WO1989002272A1 - Compositions et procedes soulageant le stress, l'anxiete et l'activite apoplectique - Google Patents

Compositions et procedes soulageant le stress, l'anxiete et l'activite apoplectique Download PDF

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Publication number
WO1989002272A1
WO1989002272A1 PCT/US1988/002827 US8802827W WO8902272A1 WO 1989002272 A1 WO1989002272 A1 WO 1989002272A1 US 8802827 W US8802827 W US 8802827W WO 8902272 A1 WO8902272 A1 WO 8902272A1
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branched
straight chain
cyclic aliphatic
aromatic radical
radical
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PCT/US1988/002827
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English (en)
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Kelvin W. Gee
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Gee Kelvin W
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Publication of WO1989002272A1 publication Critical patent/WO1989002272A1/fr
Priority to DK048790A priority Critical patent/DK48790A/da

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified

Definitions

  • 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).
  • GABA gamma-aminobutyric acid
  • BZ benzodiazepine
  • GRR complex gamma-aminobutyric acid
  • GABA gamma-aminobutyric acid
  • BZ benzodiazepine
  • GRR complex gamma-aminobutyric acid
  • GABA gamma-aminobutyric acid
  • BZ benzodiazepine
  • 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.
  • 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.
  • an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -80 mv to -50 mv).
  • 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.
  • GABA 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 thetransmembrane potential rendering the neuron less susceptible to excitatory inputs (i.e., reduced neuronexcitability).
  • GBR complex is responsible for the mediation of anxiety, seizure activity and sedation.
  • drugs that act like GABA or facilitate the effects of GABA e.g., the therapeutically useful barbiturates and benzodiazepines (BZs) such as Valium
  • BZs benzodiazepines
  • 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.
  • PND postnatal depression
  • PMS postnatal depression
  • 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.).
  • progesterone is not consistently effective in the treatment of the aforementioned syndromes.
  • 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. England Medical Journal. 290:16-17).
  • 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.
  • Figure 5 is a plot of the effect of progesterone metabolites and the progestin R5020
  • 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.
  • the compounds of the invention 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.
  • 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., Kamm, O., and McGrew, R.V.
  • 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).
  • PMS pre-menstrual syndrome
  • PND post-natal depression
  • This invention is directed to certain compounds and new pharmaceutical applications of such compounds.
  • 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.
  • 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.
  • R1 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.
  • R1 is:
  • ester -Y- (C O)-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.
  • This ester can be derived from the reactions well known in the artbetween 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, nonanoic, decanoic, undecanoic, dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic,
  • oxime N-O- R7 radical wherein R7 is a C 1 -C 20 branched, straight chain, or cyclic aliphatic or aromatic radical.
  • This oxime radical may be derived from the reaction of a 3-
  • 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.
  • R10 is an amide
  • R10 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 i-butyric, n and i 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, glucos
  • 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 i-butyric, n and i 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 cyclohe
  • R18 and R19 are individually a C 1 -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.
  • the desiredpharmacological activity will often predominate in one of the isomers.
  • these compounds display a high degree of stereospecificity.
  • those compounds having the greatest affinity for the GABA-benzodiazepine receptor complex are those with 3 .alpha. substituted-5 .alpha.-pregnane steroid skeletons.
  • 3 .alpha. substituted-5 .beta.-pregnane skeletons have been demonstrated to be active.
  • the compounds of the invention may be prepared by any known technique.
  • 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.
  • 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.
  • the composition will contain the activeingredient 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).
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, microcrystalline cellulose, polymer hydrogels and the like.
  • liquid carriers are syrup, peanut oil, and olive oil and the like emulsions.
  • 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, liposomes, and hydrogels.
  • a wide variety of pharmaceutical forms can be employed.
  • the preparation 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.
  • the preparation 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.
  • topical administration via timed release skin patches is also a suitable pharmaceutical form.
  • the method of producing anxiolyic, or anticonvulsant activity 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.
  • 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.
  • 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.
  • one dose in a skin patch may supply the active ingredient to the patientfor a period of up to one week.
  • FIGURES 1A and IB These plots describe the effect of (+)-bicuculline on alphaxalone (1A) and GABA (1B) modulation of 2 nanomolar [ 35 S]- TBPS binding to rat cerebral cortex.
  • O represents control without bicuculline;
  • ⁇ represents 0.5 micromoloar bicuculline;
  • ⁇ represents 1.0 micromolar bicuculline;
  • ⁇ represents 2.0 micromolar bicuculline; and
  • ⁇ represents 3.0 micromolar bicuculline.
  • 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.
  • 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, 1987, op. cit.).
  • 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).
  • 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 .
  • DHP alpha.-ol-20-one
  • Th-DOC 5 .alpha.-pregnan-3 .alpha.,21-diol-20-one
  • BETA beta-pregnane-3 .alpha., 20 diol

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

Procédé préconisant l'utilisation de stéroïdes 3-hydroxylés-5-réduits et de certains dérivés nouveaux dont l'effet se produit au niveau d'un site nouvellement identifié sur le complexe GBR, afin de moduler l'excitabilité du cerveau de manière à soulager le stress, l'anxiété, et l'activité apoplectique.
PCT/US1988/002827 1987-08-25 1988-08-24 Compositions et procedes soulageant le stress, l'anxiete et l'activite apoplectique WO1989002272A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK048790A DK48790A (da) 1987-08-25 1990-02-23 Steroidforbindelse og farmaceutisk praeparat indeholden en saadan forbindelse

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8936287A 1987-08-25 1987-08-25
US089,362 1987-08-25

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WO1989002272A1 true WO1989002272A1 (fr) 1989-03-23

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EP (1) EP0382790A4 (fr)
JP (1) JPH03500049A (fr)
AU (1) AU609927B2 (fr)
DK (1) DK48790A (fr)
WO (1) WO1989002272A1 (fr)

Cited By (9)

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EP0527962A1 (fr) * 1990-05-10 1993-02-24 GEE, Kelvin W. Procede, compositions et composes de modulation de l'excitabilite cerebrale
WO1993003732A1 (fr) 1991-08-13 1993-03-04 Cocensys, Inc. Modulateurs de recepteurs d'acide gamma-aminobutyrique
WO1993004687A1 (fr) * 1991-09-12 1993-03-18 Trustees Of Boston University Emploi de sulfates de pregnenolone et de derives dans le traitement de troubles du systeme nerveux central
US5206415A (en) * 1991-12-20 1993-04-27 Washington University Tricyclic steroid analogs
WO1994027608A1 (fr) * 1993-05-24 1994-12-08 Cocensys, Inc. Procedes et compositions induisant le sommeil
US5693769A (en) * 1991-12-13 1997-12-02 Transcell Technologies, Inc. Glycosylated steroid derivatives for transport across biological membranes and process for making and using same
US5795870A (en) * 1991-12-13 1998-08-18 Trustees Of Princeton University Compositions and methods for cell transformation
US7473687B2 (en) 2005-03-24 2009-01-06 Emory University Methods for the treatment of a traumatic central nervous system injury
US8614203B2 (en) 2005-03-24 2013-12-24 Emory University Methods for the treatment of a central nervous system injury via a tapered administration protocol

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CN108976272B (zh) * 2011-10-14 2021-05-25 萨奇治疗股份有限公司 3,3-二取代的19-去甲孕甾烷化合物、组合物、及其用途
CA3090724A1 (fr) * 2018-02-11 2019-08-15 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Regulateur de derive de steroide, son procede de preparation et son utilisation

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Title
See also references of EP0382790A4 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0527962A1 (fr) * 1990-05-10 1993-02-24 GEE, Kelvin W. Procede, compositions et composes de modulation de l'excitabilite cerebrale
EP0527962A4 (en) * 1990-05-10 1993-10-20 Kelvin W. Gee Method, compositions, and compounds for modulating brain excitability
WO1993003732A1 (fr) 1991-08-13 1993-03-04 Cocensys, Inc. Modulateurs de recepteurs d'acide gamma-aminobutyrique
EP0554436A1 (fr) * 1991-08-13 1993-08-11 Cocensys, Inc. Modulateurs de recepteurs d'acide gamma-aminobutyrique
EP0554436A4 (fr) * 1991-08-13 1994-01-12 Cocensys, Inc.
US5366968A (en) * 1991-09-12 1994-11-22 Trustees Of Boston University Modulation of receptor-mediated ion transport
WO1993004687A1 (fr) * 1991-09-12 1993-03-18 Trustees Of Boston University Emploi de sulfates de pregnenolone et de derives dans le traitement de troubles du systeme nerveux central
US5795870A (en) * 1991-12-13 1998-08-18 Trustees Of Princeton University Compositions and methods for cell transformation
US5693769A (en) * 1991-12-13 1997-12-02 Transcell Technologies, Inc. Glycosylated steroid derivatives for transport across biological membranes and process for making and using same
US5344826A (en) * 1991-12-20 1994-09-06 Washington University Tricycle steroid analogs
US5292906A (en) * 1991-12-20 1994-03-08 Washington University Tricyclic steroid analogs
US5206415A (en) * 1991-12-20 1993-04-27 Washington University Tricyclic steroid analogs
WO1994027608A1 (fr) * 1993-05-24 1994-12-08 Cocensys, Inc. Procedes et compositions induisant le sommeil
US7473687B2 (en) 2005-03-24 2009-01-06 Emory University Methods for the treatment of a traumatic central nervous system injury
US7915244B2 (en) 2005-03-24 2011-03-29 Emory University Methods for the treatment of a traumatic central nervous injury
US8455468B2 (en) 2005-03-24 2013-06-04 Emory University Methods for the treatment of a traumatic central nervous system injury
US8614203B2 (en) 2005-03-24 2013-12-24 Emory University Methods for the treatment of a central nervous system injury via a tapered administration protocol

Also Published As

Publication number Publication date
AU2828389A (en) 1989-04-17
AU609927B2 (en) 1991-05-09
JPH03500049A (ja) 1991-01-10
DK48790D0 (da) 1990-02-23
EP0382790A4 (en) 1991-03-27
EP0382790A1 (fr) 1990-08-22
DK48790A (da) 1990-04-25

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