COMPOSITIONS AND METHODS FOR ALLEVIATING STRESS, ANXIETY AND SEIZURE ACTIVITY

Abstract: A method of using 3-hydroxylated-5-reduced steroids and certain novel derivatives which act at a newly identified site on the GBR complex, to modulate brain excitability in a manner which will alleviate stress, anxiety, and seizure activity.

Description: COMPOSITIONS AND METHODS FOR ALLEVIATING STRESS, ANXIETY AND SEIZURE ACTIVITY BACKGROUND OF THE INVENTION The present invention is directed to compounds and a method of use of such compounds for modulating animal brain excitability via the gamma-aminobutyric acid (GABA)/benzodiazepine (BZ) receptor-chloride ionopore complex (GBR complex) . Brain excitability is defined as the level of -arousal of an animal which is a .continuum that ranges from coma to convulsions, and is regulated by various -neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential or membrane voltage of approximately -80 mv, the interior being negative with respect to the exterior of the cell. The potential is the result of ion (K " , Na + , Cl~, organic anions) balance across the neuronal membrane, which is semi- permeable. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -80 mv to -50 mv) . This effect is mediated by post-synaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na + ions. The reduced membrane potential stimulates neuronal excitability in the form of a post-synaptic action potential. In the case of the GBR complex,-the effect on brain excitability is mediated by the neurotransmitter GABA. The profound influence of GABA on overall brain excitability is related to the fact that up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GBR complex to facilitate the flow of chloride ions down a concentration gradient of the GBR complex into the cell. The increase in the levels of this anion intracellularly results in the hyperpolarization of the . -transmembrane potential rendering the neuron less susceptible to excitatory inputs (i.e., reduced neuron •excitability) . It is well-documented that the GBR complex is responsible for the mediation of anxiety, seizure activity and sedation. Thus GABA, drugs that act like- GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs) such as Valium) produce their therapeutically useful effects via their interaction with specific regulatory sites on the GBR receptor complex. It has also been observed that a series of steroid metabolites also interact with the GBR receptor complex to alter brain excitability (Majewska, M.D. et al., "Steroid hormone metabolites area barbiturate-like modulators of the GABA receptor," Science, 232:1004- 1007, 1986; Harrison, N.L. et al., Structure-activity relationships for steroid interaction with the gamma- aminobutyric acid-A receptor complex," J. Pharmacol. Exp. Ther. , 241:346-353, 1987). Prior to the present invention the potential therapeutic usefulness of these steroid metabolites was not recognized by workers in the field due to an incomplete understanding of the potency and site of action. The ovarian hormone progesterone and its metabolites have also been demonstrated to have profound effects on brain excitability (Backstrom, T. et al., "Ovarian steroid hormones: effects on modd, behaviour and brain excitability," Acta Obstet. Gynecol. Scand. Suppl. 130:19-24, 1985; Pfaff, D.W. and McEwen, B.S., "Actions of estrogens and progestins on nerve cells," Science". 219:808-814, 1983; Gyermec, et ; al., 1968. "Structure- activity relationship of some steroidal hynotic agents," J. Med. Chem. 11:117). The -levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well- documented that progesterone and its metabolites decrease prior to the onset of menses. The monthly recurrence of certain physical symptoms associated with the onset of menses has also been well documented. These symptoms which have become associated with premenstrual syndrome (PMS) include stress, anxiety, and migraine headaches (Dalton, K. , 1984. Premenstrual Syndrome and Progesterone Therapy. 2nd edition, Chicago: Chicago Yearbook ) . Patients with PMS have a monthly recurrence of symptoms which are present in premenses and absent in postmenses. In a similar fashion, the reduction in progesterone has also been temporally correlated with an increase in seizure frequency in female epileptics (i.e., catamenial epilepsy; Laidlaw, J. "Catamenial epilepsy," Lancet, 1235-1237, 1956). A more direct correlation has been observed with the reduction in progesterone metabolites (Rosciszewska et al., "Ovarian hormones, anticonvulsant drugs and seizures during the menstrual cycle in women with epilepsy," J. Neurol. Neurosurcr. Psych.. 49:47-51, 1986). In addition, for patients with primary generalized petit mal epilepsy, the temporal incidence of seizures has been correlated with the incidence of the symptoms of premenstrual syndrome (PMS) (Backstrom, T. et al. "Production of 5 .alpha.-pregnane-3, 20-dione by human corpus luteum," Acta Endrocr. Suppl. 256:257 r 1983). A syndrome also related to low progesterone levels is postnatal depression (PND) . Immediately after birth progesterone levels decrease dramatically leading to the onset of PND. Women experiencing PND -show an increased incidence of PMS (Dalton, K. 1984. op. cit.). The symptoms of PND range from mild depression to psychosis requiring hospitalization and is associated with severe anxiety and irritability. The depression associated with PND is not amenable to treatment by classic antidepressants (Dalton, K. 1984, op. cit.) . Collectively, these observations imply a crucial role for progesterone in the homeostatic regulation of brain excitability which is manifested as an increase in seizure activity or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between reduced levels of progesterone and the symptoms associated with PMS, PND and catamenial epilepsy (Backstrom, et al., 1983, op. cit.; Dalton, K. 1984, op. cit.) has prompted the use of progesterone in their treatment (Mattson, et al., 1984. "Medroxyprogesterone therapy of catamenial epilepsy," in Advances in epileptoloαv: XVth Epilepsy International Symposium. New York: Raven Press, 279- 282 and Dalton, K. 1984, op. cit.). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, no dose-response relationship exists for progesterone in the treatment of PMS (Maddocks, et al. 1986. "A double-blind placebo-controlled trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome," J. Obstet. Gynecol. 154:573- 581; Dennerstein, et al., 1986. Britain Medical Journal. 290:16-17). BRIEF DESCRIPTION OF THE DRAWINGS The present invention may be better understood and its advantages will be apparent to those skilled in the art by reference to the accompanying drawings wherein: Figures 1A and IB are plots of the percentage of binding of [ 35 S] t-butylbicyclophosphorothionate verse log concentration of Alphaxalone and GABA; Figures 2A and 2B are plots of the percentage of binding of [ 35 S] t-butylbicyclophosphorothionate verse time; Figure 3 is a plot of the effect of a single dosage of pentobarbital on 5 alpha-pregnan-3 alpha-ol- 20-one modulation of [ 3 H] flunitrazepam binding in rat hippocampal homogenates; Figure 4 is a bar graph of the time to the onset of myoclonus verse different concentrations of various types of compounds of the present invention; and Figure 5 is a plot of the effect of progesterone metabolites and the progestin R5020 (promogesterone) on the binding of [ 3 H] R5020 to the progesterone receptor in rat cerebral cortex. SUMMARY OF THE INVENTION The present invention is directed toward the use of 3-hydroxylated-5-reduced steroids and their -derivatives to be defined herein: acting at a newly identified site on the GBR complex, to modulate brain -excitability in a manner which will alleviate stress, anxiety, and seizure activity. These compounds have utility as modulators of the excitability of the central nervous system as mediated by their ability to regulate chloride ion channels associated with the GABA-benzodiazepine receptor complex. Based on the unique experimental observations disclosed herein, the compounds of the invention have anti-convulsant activity similar to the actions of known anxiolytic agents such as the benzodiazepines, but act at a distinct site on the GBR complex. The relationship of the some of the compounds of the invention, which are endogenous metabolites of progesterone, to processes associated with reproduction (estrus cycle and pregnancy) is well established (Marker, R.E., Kam , 0., and McGrew, R.V. [1937], "Isolation of epi-Pregnanol-3-one-20 from human pregnancy urine", J. Am. Chem. Soc. 59. 616-618) . Therefore, this invention is directed at methods, compounds and compositions of such compounds, and their prodrug derivatives, for use in the treatment of disorders such as pre-menstrual syndrome (PMS) and post-natal depression (PND) . DESCRIPTION OF THE INVENTION This invention is directed to certain compounds and new pharmaceutical applications of such compounds. In particular, the invention is directed to 3-hydroxylated-5-reduced-pregnan-20-one and 5-reduced- 3,21-pregnandiol-20-ones and 5-reduced-3,20- pregnandiols and various ester and oxime derivatives of such compounds which are known to those skilled in the art of pharmaceutical preparations as prodrugs. The expression "prodrug" denotes a derivative of a known active drug whose derivative enhances delivery characteristics and therapeutic value of the drug and is transformed into the active drug by an enzymatic or chemical process. It should be noted that some of the synthetic derivatives may not be true prodrugs by virtue of their intrinsic activity. Our novel studies (Gee, K.W. , et al. "GABA- dependent modulation of the Cl ~ ioonophore by steroids in rat brain," European Journal of Pharmacology. 136:419-423, 1987) have demonstrated that these 3- hydroxylated-5-reduced steroids are orders of magnitude more potent than others have reported (Majewska, M.D., et al., 1986, op. cit. and Harrison, N.L. , et al., 1987, op. cit.) as modulators of the GBR complex. Consequently, we now disclose additional experimental data from in vivo studies, which demonstrates that the high potency of these steroids will allow them to be therapeutically useful in the modulation of brain excitability via the GBR complex. The most potent steroids include major metabolites of progesterone. These steroids can be specifically used to modulate brain excitability in stress, anxiety and seizure disorders. Furthermore, we have demonstrated that these steroids interact at a unique site on the GBR complex which is distinct from other known sites of interaction (i.e. , barbiturate, benzodiazepine and GABA) where therapeutically beneficial effects on stress, anxiety, sleep and seizure disorders have been previously elicited (Gee, K.W. and Yamamura, H.I., -"Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders," -in Drugs in Central Nervous System Disorders. pages 123-147, [D.C. Horwell, ed. 1985]). Exemplary of naturally occurring metabolites of progesterone for which this invention describes a new use are those having the following structural formula: FORMULA 1 in which: Rl is a hydroxy group; R2 is acetyl group or 2-hydroxyethanone or 1- hydroxyethane; and R3 is hydrogen; R4 and R5 are each a methyl group. Exemplary of synthetic derivatives of progesterone metabolites of the invention are those having the structural formula as illustrated above (Formula 1) in which: Rl is: . (1) a pharmaceutically acceptable ester -Y- (C=0)-R6, wherein R6 is a C-i-^Q branched, straight chain, or cyclic aliphatic or aromatic radical, and wherein Y is either oxygen or sulfur. This ester can be derived from the reactions well known in the art between the hydroxyl group of the naturally Occurring .compounds discussed above with an organic acid, acid halide, anhydride, or ester, wherein the organic acids are for example: acetic, propionic, n and i-butyric, n and i. and s_ and t-valeric, hexanoic, heptanoic, octanoic, nόnanoic, decanoic, undecanoic, dodecanoic, σinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, oxalic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p_-aminobenzoic, glutamic, benzenesulfonic, and cyclohexylsulfamic; or (2) a pharmaceutically acceptable oxime =N-0- R7 radical wherein R7 is a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. This oxime radical may be derived from the reaction of a 3- " oxo derivative of progesterone by methods well know to the art with an oxyamine; or (3) a pharmaceutically acceptable acyloxyalkyloxy -0-CH 2 -0-(C=0)-R8 radical wherein R8 is a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. This acyloxyalkyloxy radical may be derived from the reaction of the 3-hydroxy group of the naturally occuring compounds discussed above by methods well known to the art with an organic acyloxyalkyl halides (1 -20 carbons) or aryloxlalkyl halides, ' and in particular acetyloxymethyl halide, diacetyloxymethyl halide, or amino-acetyloxymethyl halide. R2 is: (1) a pharmaceutically acceptable -(C=0)- CH 2 -0-R9; -(C=0)-CH 2 -0-(C=0)-R10; OR -(C=0)-CH 2 -0-CH 2 - 0-(C=0)-Rll wherein R9, RIO or Rll are a C 1 -C 0 branched, straight chain, or cyclic aliphatic or aromatic radical, or an amide -(CH 2 ) n -(C=0)-N-R16,R17 .radical wherein R16 and R17 are individually a C 1 -C 20 -branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8. An example of this type of radical wherein R10 is an amide is 5 .alpha.-pregnan-3 .alpha.-hydroxy-21-(N, N-diethylsuccinamate-20-one. These radicals may be derived from the reaction of the 21-hydroxy metabolite of progesterone by methods known in the art with an alkyl halide or organic acid, such - as acetic, propionic, n and jl-butyric, n and and s. and t-valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic, dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pamoic, succinic, bismethylenesalicylic, ethanesulfonic, ethanedisulfonic, oxalic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and cyclohexylsulfamic acids. (2) a -(C-CH 3 )=N-0-R12; -C-0-CH 2 -0-(C=0) -R13 ; -(C-CH 3 )-0-(C=0)-R14; OR -(C-CH 3 ) -0-R15 wherein R12, R13, R14 and R15 are a Cτ_-C 20 branched, straight chain, or cyclic aliphatic or aromatic radical. These radicals may be derived from progesterone or the 20 hydroxy metabolite of progesterone by methods known in the art with an alkyl halide or organic acids, such as acetic, propionic, n and jL-butyric, n and j. and s and t-valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic, dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, oxalic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p.-aminobenzoic, glutamic, benzenesulfonic, and cyclohexylsulfamic acids. (3) a pharmaceutically acceptable thiazolidine derivative of the 20-oxo position on -progesterone having the formula: wherein R18 and R19 are individually a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical, and R20 and R21 are individually hydrogen or a c l~ c 20 branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-0-R22 wherein R22 is H or a c i~ c 20 branched, straight chain, or cyclic aliphatic or aromatic radical. R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons) , aryloxy, or amino radical. R4 is an alkyl (2 to 18 carbons), aryl, halo (such as fluoro, chloro, bromo, or iodo) , or trifluroalkyl. R5 is an alkyl (2 to 18 carbons) , aryl, halo (such as fluoro, chloro, bromo, or iodo) , or trifluroalkyl. It will be obvious to one skilled in the art that the above described compounds may be present as diastereo isomers which may be resolved into d or 1 optical isomers. Resolution of the optical isomers may be conveniently accomplished by gas or liquid chromatography or isolation from natural sources. Unless otherwise specified herein, including the claims, reference to the compounds of the invention, as discussed above, is intended to include all isomers, whether separated or mixtures thereof. Where isomers are separated, the desired pharmacological activity will often predominate in one .of the isomers. As disclosed herein, these compounds -display a high degree of stereospecificity. In particular, those compounds having the greatest affinity for the GABA-benzodiazepine receptor complex are those with 3 .alpha, substituted-5 .alpha.- pregnane steroid skeletons. In addition, 3 .alpha. substituted-5 .beta.-pregnane skeletons have been demonstrated to be active. The above compounds of the invention, that being the naturally occuring metabolites of progesterone and their nontoxic pharmaceutically acceptable synthetic "prodrug" forms (synthetic derivatives of progesterone metabolites discussed above) have novel activity in the brain at the GABA- benzodiazepine receptor complex. The compounds of the invention may be prepared by any known technique. For example, the naturally occurring metabolites of progesterone may be extracted from various animal excretion sources, e,g., urine. These extracted compounds may then be chemically altered to form the desired synthetic derivative, or used directly. The pharmaceutical compositions of this invention can be prepared in conventional dosage unit forms by incorporating a compound of the invention or a mixture of such compounds, with a nontoxic pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to produce the desired pharmcoadynamic activity in a subject, animal or human. Preferably, the composition will contain the active ingredient in an active, but nontoxic amount,, selected from about 50 mg to about 500.mg of active ingredient -per dosage unit. This quantity depends on the specific biological activity desired and the condition of the patient. The most desirable ' object of the composition and methods is in the treatment of pre-menstrual syndrome, catamenial epilepsy, and post-natal depression to ameliorate or prevent the attacks of anxiety, muscle tension, and depression common with patients suffering from these central nervous system abnormalities. The pharmaceutical carrier employed may be, for example, either a solid, liquid, or time release (see standard reference Remington's Pharmaceutical Sciences which is incorporated herein by reference) . Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, microcrystalline cellulose, polymer hydrogels and the like. Exemplary of liquid carriers are syrup, peanut oil, and olive oil and the like emulsions. Similarly, the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, microcapsules, microspheres, liposo es, and hydrogels. A wide variety of pharmaceutical forms can be employed. Thus, when using a solid carrier the preparation can be tableted (however, the oral route of administration should be avoided due to first pass metabolic degradation) , placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche, lozenge or suppository. When using a liquid carrier the preparation can be in the form of a liquid, such as an ampule, or as an aqueous or nonaqueous liquid suspension. Liquid dosage forms also need -pharmaceutically acceptable preservatives and the like. In addition, because of the low doses which will be required as based on the in vitro data disclosed herein, topical administration via timed release skin patches is also a suitable pharmaceutical form. The method of producing anxiolyic, or anticonvulsant activity, in accordance with this invention, comprises administering internally to a subject in need of such activity a compound of the invention, usually prepared in a composition as described above with a pharmaceutical carrier, in a nontoxic amount sufficient to produce said activity as described above. During menses the levels of excreted metabolites varies approximately fourfold (Rosciszewska, et al., op. cit.). Therefore, therapy for controlling symptoms will involve maintaining the patient at a more uniform level of progesterone metabolite. Plasma levels of active and- major metabolites will be monitored during pre-menses and post-menses of the patient. The amount of the compounds, either singly or mixtures thereof, of the invention administered will reflect the physiological concentrations which naturally occur post-menses. The route of administration may be any route which effectively transports the active compound to the GABA- benzodiazepine receptors which are to be stimulated such as parenterally, rectally, intravaginally, intradermally, subligually, or nasally, the dermal route being preferred. For example, one dose in a skin patch may supply the active ingredient to the patient for a period of up to one week. The following is a discussion of our experimental observations in support of the invention: As stated, the naturally occurring metabolites of progesterone and their derivatives interact with high affinity at a novel and specific recognition site on the GBR complex to facilitate the conductance of chloride ions across neuronal membranes sensitive to GABA (Gee, et al., 1987). This has been shown by in vitro and in vivo experimental data. To those skilled in the art, it is known that the modulation of [ 35 S] t-butylbicyclophosphorothionate ([ 35 S]TBPS) binding is a useful measure of the potency and efficacy of drugs acting at the GBR complex which may be of potential therapeutic value in the treatment of stress, anxiety and seizure disorders (Squires, R.F.,et al., "[ 35 S]t-Butylbicyclophophorothionate binds with high affinity to brain-specific sites coupled to a gamma aminobutyric acid-A and ion recognition site," Mol. Pharmacol. 23:326, 1983; Lawrence,• .J. , et al. , "Benzodiazepine anticonvulsant action: gam a- aminobutyric acid-dependent modulation of the chloride ionophore," Biochem. Biophvs. Res. Comm.. 123:1130- 1137, 1984; Wood, et al., 1984. "In vitro characterization of benzodiazepine receptor agonists, antagonists, inverse agonists and agonist/antagonists," J. Pharmacol. EXP. Ther. 231:572-576) . We performed an assay to determine the modulation of [ 35 S] TBPS as effected by the compounds of the invention and found tha .these compounds have high potency and efficacy at the GBR complex, with stringent structural requirements for such activity. The procedures for performing this assay are -fully discussed in: (1) Gee, et al., 1987 op. cit.; and (2) Gee, K.W. , L.J. Lawrence and H.I. Yamamura, 1986, "Modulation of the chloride ionopore by benzodiazepine receptor ligands: influence of gamma-aminobutryric acid and ligand- efficacy," Molecular Pharmacology, 30. 218, both of which references are incorporated herein by reference. These procedures were performed as follows: Brains from male Sprague-Dawley rats were removed immediately following killing and the cerebral cortices dissected over ice. A P 2 homogenate was prepared as previously described (Gee, et al., 1986, op. cit.). Briefly, the cortices were gently homogenized in 0.32 M sucrose followed by centrifugation at 1000 x g for 10 minutes. The supernatant was collected and centrifuged at 9000 x g for 20 minutes. The resultant P 2 pellet was resuspended as a 10% (original wet weight/volume) homogenate in 50mM Na/K phosphate buffer (pH 714) + 200 mM NaCl. One hundred microliter aliquots of the P 2 homogenate (0.5 milligrams (mg) protein) were incubated with 2 nano olar (nM) [ 35 S]TBPS (70-110 curies/millimole; , New England Nuclear, Boston, MA) in the presence or absence of various concentrations of the desired compounds. Compounds were dissolved in dimethylsulfoxide (Baker Chem. Co., Phillipsbury, NJ) and added to the incubation mixture in 5 microliter aliquots. The incubation mixture was brought to a final volume of 1 millilitre (ml) with buffer. Non¬ specific binding was defined as binding in the presence of 2 micromolar TBPS. The effect and specificity of GABA (Sigma Chem. Co., St. Louis, MO) was evaluated by performing all assays in the presence of 5 micromolar • GABA ± (+)-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) . Filter bound radioactivity was quantitated by liquid scintillation spectrophotometry. Kinetic data and compound/[ 35 S]TBPS dose-response curves were analyzed by non-linear regression using a computerized iterative procedure to obtain rate constants and IC5 0 (concentration of compound at which half-maximal inhibition of basal [ 35 S]TBPS binding occurs) values. The experimental data obtained for this assay is also published in Gee, et al., 1987 which data and conclusions are also incorporated herein by reference. The data discussed in this incorporated reference is shown as plots in FIGURES 1A and IB. These plots describe the effect of (+)-bicuculline on alphaxalone (1A) and GABA (IB) modulation of 2 nanomolar [ 35 S]- TBPS binding to rat cerebral cortex. In these Figures (O) represents control without bicuculline; (• ) represents 0.5 micromoloar bicuculline; (□) represents 1.0 micromolar bicuculline; (■) represents 2.0 micromolar bicuculline; and (Δ ) represents 3.0 micromolar bicuculline. In this experiment the effect of (+)-bicuculline on the ability of alphaxalone or GABA to inhibit the binding of [ 35 S]TBPS has been determined. Bicuculline is known to be directly competitive with GABA and in Figure IB, a classical parallel shift in the dose-response curves is observed. In contrast, the steroid binding site is distinct from the GABA/bicuculline site as seen in Figure 1A. The shift in dose-response curves induced by (+)- bicuculline when the inhibition of [ 35 S]-TBPS binding is caused by alphaxalone is not linear. This would -definitely suggest that the GABA and steroid sites do not overlap. We also performed this assay to determine the effect of pentobarbital on the dissociation kinetics of [ 35 S]TBPS in rat cerebral cortical membranes. This assay was performed in accordance with the procedures outlined " above. This data indicates that the site of action of the compounds of the invention is unique and distinct from the previously known sites of action for the barbiturates and the BZs. The results of the in vitro assay is shown in FIGURES 2A and 2B. The plots in Figures 2A or 2B describe the effect of pentobarbital, alphaxalone, 5 .alpha.-pregnan-3 .alpha.-hydroxy-20-one on the dissociation kinetics for 2 nanomolar [ 35 S]TBPS inn cortical P2 ho ogenates. Dissociation of bound [ 35 S]TBPS was initiated by 2 micromolar TBPS in all cases. Pentobarbital (Figure 2A) at 30 micromolar induces a biphasic dissociation mechanism which is absent for alphaxalone (300 nanomolar) and 5 ,alpha.-pregnan-3 .alpha.-hydroxy-20- one (20 nanomolar) (Figure 2B) . A table of the kinetic rate constants and half lives obtained by this assay are seen below in Table 1. The information presented in Table 1 indicates that the barbiturate induces a shift in the half life of dissociation and the proportion of slow and rapidly dissociating components, hallmark effects of therapeutically useful GABA agonists, barbiturates and BZs on [ 35 S] TBPS binding (Gee, et al. , 1986; Maksay, ' G. & Ticku, M. "Dissociation of [ 35 S]t- butylbicyclophophorothionate binding differentiates .-convulsant and depressant drugs that modulate GABAergic .transmission," J. Neurochem. 44:480-486, 1985). In •contrast, the progesterone metabolite 5 .alpha.- pregnan-3 .alpha.-ol-20-one, and the progestin alphaxalone do not influence the dissociation kinetics of { 35 S]TBPS binding. Therefore, the steroid and barbiturate sites are distinct. // // // // // // // // // 20 TABLE 1 Total percentage Conditions t 2 (min) k.^ (min --l- 1 -i) of specific sites R Control 50+4 6+1 0.145+ 0.131+ 73+2 30+2 0.0008 0.016 61+6* 48+6** + 300nM 67+ 4.9+1 0.0120+ 0.0180+ 73+4 34+5 Alphaxalone 12 0.0003 0.040 + 20 nM 76+ 6.4+1 O.Oll± 0.122+ 68+3 35+3 -3α-OH-DHP 11 0.002 0.030 -Significantly different from control @ *P<0.05 and **P<0.01 by Student's t-test. S and R represent slowly and rapidly dissociating components respectively. Furthermore, 5 .alpha.-pregnan-3 .alpha.-ol- 20-one does not interact with pentobarbital in the enhancement of the binding of [ 3 H] flunitrazepam to the BZ receptor in the cortical brain homogenates (FIGURE 3) . Indicating that steroids and barbiturates do not share a common site of action. The data shown in FIGURE 3 was obtained by performing an assay to determine the effect of a single concentration of pentobarbital (1.0 millimolar) on 5 .alpha.-pregnan-3 .alpha.-ol-20-one modulation of 0.25nM [ 3 H] flunitrazepam ([ 3 H]FLU) binding to the BZ receptor in rat hippocampal homogenates. This assay was performed in accordance with the procedures outlined above. Each point on the plot of FIGURE 3 represents the mean + SEM of 4-6 independent determinations. The data points in both curves are expressed as percent enhancements of [ 3 H]FLU binding, which is defined as the percentage of [ 3 H]FLU bound in the absence of 5 .alpha.-pregnan-3 .alpha.-ol-20-one under the control conditions minus 100%. All assay were performed in the absence of GABA. The above data demonstrates that the compounds of the invention interact with a novel site distinct from previously defined regulatory sites on the GBR complex. A variety of the compounds were screened to • .-determine their potential as modulators of [ 35 S]TBPS binding in vitro. These assays were performed in -accordance with the above discussed procedures. Based on these assays we have established (1) the structure- activity requirements for their specific interaction at the GBR complex and (2) their rank order potency and efficacy (Table 2 below) . // // // // // // // // // ZZ TABLE 2 5a -ANDR0STAN-3α 15000 1000 100 17a -DIOL 2,3 5 α -PREGNAN- - >10 5 5500 100 21-DIO -11.20-OIONE S > 10 5 18000 52 5 -PREGNA INACTIVE > 10 5 33 OL-20-ONE (ALLOPREG 5-PREGNEN-3S -OL- INACTIVE >10 5 30 20-ONE (PREGNENOLON M-PREGNEN-llβ ,21 INACTIVE "10 5 21 -DIOL-3,20-DIONE (CORTICOSTERONE) M * 0M CO 176 -ESTRAD10L øSP INACTIVE INACTIVE CHOLESTEROL INACTIVE INACTIVE ^ y We also performed experiments to determine the physiological relevance of these interactions by measuring the ability of the compounds of the invention to modulate TBPS induced convulsions in Swiss-Webster mice. Mice were injected with various doses of the test compounds of the invention, as specified in Figure 4, 10 minutes prior to the injection of TBPS. The time to onset of myoclonus (presence of forelimb clonic activity) induced by TBPS was determined, by observing each mouse for a period of 45 minutes. Significant differences between the time to onset in control versus steroid treated mice were determined by Student's t- test. The relative rank order potency and efficacy of these steroids in vivo were well correlated with those observed in vitro. These observations demonstrate the therapeutic utility of these compounds as modulators of brain excitability which was predicted by their high affinity interaction with the GBR complex in vitro. The correlations between reduced levels of progesterone and the symptoms associated with PMS, PND and catamenial epilepsy (Backstrom, et al. 1983 op. cit.; Dalton, K. 1984, op. cit.) has prompted the use of progesterone in their treatment (Mattson, et al., 1984; and Dalton, 1984) . However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. • For example, no dose- response elationship exists for progesterone in the treatment of PMS (Maddocks, et al, 1987, op. cit.). These results are predictable when based upon our in vitro studies which demonstrate that progesterone has very low potency at the GBR complex, as seen in Table 2, compared to certain metabolites of progesterone. The beneficial effect of progesterone is probably related to the variable conversion of progesterone to the active progesterone metabolites. The use of specific progesterone metabolites in the treatment of the aforementioned syndromes is clearly superior to the use of progesterone based upon the high potency and efficacy of the metabolites and their derivatives (See Gee, et al., 1987 and Table 2). We have also demonstrated that -the compounds of the invention lack hormonal side effects by the lack of affinity of these compounds of the invention for the progesterone receptor (FIGURE 5) . The data plotted in FIGURE 5 was obtained by performing assays in accordance with the procedures outlined above, to determine the effect of progesterone metabolites and the progestin R5020 on the binding of [ 3 H]R5020 to the progesterone receptor in rat cerebral cortexes. All points on the plot of FIGURE 5 represent the mean of triplicate determinations. The following compounds are those listed in Figure 5: 5 .alpha.-pregnan-3 .alpha.- ol-20-one (DHP) ; 5 .alpha.-pregnan-3 .alpha. ,21-diol- 20-one (Th-DOC) ; 5 beta-pregnane-3 .alpha.,20 diol (5 BETA). While the preferred embodiment has been described and illustrated, various substitutions and modifications may be made thereto without ^ departing from the scope of the invention. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitation.

Claims: WHAT IS CLAIMED IS: l. An anticonvulsant composition comprising: a pharmaceutically acceptable carrier; and a pharmaceutically effective amount of a pharmaceutically acceptable compound having the formula: wherein: Rl a pharmaceutically acceptable ester - Y-(C=0)-R6, wherein R6 is a C ] _-C2o branched, straight chain, or cyclic aliphatic or aromatic radical, and wherein Y is either oxygen or sulfur; R2 is a pharmaceutically acceptable - (C=0)-CH 2 -C~R9; -(C=O)-CH 2 -O-(C=O)-R10; OR -(C=0)-CH 2 - C~CH -0-(C=0)-Rll wherein R9, RIO or Rll are a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical, or an amide -(CH 2 ) n -(C=0) -N-R16,R17 radical wherein R16 and R17 are individually a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8; R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons), aryloxy, or amino radical; R4 is an alkyl (2 to 18 carbons), aryl, halo (such as fluoro, chloro, bromo, or iodo) , or trifluroalkyl; and R5 is an alkyl (2 to 18 carbons) , aryl, halo (such as fluoro, chloro, bromo, or iodo) , or trifluroalkyl. 2. The composition of claim 1 wherein Rl is a pharmaceutically acceptable oxime =N-0-R7 radical wherein R7 is a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical. 3. The composition of claim 1 wherein Rl is a pharmaceutically acceptable acyloxyalkyloxy -0-CH 2 -0- (C=0)-R8 radical wherein R8 is a Cι-C 20 branched, straight chain, or cyclic aliphatic or aromatic radical. 4. The compositon of claim 1 wherein R2 is a -(C-CH 3 )=N-0-R12; -C-0-CH 2 -0-(C=0) -R13 ; -(C-CH 3 )-C~ (C=0)-R14; OR -(C-CH 3 ) -0-R15 wherein R12, R13 , R14 and R15 are a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. 5. The composition of claim 1 wherein R2 is a pharmaceutically acceptable thiazolidine derivative of the 20-oxo position on progesterone having the formula: wherein R18 and R19 are individually a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical, and R20 and R21 are individually hydrogen or a c i~ c 20 branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-0-R22 wherein R22 is H or a 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. 6. The composition of claim 1 wherein: Rl is a hydroxy group; R3 is hydrogen; R2 is acetyl group or 2-hydroxyethanone or 1-hydroxyethane; and R4 and R5 are each a methyl group. 7. A composition comprising: a pharmaceutically acceptable carrier; and a pharmaceutically effective amount of a pharmaceutically acceptable compound having- the formula: wherein: Rl is a pharmaceutically acceptable ester -Y-(C=0)-R6, wherein R6 is a C 1 -C o branched, straight chain, or cyclic aliphatic or aromatic radical, and wherein Y is either oxygen or sulfur; R2 is a pharmaceutically acceptable - (C=0)-CH 2 -0-R9; -(C=O)-CH 2 -O-(C=O)-R10; OR -(C=0)-CH 2 - 0-CH 2 -0-(C=0)-Rll wherein R9, RIO or Rll are a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical, or an amide -(CH 2 ) n -(C=0)-N-R16,R17 radical wherein R16 and R17 are individually a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8; 1 R3 is a hydroxy, keto, alkyloxy (1 to 18 2 carbons), aryloxy, or amino radical; 3 R4 is an alkyl (2 to 18 carbons) , aryl, 4 fluoro, chloro, bromo, iodo or trifluroalkyl; and 5 R5 is an alkyl (2 to 18 carbons) , aryl, 6 fluoro, chloro, bromo, iodo or trifluroalkyl. 1 8. The composition of claim 7 wherein Rl is 2 a pharmaceutically acceptable oxime =N-0-R7 radical 3 wherein R7 is a C 1 -C 0 branched, straight chain, or 4 cyclic aliphatic or aromatic radical. 1 9. The composition of claim 7 wherein Rl is 2 a pharmaceutically acceptable acyloxyalkyloxy -0-CH 2 -0- 3 (C=0)-R8 radical wherein R8 is a C 1 -C 20 branched, 4 straight chain, or cyclic aliphatic or aromatic 5 radical. 1 10. The compositon of claim 7 wherein R2 is a 2 ;-(C-CH 3 )=N-0-R12; -C-0-CH 2 -0-(C=0)-R13; -(C-CH 3 )-0- 3 (C=0)-R14; OR -(C-CH 3 )-0-R15 wherein R12, R13, R14 and 4 -R15 are a C ] _-C 2Q branched, straight chain, or cyclic 5 aliphatic or aromatic radical. 1 11. The composition of claim 7 wherein R2 is 2 a pharmaceutically acceptable thiazolidine derivative 3 of the 20-oxo position on progesterone having the 4 formula: 8 wherein R18 and R19 are individually a C- j _-C 20 branched, 9. straight chain, or cyclic aliphatic or aromatic 0 radical, and R20 and R21 are individually hydrogen or a τ.-C 20 branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-0-R22 wherein R22 is H or a ] _-C 20 branched, straight chain, or cyclic aliphatic or aromatic radical. 12. The composition of claim 7 wherein: Rl is a hydroxy group; R3 is hydrogen; R2 is acetyl group or 2-hydroxyethanone or 1-hydroxyethane; and R4 and R5 are each a methyl group. 13. A compound having the formula: -wherein: Rl is a pharmaceutically acceptable -acyloxyalkyloxy -0-CH 2 -0-(C=0)-R8 radical wherein R8 is a Cι-C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical; R2 is a pharmaceutically acceptable - (C=0)-CH 2 -0-R9; -(C=O)-CH 2 -O-(C=O)-R10; OR -(C=0)-CH 2 - o-CH 2 -0-(C=0)-Rll wherein R9, RIO or Rll are a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical, or an amide -(CH 2 ) n -(C=0)-N-R16,R17 radical wherein R16 and R17 are individually a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8; R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons) , aryloxy, or amino radical; R4 is an alkyl (2 to 18 carbons) , aryl, fluoro, chloro, bromo, iodo or trifluroalkyl; and R5 is an alkyl (2 to 18 carbons) , aryl, fluoro, chloro, bromo, iodo or trifluroalkyl. 14. The compound of claim 13 wherein R2 is a -(C-CH 3 )=N-0-R12; -C-0-CH 2 -0-(C=0)-R13; --(C-CH 3 )-0- (C=0)-R14; OR -(C-CH 3 )-0-R15 wherein R12, R13, R14 and R15 are a C ] _-C 2Q branched, straight chain, or cyclic aliphatic or aromatic radical. 15. A compound having the formula: wherein: Rl is a pharmaceutically acceptable ester .-Y-(C=0)-R6, wherein R6 is a C 1 -C 20 branched, straight -chain, or cyclic aliphatic or aromatic radical, and wherein Y is either oxygen or sulfur; R2 a pharmaceutically acceptable thiazolidine derivative of the 20-oxo position on progesterone having the formula: wherein R18 and R19 are individually a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical, and R20 and R21 are individually hydrogen or a c 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-0-R22 wherein R22 is H or a Λ Λ „„„ O 89/02272 ' ' 32 19 ^-C 20 branched, straight chain, or cyclic aliphatic or 20 aromatic radical; 21 R3 is a hydroxy, keto, alkyloxy (1 to 18 22 carbons) , aryloxy, or amino radical; and 23 R4 is an alkyl (2 to 18 carbons) , aryl, 24 fluoro, chloro, bromo, iodo or trifluroalkyl; and 25 R5 is an alkyl (2 to 18 carbons) , aryl, 26 fluoro, chloro, bromo, iodo or tri luroalkyl. 1 16. The compound of claim 15 wherein Rl is a 2 pharmaceutically acceptable acyloxyalkyloxy -0-CH 2 -0- 3 (C=0)-R8 radical wherein R8 is a C 1 -C 20 branched, 4 straight chain, or cyclic aliphatic or aromatic 5 radical. 1 17. A method of treating the symptoms of 2 premenstrual syndrome and post-natal depression 3 comprising administering a pharmaceutically effective 4 amount of a pharmaceutically acceptable compound having 5 .the formula: - 7 wherein: 8 Rl is a pharmaceutically acceptable ester 9 -Y-(C=0)-R6, wherein R6 is a C 1 -C 20 branched, straight 10 chain, or cyclic aliphatic or aromatic radical, and 11 wherein Y is either oxygen or sulfur; 12 R2 is a pharmaceutically acceptable - 13 ' (C=0)-CH 2 -0-R9; -(C=0)-CH 2 -0-(C=0)-RIO; OR -(C=0)-CH 2 - 14 0-CH 2 -0-(C=0)-Rll wherein R9, RIO or Rll are a C 1 -C 20 15 branched, straight chain, or cyclic aliphatic or aromatic radical, or an amide -(CH 2 ) n -(C=0)-N-R16,R17 radical wherein R16 and R17 are individually a Cτ_-C2o branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8; R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons), aryloxy, or a ino radical; R4 is an alkyl (2 to 18 carbons) , aryl, fluoro, chloro, bromo, iodo or trifluroalkyl; and R5 is an alkyl (2 to 18 carbons), aryl, fluoro, chloro, bromo, iodo or trifluroalkyl. 18. The method of claim 17 wherein Rl is a pharmaceutically acceptable oxime =N-0-R7 radical wherein R7 is a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical. 19. The method of claim 17 wherein Rl is a pharmaceutically acceptable acyloxyalkyloxy -0-CH 2 -0- (C=0)-R8 radical wherein R8 is a C 1 -C 2 o branched, rstraight chain, or cyclic aliphatic or aromatic .radical. 20. The compositon of claim 17 wherein R2 is a -(C-CH 3 )=N-0-R12; -C-O-CH 2 -O-(C=0)-R13; -(C-CH 3 )-0- (C=0)-R14; OR -(C-CH 3 )-0-R15 wherein R12, R13, R14 and R15 are a C]_-C2o branched, straight chain, or cyclic aliphatic or aromatic radical. 21. The method of claim 17 wherein R2 is a pharmaceutically acceptable thiazolidine derivative of the 20-oxo position on progesterone having the formula: wherein R18 and R19 are individually a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical, and R20 and R21 are individually hydrogen or a c ι-C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-0-R22 wherein R22 is H or a c ι~ c 20 branched, straight chain, or cyclic aliphatic or aromatic radical. 22. The method of claim 17 wherein: Rl is a hydroxy group; R3 is hydrogen; R2 is acetyl group or 2-hydroxyethanone or l-hydroxyethane; and R4 and R5 are each a methyl group. 23. The method of claim 17 wherein the pharmaceutically effective amount is sufficient for maintaining the amount of progesterone and its * metabolites in a patient to whom such dosage is given rat a level substantially equivalent to the level of .such progesterone and its metabolites prior to the -onset of menses for the treatment of premenstrual syndrome, or prior to birth for the treatment of post- natal depression. 24. The method of claim 22 wherein the pharmaceutically effective amount is sufficient for maintaining the amount of progesterone and its metabolites in a patient to whom such dosage is given at a level substantially equivalent to the level of such progesterone and its metabolites prior to the onset of menses for the treatment of premenstrual syndrome, or prior to birth for the treatment of post- natal depression. 25. A method of treating the frequency and occurrence of convulsions comprising administering a pharmaceutically effective amount of a pharmaceutically acceptable compound having the formula: wherein: Rl is a pharmaceutically acceptable ester -Y-(C=0)-R6, wherein R6 is a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical, and wherein Y is either oxygen or sulfur; R2 is a pharmaceutically acceptable - (C=0)-CH 2 -0-R9; -(C=O)-CH 2 -O-(C=O)-R10; OR -(C=0)-CH 2 - 0-CH 2 -0-(C=0)-Rll wherein R9, RIO or Rll are a ^-02 0 branched, straight chain, or cyclic aliphatic or ; aromatic radical, or an amide - (CR2 ) n - (C~=0)-N-R16,R17 radical wherein R16 and R17 are individually a C±-C20 -branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8; R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons), aryloxy, or amino radical; R4 is an alkyl (2 to 18 carbons) , aryl, fluoro, chloro, bromo, iodo or trifluroalkyl; and R5 is an alkyl (2 to 18 carbons), aryl, fluoro, chloro, bromo, iodo or trifluroalkyl. 26. The method of claim 25 wherein Rl is a pharmaceutically acceptable oxime =N-0-R7 radical wherein R7 is a •C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. 27. The method of claim 25 wherein Rl is a pharmaceutically acceptable acyloxyalkyloxy -0-CH 2 -0- (C=0)-R8 radical wherein R8 is a C±-C2 Q branched, straight chain, or cyclic aliphatic or aromatic radical. 28. The method of claim 25 wherein R2 is a - (C-CH 3 )=N-0-R12; -C-0-CH 2 -0-(C=0)-R13; -(C-CH 3 )-0- (C=0)-R14; OR -(C-CH 3 )-0-R15 wherein R12, R13, R14 and R15 are a Cχ-C o branched, straight chain, or cyclic aliphatic or aromatic radical. 29. The method of claim 25 wherein R2 is a pharmaceutically acceptable thiazolidine derivative of the 20-oxo position on progesterone having the formula: wherein R18 and R19 are individually a Cι-C 2 o branched, straight chain, or cyclic aliphatic or aromatic -radical, and R20 and R21 are individually hydrogen or a c ι~ c 2 0 branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-0-R22 wherein R22 is H or a c i"" c 2 0 branched, straight chain, or cyclic aliphatic or aromatic radical. 30. The method of claim 25 wherein: Rl is a hydroxy group; R3 is hydrogen; R2 is acetyl group or 2-hydroxyethanone or 1-hydroxyethane; and R4 and R5 are each a methyl group. 31. The method of claim 25 wherein said pharmaceutically effective amount is from about 50 milligrams to about 500 milligrams. 32. The method of claim 30 wherein said pharmaceutically effective amount is from about 50 milligrams to about 500 milligrams. 33. A method of modulating the excitability of neuron activity in animals comprising administering a pharmaceutically effective amount of a pharmaceutically acceptable compound having the formula: wherein: Rl is a pharmaceutically acceptable ester -Y-(C=0)-R6, wherein R6 is a CJ-C20 branched, straight chain, or cyclic aliphatic or aromatic radical, and wherein Y is either oxygen or sulfur; R2 is a pharmaceutically acceptable - (C=0)-CH 2 -0-R9; -(C=O)-CH 2 -O-(C=O)-R10; OR -(C=0)-CH 2 - o-CH 2 -0-(C=0)-Rll wherein R9, R10 or Rll are a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical, or an amide -(CH 2 ) n -(C=0)-N-R16,R17 radical wherein R16 and R17 are individually a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical and n=l-8; R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons), aryloxy, or amino radical; R4 is an alkyl (2 to 18 carbons) , aryl, fluoro, chloro, bromo, iodo or trifluroalkyl; and R5 is an alkyl (2 to 18 carbons), aryl, fluoro, chloro, bromo, iodo or trifluroalkyl. 34. The method of claim 33 wherein Rl is a pharmaceutically acceptable oxime =N-0-R7 radical wherein R7 is a C]_-C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. 35. The method of claim 33 wherein Rl is a pharmaceutically acceptable acyloxyalkyloxy -O-CH2-O- (C=0)-R8 radical wherein R8 is a Cι_-C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical. 36. The method of claim 33 wherein R2 is a - (C-CH 3 )=N-0-R12; -C-0-CH 2 -O-(C=0)-R13; -(C-CH 3 )-0- (C=0)-R14; OR -(C-CH 3 )-0-R15 wherein R12, R13, R14 and :R15 are a C ] _-C 2Q branched, straight chain, or cyclic .aliphatic or aromatic radical. 37. The method of claim 33 wherein R2 is a pharmaceutically acceptable thiazolidine derivative of the 20-oxo position on progesterone having the formula: wherein R18 and R19 are individually a C 1 -C 2 o branched, straight chain, or cyclic aliphatic or aromatic radical, and R20 and R21 are individually hydrogen or a c ι~ 2 0 branched, straight chain, or cyclic aliphatic or aromatic radical or -(C=0)-θ-R22 wherein R22 is H or a i~ c 2 0 branched, straight chain, or cyclic aliphatic or aromatic radical. 38. The method of claim 33 wherein: Rl is a hydroxy group; R3 is hydrogen; R2 is acetyl group or 2-hydroxyethanone or 1-hydroxyethane; and R4 and R5 are each a methyl group.

Inventors: GEE KELVIN W, GEE, KELVIN, W.
Applicants: GEE KELVIN W, GEE, KELVIN, W.
Application year: 1988
Main classification: A61K33
IPC codes: A61K31, C07J1, C07J5, C07J7, C07J43