MXPA97009384A - Neuroactive steroids of the androstano ypregn series - Google Patents

Abstract

The invention relates to 3a-hydroxy, 17-unsubstituted derivatives of the androstane series and 3a-hydroxy, 21-substituted derivatives of the pregnane series. These derivatives are able to act as a newly identified site on the GRC, thereby modulating brain excitability in a way that will alleviate stress, anxiety, insomnia, mood disorders that threaten active GRC agents (such as depression). ) and the attack activity. The steroid derivatives of this invention are those having the general structural formula (I), wherein R, R1, R2, R3, R4, R5, R6, R7, R8, and R10 are further defined herein and the dotted lines are single bonds or double. The structure includes androstanos pregnanes (R4 = methyl), 19-norandrostanos, and norpregnanos (r4 =

Description

NEU OACTIVE STEROIDS OF THE. SERIES OF ANDROSTANO AND PREGNANO Cross reference to related request This request is a continuation in part of Solic. No. 08 / 467,404, published June 6, 1995, the content of which is fully incorporated by reference.

Background of the Invention Field of the Invention The present invention relates to steroidal derivatives of the androstane and pregnane series, in addition to compositions and pharmaceutical methods for the modulation of cerebral excitability. More particularly, the invention relates to 3? F-hydroxy, 17- (un) substituted derivatives of the androstane series and 21-substituted derivatives of the pregnane series.

Related Art Brain excitability is defined as the level of arousal in an animal, a continuum that goes from coma to seizures, and is regulated by several neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions through the neuronal membranes. At rest, the neuronal membrane has a REF: 026154 potential (or membrane voltage) of approximately -80 mV, the inner cell is negative with respect to the outer cell. The potential (voltage) is the result of the ionic balance (IC, Na *, Cl ", organic anions) through the semipermeable neuronal membrane.The neurotransmitters are stored in the presynaptic vesicles and released under the influence of neuronal action potentials. When released within the synaptic space, an excitatory chemical transmitter such as acetylcholine will cause depolarization of the membrane (change of potential from -80 mV to -50 mV) .This effect is mediated by means of postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase the permeability of the membrane to Na * ions.The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.

In the case of the GABA receptor complex (GRC), the effect on neuronal excitability is mediated by the GABA, a neurotransmitter. GABA has a profound influence on global brain excitability, because up to 40% of neurons in the brain use GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions through the neuronal membrane. The GABA interacts with its recognition site on the GRC to facilitate the downstream chloride ion flux an electrochemical gradient of the GRC in the cell. An intracellular increase in levels of this anion causes hyperpolarization of the transmembrane potential, making the neuron less susceptible to excitatory impulses (eg, reduced neuronal excitability). In other words, the highest chloride ion concentration in the neuron, the lower the neuronal excitability (the aurosal level). It is well documented that the GRC is responsible for the mediation of anxiety, attack activity, and sedation. Thus, GABA and drugs that act as GABA or facilitate the effects of GABA (eg, therapeutically useful barbiturates and benzidiazepines (BZs), such as Valium) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC. . Accumulating evidence has now indicated that in addition to the benzodiazepine and barbituric binding site, the GRC contains a distinct site for neuroactive steroids (Lan, N.C. et al., Neurochem-Res. 16: 347-356 (1991)). Neuroactive steroids can be present endogenously. The most potent endogenous neuroactive steroids are 3c > -hydroxy-5-reduced pregnan-20-one and 3or, 21-dihydroxy-5-reduced pregnan-20-one, metabolites of steroid hormones progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Maje ska, M.D. et al., Science 232: 1004-1007 (1986); Harrison, N.L. et al., J. Pharmacol. Exp. Ther. 241: 346-353 (1987)). However, the therapeutic utility of these steroid metabolites and their derivatives (neuroactive steroids) was not recognized by workers in the area due to an incomplete understanding of the potency and site of action of these neuroactive steroids. The invention of the applicants is related in part to a pharmaceutical application of the knowledge gained from a more developed understanding of the potency and site of action of certain steroidal compounds. It has been shown that progesterone ovarian hormone and its metabolites have profound effects on the excitability of the brain (Backstrom, T. et al., Acta Qbstet, Gynecol, Scand 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); Lambert, J. et al., Trends Pharmacol. Sci. 8: 224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It is well documented that progesterone and its metabolites decrease before the onset of menstruation. The monthly repetition of certain physical symptoms before the start of menstruation is also well documented. These symptoms that have been associated with premenstrual syndrome (PMS) include stress, anxiety, and headaches (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Patients with PMS have a monthly repetition of symptoms that are present in premenstruation and absent in postmenstruation. In a similar way, a reduction in progesterone has been temporally correlated with an increase in the frequency of attacks in epileptic women, p. ex. , catamensal epilepsy (Laidla, J., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with a reduction in progesterone metabolites (Rosciszewska et al., L_ Neurol, Neurosurs, Psych 49: 47-51 (1986)). In addition, for patients with epilepsy of small generalized major malignancy, the temporal incidence of seizures has been correlated with the incidence of premenstrual syndrome symptoms (Bacstrom, T. et al., J. Psychosom., Obstet, Gynaecol., 2: 8-20 (1983)). Deoxycorticosterone steroid has been found to be effective in the treatment of patients with epileptic seasons correlated with their menstrual cycles (Aird, R.B. and Gordan, G., J. Amer. Med. 30 ^ 145: 715-719 (1951)). A syndrome also related to low levels of progesterone is postnatal depression (PND). Immediately after birth, progesterone levels decrease dramatically leading to the onset of PND. The symptoms of PND range from mild depression to psychosis that requires hospitalization. PND is also associated with severe anxiety and irritability. Depression associated with PND does not respond to treatment by classical antidepressants women who experience PND show an increase in the incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Collectively, these observations imply a crucial role of progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic regulation of cerebral excitability, which manifests as an increase in the activity of attacks or symptoms associated with catamensal epilepsy, PMS and PND. The correlation between reduced levels of progesterone and symptoms associated with PMS, P-ND, and catamensal epilepsy (Backstrom, T. et al., "L. PsychQSom. Qbstet, Gynae? Ol, 2: 8-20 (1983)) , - Dalton, K., Premenstrual Syndrome and Progesterone Therapy. 2nd edition, Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in its treatment (Matson et al., "Medroxyprogesterone therapy of catamenial epilepsy", in Advances ifl epileptology; XVtll Epilepsy International Symposium Raven Press, New York (1984), pp. 279-282, and Dalton, K., Premenstrual Syndrome and Prosesterone Therapy. 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Maddocks, et al, Obstet, Gynecol, 154: 573-581 (1986), Dennerstein, et al., Brit. Med. 16-17 (1986)). Templeton et al., Steroids 48: 339-346 (1986) disclose a stereoselective and regioselective reduction of steroid ketones to form axial alcohols at C-3. The compound l7β-methoxy-2β-methyl-5a-androstan-3a-ol is formed from I7β-methoxy-2of, 3o.-epoxy-5Qi-androstane. Grieco et al., J. Am. Chem. Soc. 11: 7799-7801 (1990) discloses the use of 17β-methoxy-5a-androstan-3a-ol as an initial material to form conjugates comprising metalloporphyrins bound to substrates Steroids Babcock et al., U.S. Patent No. 4,297,350, published on October 27, 1991, severely exposes 17 ethers of androstane and androstene steroidal and their use as contraceptives in males. Neef et al., Tetrahedron Letters 21: 903-906 (1980) discloses the compound 17β-methoxymethoxy-3β- (1-polyvinyl) -5c.-androsten-3of-ol as an intermediate in the formation of steroid derivatives. FR 1,437,361, published May 6, 1996 and U.S. Pat. No. 3,135,744, published June 2, 1964, discloses 17- (2-methyl-2-butenyl) and cycloalkenyl esters of 5OÍ-androstane-3a, 17β-diol and alkanoyl esters less than 3 thereof. The compounds are indicated to have androgenic and / or anabolic activity. Phillips et al., U.S. Pat. No. 4,197,296, published April 8, 1980, discloses steroids of the androstane series which possess a 3a-hydroxy group, a hydrogen atom 5a- or 5ß-, and a substituted amino group lla where position 17 could be replaced. The compound lla-N, N-dimethylamino-2β-ethoxy-5oi-androstan-3Qf-ol is exposed. The patent teaches that these compounds have anesthetic activity. Phillips et al., U.S. Pat. No. 3,882,151, published May 6, 1975, and Phillips et al., U.S. Pat. No. 3,969,345, published July 13, 1976, discloses 21 pregnane-3-enegenated ethers having a 3a-hydroxy group or ester thereof, a keto group at position 20, and a hydroxyl group etherified at the position 21. Substituent 21 ether is preferably an alkoxy, cycloalkoxy, aralkoxy, or aryloxy group which could carry the additional substituents. The patents state that these compounds have anesthetic activity. Phillips et al., U.S. Pat. No. 3,959,260, published May 25, 1976, teaches anesthetic steroids of pregnane and the 10-norpregnane series which possesses a 3of-hydroxy group, a 20-oxo group, and in position 21 the residue of a sulfur containing nucleophile or a sulfone or sulfoxide grouping. The 3β substituent could be hydrogen or alkyl. Clayton et al, U.S. Patent No. 3,822,298, published July 2, 1974, discloses a process for preparing 3a-hydroxy-5a! -steroids. The patent discloses the preparation of 21-benzyloxy-3? F-hydroxy-5a-pregnane-1, 20-dione.

Brief Description of the Invention The present invention is directed to new steroidal derivatives of the androstane and pregnane series, as well as pharmaceutical compositions and methods to modulate cerebral excitability. More particularly, the invention relates to 3a-hydroxy, 17- (unsubstituted) derivatives of the androstane series and 21-substituted derivatives of the pregnane series. These-derivatives are able to act at a site recently identified in the GRC, thus modulating brain excitability in a manner that alleviates stress, anxiety, insomnia, humoral disorders that respond to GRC-active agents (such as depression) and activity. of attacks. The steroid derivatives of this invention are those having the general structural formula (I): where R, R R2, R3, R «# R5 / Sf t # R -» / R9 and Rio are defined here as well and dotted lines are single or double bonds. The structure that has the Formula I includes androstanos, pregnanes (R «= methyl), 19-norandrostanos, and norpregnanos (R4 = H). The present invention also includes pharmaceutically acceptable esters and salts of the compounds of Formula I, which include salts by the addition of acid. It is believed that the 3a-hydroxyl could also be masked as a pharmaceutically acceptable ester due to the fact that the ester will break down as the prodrug is converted to the drug form. These are referred to here as breakable esters. The compounds of the present invention are modulators of central nervous system excitability as well as mediators due to their ability to regulate the chloride ion channels associated with the GABA receptor complex. Applicants' experiments have established that these compounds have anticonvulsant, anxiolytic, and hypnotic sedative activity similar to the actions of known agents such as BZs, but act at a site other than the GRC. The ratio of endogenous progesterone metabolites to processes associated with reproduction (estrus cycle and pregnancy) is well established (Marker, R.E. et al., J. Am. Chem. Soc. 59: 616-618 (1973)). However, it was just recently recognized as treating disorders to modulate brain excitability by using steroid metabolites and their derivatives. See, U.S. Pat. No. 5,208,227, published May 4, 1993; U.S. Patent No. 5,120,723, published June 9, 1992; and U.S. Patent No. 5,232,917, published August 3, 1993. The desirable objectives of the pharmaceutical compositions and methods of his invention are the treatment of stress, anxiety, PMS, PND, and attacks such as those caused by epilepsy to improve or prevent attacks. of anxiety, muscular tension, and depression common with patients suffering from these central nervous system abnormalities. A further desirable goal of the compositions and methods is to treat insomnia and produce hypnotic activity. Another desirable objective of the compounds and methods is to cause anesthesia, particularly by means of intravenous administration. The present invention is directed to new compounds and their use in pharmaceutical compositions and methods for treating such disorders by modulating brain excitability. Another aspect of the present invention relates to a method of inducing sleep and substantially maintaining the level of REM sleep found in normal sleep, where substantial repetition insomnia, as defined herein, is not induced. This method comprises administering an effective amount of a compound of the invention. The compounds of the invention are capable of increasing NREM sleep and the total sleep period, without substantially affecting the amount of REM sleep.

BRIEF DESCRIPTION OF THE DRAWING The present invention could be better understood and its advantages appreciated by referring to the accompanying drawing wherein: FIG. l is a diagram of the time course of the anti-metrazole activity of a 3o-hydroxy-17β-methoxy-5a-androstane prodrug (administered, for example, in a dose of 20.0 mg / kg).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of the present invention are derivatives of various 3-hydroxylated pregnanes and 3α-hydroxylated androstanes, and ester, ether, sulfonate, sulfate, phosphonate, phosphate, oxime, thiosulfate, heterocyclic and heteroaryl derivatives thereof. , and derivatives referred to as prodrugs. The term "prodrug" denotes a derivative of a known direct action drug, whose derivative has distribution characteristics and improved therapeutic values when compared to the drug, and is transformed into the active drug by means of an enzymatic or chemical process; see Notari, R.E., Methods in EnaimQlogy, 112: 309-323 (1985); Bodor, N., Drugs of the Future. 6 (3).-165-182 (1981); Y Bundgaard, H., "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 that form part of the present invention could not be true prodrugs because, in addition to the above characteristics, they also possess intrinsic activity. However, for purposes of this application they will be referred to as prodigies. Previous studies (Gee, KW et al., European Journal of Pharmacology, 136: 419-423 (1987)) demonstrated that certain 3o? -hydroxylated steroids are orders of magnitude more powerful as well as the modulators of GRC that have been reported by others ( Majewska, MD et al., Science 232: 1004-1007 (1986), Harrison, NL et al., J. Pharmacol. Exp. Ther- 241: 346-353 (1987)). Majewska et al. and Harrison et al. They indicated that 3cif-hydroxylated-5-reduced steroids are capable of only much lower effectiveness levels. Experimental results in vitro and in vivo have now shown that the high potency of these steroids allows them to be therapeutically useful in the modulation of cerebral excitability via GRC (Gee, KW et al., European Journal of Pharmacolosy. 136: 419- 423 (1987); Wieland et al., Psychopharmacology 118 (1): 65-71 (1995)). Several synthetic steroids have been prepared as neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917, published August 3, 1993, which discloses useful compositions of neuroactive steroids in the treatment of stress, anxiety, insomnia, seizure disorders and humoral disorders that are responsive to GRC-active agents, such as depression, a therapeutically beneficial form. In addition, it has previously been shown that these steroids interact in a unique GRC site that is distinct from other known interaction sites (ie, barbiturate, BZ, and GABA) where the therapeutically beneficial effects on stress, anxiety, sleep, humoral disorders and Attack disorders have been previously obtained (Gee, KW and Kamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders", in Central Nervous System Disorders, DC Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs," in Psychopharmacolosy: The Third Generation of Prosreas, HY Meltzer, ed., Raven Press, NY (1987), pp. 183-195; and Gee, KW et al., European Journal of Pharmacology 136: 419-423 (1987) .These compounds are desirable for their duration, potency and oral activity (together with other forms of administration).

Definitions In accordance with the present invention and as used herein, the following terms, when appearing alone or as part of a sentence, are defined with the following meaning, unless otherwise stated. The term "alkyl", as used herein in all cases, refers to saturated aliphatic groups that include straight chain, branched chain, and cyclic groups, all of which could be optionally substituted. Alkyl groups containing 1 to 10 carbon atoms are preferred. Suitable alkyl groups include methyl, ethyl, and the like, and could optionally be substituted. The term "alkenyl", as used herein in all cases, refers to unsaturated groups that contain at least one carbon-carbon double bond and include straight chain, branched chain, and cyclic groups, all of which could be optionally substituted . Preferred alkenyl groups have from 2 to 10 carbon atoms. The term "alkynyl", as used herein in all cases, refers to unsaturated hydrocarbon groups containing at least one carbon-carbon triple bond and include straight chain and branched chain groups which could be optionally substituted. Preferred alkynyl groups have from two to eighteen carbon atoms. The most preferred alkynyl groups have from two to twelve carbon atoms. The most preferred alkynyl groups have from two to seven carbon atoms. Suitable alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like which could be optionally substituted with cyano, acetoxy, halo, hydroxy or keto. The term "alkoxy" refers to the ether-O-alkyl, wherein the alkyl is as defined above. The term "aryloxy" refers to ether-O-aryl, wherein aryl is defined hereinbelow. The term "aryl" refers to aromatic groups having at least one ring having a conjugated pi electron system and includes carbocyclic aryl and biaryl, which could be optionally substituted. Preferred aryl groups have from 6 to 10 carbon atoms. Suitable aryl groups include phenyl and naphthyl. The term "carbocyclic aryl" refers to groups wherein the ring atoms in the aromatic ring are carbon atoms. Carbocyclic aryl groups include phenyl and naphthyl groups, groups which are optionally substituted. The substituted phenyl preferably has one to three, four or five substituents, with such advantageously being minor alkyl, amino, aminocarbonyl, cyano, carboxylate, hydroxy, lower alkoxy, halogen, minor acyl, and nitro. The term "aralkyl" refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, and the like, and could optionally be substituted. The term "alkanoyloxy" refers to -0-C (0) R ", wherein R 'is alkyl, alkenyl, alkynyl, aryl or aralkyl The term" carbalkoxy "refers to -C-0 (0) Rb, wherein Rb is alkyl, alkenyl, alkynyl, aryl or aralkyl The term "carboxamido" refers to -C (0) NRcRd, wherein Rc and Rd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl or aralkyl.

The term "acyl" refers to the alkanoyl group -C (0) R9, wherein R9 is alkyl, alkenyl, alkynyl, aryl, or aralkyl. The term "amino" refers to -NR11Ri, wherein Rh and R1 are independently hydrogen or lower alkyl or are joined together (with the nitrogen atom to which they are attached) to give a 5 or 6 membered ring, e.g. ex. pyrrolidine, morpholino or piperidine rings. The term "dialkylamino" refers to -NR'R1, wherein R * and R £ are independently lower alkyl groups or together with the nitrogen atom to which they are linked, they form the remainder of a morpholino group. Suitable dialkylamino groups include dimethylamino, diethylamino, and morpholino. The term "thio" refers to -SRa, wherein R * is hydrogen, alkyl, alkenyl, alkynyl, aryl or arylalkyl (minor). The term "sulfinyl" refers to -SOR ", wherein R" is alkyl, alkenyl, alkynyl, aryl or arylalkyl (minor).

The term "sulfonyl" refers to -SOaR °, wherein R ° is hydrogen, alkyl, alkenyl, alkynyl, aryl or arylalkyl (minor). The term "sulfonamido" refers to -S03NRlcR1, wherein R * and R1 are independently hydrogen or lower alkyl. The term "optionally substituted" or "substituted", unless specifically defined herein, refers to substituted groups by means of one to five substituents, independently selected from lower alkyl (acyclic and cyclic), aryl (carboaryl and heteroaryl), alkenyl, alkynyl, alkoxy, halo, haloalkyl (including trihaloalkyl, eg, trifluoromethyl), amino, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, nitro, alkanoyl, alkanoyloxy, alkanoyloxyalkanoyl, alkoxycarboxy, carbalkoxy (-COOR3, in where R3 is lower alkyl), carboxamido (-CONR'R1, wherein R * and R1 are as defined above), formyl, carboxy, hydroxy, cyano, azido, keto and cyclic ketals thereof, alkanoylamido, heteroaryloxy, heterocarbocyclic and hemisuccinate ester salts. The term "minor" is referred to herein in connection with defined organic radicals or compounds of one up to and including ten, preferably up to and including six, and advantageously one to four carbon atoms. Such groups could be straight chain, branched chain, or cyclic.

The term "heterocyclic" refers to carbon containing radicals having three, four, five, six, or seven ring members and one or two heteroatoms of O, or S, p. g., thiazolidine, tetrahydrofuran, 1,4-dioxane, 1,3,5-trioxane, pyrrolidine, piperidine, quinuclidine, dithiane, tetrahydropyran, e-caprolactone, .alpha.-caprolactam, w-thiocaprolactam, and morpholine. The term "heteroaryl" refers to carbon containing 5-14 members of cyclic unsaturated radicals containing one, two, three or four 0, N or S atoms and having 6, 10 or 14 delocalized p-electrons in one or more rings , p. ex. , 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-tetrazole, benzotriazole, 1,2,3-triazole [4,5-β] pyridine, thiazole, isoxazole, pyrazole, quinoline, cytosine, thymine, uracil, adenine, guanine, pyrazine, picolinic acid, picoline, furoic acid, furfural, furyl alcohol, carbazole, 9H-pyrido [3,4-β] indole, isoquinoline, pyrrole, thiophene, furan, 9 (10H) -acridone, phenoxazine, and phenothiazine, each of which could be optionally substituted as set forth above. The term "quaternary ammonium salt" refers to quaternary ammonium salts of amino compounds and heteroaryl compounds described above, formed by reaction of the amino compound or heteroaryl compound with an electrophilic reagent such as an alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl or aralkynyl, halide, tosylate, sulfate, mesylate or the like. Specific examples of electrophilic reagents include methyl iodide, ethyl iodide, n-butyl iodide and phenethyl iodide. The term "EDA" refers to ethylenediamine. The term "pharmaceutically acceptable esters or salts" refers to esters or salts of Formula I derived from the combination of a compound of this invention and an organic or inorganic acid, or base. The basic salts are formed by mixing a solution of a particular compound of the present invention with a non-toxic pharmaceutically acceptable base solution, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or an amino compound. , such as, choline hydroxide, Tris, bis-Tris, N-methylglucanamine, arginine and the like. The acid salts are formed by mixing a solution of a particular compound of the present invention with a solution of a non-toxic pharmaceutically acceptable organic acid or dioic acid, such as acetic, propionic, maleic, fumaric, ascorbic, pimelic, succinic, glutaric, bismethylene salicylic, methanesulfonic, ethane-disulfonic, oxalic, tartaric, salicylic, citric, gluconic, itaconic, glycolic, p-aminobenzoic, aspartic, glutamic, gamma-amino-butyric, ar - (2-hydroxyethylamino) propionic, glycine and others of-amino acids, phosphoric, sulfuric, glucuronic, and l-methyl-1,4-dihydronicotinic. The esters are formed from steroidal alcohols and an appropriately activated acid. In addition the esters are discussed here. The term "dioic acids" refers to C ^ substituted alkylene groups, with two carboxy groups, for example, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and suberic acid. The hemi-ester salts of the dioic acids include sodium, lithium, potassium, magnesium and calcium salts thereof. According to the present invention, the ketals include minor alkanol diets, e.g. ex. dimethyl and diethyl ketals, in addition to cyclic ketals which include C.sub.3 alkanediol diethers, which could be optionally substituted, e.g. ex. , ethylene ketals and propylene ketals.

Modality In its broadest aspect, the present invention relates to steroid derivatives having the general Formula I: wherein R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, halogen, lower alkoxy, alkyl, substituted alkyl, alkenyl, alkynyl or substituted alkynyl; R x is one of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, dihaloalkyl, trihaloalkyl, optionally substituted araquinyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, optionally substituted arylalkyl, arylalkenyl, optionally substituted aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, optionally substituted cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminialkynyl, mercaptoalkynyl, hydroxyalkynyl-dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl; R2 is one of hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxy, a keto group or an amino group; R3 is one of hydrogen, alkoxy, substituted alkoxy, alkenyloxy, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, sulfinyl, sulfonyl, thio, sulfonamido, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, a 1,3-dioxolan-4-one of a group optionally substituted acetyl, an 1,3-dioxane-4-one of an optionally substituted acetyl group, an l, 3-oxatolan-5-one of an optionally substituted acetyl group, a 1,3-oxathioan-5-one of an optionally substituted acetyl group, -0-C (0) -NR'R ", -C (0) -CHa-YG, -C (O) -CH.-0-D, -C (O) -CHa-0 -E, -C (0) -CHa-ZG, -C (0) -CH3-Y »-ZG, or -C (O) -CHa-Y« -ZA, where RI and R "independently represent hydrogen or optionally substituted alkyl, or taken together with the nitrogen to which they are attached form a 6-membered heterocyclic ring; And it is one of S, SO or SOs; Y * is one of 0, S, SO or S0a; Z is one of alkyl, alkenyl or alkynyl; G is one of C-linked heteroaryl, optionally substituted aryl, a quaternary ammonium salt of a nitrogen containing heteroaryl group or a quaternary salt of a substituted amino aryl group; D is heteroaryl attached to C or a quaternary ammonium salt of a nitrogen containing heteroaryl group; E is optionally substituted aryl of a quaternary ammonium salt of a substituted amino aryl group; A is one of amino, amido, cyano, thiocyano, azido, nitro, hydroxy, halo, carboxyl, alkoxy, alkoxycarbonyl, alkanoyloxy, hydrogen, sulfate, thiosulfate, sulfonate, alkylthio, alkylsulfinyl, alkylsulfonyl or mercapto; R4 is one of hydrogen or lower alkyl, Rs is hydrogen, or when a double bond occurs between C4 and C5 of the steroid ring system, then Rs is not present; Rβ is one of hydrogen, alkanoyl, aminocarbonyl or alkoxycarbonyl; R7 is one of hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, or carbalkoxy; Rβ is one of hydrogen or halogen; R9 is one of hydrogen, halogen, alkyl, alkoxy, arylalkoxy, or amino; R10 is one of hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkoxyloxy, carbalkoxyl, cyano, thiocyano or mercapto; and dotted lines indicate that a single or double link could be present; provided that: when R3 is C4 alkoxy or C -.-6 alkenyloxy and R is hydrogen or a-methyl, then R-. it is another apart from idrogen; or when R 3 is C 1 alkoxy, C 1 alkoxy, then R x is other than hydrogen or 1-propynyl; or when R3 is hydrogen and Ra is hydrogen, hydroxy, a keto group or an amino group, then Rx is not hydrogen, alkyl or cyanoalkyl; or when R3 is aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, then R .. is not hydrogen or alkyl; or when R3 is -Cio) -CHa-Y-G, and G is C-linked heteroaryl or optionally substituted aryl, then Rx is another apart from hydrogen or alkyl; or when R3 is -C (O) -CH2-0-E, and E is optionally substituted aryl, then Rx is another apart from hydrogen; or when R3 is -C (O) -CHa-Y »-Z-G, and Y1 is 0, and G is aryl, then RL is another apart from hydrogen; or when R3 is -C (0) -CHa-Y '-Z-G, and Y' is S, SO, or S0a, and G is aryl, then Rx is another apart from hydrogen or alkyl; or when R3 is -C (0) -CH.-Z-G, then RL is another apart from hydrogen; or when R3 is -C (0) -CH3-Y '-Z-A, and Y1 is 0, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino, then R-. it is another apart from hydrogen; or when R3 is -C (0) -CHa-Y '-ZA, and Y' is S, SO, or S0a, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, or amino, then Rt is another apart from hydrogen or I rent. The present invention also includes pharmaceutically acceptable esters and salts of the compounds of Formula I, including acid addition salts. It is believed that the 3a-hydroxyl could also be masked as a pharmaceutically acceptable ester due to the fact that the ester will break down as the prodrug becomes the drug form. These are referred to here as breakable esters.

Modality Ib A group of useful compounds included by the broad aspect of the present invention includes compounds of Formula I, wherein: the bond between C4 and C5 of the steroid ring system is a single bond; R is one of hydrogen, lower alkoxy, alkyl, substituted alkyl, alkynyl or substituted alkynyl; Ri Ra, i / 'ß / R7 R8 / R9 and Ro are as defined above; R3 is one of hydrogen, alkoxy, substituted alkoxy, alkenyloxy, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, -0-C (0) -NR'R ", -C (0) -CH2-YG, -C (0 ) -CH2-0-D, -C (O) -CH2-0-E, -C (0) -CH2-Y '-ZG, O-C (0) -CHa-Y'-ZA, wherein R And R "independently represent hydrogen or optionally substituted alkyl, or taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring; And, Y ', Z, G, D, E, and A are as defined above; Rs is hydrogen; and where all the relevant conditions that were previously cited for the Modality are applicable to this subgenre of compounds.

Modalities' and Ib * In the preferred aspects of the modalities la and Ib the steroid derivatives have the general Formula I, wherein R, Rlf Ra, R3, R ', R ", Y, Y', Z, G, D , E, A, R4, Rs, Rs, R7, Rs, R9 and R10 are as defined above for Modalities la or Ib.However, the following conditions apply for each of the above modalities: when R3 is alkoxy C Alkenyloxy d-β, then Rx is another hydrogen or methyl residue, or when R 3 is hydrogen and R 2 is hydrogen, hydroxy, a keto or an amino group, then R x is not hydrogen, alkyl or cyanoalkyl, or when R 3 is -C (0) -CHa-YG, and G is C-linked heteroaryl or optionally substituted aryl, then Rx is another apart from hydrogen or alkyl, or when R3 is -C (0) -CHa-ZG, then Rt is another apart from hydrogen or alkyl, or when R3 is -C (0) -CHa-0-E, and E is optionally substituted aryl, then R1 is another apart from hydrogen or methyl, or when R3 is -C (0) -CH2-Y '-ZG , and G is optionally substituted aryl, then Rx is another apart from hydrogen or alkyl; or when R3 is -C (0) -CHa-Y '-Z-A, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino, then Rx is another apart from hydrogen or alkyl.

Preferred Values for All Modalities of the Invention Each of the following preferred value groups applies to all embodiments of the present invention, unless specifically stated otherwise. Preferred compounds of Formula I include compounds wherein R is hydrogen or lower alkoxy, with hydrogen being the most preferred; R3 is as defined above, and is preferably one of the groups described below; R5, R6, R7, R8, R, and R10 are hydrogen; and R ,. is substituted arylalkyl, p. ex. RL is 4-substituted phenylalkynyl such as 4-acetylphenylethynyl, 4-methoxyphenylethynyl, 4-N, N-dimethylaminophenylethynyl, 4-cyano-phenylethynyl, 4-carboxyphenylethynyl ethyl ester, 4-N, N-dialkylaminophenylethynyl, or wherein Rx is oxoalkynyl, hydroxyalkynyl, acetoxyalkynyl, cyanoalkynyl, or alkoxyalkynyl. Additional preferred compounds are compounds of Formula I wherein R is hydrogen, halo, minor alkoxy, alkynyl or substituted alkynyl; RL is substituted arylethynyl; Ra is hydrogen, a keto group or a dimethylamino group; R "is hydrogen or methyl; Rs, Rs, R7, R ", R9 and R10 are each hydrogen; and all dotted lines represent simple links. Additional preferred compounds are compounds of Formula I which are hydroxyl ester groups in the 3-position. Preferred esters are those obtained from their corresponding dioic acids and acids: acetic, propionic, maleic, fumaric, ascorbic, pimelic, succinic, glutaric , bismethylene salicylic, methanesulfonic, ethane-di-sulfonic, oxalic, tartaric, salicylic, citric, gluconic, itaconic, glycolic, p-aminobenzoic, aspartic, glutamic, gamma-amino-butyric, a - (2-hydroxyethylamino) propionic, glycine and other ot-amino acids, phosphoric, sulfuric, glucuronic, and 1-methyl-1,4-dihydronicotinic.

DERIVATIVES 17-Ether of 3a-Hydroxy Androstanes A first sub-genus of compounds according to the present invention include 17-ether derivatives of 3a-hydroxy androstanes. The steroid derivatives of this aspect of the present invention include those having the structural Formula I, as shown above, wherein: R, RL, R2, R4, RS, Rβ, R7, Rβ, R9 and R10 are as defined previously for the Modality la; and R3 is one of alkoxy, substituted alkoxy, alkenoxy, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy or -OC (0) NR'R ", wherein R 'and R" independently represent hydrogen, optionally substituted alkyl, or taken together they form a 5- or 6-membered heterocyclic ring; provided that: when R3 is C4 alkoxy or C2-alkenyloxy and R is hydrogen or a-methyl, then Rx is another apart from hydrogen; and when R3 is C1-4alkoxy alkoxy (d-, then Rx is another apart from hydrogen or 1-propynyl. Preferred values in this aspect of the present invention include as generally preferred those values indicated above, and also the following: R3 is alkoxy, such as methoxy, ethoxy or propoxy, or substituted alkoxy, such as -OCHaCHaOH, -OCH2C = CH or OCHaC = C-PhCOMe; R 4 is hydrogen or lower alkyl, more preferably hydrogen or methyl; Rs, Rβ, R7, Rβ, R9 and R10 are each preferably hydrogen; and all dotted lines represent simple links. Preferred compounds according to this aspect of the invention include: 3a-hydroxy-3β-phenylethynyl-17β-methoxy-5β-androstane; 3-hydroxy-3β-phenylethynyl-17β-methoxy-5α-androstane; 3a-hydroxy-3β- (3 ', 4'-dimethoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3-hydroxy-3β- (4'-methylphenyl) ethynyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (2'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3o-hydroxy-3β- (4 '-carboxyphenyl) ethynyl-17β-methoxy-5β-androstane ethyl ester; 3c-hydroxy-3β- (4'-acetoxyacetylphenyl) ethynyl-17β-methoxy-5β-androstane; 3? F-hydroxy-3β- (4'-acetylphenyl) ethynyl-3a-hydroxy-17β-methoxy-5α-androstane; 3-hydroxy-3β- (4'-methylphenyl) ethynyl-17β-methoxy-5β-androstane; 3o; -hydroxy-3β- (2'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (41-carboxyphenyl) ethynyl-17β-methoxy-5β-androstane ethyl ester; 3a-hydroxy-3β- (4'-acetoxyacetylphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-acetylphenyl) ethynyl-3? F-hydroxy-17β-methoxy-5-CF-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (41-dimethylaminophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-biphenyl) ethynyl-3-hydroxy-17β-methoxy-5β-androstane; 3o * -hydroxy-3β- (4'-nitrophenyl) ethynyl-17β-methoxy-5β-androstane; 3? F-hydroxy -3- (4'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4 '-trif luoromethylphenyl) e t inyl-3 or; -hydroxy-17β-met oxy-5β-androstane; 3ß- (4 * -chlorophenyl) ethynyl-3? F-hydroxy-17β-methoxy-5β-androstane; 3ß- (4 • -cyanofenyl) ethynyl-3a! -hydroxy-17β-methoxy-5β-androstane; 3β- (4 '(R / S) -hydroxypentinyl) -3QÍ-hydroxy-17β-methoxy-5β-androstane; 3-hydroxy-3β-phenyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β-benzyl-17β-methoxy-5β-androstane; 3? F-hydroxy-3β- (2'-phenylethyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [2 (3 *, 4'-dimethoxyphenyl) ethyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [6'-oxo-1 '-heptinyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [7'-oxo-1'-octinyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [4 '-oxo-1' -pentinyl) -17β-methoxy-5β-androstane; 3β- [5 '- (R / S) -hydroxyhexinyl] -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4 '-hydroxybutynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3ß- (4'-acetoxy-en-ethynyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetyl) eniletinyl) -3α-hydroxy-19-nor-17β-methoxy-5β-androstane; 3ß- (4 * -carboxyphenylethynyl) -3a-hydroxy-19-nor-17β-methoxy-5β-androstane ethyl ester; 3ß- (4'-carboxyphenylenetinyl) -3-hydroxy-17β-me t oxy -5β- androstane ethyl; 3ß- [4 * - (N, N-diethylcarboxamido) phenyl] ethynyl-3 a-hydroxy-17β-methoxy -5ß-androstane; 3a-hydroxy-3β- [5-oxo-l-hexinyl] -17β-methoxy-5β-androstane; 3 '-hydroxy-3β- [5'-oxo-1'-hexinyl] -17β-methoxy-5β-androstane cyclic 5' - (1,2-ethanediyl acetal); 3β- (5-cyano-l-pentynyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (2-pyridyl) ethynyl-17β-methoxy-5β-androstane; 3-fi- (6-hydroxy-1 -hexinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3ß- (61-hydroxy-1 '-hexinyl) -3a-hydroxy-17β-methoxy-5β-androstane 6 * -hemisuccinate salt; 3β- (5 '-hydroxy-1 * -pentinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (5 '-hydroxy-1' -pentinyl) -3a; -hydroxy-17β-methoxy-5β-androstane 5 '-hemisuccinate salt; 3β- (41-hydroxy-1'-butynyl) -3a-hydroxy-17β-methoxy-5β-androstane 4 '-hemisuccinate sodium salt; 3β- (4'-cyano-1'-butynyl) -3β! -hydroxy-17β-methoxy-5β-androstane; 3β- (5'-acetoxy-1'-pentinyl) -3-oc-hydroxy-17β-met oxy-5β-androstane; 3β- (4"-acetoxy-1 '-butinyl) -3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetoxy-1'-butynyl) -3? F-hydroxy-17β- methoxy-5-cyc-androstane; 3ß- (6 '-acetoxy-1' -hexinyl) -3? -f-hydroxy-17β-methoxy-5β-androstane; 3o? -hydroxy-3β- [3- (2? -propynyloxy) ) - 1-propynyl] -17β-methoxy-5β-androstane; 3? F-hydroxy-3β- [3- (methoxy) -1-propynyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- ( 3-methoxy-1-propynyl) -17β-methoxy-5α-androstane; 3α-hydroxy-3β- [3- (4'-pyridinyloxy) -1-propynyl] -17β-methoxy-5β-androstane; 3? F-hydroxy-3β- [3- (1 H-1,2,3-triazol-1-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3-hydroxy-3β- [3- (2'H-1, 2,3-triazol-2 * -yl) -1-propynyl] -17β-methoxy-5β-androstane; 3c? -hydroxy-3β- (2'-thienyl) ethynyl-17β-methoxy-5β-androstane; 3?! - hydroxy-3β- (3'-phenyl-1 '-propinyl) -17β-methoxy-5β-androstane; 3-hydroxy-3β- (3'-phenylpropyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [3- (1H-pyrazol-1-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3β- (3'-acetylphenylethynyl) -3o-hydroxy-17β-methoxy-5β-androstane; and 3β- (3'-acetoxy-3'-propynyl) -3a-hydroxy-17β-methoxy-5β-androstane. The most preferred neuroactive steroids according to this aspect of the present invention include 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β- (4'-carboxy phenyl) ethynyl-3a; -hydroxy-17β-methoxy-5a-androstane ethyl ester; 3β- (4'-acetylphenyl) ethynyl-3? F-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-carboxyphenyl) ethynyl-3o; -hydroxy-17β-methoxy-5β-androstane ethyl ester; 3β- (4'-Acet-il-enyl-Jet-inyl-3? -f-hydroxy-17β-methoxy-5β-19-nanoandrostane; 3ß- (4'-carboxyphenyl) ethynyl-3a-hydroxy-17β-methoxy-5ß- ester 19-norandrostane ethyl; 3ß- (4'-dimethylaminofenyl) ethynyl-17β-methoxy-5β-androstane; 3ß- (4 * -bifinyl) and inyl-3o.! -hydroxy-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (4'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3ß- (4'-rif luoromethylphenyl) ethynyl-3a-hydroxy-17β-met oxy-5β-androstane; (4'-chlorofenyl) ethynyl-3a-hydroxy-17β-methoxy-5β-androstane; 3β- [4 '(R / S) -hydroxypentinyl] -3? F-hydroxy-17β-methoxy-5β-androstane; - (4 '-hydroxybutynyl) -3o? -hydroxy-17β-methoxy-5β-androstane; 3β- (41-hydroxybutynyl) -3o; -hydroxy-17β-methoxy-5-CY-androstane; and 3-hydroxy-3β- [ 3- (2'Hl, 2, 3-triazol-2'-yl) -17β-methoxy-5β-androstane Neuroactive steroids especially preferred according to this aspect of the present invention include 3β- (4 • -acetylphenyl) ) ethynyl-3o; -hydroxy- 17β-methoxy-5α-androstane; 3β- (4'-acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4 '-carboxyl phenyl) ethynyl -3o; -hydroxy-17β-methoxy-5-y! -androstane ethyl ester; 3β- (4'-carboxymethyl) et ini 1-3-hydroxy-17-methoxy-5β-androstane ethyl ester; 3β- (4'-dimethylaminofenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-biphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4 '-hydroxybutynyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (4 '-hydroxybutynyl) -3α? -hydroxy-17β-methoxy-5aj-androstane; 3a-hydroxy-3β- [3- (2'H-1, 2,3-triazol-2-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3β- (4'-acetyl phenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-19-nanoandrostane; and 3β- [4 '(R / S) -hydroxypentinyl] -3α-hydroxy-17β-methoxy-5β-androstane. 3a-Hydroxy Androstane Derivatives A second preferred subgenus of compounds according to the present invention includes 3o-hydroxy androstane derivatives that are unsubstituted at the I7β- position of the steroid ring system, e.g. ex. , R3 is hydrogen. Steroid derivatives of this aspect of the present invention include those having the structural Formula I as shown above, wherein R 3 is hydrogen; and R, Rlf Ra, R3, R4, R5, Rs, R7, R9, R9 and R10 are as defined above for Modality a; provided that R. is not hydrogen, alkyl or cyanoalkyl. Preferred values for R, Rj., R 2, R 3, R 4, Rs, R,., R 7, R 8, R 9 and R 10 those values listed above as preferred for all embodiments of the invention. 21-Substituted 3a-Hydroxy Pregnano Derivatives A third category of compounds useful according to the present invention include 3o; -hydroxypregnane derivatives having a 21-ether or 21-thioether linkage, or 21-alkyl, 21-alkenyl or 21-alkynyl. Compounds that could be used in this aspect of the present invention include those having the structural Formula I, shown above, wherein: R, Rlf R 2, R 3, R 4, RS, R 5, R 7, R b R 9 and R 10 are as were previously defined for Formula I; R3 is one of -C (O) -CH.-YG, -C (0) -CHa-0-D, -C (O) -CHa-0-E, -C (0) -CHa-Y'- ZG or -C (0) -CHj-Y '-ZA; And it is one of S, SO or S02; Y 'is one of 0, S, SO or S02; Z is one of alkyl, alkenyl or alkynyl; G is one of C-linked heteroaryl, optionally substituted aryl, a quaternary ammonium salt of a nitrogen containing heteroaryl group or a quaternary ammonium salt of a substituted aryl group; D is heteroaryl attached to C or a quaternary ammonium salt of a nitrogen containing heteroaryl group; E is optionally substituted aryl of a quaternary ammonium salt of a substituted amino aryl group; A is one of amino, amido, cyano, thiocyano, azido, nitro, hydroxy, halo, carboxyl, alkoxy, alkoxycarbonyl, alkanoyloxy, hydrogen, sulfate, thiosulfate, sulfonate, alkylthio, alkylsulfinyl, alkylsulfonyl or mercapto; provided that: when R3 is -C (0) -CH2-Y-G, and G is heteroaryl attached to C or optionally substituted aryl, then R-. it is another apart of hydrogen or alkyl; or when R3 is -C (0) -CHa-0-E, then R ,. it is another apart from hydrogen; or when R3 is -C (0) -CHa-Y '-Z-G, and Y' is O, and G is aryl, then Rt is another apart from hydrogen; or when R3 is -C (0) -CH2-Y '-Z-G, and Y' is S, SO, or S02, and G is aryl, then R- is another apart from hydrogen or alkyl; or when R3 is -C (0) -CH2-Y * -Z-A, and Y 'is 0, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino, then R1 is another apart from hydrogen; or when R3 is -C (0) -CH2-Y '-ZA, and Y' is S, SO, or S02, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, or amino, then Rx is another apart from hydrogen or I rent. Alternatively, R3 could also be -C (0) -CH2-Z-G; where Z and G were defined directly before, with the proviso that when R3 is -C (0) -CH2-Z-G, then Rx is another apart from hydrogen. When D or G are heteroaryl attached to C, the preferred heteroaryl radicals include pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, triazolyl, tetrazolyl, quinolinyl, indolyl, benzimidazolyl, and isoquinolinyl. When E or G are substituted aryl, preferred groups include phenyl, substituted by one, two, or three, more preferably one, of nitro, amino, dimethylamino, carboxy, methyl, hydroxy, methoxy, fluoro, chloro, bromo, cyano or pyrrolidinyl. Examples of suitable values of the substituents that could be used in the R3 position in this aspect of the invention include -C0CH2S- (4-PhNHa), -COCHaO- (4-PhN * Me3)] -C0CHa0-4-pyridyl, -COCH20-3-pyridyl, -C0CHaS- (4-pyridyl) N -methyl, -COCH2SCHaCH2OH, -COCH2OCHaCHaOH, COCH2SCHaCHaCHaOH, -COCH2SOCH2CH2CH2OH, -COCH2S02CH2CHaCHaOH, -COCH2SCH2COO-Na +, -COCH2SCH2CH2COO "Na *, -COCH2SCH2CH2OS03-TMA * (TMA is an abbreviation for trimethylammonium), -COCH2SCH2CH2CH2OS03"Na *, -COCH2SCH2CH2S03" Na *, -COCH2SCHaCH2CH2S03"Na *, COCH2S02CHaCH2CHaS03'Na * and -COCH2OCHaCH2CH2S03-Na *. Additional suitable values include -C0CH2S- (4-f luorofenyl), -COCH20- (6-quinolinyl), -COCHaSOa- (4-f-chlorophenyl), -COCH2S02- (4-pyrrolidinophenyl), -COCH2CH2- (4-pyridyl) ), -C0CH20- (4-nitrofenyl), -COCHaO- (4-dimethylaminophenyl), -COCH2SO- (4-nitrophenyl) and -C0CHaS0a- (4-nitrofenyl) The preferred compounds according to this aspect of present invention include: 3o -: - hydroxy-3β- (4-hydroxybutynyl) -21- (pyrid-4-yl thio) -5β-pregnan-20 -one; 3a-hydroxy-21- (pyrid-4-yloxy) -5β-pregnan-20-one; sodium 3a-hydroxy-2β-propoxy-21-thiopropanesulfonate-5a-pregnan-20-one salt; 3β-ethynyl-3a-hydroxy-21- (3'-hydroxypropylthio) -5β -pregnan-20-one; sodium 3ß-ethynyl-3o? -hydroxy-21- (thiopropanesulfate) -5ß-pregnan-20-one salt; iodide 3of-hydroxy-2β-propoxy-21- (pyrid-4-ylthio) ) -5of-pregnan-20-one of N-methyl; iodide 3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one of N-methyl; salt 3ß-ethynyl-3o-hydroxy- 21-thioethanesulfate-5β-pregnan-20-onade trimethylammonium; a-hydroxy-3β-methoxymethyl-21- (pyrid-4-ylthio) -5o; -pregnan-20-one; 21- (4'-Aminophenylthio) -3a-hydroxy-3β-methoxymethyl-5a! -pregnan-20-one; 21- (4'-dimethylaminophenylthio) -3a! -hydroxy-3β-methoxymethyl-5a-pregnan-20 -one; 3o-hydroxy-3β-ethoxymethyl- 21- (4'-nitrophenylthio) -5a-pregnan-20-one; 3a-hydroxy-3β-methoxymethyl-21- (4'-nitrofenylsulfinyl) -5oi-pregnan-20-one; 3o? -hydroxy-3β-methoxymethyl-21- (41-nitrofenylsulfonyl) -5? F-pregnan-20-one; 21- (4'-dimethyl ilaminofenoxi) -3oe-hydroxy-3β-methyl-5? F-pregnan-20-one; 3? F-hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5a-pregnan-20-one; 3a-hydroxy-3β-methyl-21- (4'-trimethylammoniofenoxi) -5? í-pregnan-20-one iodide salt; sodium 3β-ethynyl-3α-hydroxy-21-thiopropanesulfonate-5β-pregnan-20-one salt; 3β-ethynyl-3o ./- hydroxy-21- (3 '-hydroxpropyl sulphonyl)) -5β-pregnan-20-one; 3a-hydroxy-21- (3 '-hydroxpropylthio)) -2β-propoxy-5a-pregnan-20-one; 3α-hydroxy-21- (3 '-hydroxpropylsulfonyl)) -2β-propoxy-5? F-pregnan-20-one; sodium 3a-hydroxy-2-propoxy-21-sulphonylpropanesulf ato-5a-pregnan-20-one sodium salt; 21- (4 '-fluorophenyl thio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one; 3β-ethynyl-3c -! - hydroxy-21- (pyrid-4-ylthio) -5?!-Pregnan-20-one; 3ß- (4 • -acetyl-enyl) -ethynyl-3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one; 3a-hydroxy-2β-propoxy-21- (4 '-N, N, N-trimethylammoniofenoxi) -5a-pregnan-20-one iodide salt; 3of-hydroxy-3β-methyl-2l- (quinolin-6-yloxy) -5β-pregnan-20-one iodide N-methyl iodide; 3a-hydroxy-3β-methyl-21- (quinolin-6-yloxy) -5o-pregnan-20-one; 21- (4 '-fluorophenyl) sulfonyl-3α-hydroxy-3β-methoxymethyl-5ar-pregnan-20-one; and 3a-hydroxy-3β-methoxymethyl-21- (4'-pyrrolidinophenyl) sulfonyl-Sce-pregnan-20-one. The most preferred neuroactive steroids according to this aspect of the present invention include 3a-hydroxy-3β- (4 '-hydroxybutynyl) -21- (pyrid-4-ylthio) -5β-pregnan-20-one; 3a-hydroxy-21- (pyrid-4-yloxy) -5β-pregnan-20-one; sodium 3a-hydroxy-2β-propoxy-21-thiopropanesulfonate-5c-.f-pregnan-20-one salt; 3β-ethynyl-3α-hydroxy-21- (3 '-hydroxypropylthio)) -5β-pregnan-20-one; 3a-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylsulfinyl) -5a-pregnan-20-one; 3c-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylsulfonyl) -5a; -pregnan-20-one; 3a-hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5? F-pregnan-20-one; 3a-hydroxy-21- (3 '-hydroxypropylthio)) -2β-propoxy-5a-pregnan-20-one; 3a-hydroxy-21- (3 * -hydroxypropylsulfonyl)) -2β-propoxy-5o.r-pregnan-20-one; and sodium 3a-hydroxy-2β-propoxy-21-sulfonylpropanesulfate-5a-pregnan-20-one salt. Especially preferred neuroactive steroids according to this aspect of the present invention include 3 < x-hydroxy-3β- (4-hydroxybutynyl) -21- (pyrid-4-ylthio) -5β-pregnan-20-one; 3a-hydroxy-3β-methoxymethyl-21- (pyrid-4-ylthio) -5a-pregnan-20-one; 3a-hydroxy-21- (3 '-hydroxypropylsulfonyl)) -2β-propoxy-5a-pregnan-20-one; and 3?! -hydroxy-21- (pyrid-4-yloxy) -5β-pregnan-20-one.

Diastereomers It will be obvious to one skilled in the art that the compounds described above could be present as mixtures of diastereomers that could be separated into individual diastereomers. The resolution of the diastereomers could be conveniently accompanied by gas or liquid chromatography or isolation from natural sources. Unless otherwise specified herein, the reference in the specification and claims to the compounds of the invention, as discussed above, is intended to include all isomers, either separate or mixtures thereof. Where the isomers are separated, the desired pharmacological activity will frequently predominate in one of the diastereomers. As discussed herein, these compounds exhibit a high degree of stereospecificity. In particular, those compounds that have the highest affinity for the GABA receptor complex are those with 3β-substituted-3α-hydroxypregnane steroid structures.

Synthesis Methods The compounds according to the invention could be prepared by any convenient method, e.g. ex. , using conventional techniques as described in Djerassi, Steroid Reactions. Holden-Day, Inc., San Francisco (1963), or Fried and Edwards, Orsanic Reactions in Steroid Chemistry.

Van Nostrand-Reinhold Co., New York (1972). The C17 ethers of the present invention are prepared from 17β-hydroxy compounds by methods well known to those skilled in the art of preparing ethers from the corresponding alcohols. Most of these methods are described in Larock, Comprehensive Orsanic Transformations VCH Publishers, Ney York (1989). The initial 17β-hydroxy materials are well known to those skilled in the art. It is advisable to protect the 3-keto group before the formation of a ketal. The ketal could then be reacted by known methods to form the C17 ether and the hydrolyzed ketal to obtain the 3-keto-17-ether compounds. Several nucleophiles can be added to the 3-one of these compounds to obtain the 3β-substituted derivatives-3c? -hydroxy-C17-ether. Another method to obtain the C17 ethers is by means of the reaction of C17 ketals, obtained from the corresponding C17 onas with lithium aluminum hydride and A1C13 as described in Cross et al., Steroids 5: 557 (1965). The phenylethynyl substituents can be prepared by means of palladium (Pd) catalysis accompanied by the corresponding ethinyl derivatives with phenyliodides or phenyl bromides in the presence of an amine. The C21 bromides, used as starting materials in the examples, were all prepared using the process for preparing alpha-bromo-ketones from methyl ketones. This procedure is well known to those skilled in the art.

Pharmaceutical Uses The compounds of and used in the invention, which are non-toxic, pharmaceutically acceptable, natural and synthetic, of direct action and forms of "prodrug" of steroid derivatives, have hitherto unknown activity in the brain in the GABAA receptor complex . The present invention takes advantage of the discovery of this previously unknown mechanism and activity. The pharmaceutical compositions of this invention are prepared in conventional dosage unit forms by incorporating an active compound of the invention or a mixture of such compounds, with a non-toxic pharmaceutical carrier according to accepted procedures in a sufficient non-toxic amount to produce the pharmacodynamic activity desired in a subject, animal or human. Preferably, the composition contains the active ingredient in an active, but non-toxic, amount selected from about 1 mg to about 500 mg of active ingredient per unit dosage. This amount depends on the specific biological activity desired and the condition of the patient.

The pharmaceutical carrier employed could be, for example, a solid, liquid or prolonged release (see eg Remington's Pharmaceutical Sciences. (1970)). Representative solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, microcrystalline cellulose, polymer hydrogels, and the like. Typical liquid carriers are propylene glycol, glycofurol, aqueous solutions of cyclodextrins, syrup, peanut oil, and olive oil and similar emulsions. Similarly, the carrier or diluent could include any delay material well known in the art, such as glycerol monostearate or glycerol distearate alone or with wax, microcapsules, microspheres, liposomes, and / or hydrogels. A wide variety of pharmaceutical forms can be used. In this way, when a solid carrier is used, the preparation can be completely micronized, in oil, in tablets, placed in a hard gelatin capsule or micronized powder enteric shell or tablet form, or in the form of a pill or lozenge. The compounds of the present invention could also be administered in the form of suppositories for rectal administration. The compounds could be mixed in materials such as cocoa butter and polyethylene glycols or other suitable non-irritating material which is solid at room temperature but liquid at the rectal temperature. When a liquid carrier is used, the preparation may be in the form of a liquid, such as an ampule or an aqueous or non-aqueous liquid suspension. Liquid dosage forms also need pharmaceutically acceptable preservatives. In addition, because low doses are required, as is based on the results set forth herein, parenteral administration, nasal spray, sublingual and buccal administration, extended release skin patches are also pharmaceutically appropriate forms for topical administration. The method of anxiolytic, anticonvulsive, humoral (such as anti-depressant) or hypnotic activity, according to this invention, comprises administering to a subject in need of such activity a compound of the invention, usually prepared in a composition as is described above with a pharmaceutical carrier, in a sufficient non-toxic amount to produce said activity. During menstruation the levels of excreted progesterone metabolites vary approximately four times (Rosciszewska et al., J. Neurol-Neurosurs., Psych- 49: 47-51 (1986)). Therefore, therapy to control symptoms involves maintaining the patient at a higher level of progesterone metabolites than the normal premenstrual state of PMS patients. Plasma levels of active and major metabolites are monitored during pre-menstruation and post-menstruation of the patient. The amount of compounds of the invention administered, either singly or as mixtures thereof, are calculated in this manner to achieve a level of activity that will exert the GABA receptor »equal to or greater than the level of progesterone metabolites in the normal subject during the premenstrual state. The sleep-induced method that substantially maintains the level of REM sleep found in normal sleep, where substantial rebound insomnia is not induced, according to the present invention, comprises administration to a subject in need of such an activity of an effective amount of a steroid derivative described herein. The compounds of the invention can increase REM sleep and the total sleep period, without substantially affecting the amount of REM sleep. Rebound insomnia is defined as the reduction of NREM sleep after the hypnotic action of treatment has returned to control levels. Methods for evaluating the effects of the compounds of the invention on REM and NREM sleep are set forth in WO94 / 27608, published on December 8, 1994, the content of which is fully incorporated herein by reference.

The route of administration could be any route that effectively transports the active compound to the receptors GABAA that they will be stimulated. The administration could be carried out parenterally, enterally, rectally, intravaginally, intradermally, intramuscularly, sublingually, or nasally; oral intramuscular and dermal routes are preferred. For example, a dose in a thermal patch could provide the active ingredient to the patient for a period of up to one week. However, the parenteral route for stratus epilepticus is preferred. The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other appropriate modifications and adaptations of the variety of conditions and parameters normally found obvious to those skilled in the art are within the spirit and scope of the invention.

Example 1 3a-Hydroxy-17β-methoxy-3β- (3 * -methylbut-3 • -en-1 * -inyl) -5E-androstane A solution of 2-methyl-1-buten-3-ina (150 mg, 0.21 mL, 2. 25 mmol) in dry THF (20 mL) was treated with n-BuLi (2.5 M in THF, 2.25 mmol, 0.9 mL) at -70 ° C. After stirring the mixture at -75 ° C for 0.5 hr, a solution of 17β-methoxy-5ar-androstan-3-one (228 mg, 0.75 mmol) in THF (20 mL) was added and the mixture was stirred at - 78 ° C for 30 min. The cooling bath was removed and the mixture was quenched with NH 4 Cl solution (2 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. The solution was filtered and evaporated to obtain a crude product. This crude product was then dissolved in a small amount of CH 2 Cl and was poured onto a column of silica gel. Elution with hexanoacetone (9: 1) mixture gave 3a-hydroxy-17β-methoxy-3β- (3'-methylbut-3'-en-1-ynyl) -5β-androstane (133 mg) as a colorless solid.; mp 145-147 ° C; TLC Rf (hexanoacetone 85:15) = 0.21.

Example 2 3a- (4 * -Hydroxy-1'-butynyl) -3β-hydroxy-17β-methoxy-5β-androstane and 3β- (4 * -Hydroxy-1'-butynyl) -3a-hydroxy-17β-methoxy- 5β-a-n-threstan A solution of 3-butyn-1-ol (0.114 mL, 1.5 mmol) in dry THF (20 mL) was treated with n-BuLi (1.2 mL, 2.5 M in THF, 3 mmol, 0.9 L) at -75 ° C. After stirring the mixture at -78 ° C for 0.5 hr, a solution of 17β-methoxy-5β-androstan-3-one (152 mg, 0.5 mmol) in THF (20 mL) was added and the mixture was stirred at - 78 ° C for 5 min. Then the cooling bath was removed and the mixture was continued stirring at room temperature for 45 min. The mixture was then quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with toluene: acetone (4: 1) mixture gave 3a- (4'-hydroxy-1'-butynyl) -3β-hydroxy-17β-methoxy-5β-androstane (20 mg) and then 3β- (4 ') -hydroxy-1 * -butinyl) -3a-hydroxy-17β-methoxy-5β-androstane (70 mg) as a colorless solid; mp 132-134 ° C; TLC Rt (toluene: acetone 4: 1) = 0.19.

Example 3 3β- (4'-Hydroxy-1'-butynyl) -3a-hydroxy-17β-methoxy-5a-androstane 4'-hemisuccinate and sodium salt thereof A solution of 3β- (4 • -hydroxy-1 ') -butinyl) -3a-hydroxy-17β-methoxy-5? f-androstane (350 mg, 0.93 mmol) in pyridine (6 mL) was treated with succinic anhydride (372 mg, 3.7 mmol) and 4- (N, N. dimethyl) aminopyridine (20 mg). The mixture heated to 70-75 ° C for 3 hr. The TLC showed 100% conversion. It was cooled to room temperature and cold 2N HCl was emptied. The organics were extracted with EtOAc. The organic layer was washed with 0.2 N HCl, water and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH 2 Cl and was poured onto a column of silica gel. Elution with hexane: acetone mixture (7: 3) gave 3β- (4'-hydroxy-1-butynyl) -3a-hydroxy-17β-methoxy-5a-androstane 4'-hemisuccinate (360 mg). A mixture of above hemisuccinate (360 mg 0.76 mmol), NaHCO 3 (64 mg 0.76 mmol), water (3 mL), and CH 2 Cl 12 (5 mL) was stirred at room temperature for 1 hour. The solvent was removed and the residue was suspended in acetone (5 mL). The white solid was then collected by filtration and dried to obtain the sodium salt as a colorless solid (210 mg).

Example 4 3β- (4'-Hydroxy-1'-butyl) -3a-hydroxy-17β-netoxy-5a-androstane and 3a- (4'-Hydroxy-1 • -butinyl) -3β-hydroxy-17β-methoxy -5a-androstane A solution of 3-butin-1-ol (0.15 mL, 2 mmol) in dry THF (15 mL) was treated with n-BuLi (1.6 mL, 2.5 M in THF, 4 mmol) at -75 °. C. After stirring the mixture at -78 ° C for 0.5 hr, a solution of l7β-methoxy-5a-androstane-3-one (304 mg, 1 mmol) in THF (20 mL) was added and the mixture was stirred at - 78 ° C for 5 min. The cooling bath was then removed and stirring was continued at room temperature for 45 min. The mixture was then quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH3C12 and emptied onto a column of silica gel. Elution with toluene: acetone mixture (4: 1) gave 3β- (4'-hydroxy-1'-butynyl) -3a-hydroxy-17β-methoxy-5β-androstane (50 mg) mp 184-186 ° C; TLC Rf (toluene: acetone 4: 1) = 0.35; and then 3a- (4 '-hydroxy-l' -butinyl) -3β-hydroxy-17β-methoxy-5a-androstane (225 mg) as a colorless solid, - mp 185-187 ° C; TLC Rf (toluene: acetone 4: 1) = 0.24.

Example 5 3a-Hydroxy-17β-methoxy-3a-methyl-5a-androstane and 3β-hydroxy-17β-methoxy-3a-methyl-5a-androstane A solution of 17β-methoxy-5a-androstan-3-one (101 mg , 0. 33 mmol) in dry THF (20 mL) was treated with MeLi (1 mL, 1.5 M in THF, 1.5 mmol) at -75 ° C. After stirring the mixture at -78 ° C for 0.5 hr, the mixture was quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine.

After drying thoroughly with MqSO, anhid. The solution is filtered and evaporated to give the crude product. This crude product was dissolved in a small amount of CH2 CI2 and was emptied < 5 so | -re one of silica gel. Elution with toluene: acetone (95: 5) mixture gave 3β-methyl-3a-hydroxy-17β-methoxy-5a-androstane (30 mg) as a colorless solid; TLC Rf (hexane: acetone 7: 3) = 0.27.

Example 6 3a-Hydroxy-17β-methoxy-3β-trifluoromethyl-5α-androstane and 3β-hydroxy-17β-methoxy-3α-fluoromethyl-5α-androstane A solution of 17β-methoxy-5α-androstan-3-one (220 mg , 0.75 mmol) in dry THF (20 mL) was treated with trifluoromethyltrimethylxilane (3 mL, 0.5 M in THF, 1.5 mmol), and tetrabutylammonium fluoride (TBAF) (10 mg) at 0 ° C. A solution of TBAF (1 M in THF, 2 mL, 2 mmol) was added. The mixture was stirred at room temperature for 10 min. it was quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with a mixture of hexane: ethyl acetate (9: 1) gave 3β-trifluoromethyl-3a-hydroxy-17β-methoxy-5a-androstane (9 mg); TLC Rt (hexane: EtOAc 8: 2) = 0.51; and then 3a-trifluoromethyl-3β-hydroxy-17β-methoxy-5a-androstane (170 mg) as a colorless solid; TLC Rc (hexane: EtOAc 8: 2) = 0.45.

Example 7 3a-Hydroxy-17β-methoxy-3β-trifluoromethyl-5a-androstane A solution of l7β-methoxy-5a-androstan-3-one (304 mg, 1 mmol) in dry THF (20 mL) was treated with trifluoromethyltrimethylsilane ( 7 mL, 0.5 M in THF, 3.5 mmol), and TBAF (10 mg) at 0 ° C. After stirring the mixture at 23 ° C for 2 hr, the mixture was cooled to 0 ° C. A solution of TBAF (1 M in THF, 3.5 mL, 3.5 mmol) was added. The mixture was stirred at room temperature for 10 min. and then quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with a mixture of hexane: ethyl acetate (9: 1) gave 3β-trifluoromethyl-3a-hydroxy-17β-methoxy-5β-androstane (220 mg); mp 122-127 ° C; TLC Rr (hexane: EtOAc 8: 2) = 0.38.

Example 8 3a-Hydroxy-17β-methoxy-5β-androstane A solution of 17β-methoxy-5β-androstan-3-one (130 mg, 0.42 mmol) in dry THF (15 mL) was treated with lithium tri hydride (ter -butoxy) aluminum (1 mL, 1 M in THF, 1 mmol) at -73 ° C.

After stirring the mixture at -75 ° C for 3 hr and then at -10 ° C for 1.5 hr, the mixture was quenched with NaOH solution (1 N, 2 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product.

This crude product was then dissolved in a small amount of CH2C13 and emptied onto a column of silica gel. Elution with toluene: acetone mixture (9: 1) gave 3a-hydroxy-17β-methoxy-5β-androstane (107 mg); mp 151-156 ° C; TLC Rt (hexane: acetone 7: 3) = 0.18.

Ejepplo 9 17ß- (2-Propynyloxy) -5a-androstan-3-one A solution of cyclic 17β-hydroxy-5a-androstan-3-one 3- (1,2-ethanediilacetal) (1.03 g, 3 mmol) in THF Dry (20 mL) was treated with KOt-Bu (12 mL, 1 M in THF, 12 mmol) at 23 ° C. After stirring the mixture at 55 ° C for 2.5 hr, it was cooled to -50 ° C. Propargyl bromide (80% solution in toluene, 1.3 mL, 11 mmol) was added and the stirring was continuous at 50-55 ° C for 2.5 hr. The solvents were removed and the residue was treated with acetone (25 mL). After acidifying the mixture with 2N HCl, it was stirred at room temperature for 15 hr. The mixture was neutralized with 2 N NaOH solution. The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane: acetone (8: 2) mixture gave 17β- (2-propynyloxy) -5a-androstan-3-one (700 mg).

Example 10 3a-Hydroxy-3β-methyl-17β- (2-propynyloxy) -5a-androstane and 3β-Hydroxy-3a-methyl-17β- (2-propynyloxy) -5a-androstane A solution of 17β- (2-propynyloxy) -5a-androstan-3-one (230 mg, 0.7 mmol) in dry THF (20 mL) was treated with MeLi (5 mL, 1 M in THF, 5 mmol) at -70 ° C. After stirring the mixture at -70 ° C for 0.5 hr, the cooling bath was removed and heated to 10 ° C. The mixture was then quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with toluene-acetone mixture (98: 2) gave 3a-hydroxy-3β-methyl-17β- (2-propynyloxy) -5a-androstane (40 mg); TLC Rc (toluene: acetone 95: 5) = 0.31; and then 3β-hydroxy-3α-methyl-17β- (2-propynyloxy) -5a-androstane (70 mg) as a colorless solid; TLC Rt (hexane: acetone 7: 3) = 0.27.

Example 11 17β- [3- (4-Acetylphenyl) -2-propynyloxy] -3a-hydroxy-3β-methyl-5a-androstane A solution of 4-iodoacetophenone (16 mg, 0.06 mmol), 3a-hydroxy-3β-methyl -17β- (2-propynyloxy) -5a-androstane (22 mg, 0.06 mmol) in dry degassed triethylamine (1 mL) was stirred under argon at 23 ° C. Bis chloride was added. { triphenylphosphine) palladium (2 mg) and Cul (2 mg) and the mixture was stirred at this temp. for 45 min. CH2C12 was added and the mixture was stirred at 23 ° C for 1 hr. The TLC showed 100% conversion of the initial material, from here, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane: acetone (85:15) gave 17S- [3- (4-Acetylphenyl) -2-propynyloxy] -3a-hydroxy-3β-methyl-5a-androstane (19 mg); as a colorless solid; mp 52-55 ° C; TLC Rf (hexane: acetone 85:15) = 0.15.

Example 12 17β- (2-Hydroxyethoxy) -3α-hydroxy-5α-androstane A solution of cyclic 3α-hydroxy-5α-androstan-17-one 17- (1,2-ethanediilacetal) (166 mg, 0.5 mmol) in THF dry (10 L) was treated with LAH (18 mg, 0.5 mmol) and A1C13 (266 mg, 2 mmol) at 23 ° C. After stirring the mixture at 45 ° C for 2 hr, it was quenched with NH 4 Cl solution (2 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with dil. HCl, water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2Cl1 and was poured onto a column of silica gel. Elution with hexane: acetone (8: 2) mixture gave 17β- (2-hydroxyethoxy) -3a-hydroxy-5a-androstane (123 mg); mp 181-183 ° C; TLC Rc (hexane: acetone 7: 3) = 0.31.

Example 13 3β-Ethynyl-3α-hydroxy-17β-methoxy-5β-androstane A solution of 1,2-dibromoethylene (1.6 L, 3.7 g, 19.71 mmol) in dry THF (10 mL) was treated with n-BuLi (16.4 mL, 2.4 M in THF, 39.4 mmol) at 75 ° C. After stirring the mixture at -78 ° C for 0.25 hr, a solution of 17β-methoxy-5β-androstan-3-one (2 g, 6.57 mmol) in THF (20 mL) was added and the mixture was stirred at - 78 ° C for 15 min. Then the cooling bath was removed and the mixture was quenched with NH 4 Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product.

This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with toluene: acetone (95: 5) mixture gave 3β-ethynyl-3a-hydroxy-17β-methoxy-5β-androstane (i.70 g) as a colorless solid; mp 62-65 ° C; TLC Rt (toluene: acetone 95: 5) = 0.23.

EXAMPLE 14 3ß- (4'-Acetylphenylethynyl) -3a-hydroxy-17β-metcaci-5β-androstane A solution of 4-iodoacetophenone (112 mg, 0.45 mmol) and 3β-ethynyl-3a-hydroxy-17β-methoxy-5β-androstane (150 mg, 0.45 mmol) in dry degassed triethylamine (1 mL) was stirred under argon at 23 ° C. C. Chloride was added Bis (triphenylphosphine) palladium (5 mg) and Cul (5 mg) and the mixture was stirred at this temp. for 45 min. CH2C12 was added and the mixture was stirred at 23 ° C for 1 hr. The TLC showed 100% conversion of the initial material, from here, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane: EtOAc (7: 3) gave 3β- (4'-acetylphenylethynyl) -3a-hydroxy-17β-methoxy-5β-androstane (130 mg) as a colorless solid; mp 189-191 ° C; TLC Rf (hexane: acetone 4: 1) = 0.31.

Example 15 3a-Ethynyl-3β-hydroxy-17β-methoxy-5a-androstane and 3β-Ethynyl-3α-hydroxy-17β-methoxy-5α-androstane A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in THF Dry (25 mL) was treated with n-BuLi (16.8 mL, 2.5 M in THF, 42 mmol) at -65 ° C. After stirring the mixture at -70 ° C for 0.25 hr, a solution of 17β-methoxy-5a-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at - 78 ° C for 30 min. The cooling bath was then removed and the mixture was quenched with NH 4 Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with toluene: acetone (95: 5) mixture gave 3β-ethynyl-3a-hydroxy-17β-methoxy-5β-androstane (100 mg) as a colorless solid.; mp 138-145 ° C; TLC Rr (hexane: acetone 7: 3) = 0.45; and then 3a-ethynyl-3β-hydroxy-17β-methoxy-5β-androstane (1.6 mg) as a colorless solid.

Example 16 3ß-Ethynyl-3a-hydroxy-17β-methoxy-19-nor-5β-androstane A solution of 1,2-dibromoethylene (0.9 mL, 2.0 g, 10.85 mmol) in dry THF (10 mL) was treated with -BuLi (9 mL, 2.4 M in THF, 21.7 mmol) at -75 ° C. After stirring the mixture at -78 ° C for 0.25 hr, a solution of 17β-methoxy-19-nor-5β-androstan-3-one (1 g, 3.62 mmol) in THF (20 mL) was added and the mixture was added. it was stirred at -78 ° C for 20 min. Then the cooling bath was removed and the mixture was quenched with NH 4 Cl solution (3 mL). The solvents were removed and the residue was extracted with E. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH3C13 and emptied onto a column of silica gel. Elution with toluene: acetone (98: 2) mixture gave 3β-ethynyl-3a-hydroxy-17β-methoxy-19-nor-5β-androstane (750 mg) as a colorless solid; mp 152-154 ° C; TLC Rf (toluene: acetone 7: 3) = 0.58.

Example 17 3ß- (4 * -Acetylphenylethynyl) -3a-hydroxy-17β-methoxy-19-nor-5β-androstane A solution of 4-iodoacetophenone (117 mg, 0.47 mmol) and 3-ethynyl-3a-hydroxy-17β-methoxy-19-nor-5β-androstane (150 mg, 0.47 mmol) in dry degassed triethylamine (1 mL) was stirred under argon at 23 ° C. Bis (triphenylphosphine) palladium chloride (5 mg) and Cul (5 mg) were added and the mixture was stirred at this temp. for 45 min. CH2C12 (5 mL) was added and the mixture was stirred at 23 ° C for 1 hr. The TLC showed 100% conversion of the initial material, from here, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with toluene: acetone (95: 5) gave 3β- (4'-acetylphenylethynyl) -3a-hydroxy-17β-methoxy-19-nor-5β-androstane (105 mg) as a colorless solid; mp 148-150 ° C; TLC R £ (hexane: acetone 4: 1) = 0.52.

Example 18 3a-Hydroxy-17β-methoxy-3β-trifluoromethyl-19-ñor-5β-androstane A solution of 17β-methoxy-19-nor-5β-androstan-3-one (300 mg, 1.08 mmol) in dry THF (15 mL) was treated with trifluoromethyltrimethylsilane (5 mL, 0.5 M in THF, 2.5 mmol), and TBAF (5 mg) at 0 ° C. After stirring the mixture at 23 ° C for 2 hr, the mixture was cooled to 0 ° C. A solution of TBAF (1 M in THF, 3.5 mL, 3.5 mmol) was added. The mixture was stirred at room temperature for 10 min. and then quenched with NH 4 Cl solution (5 mL). The solvents were removed and the residue was extracted with E. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane: acetone (9: 1) mixture gave 3a-idroxy-17β-methoxy-3β-rifluoromethyl-19-ñor-5β-androstane (210 mg); mp 40-42 ° C; TLC Rr (hexane: acetone 7: 3) = 0.66.

EXAMPLE 19 3 (R) -Epiro-2'-oxirane-17β-methoxy-5a-androstane A solution of trimethylsulfoxonium iodide (2.42 g, 11 mmol) and KOt-Bu (1.12 g, 10 mmol) in dry THF (40 g). mL) refluxed for 2 hr. After cooling to room temperature, 17β-methoxy-5a-androstan-3-one (2.432 g, 8 mmol) was added and the mixture was stirred at this temperature for 3 hr. Then it was quenched with water (5 mL). The solvents were removed and the residue was extracted with E. The organic layer was washed with dil. HCl, water, and brine. After drying completely with anhyd MgSO4. The solution was filtered and evaporated to obtain the crude 3 (R) -spiro-2'-oxirane-17β-methoxy-5a! -androstane (2.5 g). This crude product was then used as such for the next step.

EXAMPLE 20 3a-Hydroxy-17β-methoxy-3β- (2 • -propinyl) -5a-andros an A solution of crude 3 (R) -spiro-2'-oxirane-17β-methoxy-5a-androstane (318 mg, 1 mmol) and lithium acetalide EDA (95%, 485 mg, 5 mmol) in DMSO (10 mL) was stirred at room temperature for 15 hr. The mixture was then quenched with water (30 mL) and extracted with E. The organic layer was washed with water and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane: acetone (8: 2) mixture gave 3a-hydroxy-17β-methoxy-3β- (2'-propynyl) -5a-androstane (200 mg); mp 145-150 ° C; TLC Rt (hexane: acetone 7: 3) = 0.6.

EXAMPLE 21 3a-Hydroxy-17β-methoxy-3β-methoxymethyl-5a-androstane A solution of crude 3 (R) -spiro-2'-oxirane-17β-methoxy-5a-androstane (318 mg, 1 mmol) and sodium ( 29 mg, 1.3 mmol) in MeOH (10 mL) was refluxed for 2.5 hr. Then it was quenched with water (1 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane: acetone (8: 2) mixture gave 3a-hydroxy-17β-methoxy-3β-methoxymethyl-5a-androstane (230 mg); mp 93-99 ° C; TLC Rt (hexane: acetone 7: 3) = 0.56.

EXAMPLE 22 3ß-Chloromethyl-3a-hydroxy-17β-methoxy-5a-androstane A solution of crude 3 (R) -spiro-2'-oxirane-17β-methoxy-5a-androstane (318 mg, 1 mmol), tetramethylammonium (166 mg, 1.5 mmol) and acetic acid (0.5 mL) in DMF (10 mL) was stirred at 90-95 ° C for 2.5 hr. It was cooled to room temperature and then quenched with water (25 mL). After neutralization with 2N NaOH, the mixture was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane acetone mixture (95: 5) gave 3β-chloromethyl-3a-hydroxy-17β-methoxy-5a-androstane (138 mg); mp 138-145 ° C; TLC Rc (hexane: acetone 8: 2) = 0.26.

EXAMPLE 23 3β-Ethenyl-3α-hydroxy-17β-methoxy-5β-androstane A solution of trimethylsulfonium iodide (632 mg, 3.1 mmol) in dry THF (10 mL) was treated with n-BuLi (2.5 M in THF, 3%). mmol, 1.2 mL) at -5 ° C. After stirring the mixture at 0 ° C for 0.5 hr, a solution of 3 (R) -spiro-2'-oxirane-17β-methoxy-5a-androstane (318 mg, 1 mmol) in THF (10 mL) was added. . The cooling bath was removed and the mixture was stirred at room temperature for 2 h. It was then quenched with NH 4 Cl solution (2 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane: acetone (7: 3) mixture gave 3β-ethenyl-3a-hydroxy-17β-methoxy-5β-androstane (220 mg) as a colorless solid; mp 104 -11 ° C; TLC Rt (hexane: acetone 7: 3) = 0.5.

Example 24 3a-Hydroxy-2β-isopropoxy-17β-methoxy-5a-androstane A solution of 3a-hydroxy-2β-isopropoxy-5a-androstan-17-one 17-dimethyl acetal (prepared initially by the epoxide of 2a, 3a -epoxy-5a-androstan-17-one with isopropoxide, followed by ketalization of 17-one) (490 mg, 1.25 mmol) in Dry THF (15 mL) was treated with LAH (48 mg, 1.33 mmol) and A1C13 (332 mg, 2.5 mmol) at -30 ° C. After stirring the mixture at 23 ° C for 1 hr, it was quenched with NH 4 Cl solution (2 mL). The solvents were removed and the residue was extracted with EtOAc.

The organic layer was washed with dil. HCl, water, and brine.

After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH2C12 and emptied onto a column of silica gel. Elution with hexane: acetone mixture (9: 1) gave 3a-hydroxy-2β-isopropoxy-17β-methoxy-5a-androstane (43 mg) as a foam; TLC Rf (hexane: acetone 7: 3) = 0.41.

Example 25 3a-Hydroxy-3β- (4-hydroxybutynyl) -21- (pyrid-4-ylthio) -5β-pregnan-20-one A solution of 21-bromo-3a-hydroxy-3β- (hydroxybutynyl) -5β- pregnan-20-one (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 room temperature for 3 h. The mixture was separated between EtOAc and water. The organic layer was washed with sat. NaCl. aq, dried with Na2SO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 35% -50% acetone in CH2C12 gave 3a-hydroxy-3β- (4-hydroxybutynyl) -21- (pyrid-4-ylthio) -5β-pregnan-20-one (196 mg) as a yellow foam; TLC Rt (hexane: CH2C12 45:55) = 0.36. They were similarly prepared: 3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one; mp 193-195 ° C; TLC Rf (hexane: EtOAc 1: 1) = 0.11; 3a-hydroxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one; mp 154-156 ° C; TLC Rc (CH2C12: acetone 4: 1) = 0.18; 3a-hydroxy-3β-methoxymethyl-21- (pyrid-4-ylthio) -5a-pregnan-2O-one; 21- (4'-Aminophenylthio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one; mp 150-156 ° C; TLC Rt (hexane: EtOAc 3: 1) = 0.045; 3a-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylthio) -5a-pregnan-20-one; TLC Rf (hexane: EtOAc 3: 1) = 0.17; 21- (4 '-fluorophenylthio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one; TLC Rt (hexane: acetone 85:15) = 0.25; 3β-ethynyl-3a-hydroxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one; TLC Rr (hexane: EtOAc 1: 1) = 0.26; and 3β- (4'-acetylphenyl) ethynyl-3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one; TLC Rr (hexane: EtOAc 2: 1) = 0.15.

Example 26 3a-Hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one N-methyl iodide A solution of 3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20 -one (62 mg, 0.145 mmol), and 1 mL of methyl iodide in 5 mL of EtOAc was heated to reflux for a few hours until the complete reaction of the TLC. The mixture was then cooled to room temperature and concentrated in vacuo to a crude residue. The residue was triturated with ether and dried in vacuo to give 3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one N-methyl iodide (70 mg) as an orange solid.

Example 27 3a-Hydroxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one N-methyl iodide A solution of 3a-hydroxy-2l- (pyrid-4-ylthio) -5a-pregnan-20 -one (29 mg, 0.068 mmol) and 100 μL of methyl iodide in 5 mL of THF was heated to reflux. After 15 min. a solid precipitated and reflux continued for a few hours. The mixture was cooled to room temperature and the excess methyl iodide evaporation was allowed. The solid was then filtered, washing with cold THF, resulting in 3a-hydroxy-2l- (pyrid-4-ylthio) -5a-pregnan-20-one N-methyl iodide (26 mg) as a light orange solid.

Example 28 3a-Hydroxy-2β-propoxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one N-methyl iodide A solution of 3a-hydroxy-2β-propoxy-2l- (pyrid-4-) iltio) -5a-pregnan-20-one (50 mg, 0.103 mmol) and 130 μL of methyl iodide in 5 mL of THF was heated to reflux for a few hours until the complete reaction of the TLC. The mixture was then cooled to room temperature and concentrated in vacuo resulting in 3a-hydroxy-2β-propoxy-2l- (pyrid-4-ylthio) -5a-pregnan-20-one N-methyl iodide (64 mg) as a light yellow solid. Likewise prepared were: 3a-hydroxy-3β-methyl-2l- (4 * -trimethylammoniophenoxy) -5a-pregnan-20-one iodide salt; 3a-hydroxy-2β-propoxy-21- (4 '-N, N, N-trimethylammoniophenoxy) -5a-pregnan-20-one iodide salt; 3a-hydroxy-3S-methyl-21- (quinolin-6-yloxy) -5a-pregnan-20-one N-methyl iodide.

Example 29 3β-Ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one A solution of 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol) , 2-mercaptoethanol (31 μL, 0.445 mmol) in 5 mL of THF was stirred at room temperature overnight. The mixture was separated between EtOAc and water. The organic layer was washed with sat. NaCl. ac, dried with Na_SO4 and concentrated in vacuo resulting in 3β-ethynyl-3a-hydroxy-2i-hydroxyethylthio-5β-pregnan-20-one (141 mg) as a white solid; mp 122-126 ° C; TLC Rt (hexane: acetone 3: 1) = 0.11. Similar: 3β-ethynyl-3α-hydroxy-21-hydroxypropylthio-5β-pregnan-20-one; TLC Rt (hexane: acetone 3: 1) = 0.12; 3a-hydroxy-2l-hydroxypropylthio-2β-propoxy-5a-pregnan-20-one; mp 133-136 ° C; TLC Rc (hexane: acetone 3: 1) = 0.175; and 3a-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one; mp 150-152 ° C.

EXAMPLE 30 Sodium 3ß-ethynyl-3a-hydroxy-21-thioethanoate-5β-pregnan-20-one solution A solution of 21-bromo-3β-ethynyl-3a-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol), mercaptoacetic acid (31 μL, 0.445 mmol) and triethylamine (124 μL, 0.89 mmol) in 5 mL of DMF was stirred at room temperature for a few hours. The mixture was separated between EtOAc and 2 N HCl. The organic layer was washed with water, sat. NaCl. ac, dried with Na2SO4 and concentrated in vacuo to a residue. The residue was dissolved in 5 mL of CH2C12 and 1 eq. of sodium bicarbonate in 1 mL of water. The mixture was stirred for 30 min. and then concentrated to dryness under high vacuum resulting in sodium 3ß-ethynyl-3a-hydro? i-2l-thioethanoate-5β-pregnan-20-one sodium salt (120 mg) as a white solid; Dec. > 120 ° C. The following were similarly prepared: sodium 3ß-ethynyl-3a-hydroxy-21-thiopropanoate-5β-pregnan-20-one salt; 3ß-ethynyl-3a-hydroxy-21-thioethanesulfonate-5ß-pregnan-20-one sodium salt; dec. > 85 ° C; TLC Rt (chloroform: methanol 4: 1) = 0.25; sodium 3β-ethynyl-3α-hydroxy-21-thiopropanesulfonate-5β-pregnan-20-one salt; TLC RE (chloroform: methanol 4: 1) = 0.21; and sodium 3a-hydroxy-2β-propoxy-2l-thiopropanesulfonate-5a-pregnan-20-one salt; TLC Rf (chloroform: methanol 4: 1) = 0.22.

EXAMPLE 31 3 3-Ethynyl-3a-hydroxy-2-hydroxyethyl-2-β-triethanesulfate-5β-pregnan-20-one salt of trimethyl ammonium A solution of 3β-ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20 -one (140 mg, 0.335 mmol), complex sulfur trioxide trimethylamine (100 mg, 0.736 mmol), and complex sulfur trioxide pyridine (50 mg) in 4 mL of chloroform was stirred at room temperature overnight. The solid was filtered and the filtrate was concentrated in a small volume. The residue was subjected to flash column chromatography. Elution with 85:15 chloroform: methanol resulted in trimethyl ammonium 3β-ethynyl-3a-hydroxy-21-thioethanesulfate-5β-pregnan-20-one salt (69 mg) as a solid; Dec > 120 ° C.

EXAMPLE 32 Sodium Sal3S-Ethynyl-3a-hydroxy-21-thiopropanosulfate-5ß-pregnan-20-one A solution of 3β-ethynyl-3α-hydroxy-21-hydroxypropylthio-5β-pregnan-20-one (50 mg, 0.115 mmol) and complex sulfur trioxide trimethylamine (19 mg, 0.139 mmol) in 5 mL of pyridine was stirred at room temperature overnight. The mixture was diluted with chloroform and washed with 2 N HCl, sat. NaCl. ac, dried with Na 3 SO 4 and concentrated in vacuo to a crude residue. The residue was subjected to rapid column chromatography. Elution with 85:15 chloroform: methanol resulted in sodium 3β-ethynyl-3a-hydroxy-21-thiopropanosulfate-5β-pregnan-20-one salt (20 mg) as a solid; TLC Rf (chloroform: methanol 85:15) = 0.12. Sodium 3a-hydroxy-2ß-propoxy-21-sulfonylpropanosulfate-5a-pregnan-20-one salt was similarly prepared; TLC Rf (chloroform: methanol 85:15) = 0.15.

EXAMPLE 33 3ß-Ethynyl-3a-histabraxy-21-hydroxypropylsulfinyl-5β-pregnan-20-one A suspension of 3β-ethynyl-3α-hydroxy-21-hydroxypropylthio-5β-pregnan-20-one (90 mg, 0.208 mmol) and sodium periodate ("200 mg in 0.5 mL of water) in methanol: THF 3: 1 was stirred at room temperature overnight at 0 ° C. The mixture was concentrated to a small volume and partitioned between EtOAc and water. The organic layer was washed with sat aq NaCl, dried with NaaSO4 and concentrated in vacuo resulting in 3β-ethynyl-3a-hydroxy-2l-hydroxypropylsulfinyl-5β-pregnan-20-one. (83 mg) as a foam; TLC Rr (hexane: acetone 2: 1) = 0.035.

Sodium 3a-hydroxy-2β-propoxy-21-sulfinylpropanesulfonate-5β-pregnan-20-one salt was similarly prepared.

EXAMPLE 34 3ß-Ethynyl-3a-l-ddroxy-21-hydroxypropylsulfonyl-5β-pregp-an-20-one A solution of 3β-ethynyl-3α-hydroxy-21-hydroxypropylsulfinyl-5β-pregnan-20-one ( 65 mg, 0.145 mmol), mCPBA 57% -86% (42 mg), and a small amount of sodium bicarbonate in 5 mL of CHaCla was stirred at 0 ° C at room temperature overnight. The mixture was partitioned between CHaCla and sodium bicarbonate aq. The organic layer was washed with sat. NaCl. ac, dried with Na 3 SO 4, and concentrated in vacuo to dryness resulting in 3β-ethynyl-3α-hydroxy-21-hydroxypropylsulfonyl-5β-pregnan-20-one (66 mg) as a white solid; TLC Rf (CHaCl2: acetone 1: 1) = 0.61. 3a-Hydroxy-21- (3'-hydroxypropylsulfonyl) -2β-propoxy-5a-pregnan-20-one was similarly prepared; TLC Rf (hexane: acetone 2: 1) = 0.26.

Example 35 3a-Hydraxy-21- (pyrid-3-yl) axi-5β-pregnan-20-one To a solution of 3a-hydroxy-2l-bromo-5β-pregnan-20-one (300 mg, 0.76 mmol) in DMF (5 mL) was added 3-hydroxypyridine (215 mg, 2.27 mmol) and K3C03 (313 mg, 2.27 mmol) and the mixture obtained was stirred at 25 ° C for 0.5 h. The reaction mixture was then poured into a separatory funnel containing water (30 mL) and the mixture was extracted with EtOAc (3x35 mL). The combined extracts were washed with water (2x25) mL and then dried completely with Na 3 SO 4. Removal of the solvent in vacuo resulted in the crude product which was purified by flash chromatography on silica gel to obtain 3a-hydroxy-21- (pyrid-3-yl) oxy-5β-pregnan-20-one (50 mg ); mp 63-66 ° C; TLC Rf (MeOH: CHaCla 5:95) = 0.15.

Example 36 2ß-Isopropoxy-3a-hydroxy-5a-androstane a. 2ß-Isopropoxy-3a-hydroxy-5-andros-an-17-onatosylhydrazone To a mixture of 2β-isopropoxy-3a-hydroxy-5a-androstan-17-one (700 mg, 2.0 mmol) and p-toluenesulfonhydrazide (450 mg, 2.4 mmol) was added ethanol (2 mL) and the mixture obtained was heated to reflux for 12 h. Then the reaction mixture was dissolved in CHaCla (150 mL) and washed with water (4x45 mL). It was then completely dried with NaaSO4 and removal of the solvent in vacuo resulted in raw 2-isopropoxy-3a-hydroxy-5a-androstan-17-one tosylhydrazone (1113 g), which was used without further purification for the next step. b. 2ß-Isopropoxy-3a-hydraxy-5a-androstane To a mixture of 2ß-isopropoxy-3a-hydroxy-5a-androstan-17-one tosylhydrazone (300 mg), NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) DMF and sulfolane (1: 1, 3 mL) were added and the mixture obtained was heated at 110 ° C for 3 h. The additional amount of NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was then added and heated for another hour. Then water was added and the mixture was extracted with EtOAc (2x45 mL). The combined extracts were dried completely with NaaSO4 and the crude product obtained by solvent removal was purified by flash chromatography on silica gel to obtain pure 2β-isopropoxy-3a-hydroxy-5a-androstane (37 mg); TLC Rt (EtOAc: hexane 1: 9) = 0.17.

Example 37 3a-Hydroxy-5β-19-norandros year a. 3a-Hydroxy-5β-19-norandrostan-17-one To a solution of 5β-19-norandrostan-3, 17-dione (0.76 g, 2.77 mmol) in THF (30 mL) at -78 ° C was added a solution of Lithium tri (tert-butoxy) aluminum hydride. Then the reaction mixture was poured into a separatory funnel containing NH4C1 solution (50 mL) and the product was extracted with EtOAc (3x50 mL). The combined extracts were dried completely with Na 2 SO 4 and removal of the solvent resulted in the crude product which was purified by flash chromatography on silica gel to obtain 3a-hydroxy-5β-19-norandrostan-17-one (605 mg); mp 159-161 ° C; TLC Rt (hexane: acetone 7: 3) = 0.30. b. 3a-Hydroxy-5β-l9-norandrostane To a mixture of 3a-hydroxy-5β-norandrostan-17-one (0.59 g, 213 mmol) p-toluenesulfonyl hydrazide (480 mg, 2.6 mmol) was added ethanol (2 mL) and the The mixture obtained was heated to reflux for 5 h. Then the reaction mixture was dissolved in CH2C13 (100 mL) and washed with water (2x30 mL). It was then dried completely with Na 3 SO 4 and removal of the solvent in vacuo resulted in the crude product (1 g). This crude product was mixed with NaBH3CN (555 mg) and p-toluenesulfonic acid (68 mg) and a mixture of DMF and sulfolane (1: 1, 10 mL) and the mixture obtained was heated at 130 ° C for 2 h. Then the additional amount of NaBH3CN (200 mg) and p-toluenesulfonic acid (30 mg) was added and heated for another hour. Then water was added and the mixture was extracted with EtOAc (3x50 mL). The combined extracts were dried completely with NaaSO4 and the crude product obtained by removal of the solvent was purified by means of flash chromatography on silica gel to obtain pure 3a-hydroxy-5β-19-norandrostane (217 mg); mp 129-132 ° C; TLC Rt (EtOAc: hexane 1: 9) = 0.30.

Example 38 3a-Hydroxy-3β-ethynyl-5β-19-norandrostane a. 5ß-19-Norandrostan-3-one To a solution of 3a-hydroxy-5β-19-norandrostane (210 mg, 0.8 mmol) in CH2C12 (25 mL) was added NaOAc (100 mg, 1.2 mmol) and PCC (520 mg) , 2.4 mmol) and the obtained mixture was stirred at 25 ° C for 1 h. After the reaction mixture was filtered through a Florisil mesh (15 g) in a Buchner funnel it was eluted with mixtures of ether solvents and CHaCla (1: 1, 70 mL). Then the solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel to obtain 5β-19-norandrostan-3-one (190 mg); TLC Rt (EtOAc: hexane 5:95) = 0.20. b. 3ot-Hydroxy-3β-ethynyl-5 &-19-norandrostane To a solution of 1,2-dibromoethylene (410 mg, 2.2 mmol) was added n-BuLi (2.5 M, 1.8 mL, 4.4 mmol) at -78 ° C and the reaction was stirred at this temperature for 45 min. Then a solution of 5β-19-norandrostan-3-one (190 mg, 0.73 mmol) in THF (10 mL) was added dropwise to the generated lithium reagent. Then the reaction mixture was poured into a separatory funnel containing NH 4 Cl solution (50 mL) and the product was extracted with EtOAc (3x40 mL). The combined extracts were dried completely with Na 2 SO 4 and the crude product obtained by removal of the resulting solvent was purified by means of flash chromatography on silica gel to obtain 3a-hydroxy-3β-ethynyl-5β-l9-norandrostane (120 mg); mp 152-154 ° C; TLC Rt (EtOAc: hexane 1: 9) = 0.19.

Example 39 3a-Hydroxy-3β- (4'-acetylphenyl) ethynyl-5β-19-norandrostane To a mixture of 3a-hydroxy-3β-ethynyl-5β-19-norandrostane (120 mg, 0.42 mmol), 4-iodoacetophenone ( 115 mg, 0.46 mmol), bis (triphenylphosphine) palladium (II) chloride (catalytic amount) and copper (I) iodide (catalytic amount) triethylamine (1.5 mL) was added and the obtained mixture was stirred under argon for 45 min. . with the flask wrapped with aluminum foil. Then CH3C12 (5 mL) was added and the reaction was stirred for 3 h. Then the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to obtain 3a-hydroxy-3β- (4 »-acetylphenyl) ethynyl-5β-19-norandrostane (37 mg); TLC Rr (EtOAc: hexane 15:85) = 0.2.

Example 40 3a-Isobutyryloxy-17β-methoxy-5β-androstane A solution of 3a-hydroxy-17β-methoxy-5β-androstane (250 mg, 0.82 mmol) in dry pyridine (2 mL) was treated with isobutyryl chloride (0.12 mL) , 1.15 mmol), and N, N-dimethylaminopyridine (5 mg) at 5 ° C. After stirring the mixture at 5-10 ° C for 1 hr, the mixture was quenched with HCl solution (0.5 N, 25 mL). The mixture was extracted with EtOAc. The organic layer was washed with dil. HCl, water, and brine. After drying completely with anhyd MgSO4. the solution was filtered and evaporated to obtain the crude product. This crude product was then dissolved in a small amount of CH3C12 and emptied onto a column of silica gel. Elution with hexane: acetone mixture (9: 1) gave 3a-isobutyryloxy-17β-methoxy-5β-androstane (266 mg); mp 82-87 ° C; TLC Rc (hexane: acetone 9: 1) = 0.6.

Example 41 3a-Hydroxy-21- (pyrid-4-yloxy) -5β-pregnan-20-one A solution of 2l-bromo-3a-hydroxy-5β-pregnan-20-one (500 mg, 1.26 mmol), -hydroxypyridine (144 mg, 1.51 mmol), and triethylamine (200 μL) in 10 mL of THF was heated to reflux for 4 h. The mixture was cooled to room temperature and separated between EtOAc and water. The organic layer was washed with sat. NaCl. ac, dried with MgSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 50% acetone in CH2Cla gave 3a-hydroxy-21- (pyrid-4-yloxy) -5β-pregnan-20-one (40 mg) as an oily solid; TLC Rf (acetone: CH3C12 1: 1) = 0.28.

Example 42 3a-Hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5a-pregnan-20-one A solution of 21-bromo-3a-hydroxy-3β-methyl-5a-pregnan-20-one (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 acetonitrile: DMF 2: 1 was stirred with heating at -60 ° C. for 6 h. The mixture was separated between EtOAc and water: sodium bicarbonate sat. ac. 1: 1 The organic layer was washed with 2 N HCl, water and sat. NaCl. ac, dried with NaaS04 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 20% acetone in hexane gave 3a-hydroxy-3β-methyl-21- (41-nitrophenoxy) -5a-pregnan-20-one (147 mg) as a solid; mp 169-172 ° C; TLC Rf (hexane: acetone 4: 1) = 0.35. Similarly, 3a-hydroxy-3β-methyl-21- (quinolin-6-yloxy) -5a-pregnan-20-one; TLC Rt (hexane: acetone 3: 1) = 0.22.

Example 43 21- (4 * -Dimethylaminophenoxy) -3a-hydraxy-3β-? Netil-5a-pregnan-20-one A solution of 3a-hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5a-pregnan -20-one (100 mg, 0.213 mmol), formaldehyde (solution in 37% water, 800 mL), and Pd / C 5% (30 mg, catalytic) in ethanol was placed under a hydrogen atmosphere at 53 psi on a Parr shaker all night. The catalyst was filtered by washing with EtOAc, and the filtrate was washed in a separatory funnel with water and sat. NaCl. ac. Then the organic layer was dried with NaaSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography.

Elution with 20% acetone in hexane gave 21- (4'-dimethylaminophenoxy) -3a-hydroxy-3-methyl-5a-pregnan-20-one (64 mg) as a foam; TLC Rr (hexane: acetone 2: 1) = 0.55.

Similarly, 21- (4'-dimethylaminophenylthio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one was prepared; TLC Rf (hexane: acetone 3: 1) = 0.35.

Example 44 3a-Hi-draxi-3β-p? Ethoxy? Netil-21- (R) - (4 • -nitrofennylsulfonyl) -5a-pregnan-20-one; 3a-Hydraxy-3β-metaxip? Ethyl-21- (S) - (4 • -nitrofenylsulfinyl) -5a-pregnan-20-one; 3a-Hydroxy-3β-methoxymethyl-21-. { 4 '-nitrofenylsulfonyl) -5a-pregnan-20-one A solution of 3a-hydroxy-3β-methoxymethyl-21- (4'-nitropyl enyl) -5a-pregnan-20 -one (120 mg, 0. 23 mmol), mCPBA 57% -86% (111 mg), and NaHCO3 (80 mg, 4 eq.) In CH3Cla was stirred at 0 ° C at room temperature for 2 h. The reaction was separated between CH2Cla and aq NaHCO3. The organic layer was washed with sat. NaCl. ac. it was then dried with NaaSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 40% -50% EtOAc in hexane gave 3a-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylsulfonyl) -5a-pregnan-20-one (65 mg) as a solid; TLC RE (hexane: EtOAc 1: 1) = 0.38, followed by 3a-hydroxy-3β-methoxymethyl-2l- (R) - (4'-nitrophenylsulfinyl) -5a-pregnan-20-one and 3a-hydroxy-3ß- methoxymethyl-21- (S) - (4'-nitrophenylsulfinyl) -5a-pregnan-20-one in indefinite order. Similarly, 21- (4 '-fluorophenyl) sulfonyl-3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one was prepared.

Example 45 3a-Hydroxy-3β-Itoxymethyl-21- (4 * -pyrrolidinophenyl) sulfonyl-5a-pregnan-20-one A solution of 21- (4'-fluorophenyl) sulfonyl-3a-hydroxy-3β-methoxymethyl- 5a-pregnan-20-one (100 mg, 0.192 mmol) and pyrrolidine (21 μL, 0.25 mmol) in 5 mL of DMSO was heated in an oil bath at 100 ° C for 5 h, then stirred at rt throughout the night. Then water was added and the mixture was extracted with CHaCla. The organic phase was dried with NaS04 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with hexane: EtOAc to give the titled compound (62 mg) as a yellow solid.

Example 46 3a-Hydroxy-2l- (4-pyridylmethylene) -5β-pregnan-20-one A solution of sodium ethoxide, prepared from 300 mg of sodium and 10 mL of ethanol, was added to a solution of 3a-hydroxy 5β-pregnan-20-one (500 mg, 1.57 mmol) and pyridine-4-carboxaldehyde (165 μL, 1.73 mmol) in 10 mL of ethanol via cannula. The mixture was stirred vigorously at rt for 30 h. A solid precipitated and was filtered and washed with ethanol, then dried in vacuo resulting in the titled compound (260 mg).

Example 47 3a-Hydroxy-21- (4-pyridylmethyl) -5β-pregnan-20-one A solution of 3a-hydroxy-21- (4-pyridylmethylene) -5β-pregnan-20-one (100 mg, 0.245 mmol) each in 4 mL of ethanol and THF containing 20 mg of Pd / C was subjected to a hydrogen atmosphere via a balloon, and stirred for 5 h. Then the catalyst was filtered and the solution was concentrated in vacuo. The residue was subjected to flash column chromatography eluting with hexane: acetone to give the titled compound (38 mg) as a solid; TLC Rf (hexane: acetone 2: 1) = 0.28.

Example 48 Salt 20, 20- [2 », 3 • -Bis (carboxy) ethylenedioxy] -3a-hydroxy-3S-trifluoromethyl-5β-19-norpregnane dipotassium A mixture of 3a-hydroxy-3β-trifluoromethyl-5β-19 -norpregnan-20-one (1 g, 2.68 mmol), dimethyl L-tartrate (l.Og, 5.61 mmol), p-toluenesulfonic acid monohydrate (13 mg, 0.068 mmol) and trimethylortoformate (0.35 ml) in 15 mL of toluene was heated to reflux with azeotropic removal of water. After 1 h, the reaction was allowed to cool to rt and solid NaHCO 3 (130 mg) was added. The resulting mixture was separated between aq NaHCO 3 solution. and ethyl acetate. The aqueous layer was separated and washed twice with ethyl acetate (2x20 mL). The combined layers of ethyl acetate were washed with a solution of sat. NaCl, dried (NaaSO4) and concentrated in vacuo. The crude residue was chromatographed (17.5% acetone / hexane), giving a white foam which was triturated with hexane the dimethyl ester as a white solid. A solution of the diester in methanol (20 mL) and water (100 mL) was treated with solid KOH (78 mg): After stirring overnight, the reaction was concentrated to dryness to give the titled compound as a light yellow solid.

Example 49 Pharmacological Activity Potency and Efficacy in the GRC Site Experimental results in vitro and in vivo show that the metabolites of progesterone / deoxycorticosterone and their naturally occurring derivatives interact with high affinity in a new and specific GRC recognition site to facilitate conduction of chloride ions through neuronal membranes sensitive to GABA (Gee, KW et al, European Journal or P armacolQgy, 136: 419-423 (1987); Harrison, N.L. et al., J. Pharmacol. Exp. Ther. 241: 346-353 (1987)). For experts in the art, it is known that the modulation of [3SS] t-butylbicyclophosphorothionate ([3SS] TBPS) bound is a measure of the potency and efficacy of the drugs acting on the GRC, such drugs could be of potential therapeutic value in the treatment of stress, anxiety, seizure disorders (Squires, RF, et al., Mol.Pharmacol. 23: 326 (1983); Lawrence, LJ et al., Biochem. Biophys. Res. Comm-. 123: 1130 -1137 (1984); Wood, et al., Pharmacol. Exp. Ther .. 231: 572-576 (1984)). Several experiments were conducted to determine the nature of the modulation of [3SS] TBPS as affected by neuroactive steroids. It was found that these compounds interact with a new site in the GRC that does not overlap with the barbiturate, benzodiazepine or any other previously known site. In addition, these compounds have high power and efficiency in the GRC, with structural requirements necessary for such activity. The procedures to perform this test are fully discussed in: (1) Gee, K.W. et al, European Journal of Pharmacolocry. 136: 419-423 (1987)); and (2) Gee, et al., Molecular Pharmacology 30: 218 (1986). These procedures are performed as follows: The brains of male Sprague-Dawley rats were removed immediately after sacrifice and the cerebral cortex was dissected on ice. A P2 homogenate was prepared as previously described (Gee, et al., Molecular Pharmacology 30: 218 (1986).) Briefly, the rinds were gently homogenized in 0.32 M sucrose followed by centrifugation at 1000 xg for 10 minutes. and centrifuged at 9000 xg for 20 minutes The resulting pellet P2 was suspended as a 10% suspension (original wet weight / volume) in 50 mM Na / K phosphate buffer (pH 7.4) 200 mM NaCl to form the homogenate.

Aliquots of one hundred microliters (mi) of homogenate P2 (0.5 milligrams (mg) of protein) were incubated with [35S] TBPS 2 nanomolar (70-110 curies / millimole; New England Nuclear, Bostan, MA) in the presence or absence of naturally occurring steroids or their synthetic derivatives to be tested. The tested compounds were dissolved in dimethylsulfoxide (Baker Chem. Co., Phillipsburg, NJ) and added to the incubation mixture in 5 μL aliquots. The incubation mixture was brought to a final volume of 1 mL with buffer. A non-specific link was defined as the link in the presence of 2 mM TBPS. The effect and specificity of GABA (Sigma Chem. Co., St. Louis, MO) was evaluated by performing all assays in the presence of GABA plus (+) bicuculline. { Sigma Chem. Co.). Incubations maintained at 25 ° C for 90 minutes (steady state conditions) were terminated by rapid filtration through glass fiber filters (No. 32, Schleicher and Schuell, Keene, NH). The radioactive binding of the filter was quantified by liquid scintillation spectrophotometry. The kinetic results and the dose / response curves of compound / [35S] TBPS were analyzed by means of non-linear regression using a computerized iterative procedure to obtain the rate constants and the IC50 values (concentration of the compound in which the half of the maximum inhibition of the basal link [3SS] TBPS). Several compounds were screened for their potential as modulators of the [35S] TBPS linkage in vitro. These tests were performed in accordance with the procedures discussed above. Based on these trials, the structure-activity requirements have been established for their specific interaction in the GRC and their degree of power and efficiency. The experimental results obtained in this test of a number of 3a-hydroxypregnan-20-one derivatives are set forth in Gee, K.W. et al., European Journal of Pharmacology. 136: 419-423 (1987) and in U.S. Pat. No. 5,232,917. Table 1 provides IC50 and maximum inhibition measurements (lMA?) For numerous compounds, including examples of compounds disclosed and claimed herein. IC50 is defined as the concentration of compounds to inhibit 50% of the [35S] TBPS control link. It is an indication of an in vitro compound potency. Maximum inhibition is an indication of an in vitro compound efficiency.

Table 1 As can be seen in Table 1, 3a-hydroxy-5a-pregnan-20-one, 3a, 2l-dihydroxy-5a-pregnan-20-one and compounds of the present invention have low IC 50 / which is the concentration necessary to reach 50% of the maximum inhibition of the [3SS] TBPS bond, while compounds such as sex steroids (R5020, estradiol and progesterone), glucocorticoids (corticosterone) and cholesterol that has a high IC50 are essentially inactive. Thus, it is anticipated that hormonal steroids and cholesterol per se will have no therapeutic value for the indications described herein. To distinguish this unique class of steroids from hormonal steroids, they are now called "neuroactive steroids". However, sex steroids such as progesterone can be metabolized in the body to steroids similar to 3a-hydroxy-5a-pregnan-20-one. Thus, progesterone can be considered as a prodrug of "neuroactive steroid". The TBPS results correlate well with the input results of the 36C1 ion enhanced by various 3a-hydroxylated steroids described in Purdy R.H., et al., J. Med. Chem. 33: 1572-1581 (1990). These results also correlate well with the results obtained by measuring the activity of the steroid to enhance the induction of GABA common in oocytes injected with human GABA receptors as described in Hawkinson, J.E. et al., Mol. Pharmacol. 46: 977-985 (1995). This indicates that the TBPS test is an approximate measure of the ability of steroids to allosterically modulate the activity of the Cl channel. " Limited Efficiency Compounds As long as the desired therapeutic activity should be available to the patient with the least undesirable side effects, this invention also includes the discovery of new agonists with partial activity. (Table 1, compounds with l "x <100%). For patients with desirable improvement in anxiety or seizures, hypnosis is undesirable. For patients with desirable improvement in insomnia, the anesthetic effects are undesirable. The compounds described as agonists with partial activity are expected to provide the desirable effect with minimal undesirable side effects.

Benefits on Progesterone Correlations between reduced levels of progesterone and symptoms associated with PMS, PND, and catamenial epilepsy (Bacstrom, T. et al., J. Psychosom, QbStet, Gyhaecq., 2: 8-20 (1983)); Dalton, K., Premenstrual Syndrome and Prosesterone Therapy. 2nd Edition, Chicago Yearbook, Chicago (1984)) indicate the use of progesterone in its treatment (Matson et al., "Medroxyprogesterone therapy of catamenial epilepsy", in Advances in epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp 279 -282; Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd Edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Maddocks, et al. (1986).) These results are predictable when considered based on the results of in vitro studies demonstrating that progesterone has very low potency in the GRC, as seen in Table 1, compared to the neuroactive steroids described in this invention.The beneficial effect of progesterone probably refers to the variable conversion of progesterone to the active progesterone metabolites which act in the GABA receptor. "The use of specific neuroactive steroids in the treatment of the aforementioned syndromes is clearly superior to the use of progesterone based on the high potency and efficiency of these compounds (See Gee, KW et al, Suropean Journal of PharmacQlogy, 136 : 419-423 (1987) and Table 1 above).

Non-Hormonal Side Effects Neuroactive steroids have also been shown to have no hormonal side effects due to the lack of affinity of progesterone and other hormanaal steroid receptors (Table 2-5). The results presented were obtained by performing tests according to the procedures previously to determine the effect of the progesterone metabolites and their derivatives and the progestin R5020 at the [3H] R5020 binding to the progesterone receptor in rat uteri. { Gee et al, Journal of Pharmacology and ximen Therapeutics 246: 803-812 (1988). 3H-progesterone (0.15 nM) was incubated with the cytosol of rat uterus in the presence of test compounds. The specific bonds were determined after the incubation and compared to the control incubation without the compounds. The results were expressed as percent inhibition of binding. If the compounds bind to the progesterone receptor with high affinity, a 100% inhibition of binding at the tested concentration would be expected. Several hormonal activities of representative neuroactive steroids were also studied by testing their potential estrogenic, mineralocorticoid and glucocorticoid activities. These activities were analyzed by monitoring the ability of the compounds to inhibit the binding of steroid hormones to their respective hormone receptors. The results are shown in Tables 3-5. They are expressed as percent inhibition of the 3H-ligand binding to the various steroid hormone receptors for the compounds at 10"d M. The control values were represented by the linkage in the absence of the compounds tested In Table 4, the rats they were adrenalectomized 3 days before sacrificing To isolate the mineralocorticoid receptor, cerebral cytosol fractions were prepared as described in Gee et al, Journal of Pharmacology and Experimental Therapeutics 246: 803-812 (1988). The drugs were incubated with 3 nM of 3H-aldosterone (the specific ligand of the mineralocorticoid receptor) in the presence of the type II selective agonist RU28362 (0.5 μM) that blocks the binding of 3H-aldosterone to type II receptors (glucocorticoid).

Table 2. Inhibition of the 3H-Progesterone Linkage for Bovine Ureral Progesterone Receptors Table 3. Inhibition of 3H-Aldosterone Linkage for Receptors of Mineralcorticoid Hippocampus For Table 4, brain cytosol fractions were prepared as for Table 3, and the compounds were incubated with 3 nM of 3 H-dexamethasone (the ligand specific for the glucocorticoid receptor).

Table 4. Inhibition of 3 H-Dexamethasone Linkage for Gluticorticoid Receptors Table 5 shows the inhibition of the 3H-estradiol linkage (the ligand specific for the estrogen receptor) for the cytosol of bovine uterus, prepared as previously described in Gee et al, Journal Qf Pharmacology and Experimental Therapeutics 246: 803-812 (1988)). 3 H-Estradiol (0.15 nM) was incubated with the cytosol in the presence of the compounds.

Table 5. Inhibition of 3 H-Estradiol Binding for Bovine Uterine Estrogen Receptors The results of these experiments clearly show that neuroactive steroids do not have a strong affinity for any of the aforementioned steroid receptors. In this way, they will not have the hormonal side effects that would be associated with the binding for such steroid receptors. The neuroactive steroid, 3a-hydroxy-3β-methyl-5a-pregnan-20-one, was further tested in vivo and was also found to have no hormonal activity when given to animals in vivo.

Anti-Convulsive Activity The experiments were also conducted to determine the psychological relevance of the interactions of the neuroactive steroid and the GABA receptor by evaluating the ability of the compounds of the present invention to prevent seizures induced by metrazole in mice. Mice were injected with several doses of the test compounds of the invention, 10 minutes before the injection of metrazole. The time for attack of myoclonus (presence of clonal activity before the limbus) induced by metrazol was determined by observing each mouse during a period of 30 minutes). In control mice, metrazol (85 mg / kg) will induce convulsion in 95% of the animals. The ability of several compounds of the present invention to protect mice from seizures is shown in Table 6.

Table 6. Antimetrazole Activity in Mice The ability of synthetic neuroactive steroids to protect animals against other chemical convulsants was further demonstrated for various compounds of the present invention. The anticonvulsant tests are similar to those described above. The following chemical anticonvulsants were used: metrazol (85 mg / kg); Suculin (2.7 mg / kg); picrotoxin (3.15 mg / kg); strychnine (1.25 mg / kg); or vehicle (0.9% saline). Immediately after injection of the anticonvulsant or vehicle, the mice were observed for a period of 30 to 45 minutes. The number of animals with tonic and / or clonic seizures was recorded. In the test the maximum electroshock, 50 mA current at 60 Hz was given by cornea electrodes for 20 msec to induce the tonic attack. The ability of the compounds to eradicate the tonic compounds was defined as the end point. The CNS potential general depression was determined by a rotating rod test 10 minutes after the injection of the compounds where the number of mice held on a rotary bar (6 rpm) was determined for 1 minute in one of the three assays. The ED50's (the dose in which half of the maximum effect occurs) were determined for each screening and are presented in Table 7, infra. The results show that neuroactive steroids, compared to other anti-seizures used clinically, are highly effective with profiles similar to that of BZ clonazepam. These observations demonstrate the therapeutic utility of these compounds as modulators of brain excitability, which is in correspondence with their high affinity interaction with GRC in vitro Table 7. Anticonvulsant Activity in Mice The abbreviations are RR (Rotary bar); MONTH (Maximum Electroshock); PTZ (metrazol); BIC (bicuculline); PICRO (picrotoxin); STR (strychnine); NP (without protection) '"Dissolved in 50% hydroxypropyl-β-cyclodextrin in water The administration route for steroids and convulsants was i.p. and s.c. respectively. b% Protected, 20 mg / Kg, i.p., 10 min., in 50% of hpbcd c% Protected, 10 mg / Kg, i.p., 10 min., in 50% of hpbcd a The results of anticonvulsants are from Swinyard & Woodhead, General principles: experimental detection, quantification and evaluation of anticonvulsants, in Antiepileptic Drugs, D.M. Woodbury, J.K. Penry and CE. Pippenger, eds. p. 111, (Raven Press, New York), 1982. ß The chemical convulsants in the progabide studies were administered i.v., all results from Worms et al., Gamma-aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra, Journal of Pharmacology and Experimental Therapeutics 220: 660-671 (1982).

Anxiolytic Effects The following experiments demonstrate that the compounds of the present invention are effective anxiolytics in two animal models of human anxiety that measures the behavioral effects of the anxiolytic compounds. The results of other compounds of the present invention in these measurements are presented in Tables 8 and 9. The two animal models used to measure the behavioral effects of the anxiolytic compounds are the highest maze tests and the Geller conflict test. Seifter.

A. Higher Labyrinth Test The theoretical basis for the higher maze test is similar to the light / dark transition test. As previously described by Pellow et al. J. Neurosci. Meth. 14: 149-167 (1985)), the higher maze apparatus is intended to utilize the natural aversion of mice to open spaces. The devices consist of two open branches and two closed branches. The highest maze test allows two measures of anxiety, the number of entries in the open branches and the time spent in the open branches, expressed as a percentage of the total number of entries and time spent inside / outside the open branches and closed branches. Four male N.I.H mice were enclosed. Swiss-Webster (Harían, Indianapolis, IN) weighing 15-20 g per cage, in polyethylene cages with sawdust mattress. The colony room was controlled environmentally (22CC) with a cycle of 12 hr light / dark (0600-1800). Food and water were available ad libitum, except during the test. The experiments ran from 0700-1500 hr and the groups were balanced by time for day effects. The mice were administered drug or vehicle only once. The method used was previously described (Lister, Psychopharmacol.92: 180-185 (1987)). The devices included two open branches perpendicular to the two closed branches raised 50 cm from the ground. Each branch was 50 cm long and the walls of the closed branches were 40 cm high. The labyrinth was made entirely of black plexiglass. Bulbs of incandescent light of 200 W were above each of the open branches to produce a strong contrast between the open branches and the closed branches. Ten minutes after an injection, the mice N.I.H. Swiss-Webster were placed in the center of the labyrinth in front of an open branch. During the 5 minutes of the test period, the number of entries in the open branches and the closed branches, and the time spent in the open branches and the closed branches were measured. The four legs had to be inside a branch to measure the dependent variable. Therefore, the time spent in the center of the labyrinth was not counted, so that the total time spent in the open branches and the closed branches could not be equal to 5 min. Table 8 shows the summary of the anxiolytic activities of the compounds of the present invention using the highest labyrinth under the same conditions described above.

Table 8 * Percent control over time spent on open branches.

B. Conflict Test Geller Seif er This animal model of human anxiety uses a state of conflict condition in rats to find out the anxiolytic properties of drugs. Rats are conditioned to press the positive reinforcement bar under two behavioral paths (Geller and Seifter, Psychopharmacologia 1: 482-492 (1960)). The first includes pressing the bar under a variable itinerary without punishment. The second component is a fixed itinerary relationship with each press bar that results in positive reinforcement and punishment. The punishment component produces a state of conflict in the animal. The component without punishment allows the observation of any depressive effect in the response that a drug could have. An anxiolytic response would increase the punishment response without affecting the response without punishment. The male Sprague-Dawley albino rats (Charles River Labs, Wilmington, MA) weighing 250-300 g were used for conflict experiments and were kept on a restricted diet of chunks of Purina Lab Chow with water available all the time to maintain 85% of the body weight of your young adult levels with free feeding. The rats were individually enclosed under a 12 hr light-dark cycle with 0700-1900 illumination. The anti-anxiety (punishment-decrease) and depressant effects in the response of compounds of the present invention were measured in rats by means of the Geller and Seifter conflict test. In this 63-min test, hungry rats developed a pressure response on the lever to obtain a reward of sweetened milk. The reinforcement itinerary consists of components of punishment and without punishment, alternated approximately every 15 min. The rats were exercised in test chambers (Coulbourn instruments) with a lever mounted on a wall, a small ladle that gave the reward milk 0.1 mL (1 part Eagle condensed milk: 2 parts water), and a mesh floor metal through which the punishment was administered by shock on the legs. A DEC PDP 11/73 minicomputer was used running the SKED (State Systems) to program and register. The rats initially learned to respond in a continuous reinforcement itinerary and variable interval (VI) itineraries rapidly increasing to 30-sec, 1-min, and 2-min. In the continuous reinforcement itinerary, the rats received reward milk always followed by pressing the lever; in VI itineraries, milk rewards were available at infrequent and variable intervals, eventually at an average of one every 2 mj ^ n. For 3 min the periods of "conflict" were introduced deptíés in the line of reference without punishment of VI; the first one started after 3 min of performing the VI and the others alternated between periods of 12 min of the VI response. During the periods of conflict, which were marked by the presentation of a light and a tone, the continuous reinforcement itinerary was again in the strength and pressure of each lever giving a milk reward and a brief shock on the legs ( 0.25 msec). The intensity of the shock was 0.2 mA initially, and was increased daily in increments of 0.02 mA to gradually suppress the lever pressure to 5 responses or less per period of conflict. This training took 4 to 6 weeks, after which there were low stable response rates during periods of conflict and high stable rates in periods without punishment. The drug induced increases in the rate of punishment responses were taken as an index of anxiety activity, while decreases in the rate of responses without punishment were taken as an index of the response of depression or sedation. Table 9 shows the summary of the anxiolytic activities of a compound of the present invention in the Geller Seifter test under the experimental conditions described above. The remaining compounds of the present invention are also expected to produce increases in the rate of punishment responses in the Geiller Seifter test, and are expected to possess anxiolytic activity.

Prodrugs The anticonvulsant activity of a prodrug (isobutyric ester 3a) of the basic compound 3a-hydroxy-17β-methoxy-5a-androstane is shown in FIG. 1. The percent protection by this prodrug of 3a-hydroxy-17β-methoxy-5a-androstane against metrazole-induced attacks is plotted against the time after administration of the compounds (FIG. 1). It is understood that this compound is used as an experimental example to illustrate the utility of prodrugs. In contrast to benzodiazepines, neuroactive steroids can also induce anesthesia. Its ability to induce anesthesia is indicated to be due to its ability to open the chloride ion channel in the absence of GABA, which is a property not possessed by benzodiazepines. Accordingly, neurosteroids can act directly in the absence of GABA, in the receptor, and also "indirectly", in the presence of GABA. This "indirect" action is called "modulation" of the receiver. Lambert et al., Trends Pharmacology Science 8: 224-227 (1987). The compounds of and used in the invention can also be used for anesthetic indications in high doses. However, the preferred route of administration to induce anesthesia is intravenous (i.v.) administration. In animals, the anesthetic properties of a drug are measured by the ability of the drug to produce a loss of correct reflex. The correct reflex loss is defined as the inability of an animal to correct itself in 30 seconds when it is placed on its back. The mice were administered i.v. in the lateral vein of the tail. Followed by administration, the mice were placed on their backs and observed for the correct reflex loss. The illustrative results are presented in Table 10.

Table 10. Anesthetic Activity in Mice It is envisaged that the prodrugs, with similar modifications as those described above, of the compounds of and used in the invention will have activity as the prodrugs.

Having now fully described this invention, it will be understood by those skilled in the art that the same can be done with a broad and equivalent range of conditions, formulations and other parameters without affecting the purpose of the invention or any modality thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety.

Claims (45)

1. A compound of the formula: or a 3- physiologically acceptable ester thereof, characterized in that R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, halogen, lower alkoxy alkyl, substituted alkyl, alkenyl, alkynyl or substituted alkynyl; Ri is one of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, dihaloalkyl, trihaloalkyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, optionally substituted arylalkyl, arylalkenyl, optionally substituted aryl, optionally substituted aralkylalkynyl, alkynyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, optionally substituted cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminialkynyl, mercaptoalkynyl, hydroxyalkynyl-dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl; Rj is one of hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxy, a keto group or an amino group; R3 is one of hydrogen, alkoxy, substituted alkoxy, alkenyloxy, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, sulfinyl, sulfonyl, thio, sulfonamido, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, a 1,3-dioxolan-4-one of a group optionally substituted acetyl, a 1,3-dioxan-4-one of an optionally substituted acetyl group, a 1,3-oxathiollan-5-one of an optionally substituted acetyl group, a 1,3-oxathioan-5-one of a optionally substituted acetyl group, -0-C (0) -NR'R ", -C (0) -CHa-YG, -C (O) -CHa-0-D, -C (0) -CHa-0- E, -C (0) -CH2-ZG, -C (0) -CHa-Y'-ZG, or -C (0) -CHa-Y '-ZA, wherein I and RII independently represent hydrogen or alkyl optionally substituted, or taken together with the nitrogen to which they are attached form a 6-membered heterocyclic ring, Y is one of S, SO or S0a, Y * is one of 0, S, SO or S02, Z is one of alkyl, alkenyl or alkynyl; G is one of C-linked heteroaryl, optionally substituted aryl, a quaternary ammonium salt of a nitrogen containing heteroaryl group or a quaternary salt of a substituted amino aryl group; D is heteroaryl attached to C or a quaternary ammonium salt of a nitrogen containing heteroaryl group; E is optionally substituted aryl of a quaternary ammonium salt of a substituted amino aryl group; A is one of amino, amido, cyano, thiocyano, azido, nitro, hydroxy, halo, carboxyl, alkoxy, alkoxycarbonyl, alkanoyloxy, hydrogen, sulfate, thiosulfate, sulfonate, alkylthio, alkylsulfinyl, alkylsulfonyl or mercapto; R4 is one of hydrogen or lower alkyl, R5 is hydrogen, or when a double bond occurs between C4 and C5 of the steroid ring system, then R5 is not present; R6 is one of hydrogen, alkanoyl, aminocarbonyl or alkoxycarbonyl; R7 is one of hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, or carbalkoxy; R "is one of hydrogen or halogen; R9 is one of hydrogen, halogen, alkyl, alkoxy, arylalkoxy, or amino; R10 is one of hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkoxyloxy, carbalkoxyl, cyano, thiocyano or mercapto; and dotted lines indicate that a single or double link could be present; provided that: when R3 is C3-6alkoxy or alkenyloxy Cx.s and R is hydrogen or a-methyl, then Rt is another apart from hydrogen; or when R.sub.3 is C.sub.4- alkoxy (C.sub.1-, then R.sub.L is another apart from hydrogen or 1-propinyl, or when R.sub.3 is hydrogen and R.sub.a is hydrogen, hydroxy, a keto group or an amino group, then R.sub.t. is hydrogen, alkyl or cyanoalkyl, or when R3 is aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, then Rt is not hydrogen or alkyl, or when R3 is -C (0) -CHa-YG, and G is heteroaryl attached to C or optionally substituted aryl , then Rx is another apart of hydrogen or alkyl, or when R3 is -C (O) -CHa-0-E, and E is optionally substituted aryl, then R. is another apart from hydrogen; or when R3 is -C (O) -CHa-Y '-Z-G, and Y' is O, and G is aryl, then R ,. it is another apart from hydrogen; or when R3 is -C (O) -CHa-Y '-Z-G, and Y' is S, SO, or S02, and G is aryl, then Rt is another apart from hydrogen or alkyl; Or when R3 is -C (0) -CHa-Z-G, then Rt is another apart from hydrogen; or when R3 is -C (0) -CH2-Y '-Z-A, and Y' is 0, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino, then Rt is another apart from hydrogen; or when R3 is -C (0) -CH2-Y '-ZA, and Y' is S, SO, or S02, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, or amino, then RL is another apart from hydrogen or I rent.

2. A compound of claim 1, characterized in that the bond between C4 and C5 of the steroid ring system is a single bond; R is one of hydrogen, lower alkoxy, alkyl, substituted alkyl, alkynyl or substituted alkynyl; R3 is one of hydrogen, alkoxy, substituted alkoxy, alkenyloxy, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, -0-C (0) -NR'R ", -C (0) -CHa-YG, -C (0 ) -CHa-0-D, -C (0) -CHa-0-E, -C (0) -CHa-Y '-ZG, O -C (0) -CHj-Y'-ZA, wherein R 'and R' independently represent hydrogen or optionally substituted alkyl, or taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring; and R5 is hydrogen.

3. A compound of claim 1 or claim 2, characterized in that it is conditional on: when R3 is alkoxy t_s or alkenyloxy CX.6 I then Rx is another apart from hydrogen or methyl; or when R3 is hydrogen and R2 is hydrogen, hydroxy, a keto or an amino group, then R-. it is not hydrogen, alkyl or cyanoalkyl; or when R3 is -C (0) -CH2-Y-G, and G is C-linked heteroaryl or optionally substituted aryl, then R is other than hydrogen or alkyl; or when R3 is -C (0) -CH2-0-E, and E is optionally substituted aryl, then R-. it is another apart from hydrogen or methyl; or when R3 is -C (O) -CH2-Y '-Z-G, and G is optionally substituted aryl, then R-. it is another apart of hydrogen or alkyl; or when R3 is -C (O) -CHa-Y '-Z-A, and A is hydrogen, halo, carboxyl, alkoxycarbonyl, alkoxy, cyano or amino, then Rx is another apart from hydrogen or alkyl.

4. A compound of claim 1, characterized in that: R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, halogen, lower alkoxy, alkyl, substituted alkyl, alkenyl, alkynyl or substituted alkynyl; RL is one of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, dihaloalkyl, trihaloalkyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, optionally substituted arylalkyl, arylalkenyl, optionally substituted aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, optionally substituted cyanoalkynyl, heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminialkynyl, mercaptoalkynyl, hydroxyalkynyl-dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl; Ra is one of hydrogen, alkoxy, a keto group or a dimethylamino group; R3 is one of alkoxy, substituted alkoxy, alkenoxy, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy or -0C (0) NR'R ", wherein R 'and R" independently represent hydrogen, optionally substituted alkyl, or taken together form a heterocyclic ring of 3 to 6 members; R 4 is hydrogen or methyl; Rs, Rs, R7, Rs, R, and R10 are each hydrogen; and all dotted lines represent simple links. provided that: when R 3 is alkoxy d-β or alkenyloxy C 1 and R is hydrogen or α-methyl, then R x is another apart from hydrogen; and when R3 is C1-4alkoxy alkoxy (Ci- ,,), then Rr is another apart from hydrogen or 1-propynyl.

5. A compound of claim 4, characterized in that: R is hydrogen, halogen, lower alkoxy, alkyl, substituted alkyl; alkynyl or substituted alkynyl; and R3 is one of alkoxy, substituted alkoxy, alkenyloxy, alkynyloxy, optionally substituted aryloxy, optionally substituted arylalkoxy, or -0C (0) NR'R ", wherein R * and R" independently represent hydrogen, optionally substituted alkyl, or taken together they form a 5- or 6-membered heterocyclic ring.

6. A compound of claim 5, characterized in that R3 is alkoxy.

7. A compound of claim 6, characterized in that RL is substituted arylethynyl.

8. A compound of claim 7, characterized in that it is 3a-hydroxy-3β- (4'-nitrophenyl) ethynyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (4'-methoxy-enyl) ethynyl-17-methoxy-5β-androstane; 3a-hydroxy-3β- [2- (3 ', 4'-dimethoxy-enyl) ethynyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (4'-methylfenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4 '-trif luoromethylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (2'-methoxyphenyl) ethynyl-17β-methoxy-5β-androstane; 3β- (4'-dimethylaminofenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetyl-enyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-chlorophenyl) ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β- (4 * -acetylphenyl) ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β- (4'-carboxymethynyl) -3a-hydroxy-17β-methoxy-5β-androstane ethyl ester; 3a-hydroxy-3β- (4'-acetoxyacetylphenyl) -17β-methoxy-5β-androstane or 3β- (4'-cyanophenyl) ethynyl-3α-hydroxy-7β-methoxy-5β-androstane.

9. A compound of claim 7, characterized in that it is 3β- (4 * -acetyl-f-phenylethyl) -3a-hydroxy-19-nor-17β-methoxy-5β-androstane; 3β- (4 '-carboxyphenylethynyl) -3a-hydroxy-19-nor-17β-methoxy-5β-androstane ethyl ester; 3β- (4 '-carboxyphenylethynyl) -3a-hydroxy-17β-methoxy-5a-androstane ethyl ester; 3β- [4 '- (N, N-diethylcarboxamido) phenyl] ethynyl-3a-hydroxy-17β-met oxy-5β-androstane; or 3ß-. { 4'-acetoxy-enylethynyl) -3a-hydroxy-17β-methoxy-5β-androstane.

10. A compound of claim 6, characterized in that Rx is one of optionally substituted aryl or optionally substituted arylalkyl.

11. A compound of claim 10, characterized in that it is 3a-hydroxy-3β-benzyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (2'-phenylethyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (3'-phenylpropyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [2 (3 ', 4'-dimethoxyphenyl) ethyl] -17β-methoxy-5β-androstane; or 3a-hydroxy-3β-phenyl-17β-methoxy-5β-androstane.

12. A compound of claim 6, characterized in that Rx is one of cyanoalkyl, oxoalkynyl, hydroxyalkynyl or a physiologically acceptable ester of hydroxyalkynyl.

13. A compound of claim 12, characterized in that it is 3a-hydroxy-3β- (5'-cyano-1'-pentinyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (4'-cyano-l '-butinyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [6'-oxo-1 '-heptinyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (7'-oxo-1'-octinyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (5'-oxo-1 '-hexinyl) -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (5'-oxo-1'-pentinyl) -17β-methoxy-5β-androstane; 3β- (4 '(R / S) -hydroxypentinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- [5 '- (R / S) -hydroxyhexinyl] -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (5 '-hydroxy-1'-pentinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3ß- (5'-hydroxy-l '-pentinyl) -3a-hydroxy-17β-methoxy-5β-androstane hemisuccinate salt; 3β- (6 '-hydroxy-l' -hexinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3ß- (6 '-hydroxy-l' -hexinyl) -3a-hydroxy-17β-methoxy-5β-androstane 6 '-hemisuccinate salt; 3ß- (4 '-hydroxy-l' -butinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (4 '-hydroxy-l' -butinyl) -3a-hydroxy-17β-methoxy-5β-androstane 4 '-hemisuccinate salt; 3ß-. { 4'-hydroxy-l '-butinyl) -3a-hydroxy-17β-methoxy-5a-androstane; 3β- (4 '-hydroxy-1-butynyl) -3a-hydroxy-17β-methoxy-5a-androstane 4' -hemisuccinate salt; 3β- (4 '-hydroxy-l' -butinyl) -3a-hydroxy-17β-methoxy-5β-19-norandrostane; 3β- (4 '-hydroxy-l-butynyl) -3a-hydroxy-17β-methoxy-5β-19-norandrostane salt 4' -hemisuccinate sodium; 3β- [3 '(R / S) -hydroxy-1' -butinyl] -3a-hydroxy-17β-methoxy-5a-androstane; or 3β- (3 '-hydroxy-1'-propynyl) -3a-hydroxy-17β-methoxy-5β-androstane.

14. A compound of claim 6, characterized in that RL is one of alkanoyloxyalkynyl, alkynyloxyalkynyl or alkoxyalkynyl.

15. The compound of claim 14, characterized in that it is 3β- (3'-acetoxy-1 '-propynyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetoxy-1 * -butinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (4'-acetoxy-1'-butynyl) -3a-hydroxy-17β-methoxy-5a-androstane; 3β- (5'-acetoxy-1 '-pentinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3β- (6'-acetoxy-1 '-hexinyl) -3a-hydroxy-17β-methoxy-5β-androstane; 3a-hydroxy-3β- [3- (2'-propynyloxy) -1-propynyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (3-methoxy-1-propynyl) -17β-methoxy-5β-androstane; or 3α-hydroxy-3β- (3-methoxy-1-propynyl) -17β-methoxy-5α-androstane.

16. A compound of claim 6, characterized in that R-. is one of heteroaryloxyalkynyl or heteroarylalkyl.

17. A compound of claim 16, characterized in that it is 3a-hydroxy-3β- (2'-thienyl) ethynyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (2-pyridyl) ethynyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- [3- (1 H-1,2,3-triazol-1'-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [3- (2'H-1,2,3-triazol-2 * -yl) -1-propynyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- [3- (1H-pyrazol-11-yl) -1-propynyl] -17β-methoxy-5β-androstane; 3a-hydroxy-3β- (5'-acetyl-2'-thienyl) ethynyl-17β-methoxy-5β-androstane; 3a-hydroxy-3β- (4-pyridyl) ethynyl-17β-methoxy-5β-androstane.

18. A compound of claim 6, characterized in that Rx is alkynyl.

19. A compound of claim 18, characterized in that it is 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β-butynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β-ethynyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β-pentynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β-cyclopropylethynyl-3α-hydroxy-17β-methoxy-5β-androstane; 3ß- (but-3 '-en-1' -inyl) -3a-hydroxy-17-β-methoxy-5β-androstane; 3ß-. { 3 '-methylbut-3' -en-1 '-inyl) -3a-hydroxy-17β-methoxy-5β-androstane; or 3β-hexynyl-3α-hydroxy-17β-methoxy-5β-androstane.

20. A compound of claim 6, characterized in that R-. is alkyl, alkenyl, trihalomethyl, halomethyl, alkoxyalkyl or cyanoalkyl.

21. A compound of claim 20, characterized in that it is 3β-ethenyl-3a-hydroxy-17β-methoxy-5β-androstane; 3β-ethenyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β-methyl-3a-hydroxy-17β-methoxy-5β-androstane; 3β-butyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β-methyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β-pentyl-3a-hydroxy-17β-methoxy-5β-androstane; 3β-hexyl-3α-hydroxy-17β-methoxy-5β-androstane; 3β-trifluoromethyl-3a-hydroxy-17β-methoxy-5a-androstane; 3β-trifluoromethyl-3a-hydroxy-17β-methoxy-5β-androstane; 3β-fluoromethyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β-bromomethyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β-iodomethyl-3α-hydroxy-17β-methoxy-5α-androstane; 3β-chloromethyl-3a-hydroxy-17β-methoxy-5β-androstane; 3β-methoxymethyl-3a-hydroxy-17β-methoxy-5a-androstane; 3β-ethoxymethyl-3a-hydroxy-17β-methoxy-5a-androstane; 3β-propoxymethyl-3a-hydroxy-17β-methoxy-5a-androstane; 3β-isopropoxymethyl-3α-hydroxy-17β-methoxy-5α-androstane; or 3β-cyanomethyl-3α-hydroxy-17β-methoxy-5β-androstane.

22. A compound of claim 4, characterized in that R is alkoxy and R3 is alkoxy.

23. A compound of claim 22, characterized in that it is 2β, 17β-dimethoxy-3α-hydroxy-5α-androstane; 2β-ethoxy-3a-hydroxy-17β-methoxy-5a-androstane; 2β-propoxy-3a-hydroxy-17β-methoxy-5a-androstane; or 2β-isopropoxy-3α-hydroxy-17β-methoxy-5α-androstane.

24. A compound of claim 1, characterized in that: R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, halogen, minor alkoxy, alkynyl or substituted alkynyl; R ,, is one of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, dihaloalkyl, trihaloalkyl, optionally substituted aralkyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, optionally substituted arylalkyl, arylalkenyl, optionally substituted aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminyalkynyl, mercaptoalkynyl, hydroxy alkynyl-dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl; Rj is one of hydrogen, alkoxy, a keto group or a dimethylamino group; R3 is one of -C (O) -CH2-YG, -C (O) -CHa-0-D, -C (O) -CHa-0-E, -C (0) -CH2-ZG, -C (0) -CHa-Y'-ZG, or -C (O) -CHa-Y '-ZA; And it is one of S, SO or S02; Y 'is one of 0, S, SO or S0a; Z is one of alkyl, alkenyl or alkynyl; G is one of C-linked heteroaryl, optionally substituted aryl, a quaternary ammonium salt of a nitrogen containing heteroaryl group or a quaternary salt of a substituted aryl amins group; D is heteroaryl attached to C or a quaternary ammonium salt of a nitrogen containing heteroaryl group; E is optionally substituted aryl of a quaternary ammonium salt of a substituted amino aryl group; A is one of amino, amido, cyano, thiocyano, azido, nitro, hydroxy, halo, carboxyl, alkoxy, alkoxycarbonyl, alkanoyloxy, hydrogen, sulfate, thiosulfate, sulfonate, alkylthio, alkylsulfinyl, alkylsulfonyl or mercapto; R4 is one of hydrogen or methyl; R5, R6, R7, R8, R, and R10 are each hydrogen; and all dotted lines represent simple links.

25. A compound of claim 22, characterized in that: R is one of hydrogen, halogen, lower alkoxy, alkynyl or substituted alkynyl; and R3 is one of -C (0) -CH2-Y-G, -C (O) -CHa-0-D, -C. { 0) -CHa-0-E, -C (0) -CHj-Y'-Z-G O -C (O) -CH2-Y'-Z-A.

26. A compound of claim 25, characterized in that R3 is one of -C (O) -CH2-Y-G, -C (O) -CH2-0-D or -C (O) -CHa-0-E.

27. A compound of claim 26, characterized in that it is 3a-hydroxy-3β- (4-hydroxybutynyl) -21- (pyrid-4-ylthio) -5β-pregnan-20-one; 3a-hydroxy-2l- (pyrid-4-yloxy) -5β-pregnan-20-one; N-methyl 3a-hydroxy-2β-propoxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one iodide; 3-hydroxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one N-methyl iodide; N-methyl 3a-hydroxy-2l- (pyrid-4-yl) thio-5β-pregnan-20-one iodide; 3a-hydroxy-3β-methoxymethyl-21- (pyrid-4-ylthio) -5a-pregnan-20-one; 21- (4'-dimethylaminophenylthio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan-20 -one; 3a-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylthio) -5a-pregnan-20-one; 3a-hydroxy-3β-methoxymethyl-21- (4'-nitrophenylsulfinyl) -5a-pregnan-20-one; 3a-Hydryxy-3β-methoxymethyl-21- (4'-nitropylsulfonyl) -5a-pregnan-20-one; 21- (4'-dimethylaminofenoxi) -3a-hydroxy-3β-methyl-5a-pregnan-20-one; 3a-hydroxy-3β-methyl-21- (4'-nitrophenoxy) -5a-pregnan-20-one; 3a-hydroxy-3β-methyl-21- (4 * -trimethylammoniofenoxi) -5a-pregnan-20-one iodide salt; 21- (4 '-f luorof enylthio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one; 3β-ethynyl-3a-hydroxy-21- (pyrid-4-ylthio) -5a-pregnan-20-one; 3β- (4'-acetylphenyl) ethynyl-3a-hydroxy-21- (pyrid-4-ylthio) -5β-pregnan-20-one; 3a-hydroxy-2β-propoxy-2l- (4 '-N, N, N-trimethylammoniofenoxi) -5a-pregnan-20-one iodide salt; 3a-hydroxy-3β-methyl-21- (quinolin-6-yloxy) -5a-pregnan-20-one iodide N-methyl iodide; 3a-hydroxy-3β-methyl-21- (quinolin-6-yloxy) -5a-pregnan-20-one; 21- (4 '-fluorophenyl) sulf onyl-3a-hydroxy-3β-methoxymethyl-5a-pregnan-20-one; 3a-hydroxy-3β-methoxymethyl-2l- (4'-pyrrole idinofenyl) sulfonyl-5a-pregnan-20 -one or 21- (4'-aminofenylthio) -3a-hydroxy-3β-methoxymethyl-5a-pregnan -20-ona.

28. A compound of claim 25, characterized in that R3 is -C (O) -CH2-Y '-Z-A, and Rt is other than hydrogen or alkyl.

29. A compound of claim 28, characterized in that it is sodium 3a-hydroxy-2β-propoxy-21-thiopropanesulfonate-5a-pregnan-20-one salt; 3β-ethynyl-3a-hydroxy-21- (3 '-hydroxypropylthio) -5β-pregnan-20-one; 3ß-ethynyl-3a-hydroxy-21- (thiopropanesulfate) -5β-pregnan-20-one sodium salt; 3β-ethynyl-3a-hydroxy-21- (2 • -hydroxyethylthio) -5β-pregnan-20-one; 3β-ethynyl-3α-hydroxy-21-thioethanesulfate-5β-pregnan-20-one trimethylammonium salt; 3β-ethynyl-3α-hydroxy-21-thiopropanesulfonate-5β-pregnan-20-onade sodium salt; 3β-ethynyl-3a-hydroxy-21- (3 '-hydroxypropylsulfonyl) -5β-pregnan-20-one; 3a-hydroxy-21- (3 '-hydroxypropylsulfonyl) -2β-propoxy-5a-pregnan-20-one; sodium 3a-hydroxy-2ß-propoxy-21-sulfonylpropanosulfate-5a-pregnan-20-one salt; or 3a-hydroxy-21- (2'-hydroxyethylthio) -5β-pregnan-20-one.

30. The compound of claim 1, characterized in that: R is one of hydrogen, amino, thio, sulfinyl, sulfonyl, halogen, lower alkoxy, alkenyl, alkynyl or substituted alkynyl; R x is one of alkenyl, alkynyl, trihaloalkyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, thiocyanoalkyl, azidoalkyl, optionally substituted arylalkyl, arylalkenyl, optionally substituted aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof , cyanoalkynyl, optionally substituted heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminyalkynyl, mercaptoalkynyl, hydroxyalkynyl-dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl; R, is one of alkoxy, a keto group or a dimethylamino group; R3 is hydrogen; R4 is one of hydrogen or methyl; R5, R6, R7, Rβ, R9 and R10 are each hydrogen; and all dotted lines represent simple links.

31. The compound of claim 30, characterized in that: R is hydrogen, halogen, lower alkoxy, alkynyl or substituted alkynyl.

32. The compound of claim 30, characterized in that R is one of substituted arylethynyl, cyanoalkynyl, oxo alkynyl, hydroxyalkynyl, alkanoyloxyalkynyl, alkynyloxyalkynyl, alkoxyalkynyl, heteroaryloxyalkynyl or heteroarylalkynyl.

33. The compound of claim 30, characterized in that R- is one of alkenyl, optionally substituted aryl, optionally substituted arylalkyl, trihalomethyl, halomethyl or alkoxyalkyl.

34. A pharmaceutical composition, characterized in that it contains the compound of claim 1 and a pharmaceutically acceptable carrier.

35. A method of modulating the chloride-ionophore receptor complex of GABAA in an animal subject during binding to the neurosteroid site on said complex, characterized in that it comprises administering to said animal subject an amount effective to modulate said complex of a compound of the claim 1.

36. A method of treatment or prevention of stress or anxiety in an animal subject, characterized in that it comprises the administration to said animal subject with the need for such treatment of an effective amount of a compound of claim 1.

37. A method of alleviation or prevention of attack activity in an animal subject, characterized in that it comprises the administration to said animal subject with the need for such treatment of an effective amount of a compound of claim 1.

38. A method of alleviating or preventing insomnia in an animal subject, characterized in that it comprises the administration to said animal subject in need of such treatment of an effective amount of a compound of claim 1.

39. A method of inducing sleep and maintaining substantially the REM sleep level found in normal sleep, characterized in that insomnia of substantial rebound is not induced, which comprises administration to said animal subject with the need for such treatment of a effective amount of a compound of claim 1.

40. A method of alleviating or preventing PMS or PND in an animal subject, characterized in that it comprises the administration to said animal subject with the need for such treatment of an effective amount of a compound of claim 1.

41. A method of treatment or prevention of mood disorders in an animal subject, characterized in that it comprises the administration to said animal subject with the need for such treatment of an effective amount of a compound of claim 1.

42. The method of claim 41, characterized in that said mood disorder is depression.

43. A method that induces anesthesia in an animal subject, characterized in that it comprises the administration to said animal subject of an effective amount of a compound of claim 1.

44. The method of any of claims 35-43, characterized in that said compound is a pharmaceutically acceptable 3-ester or 3-diester of an acid selected from the group consisting of acetic, propionic, maleic, fumaric, ascorbic, pimelic, succinic, glutaric, bismethylesalicylic, methanesulfonic, ethane-di-sulfonic, oxalic, tartaric, salicylic, citric, gluconic, itaconic, glycolic, p-aminobenzoic, aspartic, glutamic, t-amino-butyric, a- (2-hydroxyethylamino) -propionic, glycine and other α-amino acids, phosphoric, sulfuric, glucuronic, and 1-methyl-1,4-dihydronicotinic.

45. The method of any of claims 35-43, characterized in that said effective amount is from about 1 mg to about 100 mg per dosage unit when administered intravenously and from about 100 mg to about 500 mg per dosage unit when administered not -intraveniously.