed corridors height of 40 see the Maze is completely made of black plexiglass. Over each of the open corridors placed incandescent 200 watt, to create a strong contrast between open and closed corridors.

10 minutes after the injection, mice N. I. H. Swiss-Webster placed in the center of a cross maze muzzle to the open corridor. During the 5-minute test period measures the number of outputs in open corridors and covered corridors, as well as the time spent in open corridors and enclosed corridors. All four legs must be in the corridor to dependent variation was observed. As a result, time spent in the center of the maze is not considered, the total time spent in open corridors, interior corridors, mo is provided in the present invention, using the elevated plus maze in the same conditions as described above.

Century Conflict test Geller-Seifter

In this animal model, simulating an alarm condition of a person, use conditional conflict in rats to establish properties of drugs against anxiety. Rats are trained to press the plate for positive reinforcement when two behaviors (Geller and Seifter, Psychopharmacologia 1:482-492 (1960)). The first involves pressing on the plate when the mode changing speed without penalty. The second component is a regime with a fixed ratio, in which each press of the record leads to positive reinforcement and punishment. Component of the penalty constitutes a conflict of the animal. Component without punishment allows you to see any answers to the depressant effects, which may have medicinal product. Response against alarm condition would answer with a sentence without affecting the response without penalty.

In conflict experiments used male albino rats Sprague-Dawley (Charles River Labs, Wilmington, MA) weighing 250-300 g, they are kept on a restricted diet pelleted feed Purina Lab Chow with water availability at any time for the flax when the 12-hour cycle of light / dark lighting in the period 0700-1900.

Effects against anxiety (punishment-reduction of penalty) and against depression of the compounds presented in this invention, is measured in rats conflict test Geller and Seifter (1960). In this 63-minute test hungry rats in response to pressing a lever to receive a reward sweetened milk. Mode reinforcement consists of components punishment and no punishment, changing every 15 minutes. Rats trained in the test chambers (Coulbourn instruments) with lever, hung on one wall, a small drinking bowl, which issues as the promotion of 0.1 ml milk (1 part of concentrated milk Eagle:2 parts water), and a floor made of metal mesh through which produce a penalty stroke current on paws. For programming and recording use managed SKED (State Systems) minicomputer DEC PDP 11/73.

First, rats are trained to respond to continuous reinforcement and quickly learn the modes with changing 30-second, 1-minute and 2-minute intervals (VI). With continuous reinforcement rats get as encouraging milk after each push of the lever; when the mode VI incentives in the form of milk is available through infrequent and varying intervals that occur on average once every 2 minutes Then the tion VI, and the other change between the 12-minute periods of response VI. During conflict periods that are accompanied by a signal in the form of light and sound, continuous reinforcement appears again, and each press of the lever gives as a bonus in the form of milk and punishment in the form of short (0.25 MS) shock current on paws. The intensity of the shock in the beginning is 0.2 mA and rises daily at 0.02 mA for the gradual suppression of the roller on the lever up to 5 or fewer responses for conflict period. This training takes 4-6 weeks, and then note the consistently low number of responses during conflict periods and the high number of periods of absence of punishment. Induced by the drugs increased the number of punished responses taken for the rate of activity against the state of anxiety, whereas the reduction in the number of unpunished responses take for a response rate of depression or sedation.

In table. 9 represent the total activity data against anxiety compounds presented in this invention, in the test Geller-Seifer in the experiment described above. Might expect that the remaining compounds presented in the present izopet Rotel alarm condition.

Prodrugs

Anticonvulsant activity proletarienne forms (ether 3-isobutyrate) base compounds 3-hydroxy-17-methoxy-5-androstane shown in the drawing.

The percentage protection of this proletarienne form 3-hydroxy-17-methoxy-5-androstane from induced metrazole stroke count in relation to the time after the introduction of the connections (see drawing). It is clear that this compound is used as an experimental model to illustrate the application of prodrugs. In contrast to the benzodiazepines, neuroactive steroids can also induce anesthesia. Their ability to induce anesthesia, it is believed, due to their ability to open up a channel of chloride ions in the absence of GABA, this property, which do not have the benzodiazepines. Therefore, neurosteroid can act directly on the receptor in the absence of GABA, and "indirectly" in the presence of GABA. This "indirect" effect is called "modulation" of the receptor. Lambert et al., Trends Pharmacology Science 8:224-227 (1987).

The compounds presented in the invention and used in it, can also be used when indicated for anesthesia in high doses. However, the preferred method of administration for the induction of anesthesia is the activity of drugs can lead to the loss of the installation of reflex. Lost installation reflex is defined as the inability of the animal to rise for 30 s after it is put on the back. Mice injected the drug intravenously in the lateral tail vein. After the introduction of the mice put on his back and watching the losing installation of reflex. Illustrating the results are shown in table. 10.

Take that prodrugs with such modifications, as described above, compounds represented and used in the invention, will be active as prodrugs.

1. Neuroactive steroids are some of the androstane or pregnane General formula I

< / BR>
or their physiologically acceptable complex 3-ethers,

where R is hydrogen or lower alkoxygroup;

R1means hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil, Halogens1-10alkyl, trihalogen1-10alkyl, hydroxys2-10quinil, alkoxyl1-10alkyl, optionally substituted phenyl, alkoxyl2-10quinil, oxoalkyl or ketal, optionally substituted phenylalkyl, complex gemify hydroxyhomosildenafil acid;

R2means hydrogen or ketogroup;

R3means optional samewe is-C(O)-CH2-O-E, -C(O)-CH2-Z-G or-C(O)-CH2-Y-Z-A, where

Y represents O, S, SO or SO2;

Z represents C1-10alkyl;

G denotes pyridyl or optionally substituted phenyl;

D denotes the quinoline attached to the carbon atom;

E is optionally substituted phenyl;

And denotes hydroxyl, carboxyl or sulfonate;

R4denotes hydrogen or methyl;

R5is hydrogen;

R6is hydrogen;

R7is hydrogen or hydroxyl;

R8is hydrogen;

R9is hydrogen;

R10is hydrogen;

provided that when R3- C1-3alkoxygroup and R is hydrogen, R1is different from hydrogen; when R3- C1-4alkoxy(C1-4)alkoxygroup, R1is different from hydrogen or 1-propenyl; when R3IS-C(O)-CH2-Y-G and G - pyridyl attached to the carbon atom, R1is different from hydrogen or C1-10of alkyl; or when R3IS-C(O)-CH2-Z-G, R1is different from hydrogen.

2. Connection on p. 1, wherein R denotes hydrogen or lower alkoxy; R1denotes hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil, trihalogen1-10alkyl, hydroxys2-10quinil, ALCO is necessarily substituted phenylalkyl, complex gemify hydroxyhomosildenafil acid; R2denotes hydrogen or ketogroup; R3denotes optionally substituted alkoxy, alkylalkoxy or optional substituted phenylalkylamine; and R4is hydrogen or methyl; and R5, R6, R7, R8, R9and R10- each represents hydrogen, provided that when R3- C1-3alkoxygroup and R is hydrogen, R1is different from hydrogen; or when R3- C1-4alkoxy(C1-4)alkoxygroup, R1is different from hydrogen or 1-propenyl.

3. Connection on p. 2, characterized in that it is a 3-hydroxy-3-methyl-17-(2-propenyloxy)-5-androstane or 17-[3-(4-acetylphenyl)-2-propenyloxy] -3-hydroxy-3-methyl-5-androstane.

4. Connection on p. 2, wherein R3- optionally substituted alkoxygroup.

5. Connection on p. 4, wherein R3- the unsubstituted alkoxygroup.

6. Connection on p. 5, wherein R1- substituted phenylethenyl.

7. Connection on p. 6, characterized in that it is a 3-hydroxy-3-(4'-nitrophenyl)ethinyl-17-methoxy-5-androstane; 3-hydroxy-3-(4'-methoxyphenyl)timeteller)ethinyl-17-methoxy-5-androstane; 3-(4'-triptoreline)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-(2'-methoxyphenyl)ethinyl-17-methoxy-5-androstane; 3-(4'-dimethylaminophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-chlorophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxypentyl)-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-(4'-acetoxyacetyl)ethinyl-17-methoxy-5-androstane or 3-(4'-cyanophenyl)ethinyl-3-hydroxy-17-methoxy-5-androstane.

8. Connection on p. 6, characterized in that it is a 3-(4'-acetylphenylalanine)-3-hydroxy-19-nor-17-methoxy-5-androstane;

ethyl ester of 3-(4'-carboxypentyl)-3-hydroxy-19-nor-17-methoxy-5-androstane; ethyl ester of 3-(4'-carboxypentyl)-3-hydroxy-17-methoxy-5-androstane; 3-[4'-(N, N-diethylcarbamyl)phenyl] ethinyl-3-hydroxy-17-methoxy-5-androstane or 3-(4'-acetoxyphenyl)-3-hydroxy-17-methoxy-5-androstane.

9. Connection on p. 5, wherein R1is optionally substituted by phenyl.

10. Connection on p. 9, characterized in that it is a 3-hydroxy-3-benzyl-17-methoxy-5-androstane; 3-hydroxy-3-(2'-phenylethenyl)ethyl] -17-methoxy-5-androstane or 3-hydroxy-3-phenyl-17-methoxy-5-androstane.

11. Connection on p. 5, wherein R1- one of the following substituents: oxoalkyl, hydroxyalkyl or a physiologically acceptable ester of hydroxyalkyl.

12. Connection on p. 11, characterized in that it is a 3-hydroxy-3-(5'-cyano-1'-pentenyl)-17-methoxy-5-androstane; 3-hydroxy-3-(4'-cyano-1'-butenyl)-17-methoxy-5-androstane; 3-hydroxy-3-(6'-oxo-1'-heptenyl)-17-methoxy-5-androstane; 3-hydroxy-3-(7'-oxo-1'-octenyl)-17-methoxy-5-androstane; 3-hydroxy-3-(5'-oxo-1'-heptenyl)-17-methoxy-5-androstane; 3-hydroxy-3-(5'-oxo-1'-pentenyl)-17-methoxy-5-androstane; 3[4'(R/S)-hydroxypentanal)] -3-hydroxy-17-methoxy-5-androstane; 3-[5'(R/S)-hydroxyhexyl] -3-hydroxy-17-methoxy-5-androstane; 3-(5'-hydroxy-1'-pentenyl] -3-hydroxy-17-methoxy-5-androstane; sodium salt of 3-(5'-hydroxy-1'-pentenyl)-3-hydroxy-17-methoxy-5-androstane-hemisuccinate; 3-(6'-hydroxy-1'-hexenyl)-3-hydroxy-17-methoxy-5-androstane; sodium salt of 3-(6'-hyroxy-1'-hexenyl)-3-hydroxy-17-methoxy-5-androstane-6'-hemisuccinate; 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; sodium salt of 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane-4'-hemisuccinate; 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; sodium salt of 3-(4'-hydroxy-1'-

b the mill; sodium salt of 3-(4'-hydroxy-1'-butenyl)-3-hydroxy-17-methoxy-5-19-norandrosterone-4'-hemisuccinate; 3-[3'(R/S)-hydroxy-1'-butenyl)] -3-hydroxy-17-methoxy-5-androstane or 3-(3'-hydroxy-1'-PROPYNYL)-3-hydroxy-17-methoxy-5-androstane.

13. Connection on p. 5, wherein R1- alkoxy-C2-10quinil.

14. Connection on p. 13, characterized in that it is a 3-(3'-acetoxy-1'-PROPYNYL)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetoxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(4'-acetoxy-1'-butenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(5'-acetoxy-1'-pentenyl)-3-hydroxy-17-methoxy-5-androstane; 3-(6'-acetoxy-1'-hexenyl)-3-hydroxy-17-methoxy-5-androstane; 3-hydroxy-3-[3-(2'-propenyloxy)-1-PROPYNYL] -17-methoxy-5-androstane; 3-hydroxy-3-(3-methoxy-1-PROPYNYL)-17-methoxy-5-androstane or 3-hydroxy-3-(3-methoxy-1-PROPYNYL)-17-methoxy-5-androstane.

15. Connection on p. 5, wherein R1represents an optionally substituted phenylalkyl.

16. Connection on p. 15, characterized in that it is a 3-hydroxy-3-(2-pyridyl)ethinyl-17-methoxy-5-androstane or 3-hydroxy-3-(4-pyridyl)ethinyl-17-methoxy-5-androstane.

17. Connection on p. 5, wherein R1sacerdoce-17-methoxy-5-androstane; 3-butenyl-3-hydroxy-17-methoxy-5-androstane; 3-ethinyl-3-hydroxy-17-methoxy-5-androstane;

3-pentenyl-3-hydroxy-17-methoxy-5-androstane; 3-cyclopropylmethyl-3-hydroxy-17-methoxy-5-androstane; 3-(but-3'-EN-1'-inyl)-3-hydroxy-17-methoxy-5-androstane; 3-(3'-methylbut-2'-EN-1'-inyl)-3-hydroxy-17-methoxy-5-androstane or 3-hexenyl-3-hydroxy-17-methoxy-5-androstane.

19. Connection on p. 5, wherein R1means1-10alkyl, C2-10alkenyl, trihalogen1-10alkyl, Halogens1-10alkyl, alkoxy-C1-10alkyl.

20. Connection on p. 19, characterized in that it is a 3-ethynyl-3-hydroxy-17-methoxy-5-androstane; 3-ethynyl-3-hydroxy-17-methoxy-5-androstane; 3-methyl-3-hydroxy-17-methoxy-5-androstane;

3-butyl-3-hydroxy-17-methoxy-5-androstane; 3-methyl-3-hydroxy-17-methoxy-5-androstane; 3-pentyl-3-hydroxy-17-methoxy-5-androstane;

3-hexyl-3-hydroxy-17-methoxy-5-androstane; 3-trifluoromethyl-3-hydroxy-17-methoxy-5-androstane; 3-trifluoromethyl-3-hydroxy-17-methoxy-5-androstane; 3-vermeil-3-hydroxy-17-methoxy-5-androstane; 3-methyl bromide is 3-hydroxy-17-methoxy-5-androstane; 3-iodomethyl-3-

hydroxy-17-methoxy-5-androstane; 3-chloromethyl-3-hydroxy-17-methoxy-5-androstane; 3-methoxymethyl-3-hydroxy-17-methoxy-5-apoximately-3-hydroxy-17-methoxy-5-androstane; 3-cyanomethyl-3-hydroxy-17-methoxy-5-androstane.

21. Connection on p. 2, wherein R is lower alkoxygroup and R3- optionally substituted alkoxygroup.

22. Connection on p. 21, characterized in that it is a 2, 17-dimethoxy-3-hydroxy-5-androstane; 2 ethoxy-3-hydroxy-17-methoxy-5-androstane; 2-propoxy-3-hydroxy-17-methoxy-5-androstane or 2-isopropoxy-3-hydroxy-17-methoxy-5-androstane.

23. Connection on p. 1, wherein R means hydrogen or lower alkoxygroup; R1means hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil, trihalogen1-10alkyl, hydroxys2-10quinil, alkoxyl1-10alkyl, optionally substituted phenyl, alkoxyl2-10quinil, oxoalkyl or ketal, optionally substituted phenylalkyl, complex gemify hydroxyhomosildenafil acid; R2means hydrogen or ketogroup; R3means-C(O)-CH2-Y-G; Y represents S or SO;

G denotes pyridyl; R4is hydrogen or methyl; and R5, R6, R7, R8, R9and R10each means hydrogen, provided that when R3means-C(O)-CH2-Y-G and G denotes pyridyl, R1- different Oh 3-hydroxy-3-(4-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-2-propoxy-21-(pyrid-4-ylthio)-5-pregnan-20-he N-methyliodide; 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he N-methyliodide; 3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he N-methyliodide; 3-hydroxy-3-methoxymethyl-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-ethinyl-3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-(4'-acetylphenyl)ethinyl-3-hydroxy-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-3-(4'-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(pyrid-4-ylthio)-5-pregnan-20-one or 3-hydroxy-3-(4-hydroxybutyl)-21-(pyrid-4-ylthio)-5-pregnan-20-he.

25. Connection on p. 1, characterized in that it is a 21-(4'-dimethylaminophenyl)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he;

3-hydroxy-3-methoxymethyl-21-(4'-nitrophenylthio)-5-pregnan-20-he; 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-

he; 3-hydroxy-3-methoxymethyl-21-(4'-nitrophenyloctyl)-5-pregnan-20-he; 21-(4'-forfinally)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he; 21-(4'-forfinal)sulfonyl-3-hydroxy-3-methoxymethyl-5-pregnan-20-he;

3-hydroxy-3-methoxymethyl-21-(4'-pyrrolidinyl)sulfonyl-5-pregnan-20-IMT and 21-(4'-aminophenylthio)-3-hydroxy-3-methoxymethyl-5-pregnan-20-he. 26. Connection on p. 1, characterized in that it is a 3-hydroxy-21-(n is l-5-pregnan-20-he; 3-hydroxy-3-methyl-21-(4'-nitrophenoxy)-5-pregnan-20-he; iodide 3-hydroxy-3-methyl-21-(4'-trimethylammonio)-5-pregnan-20-he; iodide 3-hydroxy-2-propoxy-21-(4'-N, N, N-trimethylammoniumphenyl)-5-pregnan-20-he; 3-hydroxy-3-methyl-21-(quinoline-6-yloxy)-5-pregnan-20-he N-methyliodide; 3-hydroxy-3-methyl-21-(quinoline-6-yloxy)-5-pregnan-20-he.

27. Connection on p. 1, characterized in that it is a sodium salt of 3-hydroxy-2-propoxy-21-thiopropionate-5-pregnan-20-it; 3-ethinyl-3-hydroxy-21-(3'-hydroxypropylamino)-5-pregnan-20-he; sodium salt of 3-ethinyl-3-hydroxy-21-(thiopropionate)-5-pregnan-20-it; 3-ethinyl-3-hydroxy-21-(2'-hydroxyethylthio)-5-pregnan-20-he; trimethylammonio salt of 3-ethinyl-3-hydroxy-21-titansilver-5-pregnan-20-it; sodium salt of 3-ethinyl-3-hydroxy-21-thiopropionate-5-pregnan-20-it; 3-ethinyl-3-hydroxy-21-(3'-hydroxypropanesulfonic)-5-pregnan-20-he; 3-hydroxy-21-(3'-hydroxypropylamino)-2-propoxy-5-pregnan-20-he; 3-hydroxy-21-(3'-hydroxypropanesulfonic)-2-propoxy-5-pregnan-20-he;

sodium salt of 3-hydroxy-2-propoxy-21-sulfonylureatolerant-5-pregnan-20-or 3-hydroxy-21-(2'-hydroxyethylthio)-5-pregnan-20-he.

28. Pharmaceutical preparation for the treatment and prevention of anxiety, stress, derepression, the induction of anesthesia, induction of sleep, and maintain the level of REM-sleep, which is found in normal sleep, containing the active ingredient in combination with pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a connection on p. 1 in an effective amount.

29. Method of modulating complex receptor GABAA- chloride ionophor on the animate object by linking the plot of neurosteroid on the specified complex, characterized in that the specified animal facility impose effective for modulation of the specified complex number of connections on p. 1.

30. Method for the treatment or prevention of stress or alarm condition of the animal, characterized in that the specified animal in need of such treatment is administered an effective amount of the compounds under item 1.

31. Method for the treatment or prevention of seizure activity in animals, characterized in that the specified animal in need of such treatment is administered an effective amount of the compounds under item 1.

32. Method for the treatment or prevention of insomnia in animals, characterized in that the specified animal in need of such treatment, effective to introduce what is in normal sleep, characterized in that the object of introducing an effective amount of the compounds under item 1.

34. Method for the treatment or prevention of premenstrual syndrome or postpartum depression in animals, characterized in that the specified animal in need of such treatment is administered an effective amount of the compounds under item 1.

35. The method of treatment or prophylaxis of mood disorders in animals, characterized in that the specified animal in need of such treatment is administered an effective amount of the compounds under item 1.

36. The method according to p. 35, characterized in that specified disorders of mood is depressed.

37. Method of induction of anesthesia in animals, characterized in that the specified animal in need of such treatment is administered an effective amount of the compounds under item 1.

38. The method according to any of paragraphs. 29-37, characterized in that the compound is a pharmaceutically acceptable complex 3-ether or complex 3-W acid selected from the group consisting of acetic, propionic, maleic, fumaric, ascorbic, pipelinewall, succinic, glutaric, bis-methylanilinium, methansulfonate, ethicolegal, oxalic, tartaric, salicylic, lim-(2-hydroxyethylamino)propionic, glycine and other amino acids, phosphoric, sulfuric, glucuronic and 1-methyl-1,4-dihydrocodeinone.

39. The method according to any of paragraphs. 29-37, characterized in that the said effective amount is from 1 to 100 mg generic intravenous dose of from 100 to 500 mg generic dose in the introduction, other than intravenously.

 

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